Visceral fat accumulation is associated with cerebral small vessel disease.

BACKGROUND AND PURPOSE: Obesity is associated with the risk of coronary artery disease and stroke. Visceral fat plays a significant role in the atherogenic effects of obesity. Whether visceral fat accumulation, as measured by computed tomography (CT), is an independent risk factor for the presence of cerebral small vessel disease (SVD) was investigated. METHODS: This study comprised 506 Japanese subjects 35-74 years of age (mean 55.3 years) without a history of symptomatic cerebrovascular disease who underwent health screening tests, including brain magnetic resonance imaging, carotid echography and measurements of the visceral fat area (VFA) and subcutaneous fat area (SFA) on abdominal CT. Visceral fat accumulation was defined as VFA ≥ 100 cm(2) . Logistic regression analysis was performed to examine the associations between visceral fat accumulation and cerebral SVD such as white matter lesions (WMLs) and silent lacunar infarction (SLI). RESULTS: The prevalence of WMLs and SLI but not carotid plaque were significantly higher in subjects with VFA ≥ 100 cm(2) than those with VFA < 100 cm(2) . A VFA ≥ 100 cm(2) was associated with WMLs and SLI independent of age, cardiovascular risk factors and other measurements of obesity, such as waist circumference and body mass index. A large waist circumference was independently associated with SLI. SFA, the combination of VFA and SFA, and body mass index were not associated with WMLs or SLI. CONCLUSIONS: Visceral fat accumulation was independently associated with the presence of cerebral SVD in subjects without a history of symptomatic cerebrovascular disease.

Activation of tyrosine hydroxylase prevents pneumonia in a rat chronic cerebral hypoperfusion model.

Pneumonia is a common complication with the highest attributable proportion of deaths in patients with stroke. Cilostazol is a potent type III phosphodiesterase inhibitor, approved as an anti-platelet aggregation agent. The present study was designed to determine the protective mechanism of cilostazol against post-stroke pneumonia using a rat chronic cerebral hypoperfusion model. Rats were subjected to bilateral common carotid artery ligation (LBCCA) and divided randomly into the vehicle group (n=72) and cilostazol group (n=72). Rats of each group were sacrificed at baseline and at days 14, 28 and 42 after LBCCA. Cilostazol significantly improved the swallowing reflex by shortening the latency to elicited swallowing and increasing the numbers of swallows (P<0.05) at 14 days of hypoperfusion. It also decreased the numbers of bacterial colonies grown in cultures from homogenized lungs. Cilostazol markedly upregulated cyclic AMP responsive element binding protein (CREB) phosphorylation, increased tyrosine hydroxylase (TH) expression in the substantial nigra, and maintained dopamine (84.7+/-2.3 vs. 79.2+/-4.1% control; P=0.0512) and substance P levels (86.6+/-7.9 vs. 73.9+/-6.5% control; P<0.05) in the striatum, compared with the vehicle group. Our results indicate that cilostazol improves the swallowing reflex by enhancing the expression of TH through the CREB phosphorylation signaling pathway, and suggest that cilostazol could be useful in preventing pneumonia in the chronic stage of stroke.

The effect of magmatic activity on hydrothermal venting along the superfast-spreading East pacific rise.

A survey of hydrothermal activity along the superfast-spreading (approximately 150 millimeters per year) East Pacific Rise shows that hydrothermal plumes overlay approximately 60 percent of the ridge crest between 13 degrees 50' and 18 degrees 40'S, a plume abundance nearly twice that known from any other rige portion of comparable length. Plumes were most abundant where the axial cross section is inflated and an axial magma chamber is present. Plumes with high ratios of volatile ((3)He, CH(4), and H(2)S) to nonvolatile (Mn and Fe) species marked where hydrothermal circulation has been perturbed by recent magmatic activity. The high proportion of volatile-rich plumes observed implies that such episodes are more frequent here than on slower spreading ridges.

Induction and selective accumulation of mutant ubiquitin in CA1 pyramidal neurons after transient global ischemia.

