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Although it is well known that there are differences in approved doses between Japan and the United States, there has been no comprehensive research into the causes thereof. This study furthers the discussion of our previous investigation in 2010, with particular focus on pharmaceutical industry strategy and regulatory policy, among drugs approved in Japan between 2001 and 2009. Dose differences were observed in 73 of 190 drugs. Non-Japanese firms were more likely to have a similar dose approved between Japan and the United States, the association being more pronounced when limiting the analysis to drugs for which a Japanese dose-finding study was not conducted. Furthermore, dose differences were less frequent when non-Japanese efficacy data were included in the application data package. No relation between potential intrinsic ethnic difference and dose difference could be identified. The results suggest that the pathway of drug development is more strongly associated with dose difference than are drug characteristics.

The purpose of this study is to design a hybrid system which is a combination of radiant cooling and low temperature air conditioning integrated with ice storage system. This paper reports the observed thermal environment of the chamber and results of experiments with subjects to grasp the optimum temperature and humidity of the room. In addition, a feasibility analysis for the hybrid system using conditioned air as a refrigerant was also studied with a computer calculations. This system produces comfortable environment and it is also possible to save energy consumption due to the reduction of electricity that could have been used on a fan.

It was found that helium dilution in reactant gas on plasma-enhanced chemical vapor deposition of fluorine-doped silicon oxide film increases the film deposition rate while decreasing hygroscopicity and dielectric constant. He dilution has also been found to decrease the intensity of the infrared absorption band at 980 and 923 cm−1, but affected band intensity only negligibly at about 948 cm−1. Absorption bands at 980 and 923 cm−1 are due to silicon difluoride sites, while that at 948 cm−1 is due to silicon monofluoride sites. He presumably plays an active role in chemical vapor deposition, not acting only as a dilution gas, increasing film deposition rate and reducing fluorine at silicon difluoride sites. The selective reduction of fluorine at silicon difluoride sites is also assumed to decrease the film hygroscopicity and dielectric constant.

We proposed a strategy (cassette theory) in which non-binding peptides for murine major histocompatibility complex (MHC) class II molecules are introduced into a MHC-binding component to render the resultant hybrid peptides bound to the MHC and thus immunogenic in animals carrying the relevant MHC. It was shown that 46F/HA127-133/54A(18mer) peptide which was prepared by introducing hemagglutinin (HA)127-133 of influenza virus into the H-2Ab binding component induced significant T cell responses and antibodies (Ab) specific for HA127-133 in H-2Ab mice. Further we found that the H-2Ab binding component had a supermotif for human class II molecules (i.e. HLA-DQ6). In the present study, a new peptide vaccine, H3-H3, was prepared by combining 46F/HA127-133/54A(18mer) as a carrier and HA127-133 attached to the C terminus of 46F/HA127-133/54A(18mer) as a hapten and the effect of vaccine was examined in DQ6 mice which carry HLA-DQ6 alone as MHC class II molecules and thus may be regarded as a model of the DQ6 positive individuals. Since 46F/HA127-133/ 54A(18mer) induced merely Ab against HA127-133, it was assumed that H3-H3 induced mainly HA127-133 specific Ab in DQ6 mice without undesirable Ab production against the carrier. Indeed, H3-H3 elicited T cell responses and induced HA127-133 specific Ab in DQ6 mice. Furthermore, administration of H3-H3 inhibited growth of influenza virus until 9 weeks after the last immunization in DQ6 mice.

Summary What is known and objective External experts play an important role in shaping regulatory decisions in the new drug review process in the United States, Europe and Japan. No rigorous study has been performed addressing how and to what extent external experts, in contrast to internal reviewers in the agency, influence the regulatory decisions during new drug reviews. We examined their contributions in Japanese regulatory reviews in contrast to the internal reviewers, focusing on the labelling decision on therapeutic indications. Methods With the data set of 219 new molecular entities (NMEs) approved in Japan from 2000 to 2009, we observed how proposed indications in labelling were modified in a stepwise manner during the review process and conducted multinomial logistic analysis to examine the possible mechanism behind. Results and discussion We found that interim assessment of indications by the internal reviewers was modified substantially by the influence of the external experts in about 20% of the 219 NMEs. Our analysis suggested that internal reviewers provided their opinion mainly based on strict review discipline, whereas external experts added flexibility and reality to their reviews. Our analysis revealed different evaluations between internal reviewers and external experts during regulatory discussions in new drug reviews and how the external panel contributes to changing internal decisions. What is new and conclusion This study provides a new and quantitative approach to better label setting by emphasizing the contributions of each stakeholder in new drug reviews, which would improve the efficiency, quality and transparency of new drug reviews to enhance public health.

