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Although electroconvulsive therapy seizure duration has been shown to have limited relevance to efficacy, seizure duration remains important for clinically valid stimulus efficiency. There has been no report on seizure duration using sample entropy with Thymatron (Somatics, Inc), which is widely used in Japan. Furthermore, wavelet transform analysis is also suitable for a seizure because of the wide range of dominant frequencies. Therefore, in this study with Thymatron, the intraclass correlations of seizure duration determined by sample entropy, wavelet transform, and visual determination were investigated to determine whether these methods were applicable for clinical use. Wavelet transform, sample entropy, and the human rater had high intraclass correlations for seizure duration. The present results indicate that wavelet transform and sample entropy can be useful in the clinical electroconvulsive therapy setting, and they may also be suitable for clinical research into the mechanisms of the generalized tonic‐clonic seizures related to the efficacy of electroconvulsive therapy., The intraclass correlations of electroconvulsive therapy‐induced seizure duration determined by sample entropy, wavelet transform, and visual determination were investigated to determine whether these methods were applicable for clinical use. sample entropy, wavelet transform, and the human rater had high intraclass correlations for the seizure durations. The present results indicate that sample entropy and wavelet transform can be useful in the clinical electroconvulsive therapy setting.

Diagnosis of epilepsy usually involves interviewing the patients and the individuals who witnessed the seizure. An electroencephalogram (EEG) adds useful information for the diagnosis of epilepsy when epileptic abnormalities emerge. EEG exhibits nonlinearity and weak stationarity. Thus, nonlinear EEG analysis may be useful for clinical application. We examined only about English language studies of nonlinear EEG analysis that compared normal EEG and interictal EEG and reported the accuracy. We identified 60 studies from the public data of Andrzejak 2001 and two studies that did not use the data of Andrzejak 2001. Comorbid psychiatric disorders in patients with epilepsy were not reported in nonlinear EEG analysis except for one case series of comorbid psychotic disorders. Using a variety of feature extraction methods and classifier methods, we concluded that the studies that used the data of Andrzejak 2001 played a valuable role in EEG diagnosis of epilepsy. In the future, according to the evolution of artificial intelligence, deep learning, new nonlinear analysis methods, and the EEG association with the rating scale of the quality of life and psychiatric symptoms, we anticipate that EEG diagnosis of epilepsy, seizures, and comorbid psychiatric disorders in patients with epilepsy will be possible.

In cancer therapeutics, boron neutron capture therapy (BNCT) requires a platform for selective and efficient 10B delivery into tumor tissues for a successful treatment. However, the use of carborane, a promising candidate with high boron content and biostability, has significant limitations in the biomedical field due to its poor water-solubility and tumor-selectivity. To overcome these hurdles, we present in this study a fluorescent nano complex, combining fluorescent carborane and sodium hyaluronate for high boron concentration and tumor-selectivity. Tumor cells actively internalized the complex through binding hyaluronan to CD44, overexpressed on the tumor cell surface. Furthermore, the subcellular distribution of this complex could also be detected due to its fluorescent properties. Moreover, after thermal neutron irradiations, the complex produced excellent cytotoxicity, equal to or greater than that of the clinically-used BPA-fructose. Therefore, this novel complex could be potentially more suitable for BNCT than the boron agent.

Background There is emerging evidence for abnormal beta oscillations in psychosis. Beta oscillations are likely to play a key role in the coordination of sensorimotor information that is crucial to healthy mental function. Growing evidence suggests that beta oscillations typically manifest as transient beta bursts that increase in probability following a motor response, observable as post-movement beta rebound. Evidence indicates that post-movement beta rebound is attenuated in psychosis, with greater attenuation associated with greater symptom severity and impairment. Delineating the functional role of beta bursts therefore may be key to understanding the mechanisms underlying persistent psychotic illness. Methods We used concurrent electroencephalography and functional magnetic resonance imaging to identify blood oxygen level–dependent correlates of beta bursts during the n-back working memory task and intervening rest periods in healthy control participants (n = 30) and patients with psychosis (n = 48). Results During both task blocks and intervening rest periods, beta bursts phasically activated regions implicated in task-relevant content while suppressing currently tonically active regions. Patients showed attenuated post-movement beta rebound that was associated with persisting disorganization symptoms as well as impairments in cognition and role function. Patients also showed greater task-related reductions in overall beta burst rate and showed greater, more extensive, beta burst–related blood oxygen level–dependent activation. Conclusions Our evidence supports a model in which beta bursts reactivate latently maintained sensorimotor information and are dysregulated and inefficient in psychosis. We propose that abnormalities in the mechanisms by which beta bursts coordinate reactivation of contextually appropriate content can manifest as disorganization, working memory deficits, and inaccurate forward models and may underlie a core deficit associated with persisting symptoms and impairment.

