Randomized phase II study of TJ-54 (Yokukansan) for postoperative delirium in gastrointestinal and lung malignancy patients.

The present study evaluated the efficacy and safety of TJ-54 (Yokukansan; a traditional Japanese medicine) for the prevention and/or treatment of postoperative delirium in a randomized phase II trial of patients receiving surgery for gastrointestinal and lung malignancies. Patients ≥70 years of age who underwent surgery for gastrointestinal or lung malignancy were eligible for participation in the study. The 186 eligible patients were randomly assigned at a 1:1 ratio to receive TJ-54 or control during their peri-operative care (between 7 days prior to surgery and 4 days following surgery, except for the operation day). The signs and symptoms of delirium were assessed using the Diagnostic and Statistical Manual of Mental Disorders-IV by the investigator during the peri-operative period. A total of 186 eligible gastrointestinal or lung malignancy patients were analyzed (93, TJ-54; 93, control). There were no marked differences between the two randomized groups. The incidence of delirium was 6.5% (6 patients) in the TJ-54 group and 9.7% (9 patients) in the control group, with no significant difference (P=0.419). However, of the patients categorized with a mini-mental state examination (MMSE) score of ≤26, the incidence of postoperative delirium was 9.1% in the TJ-54 group and 26.9% in the control group [risk ratio, 0.338; 95% confidence interval (0.078-1.462), P=0.115]. Treatment with TJ-54 reduced the incidence of postoperative delirium compared with the control group. Although TJ-54 did not demonstrate any contribution to preventing or treating postoperative delirium in patients following surgery for gastrointestinal or lung malignancy, TJ-54 reduced the risk of postoperative delirium in the patients who were classified as MMSE ≤26. Further phase III studies with a larger sample size are required in order to clarify the effects of TJ-54 against postoperative delirium.

Mouse Models for Assessing the Protective Efficacy of Lactobacillus gasseri SBT2055 against Helicobacter suis Infection Associated with the Development of Gastric Mucosa-Associated Lymphoid Tissue Lymphoma.

BACKGROUND: Helicobacter suis strain TKY infection has been strongly associated with the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma in a C57BL/6J mouse model. MATERIALS AND METHODS: 1. C57BL/6J mice were intragastrically administered Lactobacillus strains once daily with 10(8)-10(9) colony-forming units (CFU), starting 2 days before intragastric infection with H. suis TKY (approximately 1 × 10(4) copies of 16S rRNA genes) or H. pylori Sydney strain 1 (SS1; 3 × 10(8) CFU) and continuing for 14 days after infection. 2. C57BL/6J mice were given powdered feed mixed with lyophilized L. gasseri SBT2055 (LG2055) cells (5 × 10(8) CFU/g), starting 2 weeks before intragastric infection with H. suis TKY and continuing 12 months after infection. RESULTS: 1. Among the 5 Lactobacillus strains that we examined, only LG2055 exhibited significantly preventive efficacy against both H. suis TKY and H. pylori SS1 at day 15 after infection. 2. Dietary supplementation with LG2055 protected mice from the formation of round protrusive lesions in the gastric fundus 12 months after infection with H. suis TKY, whereas such lesions had developed in the gastric fundus of nonsupplemented mice 12 months after infection. In addition, the formation of lymphoid follicles in gastric mucus layers was suppressed by dietary LG2055 at 3 months after infection. CONCLUSIONS: LG2055 administration is effective for suppressing the progression of gastric MALT lymphoma by reducing H. suis colonization.

Joint action syntax in Japanese martial arts.

Participation in interpersonal competitions, such as fencing or Japanese martial arts, requires players to make instantaneous decisions and execute appropriate motor behaviors in response to various situations. Such actions can be understood as complex phenomena emerging from simple principles. We examined the intentional switching dynamics associated with continuous movement during interpersonal competition in terms of their emergence from a simple syntax. Linear functions on return maps identified two attractors as well as the transitions between them. The effects of skill differences were evident in the second- and third-order state-transition diagrams for these two attractors. Our results suggest that abrupt switching between attractors is related to the diverse continuous movements resulting from quick responses to sudden changes in the environment. This abrupt-switching-quick-response behavior is characterized by a joint action syntax. The resulting hybrid dynamical system is composed of a higher module with discrete dynamics and a lower module with continuous dynamics. Our results suggest that intelligent human behavior and robust autonomy in real-life scenarios are based on this hybrid dynamical system, which connects interpersonal coordination and competition.