Effects of neurokinin A (NKA) on sympathetic neurotransmission were studied in rat vas deferens. Although neither prazosin, an alpha 1-adrenoceptor blocker, nor alpha, beta-methylene adenosine triphosphate, a P2-purinoceptor blocker, inhibited the NKA-induced contractions in the epididymal site, high concentration of NKA-induced contractions in the prostatic site were slightly decreased by either of the two blockers. Treatment with guanethidine, which prevents the release of sympathetic transmitters from presynaptic nerve endings, also had no effect on NKA-induced contractions in either site. To investigate the effects of NKA on the adrenergic and purinergic neurotransmission in more detail, we measured transmitter release by using [3H]norepinephrine or [14C]adenosine. Neither spontaneous or nor evoked 3H efflux, indicating NE release, was affected by NKA in either site. NKA enhanced 14C efflux, indicating ATP release, evoked by electrical stimulation in the epididymal site, which may be originated from smooth muscle. In the prostatic site, contractions induced by electrical stimulation were enhanced in spite of no increase in 3H or 14C efflux. These results suggest that: 1) NKA has no effect on presynaptic nerve terminals in both sites, 2) NKA potentiates the effects of neurotransmitters in the prostatic site, and 3) NKA modulates the neurotransmissions.

Lymph node dissection is an essential component of curative resection for advanced gastric cancer. To improve the survival of N2 patients, Asian surgeons have been performing D2+para-aortic lymph node dissection. The current study presents the results of lymph node status from multicenter trial of D2 and D2 + para-aortic nodal (No.16) dissection (D4 dissection).Patients enrolled in the study had potentially curable gastric adenocarcinoma in an advanced stage, T2, T3 or T4/N1 or N2. Patients were randomized to undergo either D2 or D4 gastrectomy.Two hundred and seventy patients were registered and 136 and 134 patients were allocated into the D2 or D4 group, respectively. The average nodal yield of No.16 in D4 group was 18.4 +/- 14.1, ranging from 2 to 84. No.16 metastasis was detected in 12 (9.0%) of 134 D4 patients. One, 9 and 2 patients had simultaneous involvement in N1, N2, and N3 (No.8p, 12, 13 or 14). Namely, in 39 patients who were diagnosed as N2 from the lymph node status in N1 and N2 levels, nine (23.0%) patients had No.16 metastasis. The stage migration by D4 was found in 10 (7.5%). Logistic regression analysis revealed that the stations of No.7 and No.8 were the significant predictors of No.16 involvement.The present study may strongly suggest that prophylactic D4 dissection may be indicated for patients with N2 involvement, and that No.7 and No.8 are the junctional nodes for D4 dissection.

A randomized study was performed to evaluate morbidity and mortality after D2 (level 1 and 2 lymphadenectomy) and D4 (D2 plus lymphadenectomy of para-aortic lymph nodes) dissection for advanced gastric cancer.Two hundred and fifty-six patients with advanced gastric adenocarcinoma were enrolled (128 to each group). Patients were randomly allocated into D2 (N = 128) or D4 (N = 128) group. The first and second tiers of lymph nodes are removed in D2 dissection. In D4 gastrectomy, the paraaortic lymph nodes were additionally removed.There was no indication of significant distribution bias with regard to age, sex, T-grade, and N-grade between the two groups. Operation time of D4 gastrectomy (369 +/- 120 min) was significantly longer than that of D2 gastrectomy (273 +/- 1103 min), and blood loss of the D4 group (872 +/- 683 mL) was significantly greater than that of the D2 group 571 +/- 527 mL (P0.001). Five (4%) and two (2%) medical complications developed in the D2 and D4 groups, respectively. Surgical complications developed in 28 (22%) and 48 patients (38%) after D2 and D4 gastrectomy. The most common complications were anastomotic leakage, pancreatic fistula, and abdominal abscess. Pancreatic fistula developed in 6 (19%) of 32 patients after D4 plus pancreatosplenectomy, but the incidence of pancreatic fistula after D2 gastrectomy plus pancreatosplenectomy was low (6%, 1/16). Two patients died within 30 days of operation (0.8%, 2/256), and each patient belonged to the D2 and D4 group.Although there is a significantly higher surgical complication rate in D4 dissection, D4 dissection can be done safely as D2 dissection when performed by well-trained surgeons.

