C-SH2 point mutation converts p85ß regulatory subunit of phosphoinositide 3-kinase to an anti-aging gene.

Insulin interacts with the insulin receptor, and the activated receptor promotes activity of the phosphoinositide-3 kinase (PI3K) enzyme. A decrease in insulin or insulin-like growth factor 1 (IGF-1) signaling increases the lifespan in mammalian species. We found that a point mutation in the C-SH2 domain of the p85ß regulatory subunit of PI3K results in a prolonged lifespan. In p85ß mutant cells, nerve growth factor (NGF) activates the longevity protein FOXO, and the mutant p85ß gene produces strong resistance to oxidative stress, which contributes to aging. The p85ß gene mutation causes increased serum insulin and low blood glucose in p85ß mutant transgenic mice. Our results indicate that the p85ß mutant allele alters the activity of downstream targets of PI3K by NGF and platelet-derived growth factor (PDGF) but not by insulin. We report that a point mutation in the C-SH2 domain of p85ß transforms p85ß into a novel anti-aging gene by abnormally regulating PI3K.

Cognitive functions in Parkinson's disease: relation to disease severity and hallucination.

OBJECTIVE: We wished to relate severity of Parkinson's disease (PD) with cognitive function in relation to cerebral blood flow (CBF). METHODS: Eighty-one consecutive PD patients were enrolled in this study. We used Mini-Mental State Examination (MMSE) and Wechsler Adult Intelligence Scale-Third edition (WAIS-III) to evaluate cognitive functions, and three-dimensional stereotactic ROI template (3DSRT) and Statistical Parametric Mapping (SPM) 8 to evaluate single photon emission CT (SPECT) recordings of regional CBF. RESULTS: The mean MMSE score of PD patients was 27.4 ± 2.4. The scores of most patients were higher than 23/30. On the other hand, the mean Full-scale IQ of PD patients was 88.4 ± 17.3 in WAIS-III, which was lower than that of normal controls. In particular, visuospatial function score of most patients was lower. There was significant correlation between cognitive scores and Hoehn & Yahr stage and hallucinatory episodes. PD Patients with stage III and IV showed significant deterioration in cognitive functions compared to stage II patients. Analysis of CBF revealed relative reductions in perfusion in the cerebral cortex relative to that in normal control. SPM 8 showed that cognitive functions in PD patients were positively correlated with rCBF in the thalamus and cingulate gyrus. CONCLUSIONS: This is the study to demonstrate the cognitive impairments in PD patients using WAIS-III. Visuospatial dysfunction might be caused by decrease in rCBF in the parietal and occipital lobes and dorsolateral prefrontal cortex. The severity of cognitive impairments in PD patients was correlated with disease severity and hallucinatory episodes.

Molecular cloning, sequencing, and gene expression analysis of tributyltin-binding protein type 1 in Japanese medaka fish, Oryzias latipes.

The full-length cDNA sequence of tributyltin-binding protein type 1 in Japanese medaka (Oryzias latipes) (Olat.TBT-bp1) was determined by means of rapid amplification of cDNA ends (RACE) of liver tissue. Analysis of the structure of the gene encoding Olat.TBT-bp1 revealed that the exonintron organization of this gene corresponds to that of the genes encoding lipocalin superfamily proteins, suggesting that Olat.TBT-bp1 can be categorized as a member of the lipocalin superfamily, which may play an important role in transportation, detoxification, and excretion of xenobiotic compounds. Reverse transcription - PCR revealed that Olat.TBT-bp1 was expressed mainly in the liver, and upregulation of its expression was detected 1, 2, and 4 weeks post hatching. Relative expression of the Olat.TBT-bp1 gene was significantly downregulated, compared with that in the solvent control, by exposure to tributyltin at 0.01 mg/l or triclosan at 1.7 mg/l. Further studies on Olat.TBT-bp1 expression in conjunction with other biochemical and physiological toxicities in response to chemical exposures are needed to increase our understanding and information of TBT-bps mechanisms and as molecular biomarkers of chemical exposures. The role of Olat.TBT-bp1 in xenobiotic detoxification and/or excretion needs more investigations.

