The phenotype of infiltrating macrophages influences arteriosclerotic plaque vulnerability in the carotid artery

Background: Proinflammatory (M1) macrophages and anti-inflammatory (M2) macrophages have been identified in atherosclerotic plaques. While these macrophages have been speculated to be related to plaque vulnerability, there are limited studies investigating this relationship. Therefore, we examined the association between macrophage phenotype (M1 versus M2) and plaque vulnerability and clinical events. Methods: Patients undergoing carotid endarterectomy received an ultrasound of the carotid artery before surgery. Plaques were processed for analysis by immunohistochemistry, Western blotting, and real-time polymerase chain reaction studies. Medical history and clinical data were obtained from medical records. Results: Patients were divided into 2 groups: those suffering from acute ischemic attack (symptomatic, n = 31) and those that did not present with symptoms (asymptomatic, n = 34). Ultrasound analysis revealed that plaque vulnerability was greater in the symptomatic group (P= .033; Chi-square test). Immunohistochemistry revealed that plaques from the symptomatic group had a greater concentration of M1 macrophages (CD68-, CD11c-positive) while plaques from the asymptomatic group had more M2 macrophages (CD163-positive). This observation was confirmed by Western blotting. Characterization by real-time polymerase chain reaction studies revealed that plaques from the symptomatic group had increased expression of the M1 markers CD68 and CD11c, as well as monocyte chemoattractive protein-1, interleukin-6, and matrix metalloproteinase-9. In addition, more M1 macrophages expressed in unstable plaques were defined by ultrasound analysis, while more M2 macrophages were expressed in stable plaques. Conclusions: Our data show that M1 macrophage content of atherosclerotic plaques is associated with clinical incidence of ischemic stroke and increased inflammation or fibrinolysis. We also show the benefits of using ultrasound to evaluate vulnerability in the plaques

Pathological Investigation of Congenital Bicuspid Aortic Valve Stenosis, Compared with Atherosclerotic Tricuspid Aortic Valve Stenosis and Congenital Bicuspid Aortic Valve Regurgitation

Congenital bicuspid aortic valve (CBAV) is the main cause of aortic stenosis (AS) in young adults. However, the histopathological features of AS in patients with CBAV have not been fully investigated.We examined specimens of aortic valve leaflets obtained from patients who had undergone aortic valve re/placement at our institution for severe AS with CBAV (n = 24, CBAV-AS group), severe AS with tricuspid aortic valve (n = 24, TAV-AS group), and severe aortic regurgitation (AR) with CBAV (n = 24, CBAV-AR group). We compared the histopathological features among the three groups. Pathological features were classified using semi-quantitative methods (graded on a scale 0 to 3) by experienced pathologists without knowledge of the patients' backgrounds. The severity of inflammation, neovascularization, and calcium and cholesterol deposition did not differ between the CBAV-AS and TAV-AS groups, and these four parameters were less marked in the CBAV-AR group than in the CBAV-AS (all p<0.01). Meanwhile, the grade of valvular fibrosis was greater in the CBAV-AS group, compared with the TAV-AS and CBAV-AR groups (both p<0.01). In AS patients, thickness of fibrotic lesions was greater on the aortic side than on the ventricular side (both p<0.01). Meanwhile, thickness of fibrotic lesions was comparable between the aortic and ventricular sides in CBAV-AR patients (p = 0.35).Valvular fibrosis, especially on the aortic side, was greater in patients with CBAV-AS than in those without, suggesting a difference in the pathogenesis of AS between CBAV and TAV

Role of Dok-1 and Dok-2 in Myeloid Homeostasis and Suppression of Leukemia

Dok-1 and Dok-2 are closely related rasGAP-associated docking proteins expressed preferentially in hematopoietic cells. Although they are phosphorylated upon activation of many protein tyrosine kinases (PTKs), including those coupled with cytokine receptors and oncogenic PTKs like Bcr-Abl, their physiological roles are largely unidentified. Here, we generated mice lacking Dok-1 and/or Dok-2, which included the double-deficient mice succumbed to myeloproliferative disease resembling human chronic myelogenous leukemia (CML) and chronic myelomonocytic leukemia. The double-deficient mice displayed medullary and extramedullary hyperplasia of granulocyte/macrophage progenitors with leukemic potential, and their myeloid cells showed hyperproliferation and hypo-apoptosis upon treatment and deprivation of cytokines, respectively. Consistently, the mutant myeloid cells showed enhanced Erk and Akt activation upon cytokine stimulation. Moreover, loss of Dok-1 and/or Dok-2 induced blastic transformation of chronic phase CML-like disease in mice carrying the bcr-abl gene, a cause of CML. These findings demonstrate that Dok-1 and Dok-2 are key negative regulators of cytokine responses and are essential for myeloid homeostasis and suppression of leukemia

