Synthesis and pharmacological characterization of novel 6-fluorochroman derivatives as potential 5-HT1A receptor antagonists

A series of novel 6-fluorochroman derivatives was prepared and evaluated as antagonists for the 5-HT1A receptor. N-2-[[(6-Fluorochroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylami ne (3; J. Med. Chem. 1997, 40, 1252-1257) was chosen as a lead, and structural modifications were done on the aliphatic portion of the chroman ring, the tether linking the middle amine and the terminal aromatic ring, the aromatic ring, and lastly the amine. Radioligand binding assays proved that the majority of the novel compounds behaved as good to excellent ligands at the 5-HT1A receptor, some of which were selective with respect to alpha1-adrenergic and D2-dopaminergic receptors. The antagonist activity of the compounds was assessed in the forskolin-stimulated adenylate cyclase assays in CHO cells expressing the human 5-HT1A receptors. Among the modifications attempted, introduction of an oxo or an optically active hydroxy moiety at the chroman C-4 position was effective in ameliorating the receptor selectivity. Six analogues were selected through the in vitro screens and further evaluated for their in vivo activities. A 4-oxochroman derivative (31n), having a terminal 1, 3-benzodioxole ring, demonstrated antagonist activities toward 8-OH-DPAT-induced behavioral and electrophysiological responses in rats.     

Use of fluid-attenuated inversion recovery (FLAIR) pulse sequences in perinatal hypoxic-ischaemic encephalopathy

The purpose of this study was to evaluate the usefulness of fluid-attenuated inversion recovery (FLAIR) techniques in patients with perinatal hypoxic-ischaemic encephalopathy. 13 patients with a history of perinatal hypoxic-ischaemic encephalopathy (age range 1 month to 3.6 years) underwent T1 and T2 weighted spin echo and FLAIR imaging with a 1.5 T superconducting unit. FLAIR images were qualitatively evaluated in comparison with T1 and T2 weighted images by three experienced radiologists. Quantitative analysis (contrast and contrast-to-noise ratio) was also performed. FLAIR images were preferred to T1 and T2 weighted images in the demonstration of periventricular leukomalacia (PVL), cystic PVL and subcortical lesions near the brain surface. On T1 and T2 weighted images, almost all lesions were demonstrated as hypointense or hyperintense areas, respectively. However, FLAIR images could differentiate cystic lesions by their signal intensities. FLAIR images were not diagnostic in two cases with PVL. In conclusion FLAIR sequences provide useful information in patients with perinatal hypoxic-ischaemic encephalopathy.     

The effect of wedged insoles on the thrust of osteoarthritic knees

We describe a method of quantifying the lateral/medial thrust of the knee which occurs in the early phase of walking. We have used this method to evaluate the effects of wedged insoles on the lateral and medial thrust for normal knees and knees with unicompartment osteoarthritis (OA). A laterally elevated (valgus) insole decreased the lateral thrust of both normal and osteoarthritic knees. A medially elevated (varus) insole increased the lateral thrust. In 50 symptomatic knees with medial compartment OA, decreasing the lateral thrust with a valgus insole reduced pain on walking in 27. Patients whose pain was reduced by valgus insoles tended to have earlier OA and to have a significantly greater reduction in the lateral thrust than in the 23 remaining unaffected knees. A varus insole was effective in decreasing the medial thrust and reducing pain in all ten knees with lateral compartment OA. We recommend the use of valgus insoles for patients with painful early medial compartment OA and the use of varus insoles for lateral compartment OA.     

Evaluation of ultraviolet assisted bonding between lubricant and diamond-like carbon through spreading of molecularly thin perfluoropolyether lubricant

This paper deals with the evaluation of ultraviolet assisted bonding of perfluoropolyether lubricant to the diamond-like carbon surface of a magnetic disk. Spreading of lubricant from a quasi step-shaped boundary between lubricated and non-lubricated zones was measured with irradiation time, and diffusion coefficients were obtained using a modified Boltzmann–Matano method, which enabled us to approximately calculate the coefficients under the initial condition of a non-step-shaped boundary. We found that irradiation is effective for bonding the lubricant, and that a very thin layer of the lubricant abutting the surface exhibits faster diffusion.     