In this study, we attempted to carry out the Mitsunobu 1,4-elimination using the kojic acid analog 3, which carries a hydroxymethyl group on C-6 introduced by aldol condensation, to obtain an effective Michael acceptor 4. To the ethyl acetate solution of 3 and Ph3P, diisopropyl azodicarboxylate was added quickly at 0 °C, resulting in the immediate generation of a yellow precipitate. NMR, mass spectrometry, and X-ray crystal structure analyses allowed to identify the precipitate as a diastereomeric/racemic mixture of dimeric compounds of 4. The dimerization reaction was hypothesized to occur through two major steps: (i) intramolecular dehydration of 3 by Mitsunobu reagents and (ii) homocoupling of the dehydration product 4 to form a new trans-carbon–carbon double bond. Presumably, the enol ether moiety of 4 acts as an electron donor and immediately attacks the α,β-unsaturated carbonyl group of another molecule via a reaction that can be dubbed “Mitsunobu homocoupling.”

In this study, we improved the method for the isolation and purification of the bioactive compound shikonin from the dried root of the traditional Chinese medicinal plant Lithospermum erythrorhizon without a tedious chromatographic separation. Furthermore, we also attempted the solubilization of shikonin in water with cyclodextrins (CDs) using a solid phase “high-speed vibration milling”. Among the various CDs, sulfobutylether-β-CD (SBEβ-CD) showed a highest solubilizing ability and 52.5% of shikonin was solubilized with equimolar amount of SBEβ-CD. In addition, the SBEβ-CD·shikonin complex showed higher apoptogenic activity than that of the same concentration of free shikonin against murine primary peritoneal macrophages. These results indicate that SBEβ-CD is a suitable excipient for clinical application of shikonin.

S-allyl-glutathione (SAG) is one of the metabolites of diallyl sulfide (DAS), a component of garlic. DAS has shown preventative effects on carcinogenesis in animal models. However, whether synthetic SAG can improve liver fibrosis has not been investigated. We examined the potential preventive effects of SAG on acute and chronic models of liver fibrosis by chronic carbon tetrachloride (CCl4) administration. SAG inhibited liver fibrogenesis induced by CCl4in a dose-dependent manner and reduced heat shock protein-47 (HSP47), a collagen-specific chaperone, and other fibrosis markers. In fibrosis regression models, after administration of either CCl4for 9 wk or dimethyl nitrosamine (DMN) for 6 wk, SAG markedly accelerated fibrolysis in both models. In the regression stage of DMN-treated liver, SAG normalized the ratio of M2 phenotype (expression of mannose receptor) in Kupffer cells (KCs). Consistent with these results, the culture supernatants of SAG-treated M2-phenotype KCs inhibited collagen-α1(I) chain (COL1A1) mRNA expression in primary culture-activated rat hepatic stellate cells (HSCs). However, SAG did not directly inhibit HSC activation. In an acute model of CCl4single injection, SAG inhibited hepatic injury dose dependently consistent with the inhibited the elevation of the bilirubin and ALT levels. These findings suggest that SAG could improve the fibrogenic and fibrolysis cascade via the regulation of excess activated and polarized KCs. SAG may also serve as a preventive and therapeutic agent in fibrosis of other organs for which current clinical therapy is unavailable.NEW & NOTEWORTHY S-allyl-glutathione (SAG) is a metabolite of diallyl sulfide, a component of garlic. SAG increased hepatic glutathione levels and GSH-to-GSSG ratio in normal rats. SAG treatment before or after liver fibrosis from chronic CCl4administration improved liver fibrosis and regression. SAG decreased heat shock protein-47 (HSP47), a collagen-specific chaperone, and other fibrosis markers in CCl4-treated livers. SAG-treated Kupffer cell conditioned medium also inhibited collagen-α1(I) chain (COL1A1) mRNA expression and other markers in primary culture hepatic stellate cells.