Influences of maternal B12 and methionine intake during gestation and lactation on testicular development of offspring in rats.

The influence of maternal vitamin B12 malnutrition on testicular development of offspring was examined using soy protein-based B12-deficient diets with or without 0.5% DL-methionine supplementation. Dams were fed the B12-deficient diet throughout gestation and lactation, whereas dams in a control group were fed a control diet which contained cyanocobalamin in the B12-deficient diet without methionine. Offspring born to dams fed the B12-deficient diet without methionine showed poor testicular development, e.g. decreased numbers of seminiferous tubules containing healthy spermatocytes and a high ratio of apoptotic cells per all germ cells. The abnormality was rarely observed in the group fed the B12-deficient diet with methionine. It was likely that the testicular abnormality of offspring was caused by B12-deficiency post partum and was prevented by the methionine supplementation. These observations suggested that maternal B12 nutritional status during the pre-weaning period is quite important for spermatogenesis of male offspring and that the requirement of B12 for testicular development is to produce active B12-dependent methionine synthase.

Thalamus-derived molecules promote survival and dendritic growth of developing cortical neurons.

The mammalian neocortex is composed of various types of neurons that reflect its laminar and area structures. It has been suggested that not only intrinsic but also afferent-derived extrinsic factors are involved in neuronal differentiation during development. However, the role and molecular mechanism of such extrinsic factors are almost unknown. Here, we attempted to identify molecules that are expressed in the thalamus and affect cortical cell development. First, thalamus-specific molecules were sought by comparing gene expression profiles of the developing rat thalamus and cortex using microarrays, and by constructing a thalamus-enriched subtraction cDNA library. A systematic screening by in situ hybridization showed that several genes encoding extracellular molecules were strongly expressed in sensory thalamic nuclei. Exogenous and endogenous protein localization further demonstrated that two extracellular molecules, Neuritin-1 (NRN1) and VGF, were transported to thalamic axon terminals. Application of NRN1 and VGF to dissociated cell culture promoted the dendritic growth. An organotypic slice culture experiment further showed that the number of primary dendrites in multipolar stellate neurons increased in response to NRN1 and VGF, whereas dendritic growth of pyramidal neurons was not promoted. These molecules also increased neuronal survival of multipolar neurons. Taken together, these results suggest that the thalamus-specific molecules NRN1 and VGF play an important role in the dendritic growth and survival of cortical neurons in a cell type-specific manner.

A critical interpersonal distance switches between two coordination modes in kendo matches.

In many competitive sports, players need to quickly and continuously execute movements that co-adapt to various movements executed by their opponents and physical objects. In a martial art such as kendo, players must be able to skillfully change interpersonal distance in order to win. However, very little information about the task and expertise properties of the maneuvers affecting interpersonal distance is available. This study investigated behavioral dynamics underlying opponent tasks by analyzing changes in interpersonal distance made by expert players in kendo matches. Analysis of preferred interpersonal distances indicated that players tended to step toward and away from their opponents based on two distances. The most preferred distance enabled the players to execute both striking and defensive movements immediately. The relative phase analysis of the velocities at which players executed steps toward and away revealed that players developed anti-phase synchronizations at near distances to maintain safe distances from their opponents. Alternatively, players shifted to in-phase synchronization to approach their opponents from far distances. This abrupt phase-transition phenomenon constitutes a characteristic bifurcation dynamics that regularly and instantaneously occurs between in- and anti-phase synchronizations at a critical interpersonal distance. These dynamics are profoundly affected by the task constraints of kendo and the physical constraints of the players. Thus, the current study identifies the clear behavioral dynamics that emerge in a sport setting.

Tumor local chemohyperthermia using docetaxel-embedded magnetoliposomes: Interaction of chemotherapy and hyperthermia.

