Moyamoya disease (MMD) shows progressive cerebral angiopathy characterized by bilateral internal carotid artery stenosis and abnormal collateral vessels. Although B15% of MMD cases are familial, the MMD gene(s) remain unknown. A genome-wide association study of 785 720 single-nucleotide polymorphisms (SNPs) was performed, comparing 72 Japanese MMD patients with 45 Japanese controls and resulting in a strong association of chromosome 17q25-ter with MMD risk. This result was further confirmed by a locus-specific association study using 335 SNPs in the 17q25-ter region. A single haplotype consisting of seven SNPs at the RNF213 locus was tightly associated with MMD (P¼5.3Â10 À10 ). RNF213 encodes a really interesting new gene finger protein with an AAA ATPase domain and is abundantly expressed in spleen and leukocytes. An RNA in situ hybridization analysis of mouse tissues indicated that mature lymphocytes express higher levels of Rnf213 mRNA than their immature counterparts. Mutational analysis of RNF213 revealed a founder mutation, p.R4859K, in 95% of MMD families, 73% of non-familial MMD cases and 1.4% of controls; this mutation greatly increases the risk of MMD (P¼1.2Â10 À43 , odds ratio¼190.8, 95% confidence interval¼71.7-507.9). Three additional missense mutations were identified in the p.R4859K-negative patients. These results indicate that RNF213 is the first identified susceptibility gene for MMD.

The innate immune system of humans recognizes the human pathogenic fungus Candida albicans via sugar polymers present in the cell wall, such as mannan and ␤-glucan. Here, we examined whether nucleic acids from C. albicans activate dendritic cells. C. albicans DNA induced interleukin-12p40 (IL-12p40) production and CD40 expression by murine bone marrow-derived myeloid dendritic cells (BM-DCs) in a dose-dependent manner. BM-DCs that lacked Toll-like receptor 4 (TLR4), TLR2, and dectin-1, which are pattern recognition receptors for fungal cell wall components, produced IL-12p40 at levels comparable to the levels produced by BM-DCs from wild-type mice, and DNA from a C. albicans pmr1⌬ null mutant, which has a gross defect in mannosylation, retained the ability to activate BM-DCs. This stimulatory effect disappeared completely after DNase treatment. In contrast, RNase treatment increased production of the cytokine. A similar reduction in cytokine production was observed when BM-DCs from TLR9 ؊/؊ and MyD88 ؊/؊ mice were used. In a luciferase reporter assay, NF-B activation was detected in TLR9-expressing HEK293T cells stimulated with C. albicans DNA. Confocal microscopic analysis showed similar localization of C. albicans DNA and CpG-oligodeoxynucleotide (CpG-ODN) in BM-DCs. Treatment of C. albicans DNA with methylase did not affect its ability to induce IL-12p40 synthesis, whereas the same treatment completely eliminated the ability of CpG-ODN to induce IL-12p40 synthesis. Finally, impaired clearance of this fungal pathogen was not found in the kidneys of TLR9 ؊/؊ mice. These results suggested that C. albicans DNA activated BM-DCs through a TLR9-mediated signaling pathway using a mechanism independent of the unmethylated CpG motif.

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp a murine skin graft model, 12 and inhibits tumor necrosis factor (TNF)-α expression induced by lipopolysaccharides in a rat glioma cell line in vitro. 13 In addition, low-energy SW therapy exerts anti-inflammatory effects on orthopedic diseases, such as tendinitis, epicondylitis, plantar fasciitis and several inflammatory tendon diseases. 14 Infiltration of inflammatory cells (eg, macrophages) is critically important in wound healing after AMI, while excessive inflammatory responses deteriorates LV remodeling in the chronic phase. 15-17 In the present study, we thus examined whether SW therapy exerts beneficial anti-inflammatory effects in a rat model of AMI. MethodsThe present study conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes ecent progress in emergency care and patient management has improved the prognosis of patients with acute myocardial infarction (AMI). 1-4 However, left ventricular (LV) remodeling after AMI still remains one of the unsolved problems. 5,6 Thus, it is crucial to develop new therapeutic strategies to suppress LV remodeling after AMI. We have developed a non-invasive angiogenic therapy with extracorporeal low-energy shock waves (SW), and have demonstrated its efficacy and safety in a porcine model of chronic myocardial ischemia 7 and patients with angina pectoris. 8,9 Furthermore, we have demonstrated that SW therapy ameliorates LV remodeling after AMI in pigs in vivo. 10,11 However, it remains to be examined whether SW therapy also exerts anti-inflammatory effects on AMI in addition to its angiogenic effects. Low-energy SW therapy suppresses the production of several cytokines, chemokines, and matrix metalloproteinases in Background: It has been previously demonstrated that extracorporeal low-energy shock-wave (SW) therapy ameliorates left ventricular (LV) remodeling through enhanced angiogenesis after acute myocardial infarction (AMI) in pigs in vivo. However, it remains to be examined whether SW therapy also exerts anti-inflammatory effects on AMI.

Costello syndrome and cardio-facio-cutaneous (CFC) syndrome are congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, and intellectual disability. Germline mutations in HRAS cause Costello syndrome, and mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) cause CFC syndrome. Since the discovery of the causative genes, approximately 150 new patients with each syndrome have been reported. However, the clinico-epidemiological features of these disorders remain to be identified. In order to assess the prevalence, natural history, prognosis, and tumor incidence associated with these diseases, we conducted a nationwide prevalence study of patients with Costello and CFC syndromes in Japan. Based on the result of our survey, we estimated a total number of patients with either Costello syndrome or CFC syndrome in Japan of 99 (95% confidence interval, 77-120) and 157 (95% confidence interval, 86-229), respectively. The prevalences of Costello and CFC syndromes are estimated to be 1 in 1,290,000 and 1 in 810,000 individuals, respectively. An evaluation of 15 adult patients 18-32 years of age revealed that 12 had moderate to severe intellectual disability and most live at home without constant medical care. These results suggested that the number of adult patients is likely underestimated and our results represent a minimum prevalence. This is the first epidemiological study of Costello syndrome and CFC syndrome. Identifying patients older than 32 years of age and following up on the patients reported here is important to estimate the precise prevalence and the natural history of these disorders.

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