It has been suggested that the combined effect of natural products may improve the effect of treatment against the proliferation of cancer cells. In this study, we evaluated the combination of 1'-acetoxychavicol acetate (ACA), obtained from Alpinia galangal, and sodium butyrate, a major short chain fatty acid, on the growth of HepG2 human hepatocellular carcinoma cells and found that treatment had a synergistic inhibitory effect. The number of HepG2 cells was synergistically decreased via apoptosis induction when cells were treated with both ACA and sodium butyrate. In ACA- and sodium butyrate-treated cells, intracellular reactive oxygen species (ROS) levels and NADPH oxidase activities were increased significantly. The decrease in cell number after combined treatment of ACA and sodium butyrate was diminished when cells were pretreated with catalase. These results suggest that an increase in intracellular ROS levels is involved in cancer cell death. AMP-activated protein kinase (AMPK), a cellular energy sensor, plays an essential role in controlling processes related to tumor development. In ACA- and sodium butyrate-treated cells, AMPK phosphorylation was induced significantly, and this induction improved when cells were pretreated with catalase. These results suggest that the increase in intracellular ROS is involved in the increase of AMPK phosphorylation. In normal hepatocyte cells, treatment with ACA and sodium butyrate did not decrease cell numbers or increase ROS levels. In conclusion, combined treatment with ACA and sodium butyrate synergistically induced apoptotic cell death via an increase in intracellular ROS and phosphorylation of AMPK. Our findings may provide new insight into the development of novel combination therapies against hepatocellular carcinoma.

(1′S)-acetoxychavicol acetate ((S)-ACA) exhibits chemopreventive effects on chemically induced tumor formation. It has been shown that ACA inhibited the development of azoxymethane-induced colon carcinogenesis through its suppression of cell proliferation in the colonic mucosa and its induction of glutathione S-transferase and quinone oxidoreductase 1 in vivo. In this study, we investigated how ACA induced these enzymes by using rat intestine epithelial cells (IEC6) in vitro. ACA induced glutathione S-transferase (GST) and NAD (P)H: quinone oxidoreductase 1 (NQO1) activities, increased intracellular glutathione (GSH) level, and upregulated intranuclear Nrf2 and cytosolic p21. It suggested that activation of phase II enzymes via Nrf2 associated with p21 is one of possible mechanisms of ACA to prevent advance of carcinogenesis.

Purpose Sustained hepatic inflammation derived from parenchymal liver injury is a major driving force of fibrogenesis. We synthesized S-allyl-glutathione (SAG) which regulates macrophage (MO) polarization, and investigated whether SAG can improve liver fibrosis. Method Liver fibrosis was induced by CCl4 injection twice a week for 9 weeks in rats. SAG was administered as a mixed diet from the starting CCl4. To study fibrosis regression, rats were orally administered SAG for 5 weeks after terminating CCl4. In vitro studies were performed effects of SAG (10 -14M~) on M1 or M2 polarization of isolated Kupffer cells (KCs) or bone marrow derived MO (BMDM), and its interactions with isolated hepatic stellate cells (HSCs). Result and Discussion SAG markedly inhibited liver fibrogenesis in a dose-dependent manner and various fibrosis markers. In the fibrolysis stage, SAG accelerated fibrolysis after development of liver chirrosis and decreased the amount of M2 MO. Both Col1A1 and HSP47 mRNA in day 6 HSCs were inhibited by the conditioned medium of SAG-treated MO with M2 inducers onto day 3 HSCs. SAG did not directly inhibit HSC activation. In the M1 MO, SAG also inhibited. These findings suggested that SAG could improve liver cirrhosis via the attenuation of excess polarization in KCs.