BACKGROUND AND AIM: We have studied and reported the usefulness of tumor local chemohyperthermia at a low-grade temperature below 43°C with docetaxel-embedded magnetoliposome (DML) and an applied alternating current magnetic field. However, the mechanisms of this treatment and the dynamics of the injected docetaxel were not investigated in our previous study. Thus, we investigated the interaction of chemotherapy and hyperthermia in the treated tumor. METHODS: Human MKN45 gastric cancer cells were implanted in the hind limbs of Balb-c/nu/nu mice. DML, magnetite-loaded liposome, and docetaxel were injected into the tumors with or without being exposed to an alternating current magnetic field. Docetaxel and tumor necrosis factor-α concentrations, the cell cycle, and cell death rates in the tumor were examined. RESULTS: Docetaxel concentrations were significantly higher in the DML-injected group than in the docetaxel-injected group 3 days after injection. A G2/M peak was observed 1 day after treatment in the DML-injected and exposed group and the docetaxel-injected group, while it was observed 3 days after treatment in the DML-injected without heating group and the magnetite-loaded liposome group. The tumor cell death rate gradually increased in the DML-injected group, with or without being exposed, while it gradually decreased after its peak in other groups. The tumor necrosis factor-α concentration in the tumor treated with DML with heating remained at a high level on the 7th day after treatment, while it decreased after its peak in other groups. CONCLUSION: The antitumor effect of this treatment derives from a combination of hyperthermia and chemotherapy locally in the tumor.

[Modified FOLFIRI (l-LV, 5-fluorouracil and irinotecan) therapy for Japanese patients with metastatic colorectal cancer].

PURPOSE: As a project of the Kanagawa Colorectal Cancer Study Group, we performed this study to analyze the efficacy and the safety of modified FOLFIRI (irinotecan: 150 mg/m2) therapy for Japanese patients with metastatic colorectal cancer. PATIENTS AND METHODS: We treated PS 0-1 Japanese patients with measurable or assessable colorectal cancer who either had not received preliminary treatment, or were postoperative with metastasis and had undergone radiation therapy or adjuvant chemotherapy before more than four weeks, and further had provided written acceptance of our proposed procedures. Twenty patients received modified FOLFIRI therapy as a 2-hour infusion of CPT-11 150 mg/m/2 and l-LV 200 mg/m2 followed by a bolus 5-FU 400 mg/m/2 and 46-hour infusion 5-FU 2, 400 mg/m2. Tumor response was assessed by RECIST and toxicity by NCI-CTC. RESULTS: Thirty males and seven females underwent an average 10 courses of treatment. This therapy achieved a 50% response rate, 80%disease-control rate, and 316+/-40 days PHS. Regarding hematological toxicity, 11 patients (55%) experienced leukemia, which developed to grade 3/4 in 5 (25%) of them. Twelve patients (65%) experienced neutropenia, which developed to grade 3/4 in 10 (50%) of them. Digestive toxicity was observed in 16 patients (80%), which developed to grade 3/4 in only one patient (5%) with gastric ulcer. Six patients (30%) experienced alopecia, which was grade 1/2 only. CONCLUSION: This clinical study was safely carried out. The efficacy was as good as in previous reports using a regular dose of CPT-11.

Feasibility of chemohyperthermia with docetaxel-embedded magnetoliposomes as minimally invasive local treatment for cancer.

Hyperthermia is a minimally invasive approach to cancer treatment, but it is difficult to heat only the tumor without damaging surrounding tissue. To solve this problem, we studied the effectiveness of chemohyperthermia with docetaxel-embedded magnetoliposomes (DMLs) and an applied alternating current (AC) magnetic field. Human MKN45 gastric cancer cells were implanted in the hind limb of Balb-c/nu/nu mice. Various concentrations of docetaxel-embedded DMLs were injected into the tumors and exposed to an AC magnetic field (n = 6, each). For comparison with hyperthermia alone, magnetite-loaded liposome (ML)-injected tumors were exposed to an AC magnetic field. Furthermore, the results of DML without AC treatment and docetaxel diluted into PBS with AC treatment were also compared (n = 10, each). Tumor surface temperature was maintained between 42 and 43 degrees C. Tumor volume was reduced in the DML group with a docetaxel concentration > 56.8 microg/ml, while a docetaxel concentration > 568.5 microg/ml was required for tumor reduction without hyperthermia. Statistically significant differences in tumor volume and survival rate were observed between the DML group exposed to the magnetic field and the other groups. The tumor disappeared in 3 mice in the DML group exposed to the magnetic field; 2 mice survived over 6 months after treatment, whereas all mice of the other groups died by 15 weeks. Histologically, hyperthermia with DML damaged tumor cells and DML diffused homogeneously. To the best of our knowledge, this is the first report to show that hyperthermia using chemotherapeutic agent-embedded magnetoliposomes has an anticancer effect.