Accumulation of mutant ubiquitin-B (UBB(+1)) in neurons is considered the hallmark of proteasomal dysfunction in neurodegenerative disorders, however no such evidence in ischemic brain has been reported. We investigated the contribution of UBB(+1) in delayed neuronal death after transient global ischemia. Transient global ischemia was achieved by occlusion of bilateral common carotid arteries for 5 min and reperfusion in male Mongolian gerbils (n=6 per each time point). In the CA1 region, UBB(+1) immunoreactivity appeared in the cytoplasm of pyramidal cells at 30 min post-ischemia, and the density of these neurons increased at day 2 (P<0.001) and further increased at day 4 post-ischemia. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL)-positive (apoptotic) cells appeared selectively in the CA1 region at day 3 and their density increased further at day 4 post-ischemia (P<0.001). In contrast, UBB(+1) immunoreactivity was only transiently detected from 30 min to 1 day post-ischemia in CA3, dentate gyrus, and frontal cortex, but disappeared at day 2 post-ischemia. No TUNEL-positive cells were observed in these three regions. UBB(+1) mRNA was detected by reverse transcription-polymerase chain reaction in every region of the hippocampus and frontal cortex of ischemic gerbils and even in the non-ischemic control animals, and its expression level was independent of brain region and time after ischemia. Our results indicate induction and selective accumulation of UBB(+1) protein in dying neurons of the CA1 region and suggest that UBB(+1) expression may be induced by proteasomal dysfunction after transient global ischemia.

Focal cerebral ischemia/reperfusion injury in mice induces hematopoietic prostaglandin D synthase in microglia and macrophages.

Hematopoietic prostaglandin D synthase is a key enzyme in synthesis of prostaglandin D. Hematopoietic prostaglandin D synthase is expressed in microglia of the developing mouse brain. This study determined the serial changes and cellular localization of hematopoietic prostaglandin D synthase, and its role in cerebral ischemia/reperfusion injury using C57BL/6 mice (n=84) and bone marrow chimera mice (n=16). The latter mice were selected based on their expression of enhanced green fluorescent protein in bone marrow/blood-derived monocytes/macrophages. The middle cerebral artery was occluded for 60 min, followed by reperfusion. Hematopoietic prostaglandin D synthase expression was examined by immunohistochemistry and Western blotting. Hematopoietic prostaglandin D synthase-positive cells were mainly expressed in the peri-ischemic area at 12 h (P<0.05) and 24 h (P<0.001) after reperfusion, while they were mostly found in the transition area at 48-72 h postreperfusion (P<0.001). There was a significant increase in staining intensity as well as number of hematopoietic prostaglandin D synthase-positive cells in the ischemic core at 5-7 (P<0.001) days postreperfusion. Hematopoietic prostaglandin D synthase-positive cells also co-expressed ionized calcium-binding adapter molecule 1, a marker of microglia/macrophages, and cyclooxygenase-2, but not markers of neurons, oligodendrocytes and astrocytes. Until 72 h postreperfusion, many enhanced green fluorescent protein-positive cells were negative for hematopoietic prostaglandin D synthase, but the number of hematopoietic prostaglandin D synthase-enhanced green fluorescent protein coexpressing cells increased significantly at 5-7 days after reperfusion. Our results indicate that hematopoietic prostaglandin D synthase is mainly produced by endogenous microglia until 72 h after reperfusion, but at 7 days after reperfusion, it is also produced by migrating bone marrow/blood-derived macrophages in the ischemic brain tissue. We speculate that hematopoietic prostaglandin D synthase in the brain has different functions during early and late phases of ischemia.

Carrier-mediated transport system for cephalexin in human placental brush-border membrane vesicles.

The uptake of cephalosporin antibiotics, cephalexin, was studied with brush-border microvillous plasma membrane vesicles prepared and purified from human full-term placental syncytiotrophoblasts. The uptake of cephalexin by the membrane vesicles was not stimulated in the presence of an Na+ gradient from the outside to the inside of the vesicles, whereas alpha-(methylamino)isobutyrate uptake into the vesicles of the same preparation was stimulated by an Na+ gradient. The equilibrium level of cephalexin uptake decreased with increasing osmolarity of the medium, which indicates that cephalexin is transported into the membrane vesicles. When cephalexin concentrations were varied, the initial rate of uptake obeyed Michaelis-Menten kinetics with Km and Vmax values of 2.29 mM and 2.98 nmol/mg of protein per 60 s, respectively. The uptake of cephalexin was inhibited by structural analogues and sulfhydryl modifying reagents. These results indicate the existence of a carrier-mediated transport system for cephalexin in the human placental brush-border membranes.

