Analysis of haemodynamics and angiogenic response to ischaemia in the obese type 2 diabetic model Spontaneously Diabetic Torii <i>Lepr^fa</i> (SDT fatty) rats

Peripheral artery disease (PAD) is defined as peripheral blood flow impairment, especially in the legs, caused by atherosclerotic stenosis. The disease decreases quality of life because of intermittent claudication or necrosis of the leg. The hindlimb ischaemia model, in which ischaemia is induced by femoral artery ligation, is often utilized as a PAD model. In the hindlimb ischaemia model, nonmetabolic syndrome animals are mainly used. In this study, we investigated the usefulness of Spontaneously Diabetic Torii Leprfa (SDT fatty) rats, a new model for obese type 2 diabetes, as a new PAD animal model. We found that hindlimb blood flow in SDT fatty rats was significantly lower than that in Sprague–Dawley (SD) rats under nonischaemic conditions. Furthermore, SDT fatty rats showed a significantly higher plasma nitrogen oxide level, shorter prothrombin time, and shorter activated partial thromboplastin time than SD rats. In addition, we found that the change in blood flow 7 days after induction of hindlimb ischaemia and the number of Von Willebrand factor‐positive vessels in gastrocnemius muscles were significantly lower in SDT fatty rats than in SD rats. These results suggest that excess production of reactive oxygen species and coagulation activation could be involved in lower blood flow in non‐ischaemic rats and that decreased angiogenesis could be involved in the poor recovery of blood flow in SDT fatty rats with hindlimb ischaemia. Taken together, our results suggest that SDT fatty rats might be useful as a new model for PAD with metabolic syndrome

Analytical and semi-empirical synthesis of near-field seismic waveforms for investigating the rupture mechanism of major earthquakes

For predicting strong ground motions from major earthquakes and for close investigations into complex rupture processes, two different analytical and semi-empirical approaches are used to synthesize seismic waves from a nearby fault with a large linear dimension. The former technique is to calculate Green's functions for a horizontally layered structure by the discrete wave-number/finite element method, and the latter is to use the records of minor shocks as empirical Green's functions by convolving a correction function for the differences in the source functions and the receiver responses between the main and smaller events. In both cases, the phase-delayed Green's functions are integrated over the entire fault surface. The above methods have been applied to the case of the 1969 central Gifu earthquake (M=6.6) which was followed by moderate aftershocks (M=4.3-4.8) and a number of smaller events. It was found that the waveforms synthesized from the two approaches agree reasonably well with each other. The strong-motion records, particularly of body waves and the major portion of surface waves with periods longer than 5-7 s, can be satisfactorily modeled by the theoretical synthesis with a realistic structure and also by the semi-empirical analysis using four aftershock records, if reasonable rupture velocities and rise times are assumed. However, the shorter-period waves with periods 1-2 s involved in the records cannot be simulated by either of these syntheses, unless incoherent rupture propagation over the fault is included. A stochastic fault model with variable rupture velocities over large-scale fault segments is tentatively presented to account for the short-period waves

Clinicopathologic Features, Genetics, Treatment, and Long-Term Outcomes in Japanese Children and Young Adults with Benign Recurrent Intrahepatic Cholestasis: A Multicenter Study

Background: Few reports of benign recurrent intrahepatic cholestasis (BRIC) have focused on East Asian patients. We describe the clinicopathologic features, genetics, treatment, and outcomes in Japanese BRIC patients. Methods: We recruited patients with BRIC type 1 (BRIC-1) or 2 (BRIC-2) treated at four pediatric centers and one adult center between April 2007 and March 2022. Demographics, clinical course, laboratory results, molecular genetic findings concerning ATP8B1 and ABCB11 genes, histopathology, and treatment response were examined retrospectively. Results: Seven Japanese patients with BRIC were enrolled (four male, three female; four BRIC-1 and three BRIC-2). The median age at onset for BRIC-1 was 12 years; for BRIC-2, it was 1 month. Intermittent cholestatic attacks numbered from one to eight during the 11 years of median follow-up. Six patients received a mainstream education; only one patient attended special education. None developed cirrhosis. Three with BRIC-1 showed compound heterozygosity for a variant ATP8B1 gene, while one was heterozygous; two BRIC-2 patients showed compound heterozygosity in ABCB11 and one was heterozygous. Liver biopsy specimens obtained during cholestatic attacks showed fibrosis varying from none to moderate; inflammation was absent or mild. Rifampicin administered to three patients for cholestatic attacks was effective in all, as was cholestyramine in two of three. Conclusions: To our knowledge, this is the first East Asian multicenter study of BRIC patients. Onset age and number of cholestatic attacks varied. Rifampicin and cholestyramine were effective against attacks. No patient developed cirrhosis; most had normal growth and development. The long-term outcomes were satisfactory

Discovery of Gemilukast (ONO-6950), a Dual CysLT₁ and CysLT₂ Antagonist As a Therapeutic Agent for Asthma

An orally active dual CysLT₁ and CysLT₂ antagonist possessing a distinctive structure which consists of triple bond and dicarboxylic acid moieties is described. Gemilukast (ONO-6950) was generated via isomerization of the core indole and the incorporation of a triple bond into a lead compound. Gemilukast exhibited antagonist activities with IC₅₀ values of 1.7 and 25 nM against human CysLT₁ and human CysLT₂, respectively, and potent efficacy at an oral dose of 0.1 mg/kg given 24 h before LTD₄ challenge in a CysLT₁-dependent guinea pig asthmatic model. In addition, gemilukast dose-dependently reduced LTC₄-induced bronchoconstriction in both CysLT₁- and CysLT₂-dependent guinea pig asthmatic models, and it reduced antigen-induced constriction of isolated human bronchi. Gemilukast is currently being evaluated in phase II trials for the treatment of asthma

Discovery of Gemilukast (ONO-6950), a Dual CysLT₁ and CysLT₂ Antagonist As a Therapeutic Agent for Asthma

An orally active dual CysLT₁ and CysLT₂ antagonist possessing a distinctive structure which consists of triple bond and dicarboxylic acid moieties is described. Gemilukast (ONO-6950) was generated via isomerization of the core indole and the incorporation of a triple bond into a lead compound. Gemilukast exhibited antagonist activities with IC₅₀ values of 1.7 and 25 nM against human CysLT₁ and human CysLT₂, respectively, and potent efficacy at an oral dose of 0.1 mg/kg given 24 h before LTD₄ challenge in a CysLT₁-dependent guinea pig asthmatic model. In addition, gemilukast dose-dependently reduced LTC₄-induced bronchoconstriction in both CysLT₁- and CysLT₂-dependent guinea pig asthmatic models, and it reduced antigen-induced constriction of isolated human bronchi. Gemilukast is currently being evaluated in phase II trials for the treatment of asthma