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The purpose of this study was to develop an evaluation method for animal-assisted intervention (AAI) programs involving Mood Check List-Short form.2 (MCL-S.2) and the State-Trait Anxiety Inventory (STAI) for psychiatric daycare of Japanese alcohol. dependents. A total of 36 alcohol dependents completed the study and questionnaires assessing their state. A single session of AAI reduced both subjective and physiological measures of state anxiety (A-State); and this program induced a significant reduction in the anxiety after an AAI program session with the dogs and cats involved in the intervention (p = 0.001). The Wilcoxon t-test showed that there were also significant differences in the "anxiety", "pleasantness", and "relaxation". scores for MCL-S.2 among the alcohol dependents, before and after AAI; a significantly decreased "anxiety" score (p = 0.006), and increased "pleasantness" (p = 0.002) and "relaxation" (p=0.012) scores for MCL-S.2 after AAI. The results of this study indicated that alcohol dependents who experienced a group AAI session-program exhibited significant improvements in their feeling; decreased anxiety, and increased pleasantness and relaxation.

Objectives TAS-102 is an oral combination treatment comprised of an antimetabolite, trifluridine, a thymidine-based nucleoside analog, and tipiracil hydrochloride, at a molar ratio of 1:0.5. This antimetabolite has demonstrated efficacy in clinical trials, including a global phase 3 trial in metastatic colorectal cancer. As this agent has shown activity greater than cisplatin in small cell lung cancer xenograft mouse models, the objective of this study was to evaluate TAS-102 in the second-line treatment of small cell lung cancer. Methods This was a multicenter, open-label, two-arm, randomized phase 2 study designed to compare oral TAS-102 (35mg/m 2 /dose twice daily) versus control (topotecan or amrubicin). Patients requiring second-line chemotherapy for treatment of small cell lung cancer, either refractory or sensitive to frontline platinum-based chemotherapy, were enrolled. Results Eighteen patients were enrolled. Eight of nine patients receiving TAS-102 discontinued treatment due to progressive disease and one patient died due to clinical progression during the safety follow-up. Unplanned interim futility considerations were made, and the study was terminated early because it was unlikely that superiority of TAS-102 versus comparator could be demonstrated. Six control patients discontinued therapy due to progressive disease and one due to an adverse event. Median progression-free survival was 1.4 months (range 0.9–1.8) versus 2.7 months (range 1.0–6.8) for TAS-102 and control, respectively, with a hazard ratio of 3.76 (80% CI, 1.68–8.40) favoring control. The most common adverse events with TAS-102 were neutropenia, diarrhea, anemia, anorexia, and fatigue, each in three patients. Conclusion TAS-102 showed no evidence of activity in second-line small cell lung cancer.

Introduction: TSU-68 is an oral small-molecule inhibitor that targets vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, and fibroblast growth factor receptor 1. An open-label, single-arm, phase I study was performed to evaluate escalating doses of TSU-68 in combination with standard chemotherapy in patients with advanced non-small cell lung cancer. Methods: Eligible patients received TSU-68 at 200 or 400 mg twice daily and continuously in combination with carboplatin (area under the curve, 6 mg · min/mL) plus paclitaxel (200 mg/m 2 ) on day 1 every 21 days. Results: Thirty-seven patients were enrolled at the two dose levels of TSU-68. No dose-limiting toxicities were observed with TSU-68 at the 200 mg twice a day dose level. At 400 mg twice a day, one of six patients experienced a dose-limiting toxicity (anorexia of grade 3) during the first cycle. The 400 mg twice a day dose level was determined to be the recommended dose, and a total of 34 patients were treated at this dose. Overall, adverse events were mild to moderate in severity, with the most frequently observed such events being myelosuppression, neuropathy, and gastrointestinal disorders. No drug-related bleeding was observed. The objective response rate was 39.4% (95% confidence interval, 22.9–57.9%), and median progression-free survival was 5.6 months (95% confidence interval, 3.6–7.2 months). Coadministration of TSU-68, carboplatin, and paclitaxel had no substantial impact on the pharmacokinetics of these drugs. Conclusions: TSU-68 can be safely combined with standard doses of carboplatin-paclitaxel, with the combination manifesting promising antitumor activity.

In 181 healthy Japanese volunteers we examined the relationship between personality, sensitivity to pain and a single nucleotide polymorphism (rs3813034) in the 3′ untranslated region (3′ UTR) of the serotonin transporter (5-HTT) gene (SLC6A4). Pain sensitivity was assessed by using cold and pressure thresholds. Personality was assessed by the Temperament and Character Inventory (TCI). Males without the T allele (G/G) showed a significantly higher spiritual acceptance (ST3) score than those who had the T allele (T/T and T/G). Females with the T allele (T/T and T/G) showed significantly higher transpersonal identification (ST2) and self-transcendence (ST) scores than those without the T allele (G/G). As for pain sensitivity and its relationship with TCI, we found a low negative correlation between cold water stimulation, disorderliness (NS4) and novelty seeking (NS) in males, whereas in females we found a low positive correlation between cold water stimulation, self-acceptance (SD4) and pure-hearted principles (C5), as well as pressure stimulation and SD4. It is possible that the 5-HTT 3′ UTR gene polymorphism affects the character dimensions of Cloniger’s theory, and that there might be a low correlation between pain and a part of the personality.

