Enhanced magnetotransport at high bias in quasimagnetic tunnel junctions with EuS spin-filter barriers.

In quasimagnetic tunnel junctions with a EuS spin-filter tunnel barrier between Al and Co electrodes, we observed large magnetoresistance (MR). The bias dependence shows an abrupt increase of MR ratio in high bias voltage, which is contrary to conventional magnetic tunnel junctions. This behavior can be understood as due to Fowler-Nordheim tunneling through the fully spin-polarized EuS conduction band. The I-V characteristics and bias dependence of MR calculated using tunneling theory show excellent agreement with experiment.

Surface morphology of epitaxial magnetic tunnel junctions.

The surface morphology of epitaxial Fe(001)/MgO(001)/Fe(001) magnetic tunnel junctions, which show the giant tunneling magnetoresistance effect, was investigated by in situ scanning tunneling microscopy. It was observed that an epitaxial MgO barrier layer forms flat surface structures. The surface was flatter with distinct steps and terraces after annealing, which would lead to an increase of the tunneling magnetoresistance ratio. Examination of the local electronic structures of 1.05-nm-thick MgO barrier layers by scanning tunneling spectroscopy revealed no pinholes in the layers, so they would be perfect barriers in magnetic tunnel junctions.

Spin-dependent tunneling in magnetic tunnel junctions with a layered antiferromagnetic Cr(001) spacer: role of band structure and interface scattering.

The tunnel magnetoresistance effect (TMR), which is intrinsically determined by the interface monolayer of an electrode, was realized by using magnetic tunnel junctions (MTJs) with a single-crystal Cr(001) layer inserted between a tunnel barrier and an electrode. The MTJs showed an oscillation of the TMR ratio as a function of the thickness of the Cr(001) layer with a period of 2 monatomic layers, which corresponds to the layered antiferromagnetic structure of Cr(001). These oscillations originate from electron scattering at the interface, due to the mismatching of the symmetry of the wave functions and band structure in Cr(001).

Treatment strategy for Boerhaave's syndrome.

Esophageal rupture is a potentially mortal condition. Rapid and correct diagnosis, and urgent surgical treatment with esophagectomy is indicated, but conservative and other surgical treatments have also been reported recently. The treatment strategies for esophageal rupture are discussed here, based on our experiences with four cases during the last 10 years. They were admitted urgently and each was treated by a different method. Three of them underwent emergency operations, one undergoing primary closure of the ruptured esophagus, another received a T-tube insertion from the ruptured site with omental flap, and the third an esophagogastrectomy. The fourth case was treated conservatively. All patients survived and were discharged 36-144 days post treatment. One of them was readmitted for debridement of necrotic rib. In conclusion, the prompt and accurate diagnosis of esophageal rupture is crucial for a subsequent successful treatment. Conservative treatment or operation including esophagectomy will be determined by the severity of the condition.

A novel GGNG-related neuropeptide from the polychaete Perinereis vancaurica.

The GGNG peptides are myoactive peptides so far identified from earthworms and leeches, which are the earthworm excitatory peptides (EEP) and the leech excitatory peptide (LEP), respectively. A novel GGNG peptide was isolated and structurally determined from a marine polychaete, Perinereis vancaurica, using a combination of immunological assay and high performance liquid chromatography (HPLC). The peptide was a pentadecapeptide whose amino acid sequence was similar to that of EEP and LEP, and showed myoactivity on isolated esophagus of P. vancaurica with a threshold concentration of 10(-10)M. The peptide was designated as polychaete excitatory peptide (PEP). Amidation of the alpha-carboxyl group of C-terminal residue occurred in PEP. This is the case for LEP, but not for EEP. The cDNA cloning revealed that the structure of the PEP precursor is more similar to the EEP precursor than to the LEP precursor. Immunohistochemical staining showed the presence of PEP in several neurons of central nervous system (CNS) as somata and neuropile structure, epithelial cells of the pharynx and epidermal cells throughout the body wall. Altogether these results support the physiological significance of PEP in regulation of the CNS neural activity and the peripheral myoactivity.

Spin-polarized resonant tunneling in magnetic tunnel junctions.

Insertion of a thin nonmagnetic copper Cu(001) layer between the tunnel barrier and the ferromagnetic electrode of a magnetic tunnel junction is shown to result in the oscillation of the tunnel magnetoresistance as a function of the Cu layer thickness. The effect is interpreted in terms of the formation of spin-polarized resonant tunneling. The amplitude of the oscillation is so large that even the sign of the tunnel magnetoresistance alternates. The oscillation period depends on the applied bias voltage, reflecting the energy band structure of Cu. The results are encouraging for the development of spin-dependent resonant tunneling devices.