In a previous study, we showed that (1′S)-acetoxychavicol acetate ((S)-ACA) caused a rapid decrease in glutathione (GSH) levels less than 15 min after exposure. (S)-ACA-induced cell death was reversed by the addition of N-acetylcysteine. In the current study, we investigated the inhibitory activities of 13 derivatives of (S)-ACA on tumor cell viability, intracellular GSH level and GR activity. Correlations were found among a decrease in cell viability, intracellular GSH levels and the activity of GR in Ehrlich ascites tumor cells treated with the various ACA analogues. A test of the 13 derivatives revealed that the structural factors regulating activity were as follows: (1) the para or 1′-position of acetoxyl group (or other acyl group) was essential, (2) the presence of a C2′–C3′ double or triple bond was essential, and (3) the S configuration of the 1′-acetoxyl group was preferable.

A new multifunctional gene delivery system was constructed with diphtheria toxin's functional domains. Used functional domains are T domain for endosomal escape and R domain for efficient internalization into cell. In order to conjugate these domains into PEI polyplex, diphtheria toxin T and R domains-streptavidin fusion protein (DTRS) was prepared. The conjugation of the DTRS with biotinylated PEI polyplex (DTRS-polyplex) lead to the significant enhancement of transfection efficiency when compared with plain PEI/pDNA polyplex in CHO-K1 cell. It was demonstrated that DTRS-polyplex had high endosomal escape efficiency and internalization efficiency by several measurements, such as in vitro intracellular trafficking observation and the internalization inhibition with several inhibitors. These results suggest that this multifunctional non-viral vector may contribute to the future cancer gene therapy.

Aim: Brain metabolism activated studies have indicated associations between memory and the anterior cingulate cortex and hippocampus in patients with depression. The aim of the present study was therefore to investigate memory function, measured as performance on the Wechsler Memory Scale–Revised (WMS-R), and its relationship to brain perfusion using single-photon emission computed tomography (SPECT) at rest in patients with depression. Methods: The Hamilton Rating Scale for Depression (HAMD) and WMS-R were measured for 17 patients with depression by an independent clinical evaluation team. Voxel-based correlation analyses were performed with statistical parametric mapping at an extent threshold of 200 voxels. Associations were controlled for state and trait factors. Results: WMS-R measurements of verbal, visual, and general memory were inversely correlated with brain perfusion in the right anterior cingulate cortex, left premotor cortices, and both regions, respectively. The HAMD directly correlated with brain perfusion in the right anterior cingulate cortex. Conclusion: Brain perfusion SPECT measurements of the anterior cingulate cortex at rest were associated with the severity of depression and immediate memory scores measured with the WMS-R.

The endosomal escape is a well-known serious obstacle for non-viral gene delivery. This is because of an acidic and enzymatic degradation of the contents of the endosome/lysosome. Therefore, the internalized gene needs to be efficient released into the cytosol to obtain the efficiently transfection efficiency. On the other hand, the diphtheria toxin T domain fuses with endosome membrane by pH decrease, then enhances the endosomal escape of the diphtheria toxin C fragment. In this study, we constructed diphtheria toxin T domain-conjugated poly(ethylenimine)s (PEI) polyplex for enhancing the endosomal escape of exogenous gene. The conjugation of diphtheria toxin T domain with PEI/pDNA polyplex leads to the significant enhancement of transfection efficiency when compared with plain PEI/pDNA polyplex. The pH-responsive increase in hydrophobicity of the diphtheria toxin T domain might not only trigger the perturbation of the endocytic vesicle membrane but might also increase the membrane permeability.