Schizophrenia and bipolar disorder show high comorbidity with smoking dependence. Several previous studies reported that glycogen synthase kinase 3β (GSK3β), which is widely expressed in the brain including the dopamine projection areas such as the amygdala, nucleus accumbens and hippocampus, may play a role in neuropsychiatric disorders and dopamine- and serotonin-mediated behavior. In this study, we have analyzed the association of three single nucleotide polymorphisms (SNPs) within GSK3β gene (rs3755557, rs334558, rs6438552) with the smoking habits and age at smoking initiation in a sample of 384 young adult Japanese, which included 172 smokers and 212 non-smokers. As a result, rs334558 was significantly associated with smoking habits in genotype frequency and allelic frequency (P0.05). Furthermore, higher haplotype 3 (T-T-T) and haplotype 5 (A-T-C) frequencies were observed in non-smokers than smokers (P0.05). Three functional polymorphisms examined in this study reportedly increase transcriptional activity when they have a high-activation allele such as the A allele of -1727A/T (rs3755557), the T allele of -50T/C (rs334558) or T allele of -157T/C (rs6438552). Thus, it was suggested in this study that changes in GSK3β activity may have an impact on smoking habits.

Several studies have suggested that the norepinephrine transporter (NET) may play an important role in the pathogenesis of alcohol dependence. Therefore, in this study, we investigated whether the NET gene polymorphism is a susceptibility factor for alcohol dependence in 64 alcoholics and 73 healthy controls. In addition, we examined whether the combination of the NET and serotonin transporter genotypes are associated with alcohol dependence. The NET (1287G/A, -182T/C, and -3081A/T) and serotonin transporter (5-HTT3'UTR) genotypes were determined by the polymerase chain reaction (PCR)--restriction fragment length polymorphism (RFLP) method. No significant differences in genotype and allele frequencies of the NET and serotonin transporter gene polymorphisms were found between alcoholics and controls. The haplotype frequencies of the NET gene polymorphisms were not also significantly different between them. Furthermore, the combination of the NET and serotonin transporter genotypes had not significant effects on alcohol dependence. The present study suggests that the polymorphisms of 1287G/A, -182T/C and -3081A/T in NET gene are not.risk factors in alcohol dependence.

In this study, the relationship between the haplotypes consisting of single nucleotide polymorphisms (SNPs) of serotonin 2A receptor (5HT2AR) gene (HTR2A) 102T/C (rs6313) and -1438A/G (rs6311) and smoking behavior was studied among 101 smokers and 99 non-smokers. It was shown that the genotypic and allelic frequencies of these polymorphisms were not associated with the smoking behavior. However, according to haplotype analysis, higher haplotype 1 ((-1438G) G-(102)T) frequency was observed in smokers than in non-smokers (P0.05). Pairwise D' and gamma2 values between the two SNPs in this study were 0.916 and 0.805, respectively. The two SNPs thus showed strong linkage disequilibrium with each other. This study suggests that 5-HT2AR gene haplotype (G-T) may be related to smoking behavior.

In this study, the relationship between the haplotypes consisting of single nucleotide polymorphisms (SNPs) of GSK-3beta -50T/C and -1727A/T and the derivation of smoking was studied among 102 smokers and 103 non-smokers. It was shown that the GSK-3beta -50T/C polymorphism may be linked with the smoking. There is significantly lower T-allele frequency in the smokers than non-smokers (chi2 (2) = 21.01, P = 0.000027; chi2 (1) 13.28, P = 0.00026). According to haplotype analysis, there was an association between smokers and non-smokers (global P = 0.00029). Higher haplotype 1 (T-A) frequency was observed in non-smokers than in smokers (P = 0.00036), whereas higher haplotype 2 (C-A) frequency was observed in smokers than in non-smokers (P = 0.000053). Pairwise D' and r2 values between the two SNPs in this study were 0.51 and 0.042, respectively. The two SNPs showed weak linkage disequilibrium with each other. This study suggests that GSK-3beta -50T/C polymorphism and two haplotypes may be related to smoking behavior.

As a help of the mechanism elucidation of alcoholism, we studied the relationship between brain-derived neurotrophic factor (BDNF) rs6265, 270 C/T (ID number has not yet been determined), and rs10835210 gene polymorphisms, which are reported to be related to bipolar disorder, and alcoholics. We genotyped the three polymorphisms in the BDNF gene using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) in 65 alcoholics and 71 healthy controls. In this study, there was no significant difference in the frequency of rs6265 and 270 C/T polymorphisms between alcoholics and controls (P0.05). However, there was a significant difference in the genotype frequency of rs10835210 polymorphism between alcoholics and controls (P0.05), in which the CA heterozygote genotype and A allele frequency was higher in alcoholics than in the controls. It suggests the possibility that the BDNF rs10835210 gene polymorphism affects the etiology of alcoholism.

