When investigating the relationship of different oncogenes to metastasis, we found that transfer of the v-fos oncogene into a transformed rat cell line augmented spontaneous lung metastasis. The metastatic potential of the cell lines examined depended on the manner of integration and the extent of transcription of the fos genes. Thus, the fos oncogene is probably involved in certain events related to acquisition of metastatic potential.
Although neuroimaging plays an important role in the diagnosis of idiopathic normal pressure hydrocephalus, its predictive value for response to shunt surgery has not been established. The purpose of the current study was to identify neuroimaging markers that predict the shunt response of idiopathic normal pressure hydrocephalus.
MATERIALS AND METHODS:
Sixty patients with idiopathic normal pressure hydrocephalus underwent presurgical brain MR imaging and clinical evaluation before and 1 year after shunt surgery. The assessed MR imaging features included the Evans index, high-convexity tightness, Sylvian fissure dilation, callosal angle, focal enlargement of the cortical sulci, bumps in the lateral ventricular roof, and deep white matter and periventricular hyperintensities. The idiopathic normal pressure hydrocephalus grading scale total score was used as a primary clinical outcome measure. We used measures for individual symptoms (ie, the idiopathic normal pressure hydrocephalus grading scale subdomain scores, such as gait, cognitive, and urinary scores), the Timed Up and Go test, and the Mini-Mental State Examination as secondary clinical outcome measures. The relationships between presurgical neuroimaging features and postoperative clinical changes were investigated by using simple linear regression analysis. To identify the set of presurgical MR imaging features that best predict surgical outcomes, we performed multiple linear regression analysis by using a bidirectional stepwise method.
RESULTS:
Simple linear regression analyses demonstrated that presurgical high-convexity tightness, callosal angle, and Sylvian fissure dilation were significantly associated with the 1-year changes in the clinical symptoms. A multiple linear regression analysis demonstrated that presurgical high-convexity tightness alone predicted the improvement of the clinical symptoms 1 year after surgery.
CONCLUSIONS:
High-convexity tightness is a neuroimaging feature predictive of shunt response in idiopathic normal pressure hydrocephalus.
The neuropathological hallmarks of Parkinson's disease (PD) include the appearance of α-synuclein (α-SYN)-positive Lewy bodies (LBs) and the loss of catecholaminergic neurons. Thus, a potential mechanism promoting the uptake of extracellular α-SYN may exist in susceptible neurons. Of the various differentially expressed proteins, we are interested in flotillin (FLOT)-1 because this protein is highly expressed in the brainstem catecholaminergic neurons and is strikingly up-regulated in PD brains. In this study, we found that extracellular monomeric and fibrillar α-SYN can potentiate FLOT1-dopamine transporter (DAT) binding and pre-endocytic clustering of DAT on the cell surface, thereby facilitating DAT endocytosis and down-regulating its transporter activity. Moreover, we demonstrated that α-SYN itself exploited the DAT endocytic process to enter dopaminergic neuron-like cells, and both FLOT1 and DAT were found to be the components of LBs. Altogether, these findings revealed a novel role of extracellular α-SYN on cellular trafficking of DAT and may provide a rationale for the cell type-specific, functional, and pathologic alterations in PD.-Kobayashi, J., Hasegawa, T., Sugeno, N., Yoshida, S., Akiyama, T., Fujimori, K., Hatakeyama, H., Miki, Y., Tomiyama, A., Kawata, Y., Fukuda, M., Kawahata, I., Yamakuni, T., Ezura, M., Kikuchi, A., Baba, T., Takeda, A., Kanzaki, M., Wakabayashi, K., Okano, H., Aoki, M. Extracellular α-synuclein enters dopaminergic cells by modulating flotillin-1-assisted dopamine transporter endocytosis.
Abstract The flowing behavior of individual erythrocytes in blood vessels is usually determined by their deformability, which is controlled mainly by the nature of their interior constituents and the flexibility of their surface membrane. Moreover, the physical behavior of erythrocytes passing through capillaries has been examined in vivo by light microscopy. However, little has been known about ultrastructural changes of such erythrocyte shapes flowing in blood vessels in vivo. Recently, a new technique was developed for freezing cells and tissues in vivo without stopping the blood supply, which was referred to as “in vivo cryotechnique”.This method has been also suitable for obtaining informations about dynamic morphological changes. Seven female Balb/c mice were anesthetized peritoneally with sodium pentobarbital (100μg/g body weight), and their abdomen was opened through a pararectus incision. For artificial cardiac arrest, some mice were anesthetized with an excessive dose of the anesthetic (500μg/g body weight), their respiration and heart-beat were completely stopped, and the following procedures were done within one minute. A liver was put on a plastic plate without disturbance of blood circulation, and the “in vivo cryotechnique” was performed. Briefly, a cryoknife was pushed into the liver as fast as possible and the tissue was immediately poured with liquid isopentane-propane mixture (-193°C) (Fig.la,b).