[Pharmacokinetic study of the intraperitoneal administration of CPT-11 for patients with peritoneal seedings of gastric and colonic cancers].

We studied the pharmacokinetics of the intraperitoneal administration of CPT-11 for four patients with peritoneal metastasis (2 gastric cancer cases, 2 colon cancer cases). CPT-11 was administrated in a dose of 40-60 mg and the intraperitoneal and serum levels of CPT-11, SN-38 and SN-38 glucuronized (SN-38 Glu) were measured periodically. Intraperitoneal therapy with CPT-11 was effective for the control of malignant ascites. No serious side effects were observed. The levels of CPT-11, SN-38 were no different 30 min afterwards the administration of CPT-11 either intraperitoneally or intravenously. The high concentration of CPT-11 was achieved with intraperitoneal therapy and a small fraction of CPT-11 changed into SN-38 in the abdominal cavity.

[Adjuvant short-term continuous hepatoarterial infusion of 5-FU for advanced colorectal cancer using a removable hepatoarterial catheter].

We devised a removable hepatoarterial catheter which we then implanted in patients during colorectal operations, after first making sure this system worked well in an experiment with rabbits. We have applied this devise in 21 advanced colorectal cancer patients. The procedure to place the hepatoarterial catheter followed the resection of the colorectal cancer. A 16 G 30 cm TPN catheter was inserted into the gastroduodenal artery. This artery was ligated at two points with a double loop of elastic rubber threads (Elastik, Matsuda Suture, Tokyo). The catheter was fixed with Vicryl RAIDE (4-0). After the operation, 5-FU was continuously infused through the catheter for 2 weeks. We could remove the arterial catheter without any complications or bleeding after the chemotherapy was completed.

[A patient with small-cell carcinoma of the esophagus with synchronous liver metastasis surviving 48 months after surgery].

Small-cell carcinoma of the esophagus is regarded as having a poor prognosis with frequent and early systemic metastasis. Recently, several reports have described small-cell carcinoma satisfactorily treated by chemotherapy and radiation therapy combined with surgery. We herein report a patient with small-cell carcinoma of esophagus with synchronous multiple liver metastasis who survived 44 months after surgery. A 70-year-old man was found to have a polypoid lesion at the abdominal esophagus by upper gastrointestinal endoscopy. A biopsy specimen of the lower esophagus demonstrated undifferentiated carcinoma of the esophagus. Ultrasonographic investigation demonstrated solitary SOL in the liver. The patient underwent a total gastrectomy and lower esophagectomy by an abdominal approach. As ultrasonographic evaluation during laparotomy revealed multiple liver metastases, a hepatic artery infusion catheter was inserted into the proper hepatic artery. A pathological study of the resected esophagus and a biopsy specimen of the liver revealed undifferentiated cell carcinoma of the esophagus (small-cell type). During hospitalization, hepatic artery infusion therapy (CDDP 20 mg/4 h and 5-FU 750 mg/5 h) was given for 4 days starting on days 14 and 28. After chemotherapy, liver metastasis could not be detected by ultrasonographic investigation. At the outpatient clinic bi-weekly hepatic artery infusion of 5-FU (1,500 mg/body/5 h) was continued for 30 months. The patient is alive 48 months after surgery without any evidence of recurrence.

[A case of advanced gastric cancer with multiple liver metastases partially responding to combination intra-arterial chemotherapy via the hepatic artery and abdominal aorta].

A 57-year-old female diagnosed with advanced gastric cancer with multiple organ metastases was treated by various intra-arterial chemotherapies. After surgical resection of the tumor, adjuvant chemotherapy was carried out. Continuously administered 5-fluorouracil of 250 mg/day made it possible to control the growth of the liver metastases. Extrahepatic metastases were kept under control by administering 30 mg of methotrexate, 750 mg of 5-fluorouracil and 30 mg of Leucovorin per/day/week, and 60 mg/day biweekly of cisplatinum via an abdominal artery infusion port. Owing to this multiple infusion route and chemotherapy regimen, the patient lived for 18 months after her first diagnosis of gastric cancer with multiple liver metastases. Although liver metastases may respond to hepatic arterial infusion chemotherapy, extrahepatic metastases lead to poor prognosis. Given the above results, intra-abdominal aorta chemotherapy may be effective for extrahepatic metastases since this method gives high concentration of the anticancer agents at tumor sites with a low incidence of side effects.

