Reliability and validity of the Japanese version of the Visual Function Classification System for children with cerebral palsy.

BACKGROUND: Children with cerebral palsy (CP) often experience visual dysfunction that affects motor function and activities of daily living, but no 'gold standard' classification of visual function has been established. In recent years, however, a valid and reliable Visual Function Classification System (VFCS) for children with CP has been developed. AIMS: To examine the reliability and validity of the Japanese version of the VFCS in individuals with CP. METHODS: The translation of the VFCS was performed according to international standards for the translation of measurements. We conducted questionnaires of professionals (three physicians, eight physical therapists, five occupational therapists, six speech-language-hearing therapists and a certified orthoptist) regarding the content validity of the Japanese version of the VFCS. For reliability and concurrent validity, 148 individuals with CP were classified twice by professionals using the Japanese version of the VFCS, Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), Communication Function Classification System (CFCS) and Eating and Drinking Ability Classification System (EDACS), with several weeks between each evaluation. RESULTS: The content validity of the Japanese version of the VFCS almost met the criteria set. The percentage of positive and neutral opinions given by the professionals with regard to the four items ranged from 74% to 92%. The intra-rater reliability was 0.86 (95% CI 0.75-0.96) by Cohen's kappa and 0.93 (95% CI 0.88-0.96) by intraclass correlation coefficient. The inter-rater reliability was 0.67 (95% CI 0.56-0.78) by Cohen's kappa and 0.79 (95% CI 0.69-0.86) by intraclass correlation coefficient. The Spearman correlation coefficients between the VFCS and the GMFCS, MACS, CFCS and EDACS were 0.783, 0.764, 0.738, 0.738 and 0.830, respectively. The concurrent validity was confirmed by the correlations observed with other classification systems. CONCLUSIONS: The results indicated good reliability and validity for the Japanese version of the VFCS.

Efficient production of bispecific antibody by FAST-IgTM and its application to NXT007 for the treatment of hemophilia A.

Efficient production of bispecific antibodies (BsAbs) in single mammalian cells is essential for basic research and industrial manufacturing. However, preventing unwanted pairing of heavy chains (HCs) and light chains (LCs) is a challenging task. To address this, we created an engineering technology for preferential cognate HC/LC and HC/HC paring called FAST-Ig (Four-chain Assembly by electrostatic Steering Technology - Immunoglobulin), and applied it to NXT007, a BsAb for the treatment of hemophilia A. We introduced charged amino-acid substitutions at the HC/LC interface to facilitate the proper assembly for manufacturing a standard IgG-type BsAb. We generated CH1/CL interface-engineered antibody variants that achieved > 95% correct HC/LC pairing efficiency with favorable pharmacological properties and developability. Among these, we selected a design (C3) that allowed us to separate the mis-paired species with an unintended pharmacological profile using ion-exchange chromatography. Crystal structure analysis demonstrated that the C3 design did not affect the overall structure of both Fabs. To determine the final design for HCs-heterodimerization, we compared the stability of charge-based and knobs into hole-based Fc formats in acidic conditions and selected the more stable charge-based format. FAST-Ig was also applicable to stable CHO cell lines for industrial production and demonstrated robust chain pairing with different subclasses of parent BsAbs. Thus, it can be applied to a wide variety of BsAbs both preclinically and clinically.

Discovery of evocalcet, a next-generation calcium-sensing receptor agonist for the treatment of hyperparathyroidism.

The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.

Competition between vinylidene rearrangement and 1,2-insertion of carbon-disubstituted internal alkynes at a Cp*Ir(III) complex.

Competition between vinylidene rearrangement/1,1-insertion and 1,2-alkyne insertion into the Ir-Ar bond of [Cp*Ir(ppy-F4)](+) was observed on reaction with diarylacetylenes. The former process afforded the iridacycle 2via the subsequent 1,4-Ir migration, whereas the latter led to the pyridoisoquinolinium complex 4. Detailed analysis revealed that 4 isomerizes to 2 by heating at 50 °C.

Remote rearrangement of the metal center in a (η6-C6Me6)Ru(II) complex.

Reaction of [(η(6)-C6Me6)RuCl(Ph)(PMe3)] with internal alkynes in the presence of NaBAr(F)4 gave rise to the 1,4-Ru migration to form the o-vinylaryl complex, providing the first example of 1,4-metal migration of a group 8 metal center; in one case further isomerization to an η(3)-allyl complex was observed.

1,4-Metal migration in a Cp*Rh(III) complex.

The reaction of [Cp*RhCl(Ph)(PR3)] (R = Ph or Me) with internal alkynes in the presence of NaBAr(F)4 affords the o-vinylaryl complex with a Rh-(vinyl CH) agostic interaction by way of the alkyne insertion followed by 1,4-rhodium migration, providing the first example of the 1,4-migration of a Rh(III) center.

DFT study of internal alkyne-to-disubstituted vinylidene isomerization in [CpRu(PhC≡CAr)(dppe)]+.

