Tomofumi Nishikawa

An early stage mechanism of the age-associated mitochondrial dysfunction in the brain of SAMP8 mice; an age-associated neurodegeneration animal model

In order to characterize the early stage of mitochondrial dysfunction, we investigated the redox state and oxidative phosphorylation of the brain mitochondria from 2-month-old Senescence-accelerated mouse (SAM)P8 and SAMR1 mice; SAMP8 mice exhibit various signs of age-associated neurodegeneration and rapid mitochondrial dysfunction, although SAMR1 mice do not. The redox state was estimated as the reduction rate of Cu-pyruvaldehyde-bis (N4-methylthiosemicarbazone) (Cu-PTSM), the reduction of which is closely related to the electron leakage from the mitochondrial electron transport system in the brain, using electron spin resonance spectrometry (ESRS). The oxidative phosphorylation was measured polarographically. The SAMP8 mouse brain mitochondria demonstrated higher redox state and a higher activity of mitochondrial respiration with lower respiration control ratio than the mitochondria of SAMR1 mouse brains. This indicates that an inefficient hyperactive state can exist in the mitochondrial electron transport system before the age-associated mitochondrial dysfunction develops.

Accelerated aging of dermal fibroblast-like cells from senescence-accelerated mouse (SAM). 1. Acceleration of population aging in vitro

Fibroblast-like cells were isolated from the senescence accelerated mouse (SAM) and cultured, after which evidence of accelerated senescence was sought. Fibroblast-like cell lines were established from the dorsal dermis of neonate mice of both the accelerated senescence-prone strain, SAMP11 and the accelerated senescence-resistant strain, SAMR1. All cell lines from both strains showed a crisis in growth and were immortalized. At crisis, all cultures were composed of morphologically characteristic senescent cells. However, in cell lines from SAMP11, this change was more rapid and at earlier population doublings (PDs) than seen in cell lines from SAMR1. Crises (SAMP11; SAMR1) were also operationally taken to be the point of the least change in PDs (11.2 +/- 1.1; 15.4 +/- 0.5 PDs), the least saturation density (11.3 +/- 0.8; 19.1 +/- 2.6 PDs), and the longest population doubling time (10.1 +/- 0.8; 14.2 +/- 0.6 PDs). Crisis occurred significantly earlier (P < 0.05) and the aging process was accelerated in cell lines from SAMP11, compared with lines from SAMR1. This evidence tends to support various observations made in the accelerated senescence-prone strains of SAMP, in vivo.

Cerebral microbleeds predict first-ever symptomatic cerebrovascular events.

OBJECTIVE Cerebral microbleeds (CMB) on gradient-echo T2*-weighted magnetic resonance image (MRI) are frequently seen in patients with cerebral diseases. In this observational study we assessed whether CMB are a predictive factor for first-ever cerebrovascular events. PATIENTS AND METHODS This study consisted of 698 subjects without a history of symptomatic cerebrovascular events, who received gradient-echo T2*-weighted MRI for 3 months between November 2003 and January 2004 in Kishiwada City Hospital, Osaka, Japan. These subjects were then observed as outpatients for over 3.5 years. RESULTS The prevalence of CMB at baseline was 17.0% (119/698) in this population, and the follow-up rate was 51%. A total of 36 first-ever symptomatic cerebrovascular events were observed during the 3 and a half-year follow-up period. First-ever symptomatic cerebrovascular events occurred significantly more frequently in subjects with CMB (15 cases) than those without CMB (21 cases) (p=0.001). Even after adjusting for age, sex and hypertension, it was revealed that the presence of CMB was an independent predictor for the first-ever symptomatic cerebrovascular event by using the Cox proportional hazards model (hazard ratio, 2.87; 95% CI, 1.27-6.48; p=0.01). CONCLUSION The presence of CMB is an independent predictor of first-ever symptomatic cerebrovascular diseases.

Tubular aggregates in the skeletal muscle of the senescence-accelerated mouse; SAM.

