Efficacy of intraoperative irrigation with artificial cerebrospinal fluid in chronic subdural hematoma surgery: study protocol for a multicenter randomized controlled trial.

Background: The surgical techniques for treatment of chronic subdural hematoma (CSDH), a common neurosurgical condition, have been discussed in a lot of clinical literature. However, the recurrence proportion after CSDH surgery remains high, ranging from 10 to 20%. The standard surgical procedure for CSDH involves a craniostomy to evacuate the hematoma, but irrigating the hematoma cavity during the procedure is debatable.

Intraplacental injection of AAV9-CMV-iCre results in the widespread transduction of multiple organs in double-reporter mouse embryos.

Adeno-associated virus serotype 9 (AAV9) has become a popular tool for gene transfer because of its ability to cross the blood-brain barrier and efficiently transduce genetic material into a variety of cell types. The study utilized GRR (Green-to-Red Reporter) mouse embryos, in which the expression of iCre results in the disappearance of Green Fluorescent Protein (GFP) expression and the detection of Discosoma sp. Red Fluorescent Protein (DsRed) expression by intraplacental injection.

Discovery of ASP5878: Synthesis and structure-activity relationships of pyrimidine derivatives as pan-FGFRs inhibitors with improved metabolic stability and suppressed hERG channel inhibitory activity.

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer patients harboring genetic alterations in FGFR3. We identified pyrimidine derivative ASP5878 (27) with improved metabolic stability and suppressed human ether-á-go-go related gene (hERG) channel inhibitory activity by the optimization of lead compound 1. Based on prediction of the metabolites of 1, an ether linker was introduced in place of the ethylene linker to improve metabolic stability.

Synthesis and structure-activity relationships of pyrimidine derivatives as potent and orally active FGFR3 inhibitors with both increased systemic exposure and enhanced in vitro potency.

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of patients with bladder cancer harboring genetic alterations in FGFR3. We identified pyrimidine derivative 20b, which induced tumor regression following oral administration to a bladder cancer xenograft mouse model. Compound 20b was discovered by optimizing lead compound 1, which we reported previously.

Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives as novel FGFR3 inhibitors with high selectivity over VEGFR2.

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer. We identified 1,3,5-triazine derivative 18b and pyrimidine derivative 40a as novel structures with potent and highly selective FGFR3 inhibitory activity over vascular endothelial growth factor receptor 2 (VEGFR2) using a structure-based drug design (SBDD) approach. X-ray crystal structure analysis suggests that interactions between 18b and amino acid residues located in the solvent region (Lys476 and Met488), and between 40a and Met529 located in the back pocket of FGFR3 may underlie the potent FGFR3 inhibitory activity and high kinase selectivity over VEGFR2.

Slow slip source characterized by lithological and geometric heterogeneity.

Slow slip events (SSEs) accommodate a significant proportion of tectonic plate motion at subduction zones, yet little is known about the faults that actually host them. The shallow depth (<2 km) of well-documented SSEs at the Hikurangi subduction zone offshore New Zealand offers a unique opportunity to link geophysical imaging of the subduction zone with direct access to incoming material that represents the megathrust fault rocks hosting slow slip. Two recent International Ocean Discovery Program Expeditions sampled this incoming material before it is entrained immediately down-dip along the shallow plate interface.

Unexpected biotic resilience on the Japanese seafloor caused by the 2011 Tōhoku-Oki tsunami.

On March 11(th), 2011 the Mw 9.0 2011 Tōhoku-Oki earthquake resulted in a tsunami which caused major devastation in coastal areas. Along the Japanese NE coast, tsunami waves reached maximum run-ups of 40 m, and travelled kilometers inland.

Effects of conventional anticonvulsant drugs on generalized tonic-clonic seizures in Noda epileptic rats.

Noda epileptic rats (NERs) present with clinico-pathological manifestations reminiscent of human generalized tonic-clonic epilepsy. Thus, this strain of rat has been a model of primary, generalized, tonic-clonic epilepsy. However, the infrequency of seizures in these rats makes the assessment of antiepileptic drugs (AEDs) difficult.

Intrinsic graph structure estimation using graph Laplacian.

A graph is a mathematical representation of a set of variables where some pairs of the variables are connected by edges. Common examples of graphs are railroads, the Internet, and neural networks. It is both theoretically and practically important to estimate the intensity of direct connections between variables.

Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia, oxidative stress, inflammation and liver injury in streptozotocin-induced type 1 diabetic rats.

Objective: Sodium-glucose cotransporter (SGLT) 2 plays an important role in renal glucose reabsorption and has been highlighted as a therapeutic target for the treatment of diabetes. Here, we investigated the therapeutic effects of SGLT2 selective inhibitor ipragliflozin in type 1 diabetic rats.

Methods: Type 1 diabetic rats were prepared by intravenous administration of streptozotocin (STZ).

Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice.