Internal alkyne-to-vinylidene isomerization in the Ru complexes ([CpRu(η(2)-PhC≡CC(6)H(4)R-p)(dppe)](+) (Cp = η(5)-C(5)H(5); dppe = Ph(2)PCH(2)CH(2)PPh(2); R = OMe, Cl, CO(2)Et)) has been investigated using a combination of quantum mechanics and molecular mechanics methods (QM/MM), such as ONIOM(B3PW91:UFF), and density functional theory (DFT) calculations. Three kinds of model systems (I-III), each having a different QM region for the ONIOM method, revealed that considering both the quantum effect of the substituent of the aryl group in the η(2)-alkyne ligand and that of the phenyl groups in the dppe ligand is essential for a correct understanding of this reaction. Several plausible mechanisms have been analyzed by using DFT calculations with the B3PW91 functional. It was found that the isomerization of three complexes (R = OMe, CO(2)Et, and Cl) proceeds via a direct 1,2-shift in all cases. The most favorable process in energy was path 3, which involves the orientation change of the alkyne ligand in the transition state. The activation energies were calculated to be 13.7, 15.0, and 16.4 kcal/mol, respectively, for the three complexes. Donor-acceptor analysis demonstrated that the aryl 1,2-shift is a nucleophilic reaction. Furthermore, our calculation results indicated that an electron-donating substituent on the aryl group stabilizes the positive charge on the accepting carbon rather than that on the migrating aryl group itself at the transition state. Therefore, unlike the general nucleophilic reaction, the less-electron-donating aryl group has an advantage in the migration.

[Fundamental study of three-dimensional coherent oscillatory state acquisition for the manipulation of image contrast: 3D-COSMIC in the spinal region].

Balanced sequence, three-dimensional fast imaging employ steady state acquisition (3D-FIESTA) as an example, was often used for colangiopancretography and aortagraphy in the chest and the aorta, and venography in the extremity and other body parts, because this had the high signal to noise ratio and the short acquisition time. 3D-coherent oscillatory state acquisition for the manipulation of image contrast (COSMIC) developed recently is a sequence thought about based on 3D-FIESTA. We investigated the basic property of 3D-COSMIC compared with 3D-FIESTA in phantom and volunteer scan image study. At result, 3D-COSMIC was superior to 3D-FIESTA at signal to noise ratio and contrast on phantom image, contrast and visual evaluation on volunteer scan image of detection of tissue on spinal region. 3D-COSMIC was useful sequence in spinal region.

Formation of vinylidenes from internal alkynes at a cyclotriphosphato ruthenium complex.

A ruthenium cyclotriphosphato (P(3)O(9)(3-)) complex with a labile MeOH ligand can affect the vinylidene rearrangement of general internal alkynes via the 1,2-migration of alkyl, aryl, and acyl groups. This provides the first internal alkyne-to-vinylidene isomerization with high generality. Several intermediary eta(2)-alkyne complexes could be isolated and were successfully transformed into the corresponding vinylidene complexes. The reaction mechanism is also discussed on the basis of a kinetic study and migratory aptitude of alkyl, aryl, and acyl groups; the present reaction proceeds via an intramolecular process and is viewed as an uncommon electrophilic rearrangement.

Cobalt-catalyzed trimethylsilylmethylmagnesium-promoted radical alkenylation of alkyl halides: a complement to the Heck reaction.

A cobalt complex, [CoCl2(dpph)] (DPPH = [1,6-bis(diphenylphosphino)hexane]), catalyzes an intermolecular styrylation reaction of alkyl halides in the presence of Me3SiCH2MgCl in ether to yield beta-alkylstyrenes. A variety of alkyl halides including alkyl chlorides can participate in the styrylation. A radical mechanism is strongly suggested for the styrylation reaction. The sequential isomerization/styrylation reactions of cyclopropylmethyl bromide and 6-bromo-1-hexene provide evidence of the radical mechanism. Crystallographic and spectroscopic investigations on cobalt complexes reveal that the reaction would begin with single electron transfer from an electron-rich (diphosphine)bis(trimethylsilylmethyl)cobalt(II) complex followed by reductive elimination to yield 1,2-bis(trimethylsilyl)ethane and a (diphosphine)cobalt(I) complex. The combination of [CoCl2(dppb)] (DPPB = [1,4-bis(diphenylphosphino)butane]) catalyst and Me3SiCH2MgCl induces intramolecular Heck-type cyclization reactions of 6-halo-1-hexenes via a radical process. On the other hand, the intramolecular cyclization of the prenyl ether of 2-iodophenol would proceed in a fashion similar to the conventional palladium-catalyzed transformation. The nonradical oxidative addition of carbon(sp2)-halogen bonds to cobalt is separately verified by a cobalt-catalyzed cross-coupling reaction of alkenyl halides with Me3SiCH2MgCl with retention of configuration of the starting vinyl halides. The cobalt-catalyzed intermolecular radical styrylation reaction of alkyl halides is applied to stereoselective variants. Styrylations of 1-alkoxy-2-bromocyclopentane derivatives provide trans-1-alkoxy-2-styrylcyclopentane skeletons, one of which is optically pure.

Cobalt-catalyzed Heck-type reaction of alkyl halides with styrenes.

A cobalt complex, CoCl2[1,6-bis(diphenylphosphino)hexane], catalyzes an alkylation reaction of styrenes in the presence of Me3SiCH2MgCl in ether to yield beta-alkylstyrenes. A variety of alkyl halides including alkyl chlorides can be employed as an alkyl source. A radical mechanism is strongly suggested for this alkylation reaction.