A robust low-k diffusion barrier, i.e., advanced SiC(O) (A-SiC(O), k = 3.5), was developed to attain a keff of less than 2.7 for reliable ultra-low-k/Cu integration for 45-nm node technology and beyond. A new precursor that requires that requires no oxidizing agent was introduced for deposition to obtain higher film density while maintaining the k-value. The A-SiC(O) film has a low leakage current because of its low defect density and a comparable barrier property with conventional SiC. Drastic improvement in the keff and TDDB lifetime were obtained by adopting A-SiC(O) without using underlying SiCN and oxidizing agent in the deposition, Reliable ultra-low-k/Cu integration was accomplished by combining A-SiC(O) and Aurora-ELK (k=2.3), which has a high modulus of 7.2 GPa, with a UV cure

Single damascene (SD) Cu/Aurorareg ULK interconnects with a minimum spacing of 50nm are achieved by using a metal hard mask (MHM) integration scheme, which enables to perform the resist ash before dielectric etch. This patterning scheme is used in combination with a low damage etch technique based on sidewall protection. Interconnect performance and reliability can be further improved by using Aurorareg ULK high modulus (HM), a low-k film with a reduced diffusivity as compared to Aurora ULK, and a comparable k-value of 2.7. The MHM approach results in a limited increase in integrated k-value by 0.1 for ULK HM vs. 0.3 for Aurorareg ULK. The median time dependent dielectric breakdown (TDDB) lifetime is well above the 10 years criterion for spacings down to the 50nm. Finally, the MHM integration scheme enabled fabrication of dual damascene interconnects with Aurorareg ULK HM

An ultra violet (UV) cure was investigated to improve the mechanical and electrical properties of porous carbon-doped PECVD (plasma enhanced chemical vapor deposition) oxide film (k

An expert system, VIRGO, for planning switching sequences in substations has been developed. A substation model has been developed on a knowledge database, and, based on this model, the expertise of the operator has been described in terms of production rules. These rules must be layered as metarules to reflect the understanding of the domain expert. VIRGO comprises four functions: it makes specific commands by which any equipment involved should be operated; it makes a switching sequence table in accordance with these commands by reasoning from production rules: it converts the table into an easily readable format: and it simulates the substation model with the sequences on a color CRT screen. VIRGO has been implemented in the knowledge description language, KDL, on the VAX workstation. >

A case of cutaneous metastases from gastric adenocarcinoma was presented. It was treated with combination chemotherapy producing complete response with prolongation of survival. Skin metastasis will indicate early fatal termination, therefore there has not yet been a reported case of cutaneous metastasis from gastric cancer to have complete response with long survival.

Although it is well known that the hippocampal CA1 subfield is highly vulnerable to ischemic injury, cellular mechanisms leading to this neuronal degeneration are not fully understood. Using organotypic cultures of rat hippocampal slices, we determined whether phospholipase A2 (PLA2) is activated in response to ischemic conditions (OGD; oxygen and glucose deprivation). The PLA2 activity in the pyramidal cell layer increased immediately following a 35-min exposure to OGD, which was likely to be mediated by selective activation of cytosolic Ca2+-dependent PLA2 subtype (cPLA2). This enhancement lasted for at least 24 h. Interestingly, no apparent increase was detected in the dentate gyrus. Twenty-four hours after the OGD exposure, neuronal death was detected mainly in the CA1 region of hippocampal slices. To examine whether the PLA2 activation is causally or protectively involved in the ischemic injury, we investigated the effect of pharmacological blockade of PLA2 on the OGD-induced neuronal death. The PLA2 inhibitor bromophenacyl bromide efficiently prevented the cell death in a concentration-dependent manner. Similar results were obtained for the selective cPLA2 inhibitor AACOCF3. However, the Ca2+-independent PLA2 inhibitor bromoenol lactone and the secretory PLA2 inhibitor LY311727 were virtually ineffective. These results suggest that cPLA2 plays a causative role in the neuronal death following OGD exposure. Thus, the present study may provide novel therapeutic targets for the development of neuroprotective agents.