Type 2 diabetes reduces the proliferation and survival of oligodendrocyte progenitor cells in ishchemic white matter lesions.

Diabetes mellitus (DM) is a major risk factor for stroke and it exacerbates tissue damage after ischemic insult. Diabetes is one of the important causes of the progression of white matter lesion, however, the pathological mechanisms remain unclear. The present study evaluated the influences of type 2 DM on ischemic subcortical white matter injury and the recruitment of oligodendrocyte progenitor cells (OPCs) under chronic cerebral hypoperfusion using type 2 diabetic (db/db) mice. After bilateral common carotid artery stenosis (BCAS), the rarefaction in the white matter was more severe in db/db mice than in db/+ mice, and the number of glutathione S-transferase-pi (GST-pi)-positive mature oligodendrocytes (OLG) was lower in db/db mice than in db/+ mice at 4 and 8 weeks after ischemia. There were no significant differences in the number of single-stranded DNA (ssDNA)-positive apoptotic cells in the deep white matter between the db/db and db/+ mice. We found a transient increase in the platelet-derived growth factor receptor-α (PDGFRα)-positive OPCs in white matter lesions after ischemia. However, significantly fewer PDGFRα-positive OPCs were detected in db/db than db/+ mice from 4weeks after BCAS. The number of Ki67-positive proliferating cells in the deep white matter was significantly lower in db/db mice than in db/+ mice from 4 to 8weeks after BCAS. Most of the Ki67-positive cells were PDGFRα-positive OPCs. Finally, we assessed the survival of 5-bromo-2'-deoxyuridine (BrdU)-positive proliferating cells in ischemic white matter, and found significantly poorer survival of BrdU/PDGFRα-positive OPCs or BrdU/GST-pi-positive OLGs in the db/db mice compared to the db/+ mice in the white matter after BCAS. Our findings suggest that the type 2 DM mice exhibited more severe white matter injury 8 weeks after chronic ischemia. Decreased proliferation and survival of OPCs may play an important role in the progression of white matter lesions after ischemia in diabetics.

Polymorphism of the lipoprotein lipase gene and risk of atherothrombotic cerebral infarction in the Japanese.

BACKGROUND AND PURPOSE: Lipid and lipoprotein abnormalities have been implicated in the pathogenesis of ischemic cerebrovascular disease and atherosclerosis. Lipoprotein lipase (LPL) plays an important role in plasma lipoprotein metabolism. Several studies have recently reported the presence of a relationship between Ser447Stop mutation of LPL and coronary artery disease. Other polymorphisms (HindIII and PvuII) of the LPL gene have already been shown to correlate significantly with dyslipidemia. We investigated whether these polymorphisms are associated with increased risk of ischemic cerebrovascular disease (CVD). METHODS: We recruited 177 CVD patients (atherothrombotic infarction, n=71; cardioembolic infarction, n=30; lacunar infarction, n=76) and 177 healthy control subjects. Subjects were genotyped for the Ser447Stop mutation and for HindIII/PvuII restriction fragment length polymorphisms of the LPL gene, and the findings were investigated for associations with the clinical subtypes of CVD and with lipid levels. RESULTS: The Ser447Stop mutation correlated significantly with CVD (0.107 versus 0.158; P=0.035). For the CG+GG versus CC genotype, the odds ratio between control subjects and CVD patients with atherothrombotic infarction was 0.42 (95% CI, 0.18 to 0.99) (P=0.046). Serum HDL cholesterol and triglyceride levels did not correlate significantly with the Ser447Stop genotype. HindIII polymorphism correlated significantly with CVD (0.234 versus 0.169; P=0.031), but the frequency of PvuII polymorphism was not significantly different between groups. CONCLUSIONS: Our results suggest that the Ser447Stop mutation of the LPL gene is a novel genetic marker for low risk of atherothrombotic cerebral infarction.