Abstract-Previous studies demonstrated that interleukin-10 (IL-10) overexpression decreases formation of early fatty-streak lesions in mice independent of lipoprotein levels. The present studies, using bone marrow transplantation, demonstrate that overexpression of IL-10 by T cells inhibits advanced atherosclerotic lesions in LDL receptor-null mice fed an atherogenic diet. In mice receiving bone marrow from the IL-10 transgenic mice compared with those receiving wild-type marrow, there was a 47% decrease in lesion size and a marked decrease in lesion complexity with an 80% reduction in the necrotic core. Accumulation of cholesterol and phospholipid oxidation products in the aorta was decreased by 50% to 80%, unrelated to plasma lipid or IL-10 levels. Our studies also provide insight into the mechanism of the IL-10 -mediated decrease in lesion size. Although a strong influence toward a Th1 phenotype has previously been demonstrated in atherosclerotic models, T lymphocytes in the IL-10 transgenic (Tg) group revealed a marked shift to a Th2 phenotype, with decreased IFN-␥ production and an increase in IL

BackgroundAneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture. Investigations of the pathogenic mechanisms involved in syndromic types of thoracic aortic aneurysms, such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed transforming growth factor (TGF)-β signaling.ObjectivesThis study sought to discover a novel gene causing syndromic aortic aneurysms in order to unravel the underlying pathogenesis.MethodsWe combined genome-wide linkage analysis, exome sequencing, and candidate gene Sanger sequencing in a total of 470 index cases with thoracic aortic aneurysms. Extensive cardiological examination, including physical examination, electrocardiography, and transthoracic echocardiography was performed. In adults, imaging of the entire aorta using computed tomography or magnetic resonance imaging was done.ResultsHere, we report on 43 patients from 11 families with syndromic presentations of aortic aneurysms caused by TGFB3 mutations. We demonstrate that TGFB3 mutations are associated with significant cardiovascular involvement, including thoracic/abdominal aortic aneurysm and dissection, and mitral valve disease. Other systemic features overlap clinically with Loeys-Dietz, Shprintzen-Goldberg, and Marfan syndromes, including cleft palate, bifid uvula, skeletal overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-β signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-β signaling in association with up-regulation of the expression of TGF-β ligands.ConclusionsOur findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk.

Abstract-Bone marrow transplantation (BMT) is commonly used to study the participation of bone marrow-derived cells in atherosclerosis. To determine the effect of this methodology on lesions, 16 male low density lipoprotein (LDL) receptor knockout (LDLrϪ/Ϫ) mice were reconstituted with bone marrow from syngeneic LDLrϪ/Ϫ mice after 10 Gy ␥-irradiation and compared with 12 male LDLrϪ/Ϫ littermates that did not undergo BMT (no-BMT group). Mice were fed a high fat diet (HFD) for 16 weeks to induce atherosclerosis. Sixteen additional LDLrϪ/Ϫ mice underwent BMT, and 12 male LDLrϪ/Ϫ mice that did not undergo BMT were fed a chow diet for 56 weeks. Thoracic aorta lesion areas were smaller in BMT mice than in no-BMT mice fed the HFD (PϽ0.0001). In contrast, aortic root lesion areas were greater in the BMT mice fed the HFD (PϽ0.0001) as well as in those fed the chow diet (Pϭ0.0001). Abdominal aorta free cholesterol and cholesteryl ester mass were minimal in all groups studied. Aortic root lesions from all no-BMT mice were densely collagenous and encapsulated by a cellular cap, whereas lesions in the BMT mice contained lipid cores and minimal collagen staining. Although the reason for these differences in lesion size and composition remains unresolved, this study suggests that multiple parameters of lesion formation should be examined to assess atherosclerosis. Key Words: bone marrow transplantation Ⅲ ␥-radiation Ⅲ macrophages Ⅲ collagen Ⅲ hyperlipidemia T he LDL receptor knockout (LDLrϪ/Ϫ) mouse is a particularly suitable model for studying atherosclerosis. These mice develop atherosclerotic lesions predominantly in the aortic sinus when they are fed a chow diet, whereas they develop extensive lesions throughout the aortic root and the length of the entire aorta when they are fed a high fat diet (HFD). 1 Atherosclerosis in mice has been assessed by crosssectional analysis of the aortic sinus, 2 and morphometric methods are also available to quantify the extent of lesion involvement in the entire aortic tree by measuring stained en face dissected aortas. 3 More recently, free cholesterol and cholesteryl ester mass measurements of dissected, homogenized, and lipid-extracted aortas have been used to assess atherosclerosis. 4 Lethal total body ␥-irradiation of atherosclerosis-prone mice followed by bone marrow reconstitution from donors with transgenic alterations in the innate and acquired immune systems has been used experimentally to identify the role of bone marrow-derived cells in atherosclerosis. 5 Although in all cases the experimental mice are compared with control mice that have undergone comparable irradiation and reconstitution with syngeneic wild-type bone marrow, the direct effects of lethal total body irradiation and syngeneic bone marrow transplantation (BMT) on atherosclerosis have not been examined. In this methodological study, we examined the effects of this experimental model on atherosclerosis in male LDLrϪ/Ϫ mice fed either an HFD for 16 weeks to induce rapid lesion formation or a chow diet for 56 weeks t...

During March–July 2014, rotavirus G8P[8] emerged as the predominant cause of rotavirus gastroenteritis among children in Hokkaido Prefecture, Japan. Clinical characteristics were similar for infections caused by G8 and non-G8 strains. Sequence and phylogenetic analyses suggest the strains were generated by multiple reassortment events between DS-1–like P[8] strains and bovine strains from Asia.

We developed a new antibody against an epitope in Lp(a) as a result of oxidation treatment but not in native Lp(a). The present data demonstrated in vivo the presence of oxidized Lp(a) in the atherosclerotic tissue and its elevation in hypertensive patients. The presence of oxidized Lp(a) may be important in understanding the role of Lp(a) in cardiovascular disease.