Giant Rashba-type spin splitting in bulk BiTeI.

There has been increasing interest in phenomena emerging from relativistic electrons in a solid, which have a potential impact on spintronics and magnetoelectrics. One example is the Rashba effect, which lifts the electron-spin degeneracy as a consequence of spin-orbit interaction under broken inversion symmetry. A high-energy-scale Rashba spin splitting is highly desirable for enhancing the coupling between electron spins and electricity relevant for spintronic functions. Here we describe the finding of a huge spin-orbit interaction effect in a polar semiconductor composed of heavy elements, BiTeI, where the bulk carriers are ruled by large Rashba-like spin splitting. The band splitting and its spin polarization obtained by spin- and angle-resolved photoemission spectroscopy are well in accord with relativistic first-principles calculations, confirming that the spin splitting is indeed derived from bulk atomic configurations. Together with the feasibility of carrier-doping control, the giant-Rashba semiconductor BiTeI possesses excellent potential for application to various spin-dependent electronic functions.

Switching of band inversion and topological surface states by charge density wave.

Topologically nontrivial materials host protected edge states associated with the bulk band inversion through the bulk-edge correspondence. Manipulating such edge states is highly desired for developing new functions and devices practically using their dissipation-less nature and spin-momentum locking. Here we introduce a transition-metal dichalcogenide VTe2, that hosts a charge density wave (CDW) coupled with the band inversion involving V3d and Te5p orbitals. Spin- and angle-resolved photoemission spectroscopy with first-principles calculations reveal the huge anisotropic modification of the bulk electronic structure by the CDW formation, accompanying the selective disappearance of Dirac-type spin-polarized topological surface states that exist in the normal state. Thorough three dimensional investigation of bulk states indicates that the corresponding band inversion at the Brillouin zone boundary dissolves upon the CDW formation, by transforming into anomalous flat bands. Our finding provides a new insight to the topological manipulation of matters by utilizing CDWs' flexible characters to external stimuli.

[The utility of coronary magnetic resonance angiography in children under six years of age with Kawasaki disease].

BACKGROUND: To follow up coronary arterial lesions due to Kawasaki disease (KD) using noninvasive magnetic resonance coronary angiography (MRCA), we studied a method to improve the quality of images in young children. METHOD: Non-contrast enhanced, free-breathing MRCA with the vector ECG gating real-time navigator-echo 3D steady-state free precession (SSFP) technique was performed using a 1.5-T whole-body MR imaging system (Philips) in 68 children with KD aged 4 months to less than 6 years. A flex medium coil was used. Data were acquired with a 180 to 200 mm field of view (FOV) and were reconstructed with a 512 x 360 matrix. Patients were sedated during the examination. Many parameters were optimized for each patient; i.e., FOV, acquisition delay, turbo-field echo-factor, navigator-window and resolution, which resulted in the acquisition of high-resolution and high-signal images of the coronary arteries. RESULTS: These conditions remarkably improved not only the quality of the images, but also the detection rate of coronary arterial segments (American Heart Association) in the children. The rates were as follows; Segments 1 (97%), 2 (97%), 3 (87%), 4 (66%), 5 (97%), 6 (96%), 7 (83%), 8 (56%), 9 (53%), 10 (21%), 11 (96%), 12 (29%), 13 (93%), 14 (54%), and 15 (65%). CONCLUSION: MRCA is a useful method for evaluation coronary aneurysms from the early stages of KD, even in infants and small children.

Orbital-anisotropic electronic structure in the nonmagnetic state of BaFe2(As1-xP x )2 superconductors.

High-temperature superconductivity in iron-pnictides/chalcogenides arises in balance with several electronic and lattice instabilities. Beside the antiferromagnetic order, the orbital anisotropy between Fe 3d xz and 3d yz occurs near the orthorhombic structural transition in several parent compounds. However, the extent of the survival of orbital anisotropy against the ion-substitution remains to be established. Here we report the composition (x) and temperature (T) dependences of the orbital anisotropy in the electronic structure of a BaFe2(As1-xP x )2 system by using angle-resolved photoemission spectroscopy. In the low-x regime, the orbital anisotropy starts to evolve on cooling from high temperatures above both antiferromagnetic and orthorhombic transitions. By increasing x, it is gradually suppressed and survives in the optimally doped regime. We find that the in-plane orbital anisotropy persists in a large area of the nonmagnetic phase, including the superconducting dome. These results suggest that the rotational symmetry-broken electronic state acts as the stage for superconductivity in BaFe2(As1-xP x )2.

Applicability of anti-neovascular therapy to drug-resistant tumor: suppression of drug-resistant P388 tumor growth with neovessel-targeted liposomal adriamycin.

