Early results of multicenter phase II trial of perioperative oxaliplatin and capecitabine without radiotherapy for high-risk rectal cancer: CORONA I study.

BACKGROUNDS: Perioperative introduction of developed chemotherapy into the treatment strategy for locally advanced rectal cancer (LARC) may be a promising option. However, the most prevalent treatment for high-risk LARC remains preoperative chemoradiotherapy (CRT) in Western countries. PATIENTS AND METHODS: A phase II trial was undertaken to evaluate safety and efficacy of perioperative XELOX without radiotherapy (RT) for patients with high-risk LARC. Patients received 4 cycles of XELOX before and after surgery, respectively. Primary endpoint was disease-free survival. RESULTS: We enrolled 41 patients between June 2012 and April 2014. The completion rate of the preoperative XELOX was 90.3%. Twenty-nine patients (70.7%) could start postoperative XELOX, 15 of these patients (51.7%) completed 4 cycles. Allergic reaction to oxaliplatin was experienced by 5 patients (17.2%) during postoperative XELOX. One patient received additional RT after preoperative XELOX. Consequently, the remaining 40 patients underwent primary resection. Major complications occurred in 6 of 40 patients (15.0%). Pathological complete response (pCR) rate was 12.2%, and good tumor regression was exhibited in 31.7%. N down-staging (cN+ to ypN0) and T down-staging were detected in 56.7% and 52.5%, respectively. Clinical T4 tumor was a predictor of poor pathological response (p < 0.001). CONCLUSIONS: We could show the favorable pCR rate after preoperative XELOX alone. However, the T and N down-staging rate was likely to be insufficient. When tumor regression is essential for curative resection, the use of preoperative CRT is likely to be recommended. For patients with massive LN metastasis, the additional Bev to NAC might be a promising option.

Randomized clinical trial: rikkunshito in the treatment of functional dyspepsia--a multicenter, double-blind, randomized, placebo-controlled study.

BACKGROUND: Rikkunshito, a standardized Japanese herbal medicine, is thought to accelerate gastric emptying and relieve dyspepsia, although no large-scale, randomized, placebo-controlled trials of rikkunshito have been conducted. This study aimed to determine the efficacy and safety of rikkunshito for treating functional dyspepsia (FD). METHODS: FD patients received 2.5 g rikkunshito or placebo three times a day for 8 weeks in this multicenter, randomized, placebo-controlled, parallel-group trial. The primary end point was the proportion of responders at 8 weeks after starting test drug, determined by global patient assessment (GPA). The improvement in four major dyspepsia symptoms severity scale was also evaluated. In addition, plasma ghrelin levels were investigated before and after treatment. KEY RESULTS: Two hundred forty-seven patients were randomly assigned. In the eighth week, the rikkunshito group had more GPA responders (33.6%) than the placebo (23.8%), although this did not reach statistical significance (p = 0.09). Epigastric pain was significantly improved (p = 0.04) and postprandial fullness tended to improve (p = 0.06) in the rikkunshito group at week 8. Rikkunshito was relatively more effective among Helicobacter pylori-infected participants (rikkunshito: 40.0% vs placebo: 20.5%, p = 0.07), and seemed less effective among H. pylori-uninfected participants (rikkunshito: 29.3% vs placebo: 25.6%, p = 0.72). Among H. pylori-positive individuals, acyl ghrelin levels were improved just in rikkunshito group. There were no severe adverse events in both groups. CONCLUSIONS & INFERENCES: Administration of rikkunshito for 8 weeks reduced dyspepsia, particularly symptoms of epigastric pain and postprandial fullness. (UMIN Clinical Trials Registry, Number UMIN000003954).

Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy.