[Pharmacokinetics of "subselective" arterial infusion chemotherapy].

Arterial infusion chemotherapy is mainly used for lymph node and peritoneal metastases. Generally, it is said that the concentration of a drug in abdominal organs is higher with arterial infusion chemotherapy than that with systemic chemotherapy. In this study, the pharmacokinetics of arterial infusion chemotherapy for a patient who had an arterial infusion port for lymph node metastasis and peritoneal metastasis, and a hepatic arterial infusion port for liver metastasis, was evaluated. Sequential arterial infusion chemotherapy with methotrexate (MTX) and 5-FU was given. One hundred mg of methotrexate (MTX) was infused over 20 minutes into the aorta, followed by 750 mg of 5-FU over 10 minutes 2 hours later. Blood samples from a peripheral vein and hepatic artery were collected at 10, 20 and 125 minutes from the beginning of the arterial infusion chemotherapy. Then the serum concentration of MTX and 5-FU was examined. The serum concentration of MTX in the hepatic artery was 1.4 to 2.3 times higher than that in peripheral venous blood. The serum concentration of 5-FU in the hepatic artery was 4.9 to 6.0 times higher than that in peripheral venous blood. The serum concentration of drug in abdominal organ was higher with arterial infusion chemotherapy than with systemic chemotherapy. It would thus seem that the effect of arterial infusion chemotherapy is higher than that of systemic chemotherapy.

Pharmacodynamic effects and kinetic disposition of rabeprazole in relation to CYP2C19 genotypes.

BACKGROUND: S-mephenytoin 4'-hydroxylase (CYP2C19) catalyses the metabolism of rabeprazole to some extent. Based on the metabolic and pharmacokinetic differences among other proton pump inhibitors such as omeprazole, lansoprazole and pantoprazole, rabeprazole appears to be the least affected proton pump inhibitor by the CYP2C19-related genetic polymorphism. AIM: To determine whether the pharmacodynamic effects of rabeprazole on intragastric pH and serum gastrin levels, and its pharmacokinetics depend on the CYP2C19 genotype status. METHODS: Eighteen healthy subjects, whose CYP2C19 genotype status was previously determined, participated in the study. They consisted of six each of homozygous extensive metabolisers (homo EMs), heterozygous extensive metabolisers (hetero EMs), and poor metabolisers (PMs). Helicobacter pylori status was determined by serology. After a single oral dose of 10 mg or 20 mg rabeprazole or water only (baseline data), intragastric pH values were monitored for 24 h. Plasma levels of rabeprazole and serum gastrin were also measured for 24 h post-dose. RESULTS: Five homo EM, six hetero EM and four PM subjects were H. pylori-negative. After rabeprazole administration, significant differences in intragastric mean pH values, serum gastrin AUC(0-24) and plasma levels of rabeprazole were observed among the three different genotype groups. CONCLUSION: The pharmacodynamic effects of rabeprazole and its pharmacokinetics depend on the CYP2C19 genotype status.

New method for thyroid transplantation across major histocompatibility complex barriers using allogeneic bone marrow transplantation.

BACKGROUND: It has been shown that allogeneic bone marrow transplantation (BMT) after lethal irradiation elicits donor-specific tolerance for organ or tissue transplantation across major histocompatibility complex (MHC) barriers. Recently, we have demonstrated that the portal venous (p.v.) administration of donor bone marrow cells (BMCs) elicits donor-specific tolerance across MHC barriers by only two administrations of an immunosuppressant (CsA or FK-506). In our study, using the central and intrahepatic tolerance-inducing system, we have established a new method for thyroid transplantation with BMT that would be more applicable to humans. METHODS: In addition to sublethal (6-5 Gy) irradiation, recipient B6 (H-2b) mice received injections i.p. with the myeloablative drug busulfan (BU) on day -2 to provide a sufficient "space" for the donor hematopoietic cells to expand in the recipients. To induce the intrahepatic tolerance, donor BALB/c (H-2d) BMCs were treated with neuraminidase (Neu), which enhances the trapping of i.v. injected BMCs in the liver. After the injection of Neu-treated BMCs, the thyroid organs from the BALB/c mice were engrafted under the renal capsules. RESULTS: A 90% graft survival rate was obtained over 100 days by a combination of BU administration, 6 Gy irradiation, and i.v. injection of Neu-treated BMCs [BU+6 Gy+(Neu) i.v.], and a 70% graft survival rate was obtained by [BU+5 Gy+(Neu) i.v.]. However, the graft survival rate significantly decreased when either the BU or Neu treatment was omitted. T cells collected from the tolerant recipients suppressed the proliferative responses to donor alloantigens. CONCLUSIONS: Using both BU and Neu treatments, we have succeeded in inducing long-term tolerance and preventing the rejection of thyroid allografts by the single-day protocol.

