Background and Purpose-About one half of those who develop adult-onset moyamoya disease experience intracranial hemorrhage. Despite the extremely high frequency of rebleeding attacks and poor prognosis, measures to prevent rebleeding have not been established. The purpose of this study is to determine whether extracranial-intracranial bypass can reduce incidence of rebleeding and improve patient prognosis. Methods-This study was a multicentered, prospective, randomized, controlled trial conducted by 22 institutes in Japan.Adult patients with moyamoya disease who had experienced intracranial hemorrhage within the preceding year were given either conservative care or bilateral extracranial-intracranial direct bypass and were observed for 5 years. Primary and secondary end points were defined as all adverse events and rebleeding attacks, respectively. Results-Eighty patients were enrolled (surgical, 42; nonsurgical, 38). Adverse events causing significant morbidity were observed in 6 patients in the surgical group (14.3%) and 13 patients in the nonsurgical group (34.2%). Kaplan-Meier survival analysis revealed significant differences between the 2 groups (3.2%/y versus 8.2%/y; P=0.048). The hazard ratio of the surgical group calculated by Cox regression analysis was 0.391 (95% confidence interval, 0.148-1.029).Rebleeding attacks were observed in 5 patients in the surgical group (11.9%) and 12 in the nonsurgical group (31.6%), significantly different in the Kaplan-Meier survival analysis (2.7%/y versus 7.6%/y; P=0.042). The hazard ratio of the surgical group was 0.355 (95% confidence interval, 0.125-1.009). Conclusions-Although statistically marginal, Kaplan-Meier analysis revealed the significant difference between surgical and nonsurgical group, suggesting the preventive effect of direct bypass against rebleeding. Clinical Trial Registration

Materials are typically ductile at higher temperatures and become brittle at lower temperatures. In contrast to the typical ductile-to-brittle transition behavior of body-centered cubic (bcc) steels, we observed an inverse temperature dependence of toughness in an ultrahigh-strength bcc steel with an ultrafine elongated ferrite grain structure that was processed by a thermomechanical treatment without the addition of a large amount of an alloying element. The enhanced toughness is attributed to a delamination that was a result of crack branching on the aligned {100} cleavage planes in the bundles of the ultrafine elongated ferrite grains strengthened by nanometer-sized carbides. In the temperature range from 60 degrees to -60 degrees C, the yield strength was greater, leading to the enhancement of the toughness.

Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik−/−/Apcmin/+ mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apcmin/+ mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach.

Bulk ultrafine-grained (UFG) low-carbon steel bars were produced by caliber rolling, and the impact and tensile properties were investigated. Initial samples with two different microstructures, ferrite-pearlite and martensite (or bainite), were prepared and then caliber rolling was conducted at 500°C. The microstructures in the rolled bars consisted of an elongated UFG structure with a strong a-fiber texture. The rolled bar consisting of spheroidal cementite particles that distributed uniformly in the elongated ferrite matrix of transverse grain sizes 0.8 to 1.0 lm exhibited the best strength-ductility balance and impact properties. Although the yield strength in the rolled bar increased 2.4 times by grain refinement, the upper-shelf energy did not change, and its value was maintained from 100°C to À40°C. In the rolled bars, cracks during an impact test branched parallel to the longitudinal direction of the test samples as temperatures decreased. Delamination caused by such crack branching appeared, remarkably, near the ductile-to-brittle transition temperature (DBTT). The effect of delamination on the impact properties was associated with crack propagation on the basis of the microstructural features in the rolled bars. In conclusion, the strength-toughness balance is improved by refining crystal grains and controlling their shape and orientation; in addition, delamination effectively enhances the low-temperature toughness.