Chirality Memory Stored in Magnetic Domain Walls in the Ferromagnetic State of MnP.

Chirality in a helimagnetic structure is determined by the sense of magnetic moment rotation. We found that the chiral information did not disappear even after the phase transition to the high-temperature ferromagnetic phase in a helimagnet MnP. The 2nd harmonic resistivity ρ^{2f}, which reflects the breaking down of mirror symmetry, was found to be almost unchanged after heating the sample above the ferromagnetic transition temperature and cooling it back to the helimagnetic state. The application of a magnetic field along the easy axis in the ferromagnetic state quenched the chirality-induced ρ^{2f}. This indicates that the chirality memory effect originated from the ferromagnetic domain walls.

Electric current control of spin helicity in an itinerant helimagnet.

A helimagnet is a chiral magnet in which the direction of the magnetic moment spatially rotates in a plane perpendicular to the propagation vector. The sense of the rotation known as spin helicity is a robust degree of freedom of matter and may provide a new concept of magnetic memory if it can be electrically controlled and detected. Here we show that the helicity can be controlled by magnetic fields and electric currents in an itinerant helimagnet MnP. Second-harmonic resistivity measurements allow us to read out the controlled helicity. In contract to an insulating multiferroic magnet, in which spin rotation was shown to be controllable by an electric field, we achieve helicity manipulation by using an electric current in the conducting helimagnet. The controllability of the spin helicity may pave the way to new method of realizing magnetic memories based on the spin internal degrees of freedom.

Identification of human drug-metabolizing enzymes involved in the metabolism of SNI-2011.

In vitro studies were conducted to identify human drug-metabolizing enzymes involved in the metabolism of SNI-2011 ((+/-)-cis-2-methylspiro [1,3-oxathiolane-5,3'-quinuclidine] monohydrochloride hemihydrate, cevimeline hydrochloride hydrate). When 14C-SNI-2011 was incubated with human liver microsomes, SNI-2011 trans-sulfoxide and cis-sulfoxide were detected as major metabolites. These oxidations required NADPH, and were markedly inhibited by SKF-525A, indicating that cytochrome P450 (CYP) was involved. In a chemical inhibition study, metabolism of SNI-2011 in liver microsomes was inhibited (35-65%) by CYP3A4 inhibitors (ketoconazole and troleandomycin) and CYP2D6 inhibitors (quinidine and chlorpromazine). Furthermore, using microsomes containing cDNA-expressed CYPs, it was found that high rates of sulfoxidation activities were observed with CYP2D6 and CYP3A4. On the other hand, when 14C-SNI-2011 was incubated with human kidney microsomes, SNI-2011 N-oxide was identified as a major metabolite. This N-oxidation required NADPH, and was completely inhibited by thiourea, indicating that flavin-containing monooxygenase (FMO) was involved. In addition, microsomes containing cDNA-expressed FMO1, a major isoform in human kidney, mainly catalyzed N-oxidation of SNI-2011, but microsomes containing FMO3, a major isoform in adult human liver, did not. These results suggest that SNI-2011 is mainly catalyzed to sulfoxides and N-oxide by CYP2D6/3A4 in liver and FMOI in kidney, respectively.

Severe metabolic acidosis and heart failure due to thiamine deficiency.

We report the case of a male patient with severe metabolic acidosis and heart failure caused by thiamine deficiency. He was admitted in August 1998 to the Tokai University Oiso Hospital because of severe dyspnea. The patient was diagnosed with heart failure and metabolic acidosis of unknown causes based on arterial blood gas analysis, chest x ray, and ultrasonic echocardiographic examinations. Our previous experience in treating a patient with thiamine deficiency caused by total parenteral nutrition without thiamine supplementation suggested that this patient was deficient in thiamine. The serum thiamine level was low and the lactate level was high. After intravenous administration of thiamine, the acidosis and heart failure disappeared. Dietary analysis showed that thiamine intake was low (0.32 mg/1000 kcal/d). Thiamine deficiency should be included in the differential diagnosis when encountering cases of heart failure with severe metabolic acidosis, even in developed countries.

Pretreatment with a deleted form of hepatocyte growth factor (dHGF) prevents the mortality of plasma-loss-induced hypovolemic shock in rats.

Severe trauma, infection, burn, pancreatitis and major surgery often induce circulatory collapse leading to multiple organ failure and death. It is hypothesized that therapy for the attenuation of circulatory collapse may improve the prognosis in these diseases. Previous work has documented that pretreatment with a deleted form of hepatocyte growth factor (dHGF) in normal rats increases the circulating plasma volume that reflects its accelerating action of hepatic protein synthesis. Therefore, the effects of pretreatment with dHGF on hypovolemic shock models were studied in rats. Rats were intravenously administered dHGF (1 mg/kg, twice daily for 5-6 days) or vehicle, and subjected to a 25% total body surface area full-thickness burn or a trypsin-induced acute pancreatitis. In rats that were receiving vehicle, survival rates on day 7 after injury induction were 12% in the burn model and 5% in the pancreatitis model, respectively. In both models, hematocrit values were apparently increased and circulating plasma volumes were decreased compared to sham-operated rats at 6 h after injury induction. The pretreatment of animals with dHGF increased the survival rates on day 7 to 40% in the burn model and 29% in the pancreatitis model. dHGF-treatment in normal rats decreased the hematocrit values and increased the circulating plasma volumes, and these changes of hematocrit value and circulating plasma volume were also maintained after injury induction. These findings suggest that dHGF pretreatment prevents the mortality in the severe burn and acute pancreatitis, and that its effect may contribute to ameliorating the progressing of plasma-loss-induced hypovolemia.