Elucidation of the mechanisms underlying potential anticancer drugs continues and unraveling these mechanisms would not only provide a conceptual framework for drug design but also promote use of natural products for chemotherapy. The biological effects of (1′S)-acetoxychavicol acetate ((S)-ACA) have been widely investigated. However, in most cases, a natural product or synthetic racemic compound was used in the study. In this study, we prepared (S)-ACA and its enantiomer (R)-ACA by a lipase-catalyzed esterification method and sought to determine the mechanisms of action of (S)-ACA and (R)-ACA in the growth inhibitory effect in Ehrlich ascites tumor cells (EATC). (S)-ACA caused an accumulation of tumor cells in the G1 phase of the cell cycle, which was accompanied by a decrease in phosphorylated retinoblastoma protein (Rb), an increase in Rb and a decrease in the phosphorylation of p27kip1. However, (R)-ACA caused an accumulation of tumor cells in the G2 phase of the cell cycle, an increase in hyperphosphorylated Rb and an increase in the phosphorylation of p27kip1. The results obtained in the present study demonstrate for the first time, to the best of our knowledge, that both (S)-ACA and (R)-ACA caused the inhibition of tumor cells growth but the inhibition was caused via different mechanisms.

The Hamilton Rating Scale for Depression (HAMD) is the de facto international gold standard for the assessment of depression. There are some criticisms, however, especially with regard to its inter-rater reliability, due to the lack of standardized questions or explicit scoring procedures. The GRID-HAMD was developed to provide standardized explicit scoring conventions and a structured interview guide for administration and scoring of the HAMD. We developed the Japanese version of the GRID-HAMD and examined its inter-rater reliability among experienced and inexperienced clinicians (n = 70), how rater characteristics may affect it, and how training can improve it in the course of a model training program using videotaped interviews. The results showed that the inter-rater reliability of the GRID-HAMD total score was excellent to almost perfect and those of most individual items were also satisfactory to excellent, both with experienced and inexperienced raters, and both before and after the training. With its standardized definitions, questions and detailed scoring conventions, the GRID-HAMD appears to be the best achievable set of interview guides for the HAMD and can provide a solid tool for highly reliable assessment of depression severity.

Objectives Electroconvulsive therapy (ECT) has been associated with memory and neuropsychological changes, but which features of ECT are associated with those changes have not been well investigated. The aim of this hypothesis-generation study was to examine correlations between ictal electroencephalographic (EEG) characteristics and cognitive side effects after ECT. Methods Eight patients with major depressive disorder were examined with the Wechsler Memory Scale-Revised (WMS-R), the Stroop test, the Trail Making Test, and verbal fluency before and after ECT treatment. Seven ictal EEG measurements (eg, slow-wave phase amplitude, postictal suppression) were manually rated by 3 independent psychiatrists. The correlations between ictal EEG measurements, changes in WMS-R subset scores, and non-memory-related neuropsychological assessments were examined with Spearman rank correlation. Results Verbal memory, general memory, attention/concentration, delayed memory of WMS-R subset scores, and the Stroop test scores improved significantly after ECT treatment. Postictal suppression and slow-wave amplitude correlated positively with delayed memory and visual/verbal discrepancy score. Slow-wave amplitude correlated negatively with letter fluency. The longer the polyspike wave duration, the higher the attention/concentration test results. Conclusions Certain ictal EEG measurements were associated with changes in several neuropsychological test results that had improved 2 weeks after the final ECT treatment. A hypothesis-testing study with a larger sample is needed to verify the relationships between EEG measurements and neuropsychological test performance.

Ceramides act as a second messenger of the apoptotic signaling process. The allylic alcohol portion comprising the C-3, C-4, and C-5 carbons is essential for this function. The suggestion has been made that this alcohol moiety is oxidized in mitochondria to a carbonyl moiety, with the generation of reactive oxygen species. However, there is no established precedent for the apoptotic performance of 3-ketoceramides thus presumed. In this work, we have synthesized three different types of short-chain 3-ketoceramides, that is, (2 S , 4 E )-2-acetylamino-3-oxo-4-octadecen-1-ol ( A ), (2 S , 4 E , 6 E )-2-acetylamino-3-oxo-4,6-octadecadien-1-ol ( B ), and (2 S , 4 E )-2-acetylamino-1-methoxy-3-oxo-4-octadecene ( C ), and demonstrated that these 3-ketoceramides are capable of inducing effective apoptosis in human leukemia HL-60 cells. In particular, the two monoenoic compounds, A and C , are far more powerful than the corresponding alcoholic analogue, N -acetyl- d - erythro -sphingosine. Observations of DNA fragmentation, caspase-3 activation, and cytochrome c release from mitochondria provide substantiated evidence for mitochondrial apoptosis and the effects of exogenous glutathione on these phenomena are also discussed.