Change of epigenetic control of cystathionine beta-synthase gene expression through dietary vitamin B12 is not recovered by methionine supplementation.

BACKGROUND/AIMS: Vitamin B12 (B-12) is an essential cofactor for methionine synthase, and methionine is critical for the methylation of various biological molecules including DNA. Whether changes in B-12 levels can alter specific gene expression through DNA methylation and whether dietary methionine has any effect on general DNA methylation status still remains controversial. METHODS: We raised severely B-12-deficient rats as well severely-B-12 deficient rats but supplemented with 5% methionine. mRNA levels of methionine cycle-related enzymes were analyzed. RESULTS: Gene expression patterns changed under B-12-deficient conditions but were recovered by dietary methionine supplementation to B-12-deficient rats. However, cystathionine beta-synthase mRNA levels, which had decreased under B-12-deficient conditions, did not recover with supplementary dietary methionine. The CpG island of the cystathionine beta-synthase promoter was hypomethylated in B-12-deficient rats, and showed no recovery after methionine addition. CONCLUSIONS: Dietary B-12 can affect epigenetic machinery by regulating DNA methylation status and dietary methionine may have small effects on DNA methylation.

Repeated inductive heating using a sintered MgFe2O4 needle for minimally invasive local control in breast cancer therapy.

PURPOSE: This study investigated the efficacy of repeated thermotherapy for breast cancer utilising a novel sintered MgFe(2)O(4) needle and alternating current (AC) magnetic field in xenograft animal models mimicking human breast cancer. MATERIALS AND METHODS: A sintered MgFe(2)O(4) needle and an apparatus to apply an AC magnetic field were prepared for this study. Animals bearing BT-474 tumours (mean (+/-standard deviation) volume, 471 +/- 153 mm(3)) were divided into four groups. A sintered MgFe(2)O(4) needle (length, 5 mm) was placed in the centre of each tumour. An AC magnetic field (amplitude, 4 kA/m; 2 kW; 540 kHz) was applied for 10 min once, twice or three times for the first, second and third groups, respectively, and was not applied for the control group. Temperature during treatment and tumour volume 8 weeks after first treatment were assessed. RESULTS: Maximum tumour temperature tended to increase in repeated-application groups: group 1, 59.2 +/- 4 degrees C; group 2, 58.9 +/- 3.3 degrees C and 61.2 +/- 8.9 degrees C for the first and second applications; and group 3, 60.4 +/- 4.6 degrees C, 62.1 +/- 7.8 degrees C and 71.1 +/- 6.1 degrees C for the first, second and third applications. Tumour volumes in control, groups 1, 2 and 3 at 8 weeks after treatment were 3633 +/- 2478 mm(3), 3240 +/- 1031 mm(3), 1252 +/- 1289 mm(3) and 0 mm(3), respectively. Tumours were significantly smaller in group 3 than in the control and group 1 at 8 weeks. CONCLUSIONS: The efficacy of repeated inductive heating utilising a sintered MgFe(2)O(4) needle was demonstrated. Thermotherapy using the present method may offer an effective non-surgical treatment for human breast cancer.

Lipid-soluble components of honeybee-collected pollen exert antiallergic effect by inhibiting IgE-mediated mast cell activation in vivo.