We investigated the skeletal muscles of nine strains of senescence accelerated mouse (SAM), DDD, AKR/J, C57BL/6J, A/J and BALB/c mice. We found that male SAMP8, SAMP7, C57BL/6J, A/J and BALB/c mice expressed tubular aggregates (TAs) in their skeletal muscle. Among these strains, the SAMP8 strain, which exhibits a short life span and various age-associated neurodegenerative disorders plus mitochondrial dysfunction, showed TAs more markedly than the others. Thus, we compared SAMP8 mice against SAMR1 mice, an accelerated senescence-resistant strain. Light- and electron micrographs showed that male SAMP8 mice exhibited an age-dependent aggravation of TA accumulation. There were no significant differences in the serum lactate/pyruvate levels between the SAMP8 and SAMR1 mice. However, the serum creatine kinase (CK) levels of the 3 and 6-month-old SAMP8 mice were higher than that of the corresponding SAMR1 mice. Considering the serum CK levels and the mitochondrial dysfunction of SAMP8 mice, we conclude that the TAs may be involved in the homeostasis of energy metabolism that is not appropriately regulated in the SAMP8 mouse mitochondrion.

A priority treatment of the intraventricular hemorrhage (IVH) should be performed in the patients suffering intracerebral hemorrhage with large IVH

BACKGROUND In patients suffering from intracerebral hemorrhage (ICH) with ventricular hemorrhage (IVH), the IVH severity is thought to be associated with prognosis. Therefore, treating IVH may be a beneficial therapeutic target. In this study, by examining the associations among IVH severity, hydrocephalus, initial level of consciousness and prognosis, we attempted to identify which grade of IVH severity should be considered for surgical treatment. METHODS One hundred twenty-nine patients with spontaneous supratentorial ICH treated in our hospital between 2005 and 2006 were screened in this study. Of these patients, 100 with an ICH volume less than 60 ml were categorized into either the ICH patients without IVH (no-IVH) group (n=65) or the ICH patients with IVH (IVH) group (n=35). The Karnofsky Performance Status (KPS) scale assessed at the time of discharge was employed as an outcome index, and a KPS score of <or=40 was defined as the bedridden state. Age, gender, hemorrhage location, volume of ICH, IVH grade (according to the Graeb score), acute hydrocephalus, surgical ICH removal, and ventricular drainage were selected for univariate analyses with logistic regression. RESULTS Elderly patients, IVH volume, acute hydrocephalus, and poor initial level of consciousness were significantly associated with an unfavorable prognosis in the IVH group. Poor level of consciousness was significantly dependent on acute hydrocephalus, and significantly more occurrences of acute hydrocephalus were found in patients with a high IVH volume (Graeb score >or=6) than in patients with low to moderate IVH volume (Graeb score <or=6). CONCLUSIONS IVH severity influenced the occurrence of acute hydrocephalus and initial level of consciousness, which was significantly associated with prognosis. Our results suggest that priority treatment of the IVH should be given to those ICH patients with IVH admitted with a Graeb score of 6 or more.

Correlation and association of plasma interleukin-6 and plasma platelet-derived microparticles, markers of activated platelets, in healthy individuals

INTRODUCTION The aim of this study was to clarify the correlation and association of plasma IL-6 and PDMPs, both of which are associated with metabolic syndrome, in healthy individuals. MATERIALS AND METHODS We conducted a cross-sectional study of 464 healthy Japanese volunteers (210 men and 254 women, median age 39 and 35years, respectively) who had no signs, symptoms or history of cardiovascular- or cerebrovascular disease and took no medications. We assayed their IL-6 levels with a conventional ELISA kit and their PDMP levels by ELISA and monoclonal antibodies against CD42b and CD42a (glycoprotein Ib and IX). RESULTS By multivariate analysis, the plasma level of PDMP was correlated with diastolic blood pressure (p=0.015), platelet count (p<0.001), high sensitivity C-reactive protein, and the plasma level of IL-6 (p<0.001) in men (R(2)=0.454, p<0.001) and was correlated with platelet count (p<0.001) and the plasma level of IL-6 (p<0.001) in women (R(2)=0.159, p<0.001). Quartile range of plasma level of IL-6 was associated with plasma level of PDMP after adjustment for diastolic blood pressure, platelet count, and high sensitivity C-reactive protein in men (p<0.001) and associated with plasma level of PDMP after adjustment for platelet count in women (p<0.001). CONCLUSIONS These results suggest the plasma IL-6 is correlated and associated with the plasma PDMPs, markers of activated platelets in healthy individuals.