Anti-neovascular therapy, one of the effective anti-angiogenic chemotherapy, damages new blood vessels by cytotoxic agents delivered to angiogenic endothelial cells and results in indirect eradication of tumor cells. We previously reported that liposomes-modified with a pentapeptide, Ala-Pro-Arg-Pro-Gly (APRPG-Lip) homing to angiogenic site, highly accumulated in tumor tissue, and APRPG-Lip encapsulating adriamycin (APRPG-LipADM) effectively suppressed tumor growth in tumor-bearing mice. In the present study, we examined the topological distribution of fluorescence-labeled APRPG-LipADM as well as TUNEL-stained cells in an actual tumor specimen obtained from Colon 26 NL-17 carcinoma-bearing mice. The fluorescence-labeled APRPG-Lip dominantly localized to vessel-like structure: a part of which was also stained with anti-CD31 antibody. Furthermore, TUNEL-stained cells were co-localized to the same structure. These data indicated that APRPG-LipADM bound to angiogenic endothelial cells and induced apoptosis of them. We also investigated the applicability of anti-neovascular therapy using APRPG-LipADM to ADM-resistant P388 solid tumor. As a result, APRPG-LipADM significantly suppressed tumor growth in mice bearing the ADM-resistant tumor. These data suggest that APRPG-LipADM is applicable to various kinds of tumor including drug-resistant tumor since it targets angiogenic endothelial cells instead of tumor cells, and eradicates tumor cells through damaging the neovessels.

Effects of infusion of human methemoglobin solution following hydrogen sulfide poisoning.

RATIONALE: We have recently reported that infusion of a solution containing methemoglobin (MetHb) during exposure to hydrogen sulfide results in a rapid and large decrease in the concentration of the pool of soluble/diffusible H2S in the blood. However, since the pool of dissolved H2S disappears very quickly after H2S exposure, it is unclear if the ability of MetHb to "trap" sulfide in the blood has any clinical interest and relevance in the treatment of sulfide poisoning. METHODS: In anesthetized rats, repetition of short bouts of high level of H2S infusions was applied to allow the rapid development of an oxygen deficit. A solution containing MetHb (600 mg/kg) or its vehicle was administered 1 min and a half after the end of H2S intoxication. RESULTS: The injection of MetHb solution increased methemoglobinemia to about 6%, almost instantly, but was unable to affect the blood concentration of soluble H2S, which had already vanished at the time of infusion, or to increase combined H2S. In addition, H2S-induced O2 deficit and lactate production as well as the recovery of carotid blood flow and blood pressure were similar in treated and control animals. CONCLUSION: Our results do not support the view that administration of MetHb or drugs-induced methemoglobinemia during the recovery phase following severe H2S intoxication in sedated rats can restore cellular oxidative metabolism, as the pool of diffusible sulfide, accessible to MetHb, disappears rapidly from the blood after H2S exposure.

Scintigraphic monitoring of coronary artery occlusion due to Kawasaki disease.

Noninvasive monitoring of the process of coronary occlusion will probably aid in determining the timing of therapeutic interventions for Kawasaki disease. A pair study of coronary angiography and thallium scintigraphy after dipyridamole infusion-single-photon emission computed tomography with dipyridamole infusion (Dp-SPECT) was repeated at least twice at intervals of several years in 29 patients, and these findings were compared and analyzed in a chronologic manner. The current study demonstrated that angiographic stenosis was more severe, with an increase in the severity of the perfusion defect. Positive rates determined by Dp-SPECT increased with increasing severity of stenosis on angiography. Angiographic findings from the first to the second serial study that showed worsening, no change and improvement were correctly diagnosed from scintigraphic changes in 94% of coronary arterial lesions. About half of the arteries with progression in stenotic severity could be found before complete occlusion by scintigraphic monitoring. It is concluded that Dp-SPECT can be used as a noninvasive monitor of the occurrence and progression of coronary stenoses due to Kawasaki disease.

Improvement of idarubicin induced antitumor activity and bone marrow suppression by theanine, a component of tea.

We have examined the effect of theanine, a specific amino acid in green tea, on idarubicin (IDA)-induced antitumor activity and toxicity. In combination with theanine, IDA (0.25 mg/kg per day x4 days, a dose that does not show antitumor activity) had significant antitumor activity in P388-bearing mice. The IDA concentration in the tumors in the theanine plus IDA group increased to twice the level in the IDA alone group. Furthermore, the decrease in tumor weight caused by IDA at 1.0 mg/kg per day x4 days (at this dose IDA exhibits antitumor activity) was significantly amplified by theanine. The numbers of leukocyte and bone marrow cells decreased significantly on IDA injection. Theanine significantly reversed these changes. These results suggest that theanine selectively moderates the IDA-induced toxicities. Until recently, the antitumor activity and related toxicities of this chemotherapeutic agent in leukemia could not be distinguished. Theanine increases the IDA-induced antitumor activity and ameliorates the toxicities.