It was shown previously that bee-collected pollen (bee pollen, BP), inhibited in vitro murine mast cell activation. This study further analysed the antiallergic effect of BP in vivo by measuring cutaneous mast cell activation using a passive cutaneous anaphylaxis reaction. Daily oral administration of BP to mice, dose-dependently reduced the cutaneous mast cell activation elicited by IgE and specific antigens. Administration of BP also reduced the plasma concentration of malondialdehyde (MDA), an indicator of lipid peroxidation. The inhibitory effect of BP was mostly in a lipid- but not in water-soluble fraction. The HPLC analysis of isoflavones in BP revealed that genistein was a major isoflavone. However, administration of genistein alone at the concentration found in BP, did not show an inhibitory effect as observed in whole BP, suggesting that component(s) other than genistein would be responsible for the inhibitory effect of BP. These results first reveal that lipid-soluble components of BP exert an antiallergic action by inhibiting the FcåRI-mediated cutaneous mast cell activation.

Long-term survival after multimodal therapy in a patient demonstrating intrahepatic cholangiocarcinoma with hilar invasion and intrahepatic metastases.

Cholangiocarcinoma is a therapeutically challenging malignancy. This report describes a case where the patient received multimodal therapy, including surgery, adjuvant chemoradiation therapy, and combination chemotherapy and successfully achieved long-term survival. Specifically, the patient achieved an extended complete response after combination chemotherapy with TS-1 (an orally administered drug that is a combination of tegafur, 5-chloro-2, 4-dihydroxypyridine [CDHP], and oteracil potassium [Oxo]) and cisplatin for recurrence. This result suggests that chemoradiation or combination chemotherapy regimens using oral 5-fluorouracil (5-FU) analogues might therefore be helpful in patients with this malignancy. However, further clinical trials are required.

Novel tumor-ablation device for liver tumors utilizing heat energy generated under an alternating magnetic field.

BACKGROUND AND AIMS: We have developed a novel tumor-ablation device for liver tumors utilizing heat energy induced by magnesium ferrite (MgFe(2)O(4)) particles under an alternating magnetic field (AMF) produced by electric currents. This novel device can repeatedly heat liver tumors at lower temperature than usual heating devices, such as radiofrequency ablation therapy, with slight infliction of pain. This study assesses its heating effect on rat liver tumors as local therapy. METHOD: The small needle was manufactured from MgFe(2)O(4) particles by sintering at 1100 degrees C. After a MgFe(2)O(4) needle was inserted into liver tumors comprising of dRLh-84 cells, the tumors were heated for 30 min under an AMF. We examined cellular activity by using nicotinamide adenine dinucleotide (NADH) diaphorase staining and terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling (TUNEL) staining, and evaluated the effect of suppressing tumor growth by sequentially comparing the tumor diameter with that of the control group. RESULTS: The mean temperature of the heated tumors was 60.2 +/- 1.8 degrees C. The tumor cells were constricted, and chromatin of nuclei had shrunk immediately after heating. The heat-injury area that contained the tumors was negative for NADH diaphorase activity. After 3 days, the tumor cells in the heat-injury area became positive for TUNEL staining, which detects cell death. At 7 days, the mean tumor diameters were significantly smaller in the heating group than in the control group (6.15 +/- 0.47 mm vs 16.89 +/- 2.69 mm; P < 0.05). CONCLUSION: This device, utilizing heat energy induced by ferromagnetic metal under an AMF, appears useful as local thermotherapy for human liver cancer.

Inhibitory effect of honeybee-collected pollen on mast cell degranulation in vivo and in vitro.

Bee-collected pollen (bee pollen [BP]) has been used as a folk medicine for centuries against various diseases, including allergy. There is no study elucidating how BP exerts such an anti-allergic effect. Since mast cells play a central role in the pathogenesis of various allergic diseases, we investigated the effect of BP on mast cell activation elicited by the Fc immunoglobulin E (IgE) receptor (Fc epsilon RI)-mediated pathways. The in vivo effect of orally administered BP on cutaneous mast cell activation was examined by passive cutaneous anaphylaxis reaction. In vitro mast cell degranulation and IgE binding to mast cells and the status of protein tyrosine phosphorylation were examined using bone marrow-derived mast cells. Daily oral administration of BP to mice significantly reduced the cutaneous mast cell activation elicited by IgE and specific antigens. BP also reduced in vitro mast cell degranulation and tumor necrosis factor-alpha production by inhibiting IgE binding to Fc epsilon RI on mast cells. The inhibitory effect of BP on mast cell degranulation by preventing IgE binding was confirmed by the reduced levels of protein tyrosine phosphorylation, which occurred as downstream events in activated mast cells via Fc epsilon RI. These results first revealed that the anti-allergic action of BP was exerted by inhibiting the Fc epsilon RI-mediated activation of mast cells, which plays important roles, not only in the early phase, but also in the late phase of allergic reactions.