A new method for tolerance induction: busulfan administration followed by intravenous injection of neuraminidase-treated donor bone marrow.

The portal venous (p.v.) administration of foreign cells induces donor-specific tolerance. Recently, we have demonstrated that the p.v. administration of donor cells elicits donor-specific tolerance across major histocompatibility complex barriers. In the present study, utilizing the intrahepatic tolerance-inducing system, we have established a new method for organ transplantation using both busulfan ([Bu] to provide a sufficient "space" for the donor hematopoietic cells to expand in the recipient) and neuraminidase ([Neu] to enhance the trapping of i.v.-injected cells in the liver). Radiolabeled bone marrow cells (BMCs) were found to exclusively accumulate in the livers of the recipients as a result of the Neu treatment. Furthermore, hematopoietic progenitors (forming hematopoietic foci) in the accumulated BMCs were retained in the recipient livers for at least 18 days. C57BL/6 (B6) mice that had been transplanted with skins of BALB/c mice immediately after the injection of BALB/c BMCs showed a 90% skin graft survival rate over 400 days as a result of using the combination of injecting 50 mg/kg Bu into the B6 mice and treatment of the BALB/c BMCs with 0.25 U/ml Neu (50 Bu + 0.25 Neu). However, the survival rate significantly decreased when either the Bu or Neu treatment was omitted. In tolerant recipients, microchimerism was observed in the various hematolymphoid organs. T cells collected from the tolerant recipients suppressed proliferative responses to the donor-alloantigens but enhanced the production of Th2 and Th3 cytokines. These findings suggest that the enhanced retention of donor BMCs in the recipient livers as a result of the Bu and Neu treatments efficiently induces tolerance induction. Therefore, this "single-day protocol" would be of great advantage for human organ transplantation.

Effect of T-type selective calcium antagonist on renal microcirculation: studies in the isolated perfused hydronephrotic kidney.

Although calcium antagonists exert preferential vasodilation of renal afferent arterioles, we have recently demonstrated that nilvadipine and efonidipine, possessing both L-type and T-type calcium channel blocking action, reverse the angiotensin (Ang) II-induced afferent and efferent arteriolar constriction. In the present study, we investigated the role of T-type calcium channels in mediating the Ang II-induced efferent arteriolar tone using the selective T-type calcium channel blocker mibefradil. Isolated perfused hydronephrotic rat kidneys were used for direct visualization of renal microcirculation. Administration of Ang II (0.3 nmol/L) caused marked constriction of afferent (from 13.5+/-0.6 to 9.2+/-0.6 microm, P<0.01, n=6) and efferent (from 11.5+/-1.0 to 7.4+/-0.7 microm, P<0.01, n=5) arterioles. Mibefradil (1 micromol/L) dilated both vessels, with 82+/-11% and 72+/-7% reversal of afferent and efferent arterioles, respectively. Similarly, nickel chloride (100 micromol/L) caused dilation of both arterioles, similar in magnitude in afferent (68+/-10%, n=7) and efferent (80+/-7%, n=7) arterioles. To eliminate the possibility that the mibefradil-induced dilation was mediated by L-type channel blockade, mibefradil was administered in the presence of nifedipine (1 micromol/L). Thus, nifedipine caused modest efferent arteriolar dilation (30+/-6% reversal, n=9), and subsequent addition of mibefradil elicited further dilation of this vessel (80+/-4%, P<0.01 versus nifedipine). Furthermore, mibefradil reversed the Ang II-induced efferent arteriolar constriction even in the presence of nifedipine and phentolamine. These findings demonstrate that T-type calcium antagonists markedly dilate the Ang II-induced efferent arteriolar constriction, but the action is not mediated by inhibition of catecholamine release. This potent activity would contribute to the efferent arteriolar response to nilvadipine and efonidipine and may offer benefit in light of glomerular hemodynamics.