Effects of aging and blood pressure on the structure of the thoracic aorta in SAM mice: a model of age-associated degenerative vascular changes

The effects of aging and blood pressure on the structural alterations of the thoracic aorta were examined using male, accelerated senescence-prone, short-lived SAMP11 mice or accelerated senescence-resistant, long-lived SAMR1 mice. The aortic wall thickness increased significantly by 34% in SAMR1 and by 62% in SAMP11 with advanced age. We observed branching, breakage and disorganization of the elastic lamellae, an increase in thin collagen fibrils between the medial smooth muscle cells and hypertrophy but a significant decrease in the number of medial smooth muscle cells with aging in both strains. These alterations observed in SAMP11 occurred earlier and were more exaggerated with advanced age than in SAMR1. The aortic lumen dilated gradually in SAMR1, but narrowed significantly in SAMP11 with aging. The systolic blood pressure did not differ significantly among SAMP11s aged 3-9months, or among all ages of SAMR1. However, it was elevated in SAMP11 at the terminal stage of their life. Our results suggest that the aorta in SAMR1 might reflect the physiological process of aging, whereas SAMP11 showed earlier changes due to the senescence acceleration of the vascular cells, which were exaggerated by the elevated blood pressure.

Circulating oxidized LDL, measured with FOH1a/DLH3 antibody, is associated with metabolic syndrome and the coronary heart disease risk score in healthy Japanese

BACKGROUND AND PURPOSE The objective of this study was to clarify the relationship between circulating oxidized LDL (oxLDL) and metabolic syndrome (MS) and the coronary heart disease (CHD) risk score. METHODS We conducted a cross-sectional study of healthy volunteers who had no signs, symptoms or history of cardiovascular or cerebrovascular disease and took no medications. We studied 382 Japanese volunteers, 190 men and 192 women (median age 41 and 38 years, respectively). We used an ELISA kit and a monoclonal oxLDL antibody, FOH1a/DLH3, to measure circulating oxLDL. RESULTS The odds ratio (OR) for elevated oxLDL in individuals with MS compared to those without MS, adjusted for age and sex, was 1.94 (range 1.00-3.78). In individuals with a predicted Framingham 10-year risk for CHD>5% (corresponding with the highest quartile), compared to those with a predicted 10-year risk<5%, the OR, adjusted for age, sex, smoking, and LDL cholesterol, was 2.51 (1.17-5.36). The age-, sex-, smoking- and LDL cholesterol-adjusted OR for a 10-year CHD risk score >5% was 1.03 (1.01-1.04) for LDL cholesterol and 11.7 (4.69-29.0) for smoking. CONCLUSIONS Elevated oxLDL is associated with the presence of MS and the CHD risk score in healthy people.

Early detection of metachronous brain metastases by biannual brain MRI follow-up may provide patients with non-small cell lung cancer with more opportunities to have radiosurgery

PURPOSE Those who have brain metastases smaller than 30 mm in diameter and less than 5 in number can be treated less invasively with radiosurgery. This retrospective study evaluated the optimal brain magnetic resonance image (MRI) follow-up interval for non-small cell lung cancer (NSCLC) patients to detect radiosurgically manageable metachronous brain metastases (MBM). PATIENTS AND METHODS The records of 551 patients with primary NSCLC, treated in our institute between 2002 and 2007, were reviewed. The initial brain MRI was performed within one month after diagnosis of NSCLC, and the follow-up brain MRI interval was at the discretion of physicians. The interval between the last MRI in which brain metastases were not found and the first MRI in which brain metastases were found was defined as the critical MRIs interval (CMI). The relationship between CMI and the maximum size or number of MBM was evaluated. RESULTS Among reviewed patients, the initial MRI of 38 patients showed brain metastases and 29 patients were diagnosed as MBM. In these MBM patients, the median interval from diagnosis of NSCLC to diagnosis of brain metastases was 8.9 months. The median CMI was 4.7 (range: 1.6-18.9) months. All brain metastases smaller than 30 mm in maximum diameter were found when CMI was shorter than 6.0 months, although 5 or more brain metastases in number were detected even by shorter CMI than 3 months. CONCLUSION Early detection of MBM by biannual MRI follow-up may provide NSCLC patients with more opportunities to have less invasive treatment.

Normal pressure hydrocephalus after radiosurgery for sphenoid ridge meningioma.

Normal pressure hydrocephalus after radiosurgery for meningioma has rarely been reported. We report such a case and discuss the role of radiosurgery in the development of hydrocephalus. A 75-year-old man with a growing tumor underwent linac-based radiosurgery. The tumor received 16 Gy to the 80% isodose line. He exhibited the triad of symptoms of normal pressure hydrocephalus and became bedridden three months after radiosurgery. Dilated ventricles were demonstrated with MRI. Examination of the cerebrospinal fluid revealed a high level of protein. The patient underwent a ventriculoperitoneal shunt and recovered well.