The Current Status of SME Financing under the Financial Crisis: A summary of the Survey on the Status of Transactions between Businesses and Financial Institutions (Feb. 2008) and the Survey on the Status of Transactions between Businesses and Financial Institutions following the Financial Crisis (Feb. 2009). (Japanese)

This paper summarizes the results of two questionnaires presented to small and medium size enterprises (SMEs) by RIETI in February 2008 and February 2009. Given the limited data on SMEs, the purpose of the questionnaires is to understand the current status of financing for SMEs facing this serious economic recession, triggered by the financial crisis. The Survey on the Status of Transactions between Businesses and Financial Institutions conducted in February 2008, was sent to 17,018 companies nationwide, with SMEs being the main target, and of those recipients 6,124 companies or 36.0% responded. This survey, which was designed to explain the structural characteristics of SME financing, illustrated terms and conditions such as accounts payable and bills payable for inter-firm credit, differences in the roles of major lending financial institutions including main banks, and the impact of changes in the credit guarantee system in recent years. Regarding the Survey on the Status of Transactions between Businesses and Financial Institutions following the Financial Crisis conducted in February 2009, RIETI targeted 5,979 of the companies who responded to the 2008 survey and of those companies 4,103 or 68.6% responded. The survey was conducted to understand how the relationships between companies and financial institutions and customers and suppliers changed, and what measures SMEs took to address these changes, in light of the fact that the cash management of SMEs has been extremely difficult since last autumn, when the global credit crunch set in. Although the surveys were not identical, some of the same questions were asked in both surveys. The answers to these questions were then compared to see how conditions had changed and to understand which areas of SME financing had become more difficult.

Immunohistochemical analysis of brain lesions using S100B and glial fibrillary acidic protein antibodies in arundic acid- (ONO-2506) treated stroke-prone spontaneously hypertensive rats

Stroke-prone spontaneously hypertensive rats (SHRSP) used as a model of essential hypertension cause a high incidence of brain stroke on the course of hypertension. Incidences and sizes of brain lesions are known to relate to the astrocyte activities. Therefore, relation between brain damage and the expression profile of the astrocytes was investigated with morphometric and immunohistochemical analyses using astrocyte marker antibodies of S100B and glial fibrillary acidic protein (GFAP) with or without arundic acid administration, a suppressor on the activation of astrocytes. Arundic acid extended the average life span of SHRSP. An increase in brain tissue weight was inhibited concomitant with a lower rate of gliosis/hemosiderin deposit/scarring in brain lesions. S100B- or GFAP-positive dot and filamentous structures were decreased in arundic acid-treated SHRSP, and this effect was most pronounced in the cerebral cortex, white matter, and pons, and less so in the hippocampus, diencephalon, midbrain, and cerebellum. Blood pressure decreased after administration of arundic acid in the high-dose group (100 mg/kg/day arundic acid), but not in the low-dose group (30 mg/kg/day). These data indicate that arundic acid can prevent hypertension-induced stroke, and may inhibit the enlargement of the stroke lesion by preventing the inflammatory changes caused by overproduction of the S100B protein in the astrocytes

Extraction and Utilization of Human Social Network toward the Semantic Web

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Second nationwide surveillance of bacterial pathogens in patients with acute uncomplicated cystitis conducted by Japanese Surveillance Committee from 2015 to 2016: antimicrobial susceptibility of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus saprophyticus

The Japanese Surveillance Committee conducted a second nationwide surveillance of antimicrobial susceptibility patterns of uropathogens responsible for acute uncomplicated cystitis (AUC) in premenopausal patients aged 16–40 years old at 31 hospitals throughout Japan from March 2015 to February 2016. In this study, the susceptibility of causative bacteria (Escherichia coli, Klebsiella pneumoniae, Staphylococcus saprophyticus) for various antimicrobial agents was investigated by isolation and culturing of organisms obtained from urine samples. In total, 324 strains were isolated from 361 patients, including E. coli (n = 220, 67.9%), S. saprophyticus (n = 36, 11.1%), and K. pneumoniae (n = 7, 2.2%). The minimum inhibitory concentrations (MICs) of 20 antibacterial agents for these strains were determined according to the Clinical and Laboratory Standards Institute (CLSI) manual. At least 93% of the E. coli isolates showed susceptibility to fluoroquinolones and cephalosporins, whereas 100% of the S. saprophyticus isolates showed susceptibility to fluoroquinolones and aminoglycosides. The proportions of fluoroquinolone-resistant and extended-spectrum β-lactamase (ESBL)-producing E. coli strains were 6.4% (13/220) and 4.1% (9/220), respectively. The antimicrobial susceptibility of K. pneumoniae was retained during the surveillance period, while no multidrug-resistant strains were identified. In summary, antimicrobial susceptibility results of our second nationwide surveillance did not differ significantly from those of the first surveillance. Especially the numbers of fluoroquinolone-resistant and ESBL-producing E. coli strains were not increased in premenopausal patients with AUC in Japan