Recently it has been shown that modulation of CD40 molecules on antigen (Ag) carrying dendritic cells (DC) can bypass T cell help, resulting in priming cytotoxic T lymphocytes (CTL) specific for the Ag. In the present study we attempted to prime peptide Ag-specific CTL by a new method in which a peptide Ag in liposome (liposomal peptide), consisting of phosphatidylserine and phosphatidylcholine (3:7), was administrated subcutaneously with anti-CD40 and/or CTLA-4 monoclonal antibodies (mAb) to mice. We found that the subcutaneous administration of the liposomal peptide with both anti-CD40 and anti-CTLA-4 mAb enhanced CTL responses comparing with those induced by the liposomal peptide alone or the liposomal peptide plus each mAb. It was shown that liposomes were critical for induction of the CTL activity. Flow cytometry analysis of a peptide-bearing DC in lymph nodes (LN) and measurement of serum IL-12 indicated that anti-CD40 mAb promoted migration of DC to the LN, where DC might differentiate and acquire ability of priming CTL. These findings provide a possibility that our procedure is applicable to cancer patients.

AURORA films, which have a Si-O-Si network with –CH3 terminations, were characterized and integrated into Cu single damascene structures. The relatively low carbon concentration (∼ 20%) and the very small pore size (∼ 0.6 nm) found could be advantageous during integration of AURORA. Integration of AURORA into Cu single damascene structures was successfully achieved. Suitable resist strip processes, which are critical for Si-O-C type materials, were developed, resulting in trenches with satisfactory profiles. After a complete single damascene process, a interline dielectric constant value of 2.7 was found for line spacing down to 0.25 µm.

Peptide vaccines against HIV-1 were prepared according to the cassette theory that we had proposed previously. An amino acid sequence of B subtype consensus of the HIV-1 V3 region was introduced into the MHC binding component with a supermotif for various MHC class II. The peptide vaccines induced T-cell responses in the DQ6 mice in which only DQ6 molecules were expressed as MHC class II. By contrast, an original V3 peptide including the consensus sequence was non-immunogenic in the DQ6 mice. Antibodies obtained from the DQ6 mice immunized with the peptide vaccines neutralized laboratory B subtype strains of HIV-1 in vitro. It may be anticipated that these peptide vaccines protect infection of HIV-1 in DQ6 positive individuals.

Based on the cassette theory that a core region of an immunogenic peptide is partially replaced with peptide fragments from various pathogens without any detrimental effects to their anchoring to the particular MHC class II molecules, we had prepared a peptide vaccine, 46F/HA127-133/54A (18mer) (YEGFS WTGVTQN KAKGIT), against A/Aichi/2/68 (H3N2) influenza viruses. It was shown that the 46F/HA127-133/54A (18mer) was effective in Ab mice. In the present study, we first examined whether this peptide vaccine could induce neutralizing antibodies against other H3 subtype influenza viruses. The results suggested that 46F/HA127-133/54A (18mer) would be effective for preventing infection with almost all H3 subtype influenza viruses. Since it has been demonstrated that the Ab binding component possesses a supermotif for binding to various MHC class II including HLA-DQ6, we next examined whether the peptide vaccines could be applicable to human positive of HLA-DQ6 type, using DQ6 mice that carry DQ6 alone as MHC class II molecules. The DQ6 mice had been prepared by crossing DQ6 transgenic mouse with murine class II knock out mouse and were thus regarded as a model of DQ6 positive individuals. In this particular experiment another peptide vaccine, H3-H3, which was newly prepared by adding HA127-133 to the C-terminus of 46F/HA127-133/54A (18mer) was used. It was demonstrated that the H3-H3 generated significant immunological responses and prevented infection with A/Aichi/2/68 viruses in the DQ6 mice. Altogether, it is suggested that the peptide vaccine, H3-H3, can be applicable to human positive of HLA-DQ6 type.

SUMMARYWhen certain strains of mice bearing H-2Ak are immunized with the interphotoreceptor retinoid-binding protein (IRBP), EAU is induced. Thus far uveitogenic determinant(s) has not been determined in the H-2Ak mouse system. In addition it is hard to prepare purified IRBP. In the present study, to circumvent these problems we attempted to identify uveitogenic peptides derived from bovine IRBP in H-2Ak haplotype mice. Six peptides which had been selected according to the H-2Ak binding motif (Dxxxxxxxx[A, R, T]) were synthesized. We report here that all the peptides are immunogenic but only one peptide, K2, which consisted of IRBP201–216 residues, induces EAU in various mice carrying H-2Ak. Amino acid substitution of K2 revealed that the core region interacted with both H-2Ak and T cell antigen receptor (TCR). The amino acid sequence of the core region derived from bovine IRBP was identical to the corresponding region of mouse IRBP. In addition, K2 appeared to be a natural peptide antigen processed from bovine IRBP. Altogether, we concluded that K2 is one of the natural autoantigens involved in induction of EAU in H-2Ak mice.