Citicoline supplementation has been used to ameliorate memory disturbances in older people and those with Alzheimer's disease. This study used MRS to characterize the effects of citicoline on high-energy phosphate metabolites and constituents of membrane synthesis in the frontal lobe. Phosphorus ((31)P) metabolite data were acquired using a three-dimensional chemical-shift imaging protocol at 4 T from 16 healthy men and women (mean +/- SD age 47.3 +/- 5.4 years) who orally self-administered 500 mg or 2000 mg Cognizin Citicoline (Kyowa Hakko Kogyo Co., Ltd, Ibaraki, Japan) for 6 weeks. Individual (31)P metabolites were quantified in the frontal lobe (anterior cingulate cortex) and a comparison region (parieto-occipital cortex). Significant increases in phosphocreatine (+7%), beta-nucleoside triphosphates (largely ATP in brain, +14%) and the ratio of phosphocreatine to inorganic phosphate (+32%), as well as significant changes in membrane phospholipids, were observed in the anterior cingulate cortex after 6 weeks of citicoline treatment. These treatment-related alterations in phosphorus metabolites were not only regionally specific, but tended to be of greater magnitude in subjects who received the lower dose. These data show that citicoline improves frontal lobe bioenergetics and alters phospholipid membrane turnover. Citicoline supplementation may therefore help to mitigate cognitive declines associated with aging by increasing energy reserves and utilization, as well as increasing the amount of essential phospholipid membrane components needed to synthesize and maintain cell membranes.

Dietary intake of the flower extracts of German chamomile (Matricaria recutita L.) inhibited compound 48/80-induced itch-scratch responses in mice.

The antipruritic effects of the diets containing German chamomile on the compound 48/80-induced scratching in ddY mice were examined. Since it is reported that an injection of compound 48/80, but not histamine, induced scratching behaviour due to itch but not to pain in ddY mice (Kuraishi et al., 1995), compound 48/80-induced scratching in ddY mice seems to be a suitable parameter for evaluating antipruritic agents independent of histamine receptor antagonism. In the mice fed the diet containing 1.2 w/w % of the ethyl acetate extract of dried flower of German chamomile (Matricaria recutita L.) for 11 days, the compound 48/80-induced scratching behaviour was significantly suppressed. The ethyl acetate extract of German chamomile dose dependently suppressed compound 48/80-induced scratching without affecting body weight increase. The ethyl acetate fraction of the ethanol extract and the ethanol extract of hot water extraction residue of German chamomile flower also showed strong inhibition on the compound 48/80-induced scratching. The inhibitory effects of the dietary intake of the German chamomile extracts on compound 48/80-induced itch-scratch response were comparable to oxatomide (10 mg/kg, p.o.), an anti-allergic agent.

The progression of aging in klotho mutant mice can be modified by dietary phosphorus and zinc.

Reduction in klotho gene expression causes accelerated senescence in klotho mutant mice. We have now found two key substances, phosphorus and zinc, which affect the appearance of klotho phenotypes. Klotho mutant homozygotes fed nonpurified diet with a phosphorus concentration of 1.03 g/100 g showed typical klotho phenotypes. However, most of the klotho phenotypes no longer appeared in male homozygotes fed a 0.4 g/100 g phosphorus diet. These homozygotes were capable of spermatogenesis. In the kidneys of the rescued male homozygotes, klotho protein expression was clearly detected. On the other hand, female klotho mice required supplementation of 0.25 g/100 g zinc orotate to the 0.4 g/100 g phosphorus diet to be rescued. Unlike in the rescued male mice, klotho protein levels in the kidneys of the rescued females were quite low. Wild-type (C3H/He) mice fed 1.5 or 1.0 g/100 g phosphorus diets had lower klotho protein expression in the kidneys than those fed a 0.4 g/100 g phosphorus diet (Kruskal-Wallis test, P < 0.05). These results indicate that dietary phosphorus and zinc modulate the phenotypes of klotho mice, and that klotho expression in the kidneys is regulated not only in klotho mutant mice, but also in wild-type mice.

Capsaicin-like anti-obese activities of evodiamine from fruits of Evodia rutaecarpa, a vanilloid receptor agonist.