Exercise exerts neuroprotective effects on Parkinson's disease model of rats.

Recent studies demonstrate that rehabilitation ameliorates physical and cognitive impairments of patients with stroke, spinal cord injury, and other neurological diseases and that rehabilitation also has potencies to modulate brain plasticity. Here we examined the effects of compulsive exercise on Parkinson's disease model of rats. Before 6-hydroxydopamine (6-OHDA, 20 microg) lesion into the right striatum of female SD rats, bromodeoxyuridine (BrdU) was injected to label the proliferating cells. Subsequently, at 24 h after the lesion, the rats were forced to run on the treadmill (5 days/week, 30 min/day, 11 m/min). As behavioral evaluations, cylinder test was performed at 1, 2, 3, and 4 weeks and amphetamine-induced rotational test was performed at 2 and 4 weeks with consequent euthanasia for immunohistochemical investigations. The exercise group showed better behavioral recovery in cylinder test and significant decrease in the number of amphetamine-induced rotations, compared to the non-exercise group. Correspondingly, significant preservation of tyrosine hydroxylase (TH)-positive fibers in the striatum and TH-positive neurons in the substantia nigra pars compacta (SNc) was demonstrated, compared to the non-exercise group. Additionally, the number of migrated BrdU- and Doublecortin-positive cells toward the lesioned striatum was increased in the exercise group. Furthermore, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor increased in the striatum by exercise. The results suggest that exercise exerts neuroprotective effects or enhances the neuronal differentiation in Parkinson's disease model of rats with subsequent improvement in deteriorated motor function.

Identification of glioma-specific RFX4-E and -F isoforms and humoral immune response in patients.

For regulatory factor X4 (RFX4), two alternatively spliced variants, RFX4-A and -B, were reported in the testis. In this study, we identified transcript variants RFX4-C, -D, -E, and -F, and demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) that RFX4-A, -B and -C mRNAs were expressed only in the testis, and RFX4-D mRNA was expressed only in normal brain tissues. In tumors, RFX4-E and -F in addition to RFX4-D mRNA were expressed in gliomas by rapid amplification of cDNA ends and RT-PCR analyses. Expression of RFX4 mRNA was not observed in other tumors, such as lung, esophageal, stomach, colon or liver cancers. Quantitative real-time RT-PCR using common primer pairs detecting all of the variant transcripts showed high expression in normal testis, low expression in the brain (1% compared to the expression in testis), and overexpression in 17 of 61 gliomas (28%). Western blot analysis using DC28 monoclonal antibody (mAb) produced against recombinant RFX4-D C-terminus protein showed expression of RFX4-A and -C proteins, but not RFX4-B protein, in the testis, and expression of RFX4-D protein in the brain. Moreover, expression of RFX4-E and -F proteins, but not RFX4-D protein, was observed in gliomas. Immunohistochemistry analysis using DC28 mAb showed positive staining in the nuclei of spermatocytes in the testis and glioma cells. Antibody against RFX4 was detected in the sera of 3 of 58 (5%) glioma patients by enzyme-linked immunosorbent assay, suggesting the immunogenicity of RFX4-E and -F proteins in glioma patients.

[Clinical application of Japan Stroke Scale Higher Cortical Function (JSS-H)].

To clarify the characteristics of Japan Stroke Scale Higher Cortical Function (JSS-H), we compared the results of JSS-H with those of Revised Hasegawa Dementia Scale (HDS-R), on the 47 patients with cerebrovascular disease visiting to the day-care center of the Yoshinaga Municipal Hospital. The scores of the two scales significantly correlated. Especially, among the patients who gained over 21 points (non-dementia) in HDS-R, the results of both scales were almost parallel, but among those who gained less than 20 points(dementia), the scores showed some discrepancy. Most of the patient with discrepancy had higher scores in JSS-H than in HDS-R, and were independent in their daily life despite of their memory disturbance. These results suggest that JSS-H can assess more global cerebral function than HDS-R and will be useful for estimating the characteristics of the higher cortical function of the patients, although it has some problems to be solved for clinical application.