As a help of the mechanism elucidation of nicotine dependence, we studied the relationship between glycogen synthase kinase (GSK) - 3beta -1727A/T and -50T/C genetic polymorphisms, which are reported to be related to bipolar disorder. We genotyped the two polymorphisms in the GSK-3beta gene using a polymerase chain reaction (PCR) in 103 healthy controls (never smokers) and 71 smokers with FTND scores of 3 or above. There is no significant relationship between the polymorphism of GSK-3beta -1727A/T and the nicotine addicts. However, it was shown that GSK-3beta -50T/C polymorphism was significantly associated with the nicotine dependence. There was significantly lower T-allele frequency in the smokers than controls (chi2 (2) = 23.42, P = 0.01; chi2 (1) = 12.17, P = 0.01).

The effects of CYP2E1 genotypes on the blood ethanol and acetaldehyde levels were investigated in a pair of Japanese volunteers whose ADH2, ADH3 and ALDH2 genotypes were identical but whose CYP2E1 genotypes were different. In the same way, the effects of ALDH2 and ADH2 on the ethanol elimination kinetics were also studied. The predicting 95% confidence bounds determined on regression analysis of the data suggested that after venous injection of ethanol, the blood ethanol and acetaldehyde concentrations in a volunteer normal homozygous for ALDH2 (ALDH2*1/1) were lower than in a heterozygous one (ALDH2*1/2). Also, the blood ethanol and acetaldehyde concentrations in a volunteer with the c2 and C alleles of CYP2E1 (c1/c2 and C/D) were lower than in one without the c2 and C alleles (c1/c1 and D/D). However, there were no significant differences in the blood ethanol and acetaldehyde concentrations between volunteers with ADH2*1 (ADH2*1/1) and without ADH2*1 (ADH2*1/2).

GSK-3beta codes for an enzyme which is a target for the action of mood stabilizers, lithium and possibly of valproic acid. The relationship between the polymorphisms (SNPs) of GSK-3beta-50T/C and -1727A/T and the effect of lithium was studied among 29 Japanese bipolar patients. It was shown that GSK-3beta-50T/C may be linked with the effect of lithium treatment. There is a significantly higher T-allele frequency in the lithium responders than non-responders (df = 1, chi2 = 6.971, 0.01P0.001; Yates' continuity correction). However, there is not a significant relationship between the polymorphisms of GSK-3beta-1727A/T and the effect of lithium treatment.

There is no particular electroencephalographic activity known to be associated with consciousness disturbance in uremic patients; however, a slow wave activity is generally observed during consciousness disturbance. Abnormal electroencephalographic activity was observed in 30 (67%) of 45 chronic renal failure patients during chronic hemodialysis without consciousness disturbance, and slow wave activity was observed in 58%. The frequency of the electroencephalographic background activity correlated with blood urea nitrogen (BUN) and serum Ca levels, but not with K, IP, and creatinine levels. Electroencephalographic activity can be estimated with reference to BUN or serum Ca levels in the blood of uremic patients.

During daycare programs of animal assisted therapy (AAT), we collected data on the brain function of two affective disorder patients who received psychotropic drug therapy with fNIRS, after written informed consent was obtained. A male patient at first showed a bloodstream drop, seen in the lower inside part of frontal lobe. In both patients, at least a slight activation of the function of the frontal lobe was seen during the therapy. Therefore, an activation effect of AAT was seen at least objectively by fNIRS.

It has been reported that electroencephalographic (EEG) examinations of alcohol dependents reveal a few abnormal findings. However, we show abnormal findings in 47 (64%) of 73 alcohol dependents in whom disturbance of consciousness, convulsions, disturbance of memory, emotional disorders and hallucination were present. Our results indicate that EEG examination may be necessary for real time assessment of brain function in alcoholism.

The purpose of this study was to determine the relationship between organic changes in carotid artery walls and candidate gene polymorphism in Japanese sufferers of essential hypertension. Carotid Ultrasonography was used to measure intima-media thickness (IMT) and presence of plaque formation. Patients were divided into two groups; a hypertension (HT) group and a healthy control (C). Group HT consisted of 273 subjects (56.5 +/- 11.3y) and group C consisted of 500 subjects (55.6 +/- 11.4y). 5HTR2A (T102C, A-1438G) and beta3-AR (Trp64Arg) genetic polymorphism for genetic analysis were performed on 43 subjects (63.5 +/- 8.5y) in group HT and 24 subjects (60.3 +/- 6.8y) in group C. IMT showed 0.81 +/- 0.28mm in Group C and 1.05 +/- 0.22mm in Group HT in patients aged 50 or above, respectively. The thickening was significantly greater in Group HT than in Group C (p0.01). Plaque was present in 45.1% in Group C and 70.2% in Group HT in patients aged 50 or above, respectively. It was significantly present greater in Group HT than in Group C (p0.01). Results of genetic analysis showed no difference between Group HT and Group C for either genotype of allele frequency of T102C and A-1438G, or of beta3-AR. It is suggested that increase of IMT and formation of plaque are risk factors in patients aged 50 or above with hypertension, and that careful observation of the carotid artery will be effective for early detection of arteriosclerosis, and to predict the symptoms thereof.