Feasibility of new heating method of hepatic parenchyma using a sintered MgFe2O4 needle under an alternating magnetic field.

BACKGROUND: Magnetic metal particles such as magnesium ferrite (MgFe2O4) induce heat energy under an alternating magnetic field that was produced by electric current. We have developed a new heating device using a sintered MgFe2O4 needle under an alternating magnetic field. This device can repeatedly heat target tissue at lower temperatures than that for radiofrequency ablation therapy. This study aims to assess whether the new heating device has the ability to heat rat liver tissue. METHOD: A small needle made from MgFe2O4 particles was prepared by sintering at 1100 degrees C and inserted into rat liver tissue. The rat liver was then heated under an alternating magnetic field, 4 kA/m, for 30 min. We measured the temperature of rat tissue during the heat treatment, and sequentially evaluated histological changes and hepatocyte cellular activity after heat stimulus by using nicotinamide adenine dinucleotide diaphorase staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. RESULTS: The mean temperature of the liver tissue during heating was 60.7 +/- 1.1 degrees C. Immediately after heating, nuclei of the hepatocytes were hyper-chromatin, with hepatocytes negative for nicotinamide adenine dinucleotide diaphorase activity in the heat-injury area. The injury area spread progressively until 3 d after heating, when the area was surrounded by fibroblasts, with hepatocytes positive for terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. CONCLUSIONS: This is the first time that a ferromagnetic metal heating device under an alternating magnetic field has achieved a temperature beyond 60 degrees C and led hepatocytes to complete cell death. This device would be of future use as a local heat-treatment for human liver cancer.

Suppressive effect of viscous dietary fiber on elevations of uric acid in serum and urine induced by dietary RNA in rats is associated with strength of viscosity.

This study was performed to clarify how dietary fiber (DF) with different viscosities would be associated with dietary RNA metabolism. Male Wistar strain rats, four weeks old, were fed diets containing a 3% (w/w) yeast RNA and a 5% (w/w) viscous DF for five days. Viscosity of DF samples used, in order of strength, were xanthan gum (XG) > guar gum (GG) > locust bean gum (LBG) > karaya gum (KG) > pectin (PE) = arabic gum (AG) > CM-cellulose (CMC) = inulin (IN). The serum uric acid concentration in the viscous DF groups significantly decreased as compared with that in the cellulose (CL) group. The urinary excretions of uric acid and allantoin in the respective groups given AG, GG, IN, KG, PE, and XG were significantly suppressed as compared with those in the CL group. The fecal RNA excretion was markedly increased in the IN, KG, PE, and XG groups in comparison to the CL group. The DF with high viscosity significantly suppressed RNA digestion by RNase A and decreased uptakes of 14C-labeled adenosine and adenosine 5'-monophosphate (5'-AMP) in rat jejunum. The results reveal that the suppressive effect of DF on elevation of serum uric acid concentration induced by dietary RNA in rats is associated with the strength of DF viscosity. The mechanism by which this is accomplished is suggested to be attributed to the inhibitions of digestion for dietary RNA and/or absorption of the hydrolyzed compounds.

[Cisplatin, 5-fluorouracil, and high-dose leucovorin for advanced esophageal cancer].

We report the effects and toxicities of intravenous administration of cisplatin, 5-FU and high-dose leucovorin for advanced esophageal cancer. Eight patients were registered and sixteen lesions were measurable. Of these sixteen lesions, thirteen were primary or synchronous metastatic lesions, and the response was 69%. Three were recurrence lesions, and the response rate for them was 0%. Including seven neoadjuvant cases, ten patients had oral mucositis, and seven patients had appetite loss. Other toxicities were diarrhea, myelosuppression, renal dysfunction, and alopecia. All were reversible after administration. It is suggested that this treatment regimen is a superior neoadjuvant chemotherapy with low toxicity.