Synchronized crystal dissolution behavior for tooth enamel and synthetic (NBS) hydroxyapatite.

The synchronized cyrstal dissolution hypothesis previously proposed to explain the unusual dissolution behavior of human dental enamel and hydroxyapatite in partially saturated acidic media has been critically examined with dissolution-dialysis transport experiments. The findings are in accord with the hypothesis. A model based upon a variable effective solubility for the hydroxyapatite crystal is proposed.

Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance.

Considering of novel biochemical modulation by some foods and beverages, we have performed screening for green tea components that have enhancing effects on doxorubicin (DOX) induced antitumor activity. Components, such as caffeine, theanine, (-)-epigallocatechin gallate (EGCG) and flavonoids have inhibitory effects on the DOX efflux from Ehrlich ascites carcinoma cells. Thus, it is suggested that EGCG and flavonoids may enhance DOX induced antitumor activity and increase the DOX concentrations in tumors through the inhibition of DOX efflux. It is expected that these components in green tea exhibit low toxicity and that there are few side effects of drinking green tea in combination with an antitumor agent. We think that the intake of a favorite beverage favors a positive mental attitude of a patient and increases the efficacy of the chemotherapeutic index, and that this efficacy is useful for improving the quality of life on cancer chemotherapy. In DOX resistant P388 leukemia cell bearing mice theanine increased the DOX induced efficacy through an increase in the DOX concentrations in the tumors. Theanine attacked the same transport process for DOX in both types of cells, elevated the DOX concentration and increased the DOX induced antitumor activity.

Intraperitoneal administration of doxorubicin encapsulating liposomes against peritoneal dissemination.

To improve therapy for peritoneal dissemination, and the distributions of doxorubicin (DOX) in the abdominal cavity, solid tumor and normal tissues after intraperitoneal administration of DOX-encapsulating liposomes was examined. In small negatively charged liposomes, lipid composition did not affect the clearance or stability of liposomes in the abdominal cavity. Whereas, for the treatment of solid tumor and the reduction of side effects, L-alpha-distearoylphosphatidylcholine-containing liposomes were most effective. On the other hand, large liposomes (DS(L)-Lip) were most abundant in the abdominal cavity. As the DOX levels in the heart, liver and solid tumor after DS(L)-Lip injection were lower than the corresponding values for the small liposome group, we considered that DS(L)-Lip were disrupted in the abdominal cavity and DOX was released from the liposomes. DS(L)-Lip remain in the abdominal cavity for a long time inducing cytotoxicity. The survival of Ehrlich ascites carcinoma-bearing mice was considered to be prolonged by DS(L)-Lip. Liposomes, both small and large in size appear to be effective against solid tumors except in the abdominal cavity, and against peritoneal dissemination in the abdominal cavity, respectively.

Enhancement of the activity of doxorubicin by inhibition of glutamate transporter.

Theanine enhanced doxorubicin (DOX) induced antitumor activity by increasing the concentration of DOX in the tumor through the inhibition of efflux of DOX from tumor cells. As theanine reduced the level of glutamate via suppression of the glutamate transporter in tumor cells, we studied the change in the intracellular concentration of glutathione (GSH) and the correlation with the GSH S-conjugate export (GS-X) pump. The reduction in the concentration of glutamate in tumor cells caused by theanine, induced decreases in the intracellular GSH and GS-DOX levels. The expression of MRP5 in M5076 cells, was confirmed. We concluded that the GS-DOX conjugate was transported extracellularly via the MRP5/GS-X pump in M5076 cells and that theanine affected this route. Namely, theanine increases the concentration of DOX in a tumor in vivo through inhibition of the glutamate transporter via the GS-X pump.

Inhibition of glutamate transporter by theanine enhances the therapeutic efficacy of doxorubicin.