Deleted form of hepatocyte growth factor ameliorates the mortality rate of severe thermal injury in rats.

BACKGROUND: The modulating effects of the deleted form of hepatocyte growth factor (dHGF) on burn-induced mortality rates and hepatic protein synthesis were studied in rats. METHODS: Rats were anesthetized, subjected to a 40% full-thickness scald burn, and divided into 2 groups receiving dHGF and vehicle. RESULTS: In normal rats, dHGF-treatment (1 mg/kg intravenously, twice daily) for 5 days increased the circulating plasma volume. In burned rats that were receiving vehicle, the survival rate on day 23 after the burn was 27%. The serum albumin levels were decreased and did not reverse to the normal levels until day 23 after the burn. Serum alpha 2-concentration in the injured rats was increased, whereas serum levels of transferrin, total protein, and high-density lipoprotein-cholesterol were decreased. The treatment of animals with dHGF (1 mg/kg intravenously, 3 times daily) for 3 days increased the survival rate on day 23 by 64%. In the animals treated with dHGF for 3 or 6 days, serum alpha 1-, alpha 2-, and beta-globulin concentrations were increased by the dHGF treatment. The serum levels of albumin, transferrin, total protein, and high-density lipoprotein-cholesterol reversed to normal levels or higher. CONCLUSIONS: Our data show that dHGF treatment may attenuate the decrease of the circulating plasma volume after burn and reduce a high risk of burn shock. It is also indicated that dHGF accelerates synthesis of not only acute-phase reactants but also other hepatic proteins such as albumin and transferrin on severe burn injury. These findings suggest that the appropriate upregulation of hepatic protein synthesis induced by dHGF may accelerate the physiologic recovery process after thermal injury and contribute to ameliorating the burn-induced death.

(+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] hydrochloride, hemihydrate (SNI-2011, cevimeline hydrochloride) induces saliva and tear secretions in rats and mice: the role of muscarinic acetylcholine receptors.

We investigated effects of (+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] hydrochloride, hemihydrate (SNI-2011, cevimeline hydrochloride), a rigid analogue of acetylcholine, on saliva and tear secretions in rats and mice to evaluate its therapeutical efficacy for xerostomia and xerophthalmia in patients with Sjogren's syndrome and X-ray exposure in the head and neck. Intraduodenal administrations of SNI-2011 increased saliva secretion in a dose-dependent manner at doses ranging from 3 to 30 mg/kg in normal rats and mice, two strains of autoimmune disease mice and X-irradiated saliva secretion defective rats. The salivation elicited by SNI-2011 was completely inhibited by atropine. A similar atropine-sensitive response was observed in tear secretion. In rat submandibular/sublingual gland membranes, [3H]quinuclidinyl benzilate (QNB) binding was saturable, and Scatchard plot analysis revealed a single population of binding sites with a Kd of 22 pM and a maximal binding capacity of 60 fmol/mg protein. The competitive inhibition curve of the [3H]QNB binding by SNI-2011 was obtained, and its dissociation constant value calculated from IC50 was 1-2 microM. These results suggest that SNI-2011 increases saliva and tear secretions through a direct stimulation to muscarinic receptors in salivary and lacrimal glands, and they suggest that SNI-2011 should be beneficial to patients with Sjögren's syndrome and X-ray exposure in the head and neck.

Modulation of rhythmical slow activity, long-term potentiation and memory by muscarinic receptor agonists.

We investigated the cholinergic modulation of hippocampal rhythmical slow activity (or theta activity), long-term potentiation and a behavioral memory task. The intravenous administration of the muscarinic receptor agonists, AF102B ((+/-)-cis-2-methyl-spiro(1,3-oxathiolane-5,3') quinuclidine hydrochloride hemihidrate) and oxotremorine, induced rhythmical slow activity at doses of 1.0 mg/kg and 0.01 mg/kg, respectively. Long-term potentiation of population spike amplitude in the hippocampal CA1, which was induced by tetanic stimulation to the Schaffer collateral/commissural fiber, was increased by AF102B (1.0 mg/kg i.v.) and oxotremorine (0.01 mg/kg i.v.). Oral administration of AF102B and oxotremorine improved scopolamine-induced memory deficits in a passive avoidance task in mice at doses of 1.0 mg/kg and 0.2 mg/kg, respectively. The correspondence of the effective doses of muscarinic receptor agonists in these three experiments suggested the cholinergic correlation of rhythmical slow activity, long-term potentiation and memory.