PyNPase activity, MMPs activity and serum IAP values were measured in tumor tissues from colorectal cancer patients who had been divided into two groups, one given preoperative 5'-DFUR and the controls. PyNPase activity of the preoperative administration group was approximately equivalent to that of the controls. In the control group, correlations were assessed between PyNPase activity and activities of MMP1 and MMP3. To assess the effect of 5'-DFUR on the activity of MMPs, we divided patients into two groups, a high and a low PyNPase activity group. Although there was no correlation with MMPs activity of the preoperative administration group and the control group in the low PyNPase activity group, the activities of MMP1 and MMP9 of the control group were significantly higher in the high PyNPase activity group. Moreover, the serum IAP value of the administration group was significantly lower than that of the control group. These results indicated that PyNPase activity was thus suggested to be somehow related to MMPs activity and serum IAP values.

We determined that a pigeon cytochromec-derived peptide, p43–58, possesses two anchor residues, 46 and 54, for binding with the I-Abmolecule that are compatible to the position 1 (P1) and position 9 (P9) of the core region in the major histocompatibility complex (MHC) class II binding peptides, respectively. In the present study to analyze each binding site between P1 and P9 of p43–58 to either I-Abor T cell antigen receptor (TCR), we investigated T cell responses to a series of peptides (P2K, P3K, P4K, P5K, P6K, P7K, and P8E) that sequentially substituted charged amino acid residues for the residues at P2 to P8 of p43–58. T cells from C57BL/10 (I-Ab) mice immunized with P4K or P6K did not mount appreciable proliferative responses to the immunogens, but those primed with other peptides (P2K, P3K, P5K, P7K, and P8E) showed substantial responses in an immunogen-specific manner. It was demonstrated by binding studies that P1 and P9 functioned as main anchors and P4 and P6 functioned as secondary anchors to I-Ab. Analyses of Vβ usage of T cell lines specific for these analogs suggested that P8 interacts with the complementarity-determining region 1 (CDR1)/CDR2 of the TCR β chain. Furthermore, sequencing of the TCR on T cell hybridomas specific for these analogs indicated that P5 interacts with the CDR3 of the TCR β chain. The present findings are consistent with the three-dimensional structure of the trimolecular complex that has been reported for TCR/peptide/MHC class I molecules.

In the present study using an experimental BMT system we analyzed the effects of disparity at non-MHC Ag including minor lymphocyte stimulatory-1a (Mls-1a) Ag on the acute GVH reaction (GVHR) induced by MHC class I Ag. Mismatch at MHC (class I) Ag alone did not induce clinically detectable acute GVHR in this model. However, BMT mice prepared with a combination of both class I and non-MHC Ag mismatches showed signs of clinical GVHR and various cytokines were produced by the spleen cells at an early stage (4 days) after BMT. Although no clinical GVHR was detected in BMT chimeras prepared with a non-MHC mismatched but MHC matched combination, large amounts of various cytokines were secreted by spleen cells. Cytokine production in the latter two kinds of chimeras paralleled the increase of Mls-1a reactive Vbeta6+ T cells in the host spleen. Marked cytokine production induced by Mls-1a Ag was confirmed by MLR. Thus, these cytokines appeared to be produced by T cells responding to Mls-1a (ie Vbeta6+ T cells) and to augment the T cell responses to MHC class I which resulted in clinically detectable GVHR in chimeras prepared with the combination mismatched at both MHC class I and non-MHC loci.

The surgical results for patients with stage IV gastric cancer are very poor. This study was performed to clarify the morphologic changes and survival after neoadjuvant chemotherapy for the stage IV gastric cancer patients.Forty-three patients with stage advanced gastric cancer were treated with preoperative PMUE therapy by a combination use of cisplatin 75 mg/m2, mitomycin C 10 mg/body, etoposide 150 mg/body and UFT 400 mg/day. Among them, 32 patients underwent gastrectomy. Resected specimens were precisely examined histologically, and the histologic changes were correlated with clinical response and survival.Histologic manifestations of neoadjuvant chemotherapy included coagulation necrosis of cancer cell, appearance of the giant cell with foamy degeneration, extracellular mucin pools, aggregates of foamy histiocytes and/or stromal fibrosis. Histological responses were obtained in 24 (75%) of 32 primary tumors, 13 (81%) of 16 liver metastases, 20 (76%) of 28 lymph node metastases and 3 (18%) of 17 peritoneal disseminations, respectively. Clinical responses were observed in 21 (49%), but there was no statistical survival difference between clinical responders and nonresponders. In contrast, histologic responders survived significantly longer than non-responders.These results indicate that the grading of the histologic changes is a good prognosticator of patients treated with neoadjuvant chemotherapy, and yields an important information for the selection of postoperative chemotherapy.

