Takahiko Asano

High-Intensity Signal on Time-of-Flight Magnetic Resonance Angiography Indicates Carotid Plaques at High Risk for Cerebral Embolism During Stenting

Background and Purpose— A major disadvantage of carotid artery stenting (CAS) compared to carotid endarterectomy is the increased risk of cerebral embolism. Thus, establishing a simple method to discriminate fragile plaques on preoperative routine examination is important. The present study examined whether high-intensity signal (HIS) in the plaque on time-of-flight (TOF) MRA, performed for screening, can discriminate plaque at high risk for cerebral embolism during CAS. Methods— In the 30 patients treated using carotid endarterectomy, relationships between pathological findings of the plaques and TOF-MRA findings were analyzed. In the 112 patients treated using CAS, postoperative ipsilateral ischemic lesions on diffusion-weighted imaging and periprocedural ischemic symptoms were analyzed. Results— The percentage area of intraplaque hemorrhage stained by glycophorin A was significantly larger in HIS-positive plaques (51.8%±9.8%) than in HIS-negative plaques (8.6%±9.4%; P<0.001). Postoperative ischemic lesions on diffusion-weighted imaging were more frequent in the HIS-positive plaques (25/38; 65.8%) than in the HIS-negative plaques (26/74; 35.1%; P=0.002). Periprocedural ischemic symptoms were more frequently observed in HIS-positive plaques (7/38; 18.4%) than in HIS-negative plaques (1/74; 1.4%; P=0.003). Multivariate logistic regression analysis identified HIS on TOF-MRA as an independent predictor of periprocedural ischemic symptoms (odds ratio, 15.08; 95% confidence interval, 1.76–129.0). Conclusions— HIS in the plaque on TOF-MRA performed for screening could discriminate plaques at high risk for cerebral embolism during CAS.

Tumor Necrosis Factor Alpha-Induced Interleukin-8 Production via NF-κB and Phosphatidylinositol 3-Kinase/Akt Pathways Inhibits Cell Apoptosis in Human Hepatocytes

ABSTRACT Tumor necrosis factor alpha (TNF-α) not only induces apoptotic signals but also causes antiapoptotic and regenerative responses in the liver. However, the molecular mechanism(s) of the latter events remains unclear. In the present study, we examined TNF-α-induced genes in Hc human normal (unsensitized) hepatocytes by cDNA microarray analysis. Interleukin-8 (IL-8) induction was the most pronounced of the upregulated genes. The IL-8 protein level was also increased. IL-8 belongs to the ELR-CXC chemokine family and appears to exert mitogenic and antiapoptotic functions in other cell systems. IL-8 expression by TNF-α was inhibited when two survival signals, nuclear factor κB (NF-κB) and phosphatidylinositol 3-kinase (PI3K)/Akt, were inhibited by a mutant form of inhibitor of NF-κB (IκB); by dominant negative (kinase-dead) Akt; or by treatment with LY 294002, an inhibitor of PI3K. TNF-α induced apoptosis in Hc cells that were sensitized by inhibition of NF-κB and PI3K activation. IL-8 administration protected mice against concanavalin A-induced hepatitis in vivo. IL-8 also rescued the sensitized Hc cells, at least in part, from TNF-α-induced apoptosis in vitro. TNF-α inhibited DNA synthesis in unsensitized Hc cells in the absence of serum. Exogenous IL-8 reversed, though anti-IL-8 neutralization antibody enhanced, growth inhibition by TNF-α. These results indicate that IL-8, the production of which is stimulated by TNF-α, inhibits apoptosis of sensitized hepatocytes and releases normal (unsensitized) hepatocytes from growth inhibition induced by TNF-α.

Prediction of silent ischemic lesions after carotid artery stenting using integrated backscatter ultrasound and magnetic resonance imaging