Heat shock induces neurite outgrowth in PC12m3 cells via the p38 mitogen-activated protein kinase pathway.

We investigated the role of the p38 mitogen-activated protein kinase (MAPK) pathway in heat-shock-induced neurite outgrowth of PC12 mutant cells in which nerve growth factor (NGF)-induced neurite outgrowth is impaired. When cultures of the PC12 mutant (PC12m3) cells were exposed to heat stress at 44 degrees C for 10 min, activity of p38 MAPK increased and neurite outgrowth was greatly enhanced. The neurite extension was inhibited by the p38 MAPK inhibitor BS203580. Longer heat treatment of PC12m3 cells provoked cell death, which was enhanced by SB203580. These findings suggest that heat-induced activation of p38 MAPK is responsible for the neurite outgrowth and survival of PC12m3 cells.

Radiation damage to the normal monkey brain: experimental study induced by interstitial irradiation.

Radiation damage to normal brain tissue induced by interstitial irradiation with iridium-192 seeds was sequentially evaluated by computed tomography (CT), magnetic resonance imaging (MRI), and histological examination. This study was carried out in 14 mature Japanese monkeys. The experimental area received more than 200-260 Gy of irradiation developed coagulative necrosis. Infiltration of macrophages to the periphery of the necrotic area was seen. In addition, neovascularization, hyalinization of vascular walls, and gliosis were found in the periphery of the area invaded by the macrophages. All sites at which the vascular walls were found to have acute stage fibrinoid necrosis eventually developed coagulative necrosis. The focus of necrosis was detected by MRI starting 1 week after the end of radiation treatment, and the size of the necrotic area did not change for 6 months. The peripheral areas showed clear ring enhancement with contrast material. Edema surrounding the lesions was the most significant 1 week after radiation and was reduced to a minimum level 1 month later. However, the edema then expanded once again and was sustained for as long as 6 months. CT did not provide as clear of a presentation as MRI, but it did reveal similar findings for the most part, and depicted calcification in the necrotic area. This experimental model is considered useful for conducting basic research on brachytherapy, as well as for achieving a better understanding of delayed radiation necrosis.

[Pituitary adenoma associated with neurofibromatosis type 1: case report].

A case of pituitary adenoma associated is neurofibromatosis type 1 is reported. On June 6, 2000, a 49-year-old man was admitted to the Department of Neurological Surgery, Okayama University Hospital, for bitemporal hemianopsia. Twenty-nine years previously, he had been operated on for a left inguinal tumor that proved to be a neurofibroma. Based on the presence of other manifestations, such as café-au-lait spots and subcutaneous nodules, he had been diagnosed with neurofibromatosis type 1, the same as his father, sister, and daughter. Computed tomography and magnetic resonance imaging demonstrated an intrasellar mass lesion with a cystic portion in the suprasellar region. Endocrinologically, almost all of his basic hormone levels were normal. A right front-temporal craniotomy was performed for a preoperative diagnosis of craniopharyngioma, and total intracapsular tumor extirpation was achieved. The histological diagnosis was clinically silent corticotroph pituitary adenoma. Neurofibromatosis is sometimes associated with neoplasms of the central nervous system, usually optic gliomas. Associations between pituitary adenomas and NF 1 are very rare and have been reported in only four cases, including the present case.

[Peduncular hallucinosis due to a small hemorrhage around the substantia nigra: a case report].

An 81-year-old female developed peduncular hallucination due to a small hemorrhage around the right substantia nigra is reported. Her hallucination was visual, not accompanying any other type of hallucination. It was vivid, colorful, well described, and recognized as unreal by herself. Different from most of the previous reports, she had no sleep abnormality and the hallucination occurred in daytime and at night, not relating to eye opening or closing. As the lesion of this case was quite restricted to around the right substantia nigra and not affecting the brainstem reticular formation, we speculate that the hallucination itself was induced by the stimulation of mesocorticolimbic system. The other characteristics of the hallucination such as appearing in evening, occurring with eye closing, and accompanying sleep disturbance might be induced when the brainstem involved more widely.