Theanine, a major amino acid existing in green tea, enhanced the antitumor activity of doxorubicin (DOX) due to inhibition of DOX efflux from tumor cells. In order to clarify the mechanism, we have investigated the contribution of glutamate transporters to the action of theanine, because theanine is a glutamate analogue. In M5076 ovarian sarcoma cells, glutamate transport inhibitors reduced the efflux of DOX, as well as theanine. Incidentally, theanine significantly inhibited the glutamate uptake by M5076 cells in a concentration-dependent manner similar to specific inhibitors. These results suggested that the inhibition of DOX efflux was induced by the inhibition of glutamate transport by theanine. In addition, RT-PCR and Western blot analysis revealed the expression of GLAST and GLT-1, astrocytic high-affinity glutamate transporters, in M5076 cells. Thus, theanine was shown to competitively inhibit the glutamate uptake by acting on these glutamate transporters. This action suggested the contribution of glutamate transporters to the inhibition of DOX efflux by theanine. We revealed the novel mechanism of enhancement of the antitumor efficacy of DOX via the inhibition of glutamate transporters by theanine.

Digoxin degradation in acidic dissolution medium.

The release of digoxin and its simultaneous conversion to digoxigenin bisdigitoxoside, digoxigenin monodigitoxoside, and digoxigenin in a USP dissolution test medium were followed by high-pressure liquid chromatography. Two products, Tablets A and B, were manufactured by solvent deposition and simple blending methods, respectively. Tablet A released digoxin faster than Tablet B in distilled water and in artificial intestinal juice, and no decomposition was observed. In the USP dissolution test medium, the rate of hydrolysis to digoxigenin bisdigitoxoside was almost equal to that of hydrolysis to digoxigenin monodigitoxoside, and a comparatively large formation rate of digoxigenin was observed. Concentrations of digoxin and its decomposition products were described by differential equations that included dissolution rates of digoxin (rapidly dissolving digoxin and digoxin crystals) and an apparent hydrolysis rate. In the earlier stage of dissolution, hydrolysis was rate determining; in the later stage, dissolution became the rate-determining step for overall digoxin degradation. To suppress digoxin hydrolysis in the USP dissolution test medium, a developmental formulation study was performed. The incorporation of magnesium oxide and magnesium hydroxide-aluminum hydroxide in the tablet formulations inhibited digoxin hydrolysis by 15.3 and 14.5%, respectively, after dissolution for 30 min without serious delay of drug release.

Stabilization of minodronic acid in aqueous solution for parenteral formulation.

The composition, concentration, and buffer pH of potential minodronic acid formulations were evaluated for their drug stability and for their tendency to generate particles after storage for up to 4 weeks at 60 degrees C. The results indicate that citrate and tartrate buffers maintain drug stability and inhibit the formation of particles. The stability of minodronic acid in these solutions increased slightly as the buffer concentration increased, exhibiting less particle formation than in other buffers. Since citrate buffer was considered the most promising stabilizer for minodronic acid, the pH-stability relationship in 100 mM citrate with pH ranging from 3 to 7 was evaluated during storage for 4 weeks at 60 degrees C. The results demonstrate that solution pH of 3-5 result in optimal stability of minodronic acid with no formation of precipitates. A white precipitate was observed in citrate-containing sample solutions with pH of 6 and 7. Analysis of the isolated precipitate provided support for the hypothesis that the precipitate is a complex between minodronic acid and aluminum ions apparently leached from the glass of the ampoules.

Determination of incorporated amounts of poly(ethylene glycol)-derivatized lipids in liposomes for the physicochemical characterization of stealth liposomes.

We describe a method for determining incorporated amounts of poly(ethylene glycol) (PEG)-derivatized lipids in liposomes for the physicochemical characterization of PEG-coated liposomes. This method is based on the spectrophotometric determination of complexes of polyethers with sodium ions after their extraction as picrates into 1,2-dichloroethane, developed by Favretto for measuring levels of polyoxyethylene alkylphenyl-ether non-ionic surfactants in waste water. The same assay was applied to the estimation of PEG-derivatized lipids in liposomes and percent incorporation of PEG-derivatized lipids into liposomes was successfully determined. To prevent the interference from liposomal lipids other than PEG-derivatized lipids in this assay, liposomal samples were diluted at least to a concentration of less than 0.2 mM. The percent incorporation of PEG-lipids varied, depending on the molecular weight of PEG and anchor acyl chain length in PEG-lipids and it was suggested that the percent incorporation of PEG-lipids into liposomes would be a good parameter of quality control of PEG-liposomes in manufacturing facility and the picrate method used in the present study allows for the determination of this parameter without the need for hazardous radioisotopes.

Release of recombinant human bone morphogenetic protein 2 from a newly developed carrier.