In a previous study, we identified T cell receptor and major histocompatibility complex (MHC) contact sites on the pigeon cytochrome c p43-58 peptide. Positions 46 and 54 of p43-58 were shown to be the MHC-binding sites. Specific amino acids were identified on the MHC-binding sites which bound to the relevant I-A molecule. In the present study, using NOD (I-Ag7) mice, we established a T cell hybridoma, NOE33-1-2, specific for a p43-58 analog 46R50E54A with arginine (R) and alanine (A) at positions 46 and 54, respectively. Interestingly, NOE 33-1-2 recognized 46R50E54A in the presence of not only I-Ag7, but also I-Ad, s, u and v. In contrast to previous reports that promiscuous T cells were able to recognize peptide antigens with various HLA-DR or I-E molecules consist of monomorphic α and polymorphic β chains, the promiscuous T cell clone NOE33-1-2 recognized peptides with various I-A molecules lacking the monomorphic chain.

When irradiated minor lymphocyte stimulatory-la (Mls-1a) mice were reconstituted with bone marrow cells plus mature T cells from Mls-lb and H-2 class I incompatible mice, acute GVHR was induced in the recipients. Majority of responding cells were shown to be CD4+Vs6+ T cells derived from donor mature T cells. It appeared that Mls-la antigen (Ag) was a major target Ag. However, when Mls-lb donor and Mls-la recipient mice were H-2 matched, the severity of GVHR was mar-kedly reduced. Thus, disparity at the Mls-l locus alone appeared not to be sufficient to induce dete-ctable GVHR. In mixed lymphocyte reaction (MLR), T cell proliferation against Mls-1a plus H-2 class I Ag was as high as that against H-2 class I Ag alone. On the other hand, production of IL-2, IL-4 and TNF-α by the T cells responding to H-2 class I plus Mls-1aAg was considerably greater than that by T cells responding to class I Ag alone. The present findings suggest that CD4+Vs6+ T cells responding to Mls-laAg and producing IL-2, IL-4 and TNF-α play a significant role, which may result in augmentation of allo-responses to the host H-2 class I Ag and substantial GVHR.

A case of cutaneous and brain metastasis of gastric carcinoma, treated effectively by chemotherapy, is reported. The patient was a 67-year-old female. She underwent total gastrectomy for advanced gastric carcinoma with direct invasion to liver. Six months later, she was admitted with headache and multiple skin nodules on the trunk. CT showed two round tumor shadows on the left side of brain, and a skin biopsy specimen revealed poorly differentiated adenocarcinoma. Chemotherapy with 10mg of CDDP, 2mg of MMC, 150mg of etoposide and 300mg/day of 5'-DFUR was performed. After the third course of chemotherapy, cutaneous and brain metastasis disappeared. Although the patient died of pulmonary metastasis 24 weeks after, cutaneous and brain metastasis disappeared 12 weeks.

We have previously reported that fatty liver is easily induced in a novel experimental animal, Suncus murinus (suncus) by withholding food, and that apolipoprotein B (apo B) is not actively synthesized in the liver. In the present paper we describe the effect of starving and refeeding on lipid and lipoprotein metabolism in suncus, in order to explore the mechanisms of induction of fatty liver by starving and of its improvement by refeeding. Starvation induced increase in triglyceride content and decrease in glycogen content of the liver. Although the glycogen content returned to the level before starvation at 12 h after refeeding, the triglyceride content decreased gradually but did not reach the prestarvation level even at 24 h after refeeding in suncus. Plasma lipids, glucose, and insulin levels were decreased by starvation and returned to the levels before starvation between 8 and 24 h after refeeding. On the other hand, the plasma levels of free fatty acid and ketone bodies were elevated significantly by starvation and decreased rapidly by refeeding. These responses to starvation and refeeding, except for the change in hepatic triglyceride, are in common with other experimental animals, suggesting that there are no abnormalities in glucose metabolism or in fatty acid metabolism in suncus. In conclusion, the fatty liver induced by starvation in suncus may be caused by impaired triglyceride transport out of the liver, for which apolipoprotein B is mostly responsible, as reported previously.