Preformulation studies of EFdA,a novel nucleoside reverse transcriptase inhibitor for HIV prevention

4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) is a novel nucleoside analog of great interest because of its superior activity against wild-type and multidrug-resistant HIV-1 strains, and favorable safety profiles in vitro and in vivo. The aim of this work was to provide preformulation information of EFdA important for delivery system development. A simple, accurate and specific reverse-phase high performance liquid chromatographic (RP-HPLC) method with UV detection was developed for quantification of EFdA. In addition, physicochemical characterizations including pH solubility profile, octanol/water partition coefficient (Log P_o/w), DSC analysis, field emission scanning electron microscopy, and stability studies under various conditions were conducted. EFdA existed in planar or flake shape, with a melting point of ～130?°C, and had a pH dependent solubility. The log P_o/w value of EFdA was ?1.19. The compound was stable upon exposure to pH levels from 3 to 9 and showed good stability at elevated temperature (65?°C). In vitro cytotoxicity assessments were performed in two different epithelial cell lines. In cell-based studies, the EFdA selectivity index (50% cytotoxic concentration [CC₅₀] values/50% effective concentration [EC₅₀]) was found to be greater than 1?×?10³. Permeability studies using cell- and tissue-based models showed that EFdA had an apparent permeability coefficient (P_app)??6?cm/s and that the paracelluar pathway was the dominant transport route for EFdA. Overall, EFdA possesses favorable characteristics for further formulation development.     

Energy Problems and Energy Control System in the Japanese Steel Industry

With the second oil crisis as a turning point, energy issues have come to occupy a most vital position in business. For the steel industry in particular, which is a heavy oil consumer, energy conservation is as vital as it is anywhere. Steelmakers are therefore committed to a variety of energy-conserving measures, including (1) the installation of waste heat recovery facilities, (2) the organization of elaborate economizing campaigns, (3) the orientation toward continuous operations (continuous casting, etc.) by integrating indispensable processes and excluding dispensable ones, and (4) the increased use of hot rolling and direct rolling, etc.

On the other hand, the steel industry has energy-generating facilities and by-product energy-generating processes that form a complicated energy supply-demand structure. Energy balance is intimately related to the operating rate and the operating method of each steel works, and this so much so that the minimization of specific energy costs does not necessarily entail total cost minimization.

Because of this, there is a rapidly expanding need for a scientifically built “software system” within which the aforementioned relationships are quantitatively analyzed to minimize overall plant costs in relation to the changing external environment. This paper discusses this system by referring to the developments and achievements made so far by the Yawata works of Nippon Steel Corporation.     

Interfacial properties of a direct bonded Nd-doped YVO4 and YVO4 single crystal

Laser crystal bonding of a neodymium-doped yttrium orthovanadate (Nd : YVO₄) and a non-doped yttrium orthovanadate (YVO₄) crystal as a cold finger has been demonstrated. Instead of a traditional chemical treatment, a newly developed dry etching process was applied to the preparation for contact of mechanically polished surfaces. In the subsequent heat treatment process, stable heating at 873 K was required to prevent precipitation at the bonded interface. The bonded interface of 3 mm×3 mm was investigated by optical scattering and wavefront distortion measurements. The scattering density around the bonded interface was less than 4.6×10⁶/cm³ and the wavefront distortion caused by the bonded region was assumed to be around 0.04 at 633 nm. Additional magnified inspection showed that atoms in the bonded region were well arranged with the same regularity as the bulk crystal. The diffusion coefficient of Nd³⁺ ions in the YVO₄ crystal was estimated at 2.3×10^–23 m²/s at 873 K.     

Molecular dynamics simulations of oxygen Frenkel pairs in cerium dioxide

Molecular dynamics simulations of oxygen Frenkel pairs (FPs) in cerium dioxide (CeO₂) were carried out in order to understand their kinetic behavior. The results show that an oxygen FP recombine with the vacancy and the interstitial after the vacancy jump preferentially along the 〈1 0 0〉 direction. When multiple oxygen FPs are introduced, the interstitials aggregate into a (1 1 1) plate-like cluster at relatively lower temperature lower than 600 K, while they recombine with vacancies at elevated temperatures higher than 900 K within 10 ps. Molecular mechanics calculations of oxygen FPs on a (1 1 1) plane show that the formation energy per a FP decreases with increase of the number of FPs. The theoretical results are consistent with the transmission electron microscopy observations of formation of 1/9〈1 1 1〉{1 1 1} oxygen interstitial platelets in CeO₂ under electron irradiation.