Fosfluconazole for Antifungal Prophylaxis in Very Low Birth Weight Infants

We conducted a retrospective case series study to evaluate the safety of fosfluconazole prophylaxis for preventing invasive fungal infection in VLBW infants with a central vascular access. Fosfluconazole was administered intravenously at a dose of 6 mg/kg everyday during which time a central venous catheter was placed. A total of 23 infants met the criteria for enrollment in our study. No cases of fungal infection were detected during the central venous catheter placement in the group. None of the infants had an elevated β-D-glucan, and all of them were still alive at discharge. Regarding the liver and renal function, no statistically significant differences were observed before and at the end of fosfluconazole prophylaxis. The results of this study demonstrate that fosfluconazole prophylaxis in preventing invasive fungal infection was well tolerated by VLBW infants. This is a first report to describe antifungal prophylaxis using fosfluconazole for VLBW infants

On-Surface Synthesis of Silole and Disilacyclooctaene Derivatives

Sila-cyclic rings are a class of organosilicon cyclic compounds and have abundant application in organic chemistry and materials science. However, it is still challenging to synthesize compounds with sila-cyclic rings in solution chemistry due to their low solubility and high reactivity. Recently, on-surface synthesis was introduced into organosilicon chemistry as 1,4- disilabenzene bridged nanostructures were obtained via coupling between bromo-substituted molecules and silicon atoms on Au(111). Here, we extend this strategy for syntheses of silole derivatives and graphene nanoribbons with eight-membered sila-cyclic rings from 2,2',6,6'- tetrabromobiphenyl and 1,4,5,8-tetrabromonaphthalene on Au(111), respectively. Their structures and electronic properties were investigated by a combination of scanning tunneling microscopy/spectroscopy and density functional theory calculations. This work demonstrates a generality of this synthesis strategy to fabricate various silicon incorporated nanostructures

Involvement of Multidrug Resistance-Associated Protein 1 in Intestinal Toxicity of Methotrexate

金沢大学医薬保健研究域薬学系Purpose: Methotrexate (MTX) causes dose-limiting gastrointestinal toxicity due to exposure of intestinal tissues, and is a substrate of the multidrug resistance-associated protein (MRP) 1. Here we examine the involvement of MRP1, which is reported to be highly expressed in the proliferative crypt compartment of the small intestine, in the gastrointestinal toxicity of MTX. Methods: MTX was intraperitonealy administered to mrp1 gene knockout (mrp1(-/-)) and wild-type (mrp1(+/+)) mice. Body weight, food and water intake were monitored, intestinal histological studies and pharmacokinetics of MTX were examined. Results: mrp1(-/-) mice more severely decreased body weight, food and water intake than mrp1(+/+) mice. Almost complete loss of villi throughout the small intestine in mrp1(-/-) mice was observed, whereas the damage was only partial in mrp1(+/+) mice. Plasma concentration and biliary excretion profiles of MTX were similar in mrp1(-/-) and mrp1(+/+) mice, though accumulation of MTX in immature proliferative cells isolated from mrp1(-/-) mice was much higher compared to mrp1(+/+) mice. Immunostaining revealed localization of Mrp1 in plasma membrane of the intestinal crypt compartment in mrp1(+/+) mice, but not in mrp1(-/-) mice. Conclusion: Mrp1 determines the exposure of proliferative cells in the small intestine to MTX, followed by gastrointestinal toxicity. © 2009 Springer Science+Business Media, LLC

Local Probe Isomerization in a One-Dimensional Molecular Array

Synthesis of one-dimensional molecular arrays with tailored stereoisomers is challenging yet has a great potential for application in molecular opto-, electronic- and magnetic-devices, where the local array structure plays a decisive role in the functional properties. Here, we demonstrate construction and characterization of dehydroazulene isomer and diradical units in three-dimensional organometallic compounds on Ag(111) with a combination of low-temperature scanning tunneling microscopy and density functional theory calculations. Tip-induced voltage pulses firstly result in the formation of a diradical species via successive homolytic fission of two C-Br bonds in the naphthyl groups, which are subsequently transformed into chiral dehydroazulene moieties. The delicate balance of the reaction rates among the diradical and two stereoisomers, arising from an in-line configuration of tip and molecular unit, allows directional azulene-to-azulene and azulene-to-diradical local probe isomerization in a controlled manner. Furthermore, we found that the diradical moiety hosts an open-shell singlet with antiferromagnetic coupling between the unpaired electrons, which can undergo an inelastic spin transition of 91 meV to the ferromagnetically coupled triplet state