Evodiamine, a major alkaloidal principle of Evodia fruits (Evodia rutaecarpa, Rutaceae), showed vanilloid receptor agonistic activities comparable to capsaicin. The Chinese literature refers to Evodia fruits as a "hot nature" herb. In spite of the similarities in the actions of evodiamine and capsaicin in vitro, evodiamine has no perceptible taste, including a peppery hot taste. Therefore, the effectiveness of evodiamine and the extract of Evodia fruits in preventing obesity on male C3H mice, or male SD rats were examined. When evodiamine was supplemented at 0.03% of the diet and fed to mice for 12 days, the perirenal fat weight became significantly lower than in the control group. The epididymal fat mass was also decreased in the evodiamine diet group. When evodiamine was supplemented at 0.02% in the form of ethanol extract of Evodia fruits to the high-fat diet and fed to rats for 21 days, the body weight, the perirenal fat weight, epididymal fat weight, the levels of serum free fatty acid, total lipids in the liver, triglyceride in the liver, and cholesterol level in the liver were significantly reduced as compared with the control diet group. Furthermore, both lipolytic activity in the perirenal fat tissue and specific GDP binding in brown adipose tissue mitochondria, as the biological index of enhanced heat production, were significantly increased in the evodiamine fed rats. Fasting mice subcutaneously administered 1-3 mg/kg evodiamine showed decreased core body temperature by 1-2 degrees C. This hypothermic effect was prevented by the pretreatment of intraperitoneally administered 10 mg/kg capsazepine, a vanilloid receptor antagonist. On the other hand, food-sated mice subcutaneously administered 1-3 mg/kg evodiamine showed unchanged core body temperature and increased tail skin temperature by more than 5 degrees C, suggesting the increased energy expenditure by enhanced heat dissipation. In conclusion, we have demonstrated that a novel non-pungent vanilloid receptor agonist, evodiamine, mimics the characteristic anti-obese effects induced by capsaicin. Evodiamine would induce heat loss and heat production at the same time and dissipate food energy, preventing the accumulation of perivisceral fat and the body weight increase.

The positive inotropic and chronotropic effects of evodiamine and rutaecarpine, indoloquinazoline alkaloids isolated from the fruits of Evodia rutaecarpa, on the guinea-pig isolated right atria: possible involvement of vanilloid receptors.

Cardiotonic effects of evodiamine and rutaecarpine, constituents of the fruits of Evodia rutaecarpa Bentham Rutaceae, were evaluated on guinea pig isolated atria. Comparison with capsaicin, a vanilloid receptor agonist, revealed similar positive inotropic and chronotropic activity, as judged from antagonistic effects of the competitive vanilloid receptor (capsaicin receptor) antagonist capsazepine, the non-competitive vanilloid receptor antagonist ruthenium red, the calcitonin gene related peptide antagonist CGRP(8-37), the P2X purinoceptor antagonist PPADS, and various desensitization studies. Evodiamine and rutaecarpine produced transient positive inotropic and chronotropic effects on the guinea-pig isolated atria, followed by a desensitizing effect to additional administration. Dose-response relationships for evodiamine, rutaecarpine and capsaicin were obtained. All the compounds evoked positive inotropic and chronotropic effects in a concentration-dependent manner. Maximal contractions for evodiamine, rutaecarpine and capsaicin were observed at concentrations of 1 microM, 3 microM and 0.3 microM, respectively. The cardiotonic responses evoked by both evodiamine and rutaecarpine were shifted to the right by capsazepine, an established antagonist of vanilloid receptor (capsaicin-receptor). The effects of both evodiamine (1 microM) and rutaecarpine (3 microM) were abolished by pretreatment with a desensitizing dosage of capsaicin (1 microM), developing cross-tachyphylaxis between these compounds. The effects of evodiamine (1 microM), rutaecarpine (3 microM) and capsaicin (0.3 microM) were also significantly reduced by pretreatment with ruthenium red (10 microM) and CGRP (8-37) (10 microM). The effects of evodiamine, rutaecarpine and capsaicin were not affected by pretreatment with PPADS (100 microM), a highly selective P2X purinoceptor antagonist, and the possibility of the involvement of the P2X purinoceptor was excluded. These results suggest that the positive inotropic and chronotropic effects on the guinea-pig isolated right atria induced by both evodiamine and rutaecarpine could be attributed to their interaction with vanilloid receptors and the resultant release of CGRP, a cardiotonic neurotransmitter, from capsaicin-sensitive nerves as with capsaicin.

KF19418, a new compound for hair growth promotion in vitro and in vivo mouse models.