We have previously reported that fatty liver was induced in a novel experimental animal, Suncus murinus (suncus), by 24-h fasting and that apolipoprotein B (apo B) was not actively synthesized in the liver. However, a faint signal of apo B mRNA was detected in the liver, suggesting possible synthesis of apo B. Small amounts of VLDL and LDL have been separated from suncus serum by ultracentrifugation. Electron microscopic study of the lipoproteins revealed the existence of small particles in VLDL. High performance liquid chromatographic analysis of the lipoproteins showed that the peaks of TG and cholesterol were mainly at the HDL fraction. These results indicate the existence of lipoproteins as small as HDL which were rich in TG and floated at the density of VLDL upon ultracentrifugation. Apolipoprotein analysis showed two bands of 500- and 200-kDa proteins in VLDL and LDL. Western blot analysis using antibody against the 500-kDa protein revealed reaction not only with suncus 500- and 200-kDa proteins but also with human apo B-100. In conclusion, a small amount of apo B is transported in the suncus serum as VLDL and LDL, although almost all lipid is packed in HDL-size particles.

Blood pressure and heart rate and responses to various physiological substances in suncus were characterized and compared with those in mice. The blood pressures of the two species were similar, but the heart rate of suncus (about 400 beat/min) was significantly lower than that of mice. Norepinephrine increased the blood pressure but decreased the heart rate in suncus. The latter was blocked by cervical vagotomy. Sensitivities to acetylcholine and isoproterenol were lower in suncus. These results suggest that regulation of blood pressure and heart rate in suncus is very unique and different from the well-defined system of the rodents.

We have shown previously that Suncus murinus, a species of the insectivore, can vomit in response to various emetogenic stimuli. In the present study we investigated whether or not Sorex unguiculatus, which belongs to different subfamily (Soricinae) of insectivore, vomits in response to emetogenic drugs. Subcutaneous injection of veratrine and oral administration of copper sulfate caused emesis in the animal. Histological study showed that bilateral structure of the area postrema was not important for the emetic reflex. Therefore, the capability of emesis may be common to the family of soricidae of the insectivore, and the Sorex unguiculatus is the smallest known mammal which can vomit.

The levels of histamine (HA) and tele-methylhistamine (t-MH) were determined in five brain regions of Suncus murinus (suncus) and the effects of motion stimulus or drugs influencing the turnover of these amines were studied to elucidate the role of histamine in motion sickness. Shaking the animals for 2 min increased HA contents in telencephalon and diencephalon without significantly changing the t-MH levels. alpha-Fluoromethylhistidine (alpha-FMH), which is presumed to deplete the neuronal HA, tended to raise the HA levels. alpha-FMH slightly alleviated the vomiting response to motion stimulus and suppressed the HA increase in diencephalon caused by shaking. Compound 48/80, which releases HA from mast cells, did not alter the control HA levels, but effectively prevented the motion sickness and completely suppressed the motion-induced rises in HA levels. These results provide further evidence that brain HA plays an important role in the development of motion sickness.

Following the resection of its primary lesion, continuous hyperthermic peritoneal perfusion (CHPP) with anticancer drug (mitomycin C, cisplatin) containing warmed physiological saline was performed on gastric cancer having peritoneal dissemination, and the effect of CHPP was examined by second look operation (SLO). The subjects were 41 cases of gastric cancer with peritoneal dissemination but without hepatic metastasis, which we have experienced in the past 7 years. The prognosis of these CHPP-treated cases was such that 50% survival period, 3 year survival rate and 5 year survival rate were 398 days, 28.5 and 12%, respectively. Comparison of the effects of CHPP by SLO revealed remarkable diminution of the peritoneal dissemination in 7 (44%) of 16 cases and disappearance of the ascites with a single course of CHPP in 7 of ascitic cases. Long-term survival (greater than 3 years) was noted in 4 of the CHPP-treated cases. Side effects were renal insufficiency, leukopenia and small intestinal perforation in 2(5), 2(5) and 1 cases (2%), respectively. The above results suggested the effectiveness of CHPP for the treatment of gastric cancer having peritoneal dissemination.