OBJECTIVE A major concern with carotid artery stenting (CAS) is the potential for cerebral embolism. The purpose of this study was to determine whether integrated backscatter (IBS) ultrasound and black-blood magnetic resonance imaging (BB-MRI) can predict the risk of a silent ischemic lesion after CAS. METHODS We performed quantitative analysis of plaque characteristics in carotid arteries using IBS ultrasound and BB-MRI before CAS in 50 patients. We measured IBS values and the signal intensity ratio (SIR) from T1 weighted images of all plaques. We also performed diffusion-weighted (DWI) MRI of the brain before and after CAS. RESULTS In the patient group that was positive (n=19) for newly appearing ipsilateral silent ischemic lesions (NISIL), relative unstable component area (%UCA) evaluated by IBS analysis (60.2+/-23.4% and 35.3+/-19.2%, p<0.001) and SIR (1.40+/-0.19 and 1.18+/-0.25, p<0.01) in most stenotic lesions were higher than in the NISIL-negative group (n=31). From the analysis of receiver operating characteristic curves, 50% of the %UCA measured by IBS and an SIR of 1.25 measured by BB-MRI were the most reliable cutoff values for predicting NISIL. In multivariate logistic regression analysis, the independent predictors of NISIL were SIR (p=0.030), the CRP level (p=0.041) and the %UCA measured by IBS (p=0.049). CONCLUSIONS Quantitative tissue characterization of carotid plaques using IBS ultrasound and BB-MRI was useful to predict NISIL after CAS. The plaque components in carotid arteries should be evaluated by BB-MRI or IBS ultrasound before CAS to improve the clinical outcome of this procedure.

Leflunomide protects from T‐cell–mediated liver injury in mice through inhibition of nuclear factor κB

Leflunomide is a novel immunosuppressive and anti‐inflammatory agent for the treatment of autoimmune disease. The aim of this study was to investigate whether leflunomide protects from liver injury induced by concanavalin A (Con A), a T‐cell–dependent model of liver damage. BALB/c mice were injected with 25 mg/kg Con A in the presence or absence of 30 mg/kg leflunomide. Liver injury was assessed biochemically and histologically. Levels of circulating cytokines and expressions of cytokine messenger RNA (mRNA) in the liver and the spleen were determined. Treatment with leflunomide markedly reduced serum transaminase activities and the numbers of dead liver cells. Leflunomide significantly inhibited increases in plasma tumor necrosis factor alpha (TNF‐α) and interleukin 2 concentrations, and also reduced TNF‐α mRNA expression in the liver after administration of Con A. These findings were supported by the results in which leflunomide administration decreased the number of T lymphocytes infiltrating the liver as well as inhibiting their production of TNF‐α. Activation of nuclear factor κB (NF‐κB), which regulates TNF‐α production, was inhibited in the liver of mice treated with leflunomide, resulting in a reduction of TNF‐α production from lymphocytes infiltrating the liver. In conclusion, leflunomide is capable of regulating T‐cell–mediated liver injury in vivo and that this event may depend on the decrease of TNF‐α production in the liver through inhibition of NF‐κB activation caused by leflunomide. (HEPATOLOGY 2004.)

High frequency of calcification in basal ganglia on brain computed tomography images in Japanese older adults

To investigate the frequency of calcification in the basal ganglia and the dentate nuclei in the cerebellum, and compare the difference in age and area, we examined the brain computed tomography (CT) images of all patients in two representative university hospitals in Japan.

Molecular analysis of B-cell differentiation in selective or partial IgA deficiency

Selective IgA deficiency is the most common form of primary immunodeficiency, the molecular basis of which is unknown. To investigate the cause of selective IgA deficiency, we examined what stage of B‐cell differentiation was blocked. DNA and RNA were extracted from three Japanese patients with selective IgA deficiency and three with a partial IgA deficiency. In selective IgA deficiency patients, Iα germline transcript expression levels decreased and α circle transcripts were not detected. Stimulation with PMA and TGF‐β1 up‐regulated Iα germline and α circle transcripts. In some patients, IgA secretion was induced by stimulation with anti‐CD40, IL‐4 and IL‐10. In partial IgA deficiency patients, Iα germline, α circle transcripts and Cα mature transcripts were detected in the absence of stimulation. Our findings suggest that the decreased expression level of Iα germline transcripts before a class switch might be critical for the pathogenesis of some patients with selective IgA deficiency. However, in patients with a partial IgA deficiency, B‐cell differentiation might be disturbed after a class switch.

Effects of Atorvastatin on Carotid Atherosclerotic Plaques: A Randomized Trial for Quantitative Tissue Characterization of Carotid Atherosclerotic Plaques with Integrated Backscatter Ultrasound