KF19418, a newly synthesized compound, stimulated proliferation of cultured hair bulb cells from new born mice in concentration-dependent manner in the range under 10 microM. In the culture system of whole skin pieces from 4-week-old mice which we earlier established, KF19418 promoted hair follicle elongation as in the case of minoxidil. After topical application for 2 weeks of KF19418 or minoxidil to dorsal skin of hair-clipped mouse alopecia model, KF19418 at 1% suspension accelerated hair regrowth at a rate comparable to 1% minoxidil solution. Thus, it was shown that KF19418 directly stimulated hair follicle in vitro and had hair growth promoting activities in vivo.

The bronchoconstrictive action of evodiamine, an indoloquinazoline alkaloid isolated from the fruits of Evodia rutaecarpa, on guinea-pig isolated bronchus: possible involvement on vanilloid receptors.

Evodiamine, a constituent of Evodiae Fructus (Evodia rutaecarpa Benth., Rutaceae), produced a bronchial contraction that is resistant to atropine and abolished by pretreatment with a mixture of the NK1 and NK2 receptor antagonists. Contractile responses to evodiamine were examined in guinea-pig isolated bronchus and compared with those to capsaicin. Both compounds evoked bronchial contraction in a concentration-dependent manner. Maximal contractions for evodiamine and capsaicin were observed at concentrations of 3 microM and 1 microM, respectively. Capsazepine (10 microM), an established antagonist of vanilloid receptor (capsaicin receptor), competitively inhibited the bronchial contraction evoked by evodiamine, suggesting that evodiamine activated vanilloid receptors. Evodiamine (3 microM) and capsaicin (1 microM) produced complete crossed tachyphylaxis. Both compounds desensitized tissues to subsequent additions of either evodiamine or capsaicin. These results suggest that the evodiamine-induced contractile response of the bronchus could be attributed to the resultant tachykinin release from sensory neurons by binding of evodiamine to vanilloid receptors. Rutaecarpine, which belongs to the same indoloquinazoline-type alkaloid as evodiamine, showed neither bronchoconstrictive, desensitizing effects nor vanilloid antagonistic effects at all the concentrations examined (up to 200 microM).

Hereditary spastic paraplegia with a thin corpus callosum and thalamic involvement in Japan.

The authors examined two Japanese siblings with a recessive hereditary spastic paraplegia (HSP) with dementia and a thin corpus callosum. Both showed thalamic glucose hypometabolism on PET. Recessive HSP with a thin corpus callosum is a rare disorder, with less than 20 reported patients, that may be a Japanese subtype of HSP.

Proanthocyanidins from grape seeds promote proliferation of mouse hair follicle cells in vitro and convert hair cycle in vivo.

For the purpose of discovering natural products which possess hair growing activity, we examined about 1000 kinds of plant extracts concerning growth-promoting activity with respect to hair follicle cells. After an extensive search, we discovered that proanthocyanidins extracted from grape seeds promote proliferation of hair follicle cells isolated from mice by about 230% relative to controls (100%); and that proanthocyanidins possess remarkable hair-cycle-converting activity from the telogen phase to the anagen phase in C3H mice in vivo test systems. The profile of the active fraction of the proanthocyanidins was elucidated by thiolytic degradation and tannase hydrolysis. We found that the constitutive monomers were epicatechin and catechin; and that the degree of polymerization was 3.5. We demonstrated the possibility of using the proanthocyanidins extracted from grape seeds as agents inducing hair growth.

P300 and the thought disorder factor extracted by factor-analytic procedures in schizophrenia.

BACKGROUND: In order to clarify the clinical significance of P300 as a biologic marker that can reflect schizophrenic symptomatology, many previous studies have evaluated the relationship of P300 with the symptoms on the basis of a positive/negative dichotomy, but yielded inconsistent conclusions. Such a dichotomy has been criticized as being too reductionistic. Recently, most studies with factor-analytic procedures have extracted some symptom factors outside this dichotomy. Therefore, it is important to examine associations of P300 with the symptom factors extracted by these statistical analyses. METHODS: In the present study, the amplitudes of P300 were measured by using an auditory oddball paradigm for 73 schizophrenics whose psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). RESULTS: The principal component analysis of the PANSS items revealed five factors labeled the thought disorder, negative, hostile/excitable, delusional/hallucinatory, and depressive factors. The score for the thought disorder factor correlated negatively with the amplitude of P300 recorded at Pz T5, and T6, but that for the other factors did not. CONCLUSIONS: These findings suggest that the reduction of P300 amplitudes recorded at the midline parietal and bilateral temporoparietal regions may be one of the electrophysiologic indices representing the thought disorder clinically observed in schizophrenia.