Abstract Introduction The neural substrates associated with the development of micrographia remain unknown. We aimed to elucidate the neural substrates underlying micrographia in Parkinson's disease (PD) patients. Methods Forty PD patients and 20 healthy controls underwent handwriting tests that involved free writing and copying. We measured the size of each letter and the resting cerebral glucose metabolic rate of the PD patients and another group of age‐ and sex‐matched 14 healthy controls (HCs), who had not participated in the writing tests, using resting‐state 18F‐fluorodeoxyglucose positron emission tomography. Results In the PD patients, the prevalence of consistent micrographia (CM) associated with free writing was 2.5% for both tasks. Alternatively, the prevalence of progressive micrographia (PM) was 15% for free writing and 17.5% for copying. In the PD patients, there was no significant difference in the letter sizes between these tasks, whereas the variability of the letter sizes for copying was significantly different from that for free writing. The means and decrements in letter sizes in either task were not significantly correlated with the severity of brady/hypokinesia in the PD patients. For free writing, the PD patients with PM showed glucose hypometabolism in the anterior part of the right middle cingulate cortex, including the rostral cingulate motor area, compared with those without PM. For copying, the PD patients with PM showed glucose hypometabolism in the right superior occipital gyrus, including V3A, compared with those without PM. Conclusions These findings suggest that PM in free writing in PD patients is caused by the difficulty of monitoring whether the actual handwriting movements are desirable for maintaining letter size during self‐paced handwriting. By contrast, PM in copying in PD patients is evoked by a lack of visual information about the personal handwriting and hand motions that are used as cues for maintaining letter sizes.
Corticobasal syndrome (CBS) is pathologically characterized by tau deposits in neuronal and glial cells and by reactive astrogliosis. In several neurodegenerative disorders, 18 F-THK5351 has been observed to bind to reactive astrocytes expressing monoamine oxidase B. In this study, the aim was to investigate the progression of disease-related pathology in the brains of patients with CBS using positron emission tomography with 18 F-THK5351.Baseline and 1-year follow-up imaging were acquired using magnetic resonance imaging and positron emission tomography with 18 F-THK5351 in 10 subjects: five patients with CBS and five age-matched normal controls (NCs).The 1-year follow-up scan images revealed that 18 F-THK5351 retention had significantly increased in the superior parietal gyrus of the patients with CBS compared with the NCs. The median increases in 18 F-THK5351 accumulation in the patients with CBS were 6.53% in the superior parietal gyrus, 4.34% in the precentral gyrus and 4.33% in the postcentral gyrus. In contrast, there was no significant increase in the regional 18 F-THK5351 retention in the NCs.Longitudinal increases in 18 F-THK5351 binding can be detected over a short interval in the cortical sites of patients with CBS. A monoamine oxidase B binding radiotracer could be useful in monitoring the progression of astrogliosis in CBS.
Dynamin is the mammalian homologue to the Drosophila shibire gene product. Mutations in this 100-kD GTPase cause a pleiotropic defect in endocytosis. To further investigate its role, we generated stable HeLa cell lines expressing either wild-type dynamin or a mutant defective in GTP binding and hydrolysis driven by a tightly controlled, tetracycline-inducible promoter. Overexpression of wild-type dynamin had no effect. In contrast, coated pits failed to become constricted and coated vesicles failed to bud in cells overexpressing mutant dynamin so that endocytosis via both transferrin (Tfn) and EGF receptors was potently inhibited. Coated pit assembly, invagination, and the recruitment of receptors into coated pits were unaffected. Other vesicular transport pathways, including Tfn receptor recycling, Tfn receptor biosynthesis, and cathepsin D transport to lysosomes via Golgi-derived coated vesicles, were unaffected. Bulk fluid-phase uptake also continued at the same initial rates as wild type. EM immunolocalization showed that membrane-bound dynamin was specifically associated with clathrin-coated pits on the plasma membrane. Dynamin was also associated with isolated coated vesicles, suggesting that it plays a role in vesicle budding. Like the Drosophila shibire mutant, HeLa cells overexpressing mutant dynamin accumulated long tubules, many of which remained connected to the plasma membrane. We conclude that dynamin is specifically required for endocytic coated vesicle formation, and that its GTP binding and hydrolysis activities are required to form constricted coated pits and, subsequently, for coated vesicle budding.