In 93 cases of stomach cancer with liver metastasis, the influence of surgery and chemotherapy on the patients' prognosis was examined. Chemotherapy comprised systemic administration of mitomycin C (MMC) (39 cases), intra-hepatoarterial administration of MMC (19 cases) and intra-hepatoarterial infusion of cisplatin (CDDP) + MMC (PM intra-arterial chemotherapy) (24 cases) in the first 1-2 postoperative weeks. MMC and CDDP were given by 1-4 courses every 1-3 weeks. Examination of the prognosis factors by generalized Wilcoxon test revealed significant differences in the extent of lymph node metastasis (N0-2 vs N3,4), possible resection of primary lesion, and chemotherapeutic regimen (PM intra-arterial chemotherapy and other chemotherapeutic regimens). The response rate was 4.3% (1/23), 29.4% (5/17) and 73.8% (17/23) for MMC systemic administration, MMC intra-arterial chemotherapy and PM intra-arterial chemotherapy, respectively, with a significantly high response rate for the latter. Also for the 50% survival period, the latter showed 11.8 months compared with 2.7 months for other chemotherapeutic treatments, indicating its good prognosis regardless of possible resection of the primary lesion. Cox proportional hazard model revealed the latter alone to be a significant independent factor. The above results suggest that the PM intra-arterial chemotherapy is an effective approach to stomach cancer with liver metastasis.

Changes in intracellular free Ca2+ concentration ([Ca2+]i) by activation of alpha 1- and alpha 2-adrenoceptors were microfluorometrically measured in rat tail arteries loaded with the Ca2(+)-sensitive fluorescent dye fura-2. Under the normal condition (1.8 mM Ca2+), stimulation with the selective alpha 1-adrenoceptor agonist phenylephrine very rapidly raised [Ca2+]i to the peak concentration, plateauing at this level, whereas the stimulation with the selective alpha 2-adrenoceptor agonist UK-14,304 gradually increased [Ca2+]i. In Ca2(+)-free solution, the stimulation of alpha 1-adrenoceptors caused a transient increase in [Ca2+]i, whereas the stimulation of alpha 2-adrenoceptors had no effect. These results directly prove that alpha 1-adrenoceptor activation induces both the release of intracellular Ca2+ and the influx of extracellular Ca2+, whereas activation of alpha 2-adrenoceptors evokes only the influx of extracellular Ca2+. Plotting the increase in [Ca2+]i against the developed contraction revealed that it was always linearly related regardless of the type of alpha-adrenoceptor stimulated. Therefore, the intracellular mechanisms after the increase in [Ca2+]i are probably common to the vasocontractile responses mediated by alpha 1- and alpha 2-adrenoceptors.

Characteristics of beta-adrenoceptor in the tracheal smooth muscle of Suncus murinus (suncus) were studied in comparison with those of rats and guinea pigs. Isoproterenol induced concentration-dependent relaxation of suncus trachea. However, the maximal relaxation was very small, and about 1000 times higher concentration was necessary compared to the case of the guinea pig. The order of the sensitivity to isoproterenol and the maximal relaxation was guinea pig much greater than rat greater than suncus. Tracheae from younger suncus were more sensitive to isoproterenol, but the maximal relaxation was not significantly different from the results using adult animals. Forskolin, a direct activator of adenylate cyclase, relaxed tracheae to similar extents in the three species. Though the affinity of specific [3H]dihydroalprenolol binding was not significantly different, the maximal number of binding sites was in the order of rat greater than guinea pig greater than suncus. However, the differences in density of the binding among the three species were not as great as differences in isoproterenol-induced relaxation. These results suggest that 1) beta-adrenoceptor-mediated relaxation of tracheal smooth muscle is not well-developed in the suncus and 2) the deficient relaxation is probably caused by insufficient coupling between adrenoceptors and adenylate cyclase.

Effects of various types of motion stimuli were compared to investigate optimum method to elicit motion sickness and adaptation in Suncus murinus (suncus). Three different direction of shaking in the horizontal plane, back and forth, right and left and revolving, induced emetic response to the similar extent. However, vertical shaking was far less effective in inducing motion sickness. Mild and severe horizontal shaking (15 min per day) was continued for 14 days and emetic response to standard motion stimulus was compared before and after the training. The severe daily acceleration strongly depressed the susceptibility to motion stimulus. The mild acceleration which was not emetic stimulus in itself also remarkably attenuated the vomiting response to standard motion stimulus. These results indicate that 1) the emetic responsiveness of the suncus does not depend on the modes of shaking as long as the direction is in the horizontal plane, 2) the suncus is relatively refractory to the vertical linear acceleration and 3) the adaptation to motion stimulus does not develop on the latest peripheral steps of the vomiting reflex pathways.