Simultaneous observation of regional cerebral blood flow and event-related potential during performance of an auditory task.

Reduced amplitude of the P300 component has been reported consistently in patients with neurological and psychiatric disorders. It is unclear, however, how such patients' cognitive dysfunction is related to their P300 abnormality. Further basic knowledge regarding neural substrates for P300 generation is required for gaining an understanding of the pathological significance of the P300 amplitude reduction. To determine the brain structures involved in P300 generation, we observed the event-related potential and the regional cerebral blood flow (rCBF) in 10 normal subjects performing an oddball discrimination of pure tones. The rCBF value was assessed quantitatively with the aid of single photon emission computed tomography using technetium-99m hexamethylpropylene amine oxime. During the task performance, significant activation was observed in the posterior superior temporal and inferior parietal regions of the right hemisphere. In addition, positive correlation of the task-related increase in rCBF with the simultaneously recorded P300 amplitude was observed in the right but not the left posterior superior temporal region. These findings indicate that activation of the right non-verbal auditory area might modulate P300 generation during pure-tone discrimination.

[Progress in targeting therapy for hepatic cancer].

Targeting therapy for hepatic cancer is divided into a method using Lipiodol as drug carrier and a method employing immunological responses of monoclonal antibodies to the tumor antigens. For the latter method, immuno-conjugates of antibodies and cytotoxic agents have been studied. Because of the lower response rates of conventional chemotherapy. Lipiodol as drug carrier provides the most effective targeting therapy on hepatic cancer at the present time. Immunotherapy using cytotoxic cells, however, did not result in sufficient clinical efficacy on the liver cancer. The system for accumulation of the effective and sufficient number of cytotoxic cells or immunoconjugates in the targeting tumor tissues are expected to be investigated.

Effect of a new hyperosmotic agent, NIK-242 injection, on brain water content, metabolites and cerebral blood flow in cerebral ischemia in the spontaneously hypertensive rat.

We examined the effects of a new hyperosmotic agent (NIK-242inj.) on brain edema, energy metabolites and regional cerebral blood flow (r-CBF) during acute cerebral ischemia. Cerebral ischemia was induced by bilateral common carotid artery ligation (BLCL) using spontaneously hypertensive rats (SHR). The experimental animals were divided into 4 groups, A:20% NIK-242inj., B:20% mannitol, C:10% glycerol in 5% fructose, D:normal saline. All the animals were administered the agent or saline intravenously beginning at 1h after BLCL and continuing for 2h for a total dose of 6.8 ml/kg body weight. Brain water content and metabolites (ATP, lactate, pyruvate) were determined 3h after BLCL. Regional cerebral blood flow (r-CBF) in thalamus was also measured by the hydrogen clearance technique. The brain water content in the NIK-242inj. group was significantly lower than that of saline group. The concentration of brain ATP in the NIK-242inj. group remained higher than those of saline group. Accumulation of lactate in the NIK-242inj. group was less than in the mannitol and saline groups. The lactate/pyruvate ratio of the NIK-242 inj. group was significantly lower than that of the saline and mannitol groups. At 3h after BLCL, the reduction of r-CBF in the NIK-242inj. group was smaller than that of saline group. The present study suggests that NIK-242inj. as well as glycerol could ameliorate brain edema, disruption of brain energy metabolism and reduction of r-CBF in acutely induced cerebral ischemia.

[A case of three malignant tumors of the duodenal bulb and large intestine].

A 75-year-old woman with anemia admitted to our hospital and was found to have a polyp in the duodenal bulb. The biopsy specimen was histologically diagnosed as an adenoma. A barium enema examination showed an obstruction in the ascending colon and a biopsy done on a specimen of the ascending colon revealed colonic cancer. A histology of the resected specimen of the duodenal bulb revealed a tubular adenocarcinoma in an adenoma, and a similar examination of a colonic resected specimen revealed a mucinous, papillary carcinoma. A primary malignant tumor in the duodenum is an uncommon tumor and our case is first in Japan showing three malignant tumors with an early duodenal cancer.