P-Glycoprotein (Abcb1) is involved in absorptive drug transport in skin

金沢大学医薬保健研究域薬学系 金沢大学医薬保健研究域医学系The purpose of the present study was to investigate the role of P-glycoprotein (P-gp) in drug disposition in skin. The distribution of P-gp substrates (rhodamine 123 and itraconazole) to the skin after administration from the epidermal side was lower in P-gp gene knockout (mdr1a/1b-/-) mice than that in wild-type mice. Coadministration of propranolol, a P-gp inhibitor, decreased the distribution of itraconazole to the skin in wild-type mice, but not in mdr1a/1b-/- mice. These results suggest that P-gp contributes to the influx (from the epidermal side) of its substrates into skin, although P-gp is generally involved in efflux of drugs from various tissues. This finding was supported by the lower vectorial transport of rhodamine 123 from the epidermal to the hypodermal side in mdr1a/1b-/- mice in Ussing-type chamber experiments and by the immunohistochemical localization of P-gp throughout the dermal layer. Distribution of itraconazole after intravenous administration, on the other hand, was higher in mdr1a/1b-/- mice than that in wild-type mice, suggesting that P-gp transports this drug from the skin to the circulation. The present findings are the first to demonstrate involvement of P-gp in dermal drug disposition. © 2008

Multi-Wavelength Observation of Electron Acceleration in the 2006 December 13 Flare

We present a multi-wavelength observation of a solar flare occurring on 2006 December 13 with Hinode, RHESSI, and the Nobeyama Radio Observatory, to study the electron acceleration site and mechanism. The Solar Optical Telescope (SOT) on board Hinode observed elongated flare ribbons, and RHESSI observed double-footpoint hard X-ray (HXR) sources appearing in part of the ribbons. A photospheric vector magnetogram obtained from SOT reveals that the HXR sources are located at the region where horizontal magnetic fields change the direction. The region is interpreted as the footpoint of magnetic separatrix. Microwave images taken with the Nobeyama Radioheliograph show a loop structure connecting the HXR sources. The brighter parts of the microwave intensity are located between the top and footpoints of the loop. We consider these observations as an evidence of the electron acceleration near the magnetic separatrix and injection parallel to the field line.Comment: 20 pages, 7 figures, accepted by Ap

Gene Knockout and Metabolome Analysis of Carnitine/Organic Cation Transporter OCTN1

金沢大学医薬保健研究域薬学系Purpose: Solute carrier OCTN1 (SLC22A4) is an orphan transporter, the physiologically important substrate of which is still unidentified. The aim of the present study was to examine physiological roles of OCTN1. Methods: We first constructed octn1 gene knockout (octn1-/-) mice. Metabolome analysis was then performed to identify substrates in vivo. The possible association of the substrate identified with diseased conditions was further examined. Results: The metabolome analysis of blood and several organs indicated complete deficiency of a naturally occurring potent antioxidant ergothioneine in octn1-/- mice among 112 metabolites examined. Pharmacokinetic analyses after oral administration revealed the highest distribution to small intestines and extensive renal reabsorption of [3H]ergothioneine, both of which were much reduced in octn1-/- mice. The octn1-/- mice exhibited greater susceptibility to intestinal inflammation under the ischemia and reperfusion model. The blood ergothioneine concentration was also much reduced in Japanese patients with Crohn\u27s disease, compared with healthy volunteers and patients with another inflammatory bowel disease, ulcerative colitis. Conclusions: These results indicate that OCTN1 plays a pivotal role for maintenance of systemic and intestinal exposure of ergothioneine, which could be important for protective effects against intestinal tissue injuries, providing a possible diagnostic tool to distinguish the inflammatory bowel diseases. © 2010 Springer Science+Business Media, LLC

Common Variants in a Novel Gene, FONG on Chromosome 2q33.1 Confer Risk of Osteoporosis in Japanese

Osteoporosis is a common disease characterized by low bone mass, decreased bone quality and increased predisposition to fracture. Genetic factors have been implicated in its etiology; however, the specific genes related to susceptibility to osteoporosis are not entirely known. To detect susceptibility genes for osteoporosis, we conducted a genome-wide association study in Japanese using ∼270,000 SNPs in 1,747 subjects (190 cases and 1,557 controls) followed by multiple levels of replication of the association using a total of ∼5,000 subjects (2,092 cases and 3,114 controls). Through these staged association studies followed by resequencing and linkage disequilibrium mapping, we identified a single nucleotide polymorphism (SNP), rs7605378 associated with osteoporosis. (combined P = 1.51×10−8, odds ratio = 1.25). This SNP is in a previously unknown gene on chromosome 2q33.1, FONG. FONG is predicted to encode a 147 amino-acid protein with a formiminotransferase domain in its N-terminal (FTCD_N domain) and is ubiquitously expressed in various tissues including bone. Our findings would give a new insight into osteoporosis etiology and pathogenesis