The sodium-glucose cotransporter 2 (SGLT2) is responsible for most glucose reabsorption in the kidney and has been proposed as a novel therapeutic target for the treatment of type 2 diabetes. In the present study, the therapeutic effects of SGLT2 selective inhibitor ipragliflozin were examined in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice which exhibit impaired insulin secretion, insulin resistance, hyperlipidemia, hepatic steatosis, and obesity. Single administration of ipragliflozin dose-dependently increased urinary glucose excretion, reduced blood glucose and plasma insulin levels, and improved glucose intolerance.

Synthesis and biological evaluation of C-glucosides with azulene rings as selective SGLT2 inhibitors for the treatment of type 2 diabetes mellitus: discovery of YM543.

Here, a series of C-glucosides with azulene rings in the aglycon moiety was synthesized and the inhibitory activities toward hSGLT1 and hSGLT2 were evaluated. Starting from the azulene derivative 7 which had relatively good SGLT2 inhibitory activity, compound 8a which has a 3-[(azulen-2-yl)methyl]phenyl group was identified as a lead compound for further optimization. Introduction of a phenolic hydroxyl group onto the central benzene ring afforded a potent and selective SGLT2 inhibitor 8e, which reduced blood glucose levels in a dose-dependent manner in rodent diabetic models.

Pharmacological Characterization of YM543, a Newly Synthesized, Orally Active SGLT2 Selective Inhibitor.

Background And Aim: Sodium-glucose cotransporter (SGLT) 2 is a specifically expressed transporter in the kidney that plays an important role in renal glucose reabsorption, and its inhibition may present a novel therapeutic strategy for treating diabetes. Here, we pharmacologically characterized YM543, a newly synthesized SGLT2 selective inhibitor to test this theory.

Results: In vitro studies revealed that YM543 potently and selectively inhibited mouse and human SGLT2 activities at nanomolar ranges.

Antidiabetic effects of SGLT2-selective inhibitor ipragliflozin in streptozotocin-nicotinamide-induced mildly diabetic mice.

Sodium-glucose cotransporter (SGLT) 2 plays an important role in renal glucose reabsorption, and inhibition of renal SGLT2 activity represents an innovative strategy for the treatment of hyperglycemia in diabetic patients. The present study investigated the antidiabetic effects of ipragliflozin, a SGLT2-selective inhibitor, in streptozotocin-nicotinamide-induced mildly diabetic mice, which exhibited a mild decline in glucose tolerance associated with the loss of early-phase insulin secretion. Oral administration of ipragliflozin increased urinary glucose excretion in a dose-dependent manner, an effect which was significant at doses of 0.

Discovery of Ipragliflozin (ASP1941): a novel C-glucoside with benzothiophene structure as a potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus.

A series of C-glucosides with various heteroaromatics has been synthesized and its inhibitory activity toward SGLTs was evaluated. Upon screening several compounds, the benzothiophene derivative (14a) was found to have potent inhibitory activity against SGLT2 and good selectivity versus SGLT1. Through further optimization of 14a, a novel benzothiophene derivative (14h; ipragliflozin, ASP1941) was discovered as a highly potent and selective SGLT2 inhibitor that reduced blood glucose levels in a dose-dependent manner in diabetic models KK-A(y) mice and STZ rats.

Pharmacological profile of ipragliflozin (ASP1941), a novel selective SGLT2 inhibitor, in vitro and in vivo.

The pharmacological profile of ipragliflozin (ASP1941; (1S)-1,5-anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D: -glucitol compound with L: -proline (1:1)), a novel SGLT2 selective inhibitor, was investigated. In vitro, the potency of ipragliflozin to inhibit SGLT2 and SGLT1 and stability were assessed. In vivo, the pharmacokinetic and pharmacologic profiles of ipragliflozin were investigated in normal mice, streptozotocin-induced type 1 diabetic rats, and KK-A(y) type 2 diabetic mice.

Reproductive and developmental toxicity screening test of tetrahydrofurfuryl alcohol in rats.

Twelve male and female rats per group were given tetrahydrofurfuryl alcohol (THFA) by gavage at 0, 15, 50, 150 or 500 mg/kg/day. Males were dosed for 47 days, beginning 14 days before mating, and females were dosed for 42-52 days beginning 14 days before mating to day 4 of lactation throughout the mating and gestation period. Changes in locomotor activity, inhibition of body weight gain, and/or histopathological changes in the thymus, spleen, testes and/or epididymides were observed in males and females at 150 mg/kg and above.

Higher susceptibility of newborn than young rats to 3-methylphenol.

To determine susceptibility of infants to 3-methylphenol, a repeated dose toxicity study was conducted with oral administration to newborn and young rats. In an 18-day newborn study from postnatal days 4 to 21 at doses of 30, 100 and 300 mg/kg/day, various clinical signs including deep respiration, hypersensitivity on handling and tremors under contact stimulus, and depressed body weight gain were observed at 300 mg/kg. At 100 mg/kg, hypersensitivity and tremors were also noted in a small number of males only on single days during the dosing period.