Background: Instability of carotid plaques has been reported to be associated with stroke and other cerebrovascular events. The purpose of this study was to examine whether cholesterol-lowering therapy with atorvastatin in nonhypercholesterolemic patients reduces carotid plaque instability as assessed by ultrasound integrated backscatter (IBS) analysis. Methods: Consecutive non- or slightly hypercholesterolemic patients with moderate carotid artery stenosis were randomly assigned to a diet group (n = 20) or a statin group (atorvastatin; n = 20). Carotid plaques were monitored by measuring intima media thickness (IMT) and IBS values at baseline and after 6 months. Results: Three-dimensional IBS imaging showed that relative lipid volume of carotid plaques significantly decreased from 58.4 ± 25.6 to 47.8 ± 23.5% in the statin group (p < 0.01), whereas there was no significant decrease in the diet group. Significant regression of IMT was not observed in either group. The changes of IBS values and relative lipid volume between baseline and 6 months were correlated with the change in low-density lipoprotein cholesterol (r = 0.31, p < 0.05, and r = 0.34, p < 0.05, respectively). Conclusions: Lipid-lowering therapy by atorvastatin decreased relative lipid volume without significant regression of plaque volume during short-term follow-up in patients with moderate carotid artery stenosis. Quantitative assessment of carotid plaques by IBS analysis was clinically useful for monitoring atherosclerotic lesions.

Inhibition of nuclear factor κB and phosphatidylinositol 3-kinase/Akt is essential for massive hepatocyte apoptosis induced by tumor necrosis factor α in mice

Background/aims: Tumor necrosis factor (TNF)‐α itself does not induce liver injury in normal mice or hepatocytes. Rather, this event, especially in vitro, is explained by the fact that the TNF‐α/TNF receptor system not only triggers downstream signals leading to apoptosis but also induces an antiapoptotic pathway through the activation of nuclear factor (NF)‐κB. The aim of this study was to determine whether inhibition of antiapoptotic pathways influences the susceptibility of mice to TNF‐α. Here, we focused on the roles of NF‐κB and phosphatidylinositol 3‐kinase (PI3K)‐regulated serine/threonine kinase Akt.

Predominant copper deficiency during prolonged enteral nutrition through a jejunostomy tube compared to that through a gastrostomy tube

BACKGROUND & AIMS Trace element deficiencies are known to occur during long-term enteral nutrition feeding. We compared the serum concentrations of trace elements between patients treated with gastrostomy and those treated with jejunostomy. METHODS Our subjects were 36 patients who underwent percutaneous endoscopic gastrostomy (PEG group) and 23 patients who underwent percutaneous endoscopic jejunostomy (PEJ group) and were maintained with enteral tube feeding for more than one year. The serum concentrations of copper, zinc, selenium, and iron were measured in the two groups. Clinical manifestations and the effectiveness of supplementation therapy against copper deficiency were also investigated. RESULTS From 6 months after the onset of enteral feeding, the copper concentration of the PEJ group was significantly decreased compared with that of the PEG group (p<0.001). There were no significant differences in the concentrations of zinc, selenium, or iron between the two groups. Severe copper deficiency was observed in 6 patients of the PEJ group and was accompanied with neutropenia and anemia. The copper deficiency was successfully treated in all of these patients by supplementation with 10-40 g of cocoa powder a day which was equivalent to a total daily dose of 1.36-2.56 mg of copper. CONCLUSIONS Prolonged PEJ tube nutrition tends to result in copper deficiency, and cocoa supplementation is effective for treating such copper deficiency.

Development of an Automated Method for the Detection of Chronic Lacunar Infarct Regions in Brain MR Images

The purpose of our study is to develop an algorithm that would enable the automated detection of lacunar infarct on T1-and T2-weighted magnetic resonance (MR) images. Automated identification of the lacunar infarct regions is not only useful in assisting radiologists to detect lacunar infarcts as a computer-aided detection (CAD) system but is also beneficial in preventing the occurrence of cerebral apoplexy in high-risk patients. The lacunar infarct regions are classified into the following two types for detection: “isolated lacunar infarct regions” and “lacunar infarct regions adjacent to hyperintensive structures.” The detection of isolated lacunar infarct regions was based on the multiple-phase binarization (MPB) method. Moreover, to detect lacunar infarct regions adjacent to hyperintensive structures, we used a morphological opening processing and a subtraction technique between images produced using two types of circular structuring elements. Thereafter, candidate regions were selected based on three features — area, circularity, and gravity center. Two methods were applied to the detected candidates for eliminating false positives (FPs). The first method involved eliminating FPs that occurred along the periphery of the brain using the region-growing technique. The second method, the multi-circular regions difference method (MCRDM), was based on the comparison between the mean pixel values in a series of double circles on a T1-weighted image. A training dataset comprising 20 lacunar infarct cases was used to adjust the parameters. In addition, 673 MR images from 80 cases were used for testing the performance of our method; the sensitivity and specificity were 90.1% and 30.0% with 1.7 FPs per image, respectively. The results indicated that our CAD system for the automatic detection of lacunar infarct on MR images was effective.