After implantation of a polymer-coated gelatin sponge (PGS) containing either 0.4 or 1.0 mg of 125I-rhBMP-2 for each 1 cm(3) of PGS into the right ulnar of rabbits, changes in the level of radioactivity at the implant site and in the blood were measured for 21 days after implantation, and the cumulative excretion ratio of radioactivity in the urine and feces was calculated. For both doses, radioactivity at the implant site was eliminated biphasically. The concentration of trichloroacetic acid (TCA)-precipitable radioactivity in the blood reached a maximum 6 h after implantation, at which time it was equivalent to 1.41% of the administered dose (0.4 mg/cm(3)). The remaining radioactivity was eliminated rapidly thereafter, falling below the detection limit within 48 h. The t(1/2alpha) was about 0.1 days, the t(1/2beta) was about 3 days, and the mean resident time (MRT) value was about 4 days. By 17 days after implantation, 88.1% of the administered radioactivity had been excreted in the urine, and 1.7% had been excreted in the feces. TCA precipitation test results indicated that most of the radioactivity excreted in urine was a low-molecular weight decomposition product. At 21 days after implantation, the radioactivity of the PGS implant site had declined to 0.5% of the administered amount. Autoradiographs of the implant site taken 28 days after implantation revealed that, at both doses, the residual radioactivity was confined to the area of the implanted PGS. These results indicate that PGS retains an appropriate amount of recombinant human bone morphogenetic protein 2 (rhBMP-2) at the orthotopically implanted site for at least 21 days enough to induce bone regeneration. Thus, PGS shows great clinical potential as a carrier for rhBMP-2.

A new recombinant human bone morphogenetic protein-2 carrier for bone regeneration.

A gelatin sponge was formed by foaming and heat treating a gelatin solution, followed by coating the solid with poly(D,L-lactic-co-glycolic acid) to reinforce the gelatin framework. This sponge was tested for its suitability as a biodegradable porous, recombinant human bone morphogenetic protein (rhBMP)-2 carrier. Incorporation of rhBMP-2 into the sponge was closely related to its bulk density of gelatin sponge. The calcium content in the sponges, as assessed by an ectopic bone formation assay in rats, increased with the increasing sponge bulk density. Histologic and peripheral quantitative computed tomography analysis of implants in this ectopic assay system revealed cell growth throughout the carrier in 4 weeks after implantation regardless gelatin bulk density. The carrier containing rhBMP-2 maintained its three-dimensional structure after implantation; the carrier resisted collapse caused by soft tissue pressure during rapid bone formation as assessed by soft X-ray photographs. These results indicate that this newly developed sponge has excellent carrier characteristics to introduce rhBMP-2 into areas needed for bone regeneration.

Deterministic chaos in the hemodynamics of an artificial heart.

To analyze the hemodynamic parameters during prosthetic circulation as an entity, non linear mathematical techniques were used. To compare natural and prosthetic circulation, two pneumatically actuated ventricular assist devices were implanted as biventricular bypasses in chronic animal experiments using adult goats to consitute the biventricular bypass complete prosthetic circulation model with ventricular fibrillation. After implantation, these goats were placed in a cage and extubated after waking. All hemodynamic parameters with the natural circulation without biventricular bypass pumping, and the artificial circulation with biventricular bypass pumping under ventricular fibrillation were recorded under awake conditions. By the use of a non linear mathematical technique, the arterial blood pressure waveform was embedded into a four dimensional phase space and projected into three dimensional phase space. The Lyapunov numeric method is used as an adjunct to the graphic analysis of the state space. A phase portrait of the attractor showed a high dimension complex structure, with three dimensional solid torus suggesting deterministic chaos during natural circulation. However, a simple attractor, such as a limit cycle attractor, was observed during artificial circulation. Positive Lyapunov exponents during artificial circulation suggest the lower dimensional chaotic system. Thus, hemodynamic parameters during prosthetic circulation must be carefully controlled when unexpected stimuli are fed from outside.

Fundamental rhythm of sympathetic nerve discharges in animals with total artificial hearts.

To evaluate the effect of total artificial heart replacement on the autonomic nervous system, sympathetic neurograms were analyzed by power spectrum and coherence function. Two pneumatically driven, sac type ventricular assist devices were implanted as biventricular bypasses (BVB) in adult, mongrel dogs. After initiation of BVB pumping, the natural heart was electrically fibrillated to form a BVB TAH model. Renal sympathetic nerve activity (RSNA) was recorded using a bipolar electrode attached to the left renal sympathetic nerve. RSNA was amplified and integrated by use of an R-C integrator. Power spectra of the RSNA and values of squared coherence between the arterial pressure wave form and the RSNA were calculated by computer. In animals with total artificial hearts (TAHs), coherence at the cardiac rhythm frequency was decreased, and coherence at the TAH pumping rhythm frequency was increased. These results indicate that the arterial pulse wave observed in TAH animals contributed to the sympathetic neurogram.