Ictal electroencephalography (EEG) parameters in electroconvulsive therapy (ECT) for depression reportedly correlate with therapeutic response and stimulus dosage, particularly in right unilateral (RUL) ECT. The authors examined ictal EEG parameters as predictors of therapeutic effectiveness in bilateral (BL) sine and pulse wave ECT. A total of 30 consecutive depressed inpatients who had not responded to standard pharmacotherapy were treated using BL ECT given in either sine or pulse wave mode. Ictal EEG parameters (e.g. regularity, postictal suppression) were manually rated by three trained psychiatrists. Polyspike phase duration was significantly longer in sine wave ECT than in pulse wave ECT. Postictal suppression emerged as the only significant predictor of therapeutic outcome when baseline Hamilton Rating Scale for Depression and mode of stimulation were controlled for. Postictal suppression appears to offer a useful predictor of clinical outcome of depression in BL ECT. No EEG parameters were found to be differentially predictive between sine and pulse wave ECT.

This study investigated longitudinal changes and predictive factors for psychological distress among 85 newly diagnosed advanced non-small cell lung cancer (NSCLC) patients. Whereas tension-anxiety after diagnosis (T1) was significantly reduced at two months (T2) and six months (T3) after diagnosis and depression-dejection at T1 was significantly reduced at T2, other forms of psychological distress, including anger-hostility, vigor, fatigue, and confusion, did not show significant changes. Total mood disturbance did not show significant change. Only a higher total mood disturbance at T1 was a significant predictor of total mood disturbance at T3. These findings demonstrate that most types of psychological distress experienced by advanced NSCLC patients is likely to persist during the subsequent clinical course. The findings also suggest that initial psychological distress itself after cancer diagnosis is the most important predictor for subsequent psychological distress and that early intervention beginning immediately after the disclosure of a diagnosis of cancer is one way to prevent and/or reduce subsequent psychological distress in advanced NSCLC patients.

Objective: Worldwide use of the Hamilton Rating Scale for Depression (HRSD) presupposes that depression symptomatology can be measured the same way across countries but no empirical study has yet examined this issue. We therefore examined cross-cultural consistency of factor structure of HRSD. Method: A 17-item HRSD data were sought for 5185 individuals diagnosed with major depression in Japan, Europe and North America. Candidate factor structures were obtained with simultaneous component analysis (SCA) across the three cultures. They were then submitted to multiple-group confirmatory factor analysis (CFA). Results: According to SCA, 3-, 4- or 5-factor solutions were found to optimally and adequately summarize the variables for all the three populations. When submitted to CFA, the 5-factor solution was the best fitting and the most parsimonious: they were ‘anhedonia/retardation,’‘guilt/agitation,’‘bodily symptoms,’‘insomnia’ and ‘appetite.’ Conclusion: Common underlying factors exist for HRSD among Japanese, European and American patients with major depression.

(2 R ,3 Z )-, (2 R ,3 E )-, (2 S ,3 Z ) and (2 S ,3 E )-2-Acetylamino-3-octadecen-1-ol, and (2 R )- and (2 S )-2-acetylamino-octadecan-1-ol were prepared using the Wittig olefination of Garner's aldehyde ( N -Boc- N , O -isopropylidene- l - or d -serinal) from l - or d -serine. The apoptotic activities of these saturated and unsaturated 2-acetylaminoalcohols were examined in human leukemia HL-60 cells using MTT assay. Among the newly synthesized compounds, the cis -isomers were the most potent. Despite their simple structures, (2 R ,3Z)- and (2 S ,3 Z )-2-acetylamino-3-octadecen-1-ol showed high and comparable apoptotic activities compared with N -acetyl- d - erythro -sphingosine (D- e -C2-Cer, a well-known inducer of apoptosis). Their apoptotic activities were in the order d - e -C2-Cer≈ l - e -C2-Cer≈(2 R ,3 Z )-≈(2 S ,3 Z )->>(2 R ,3 E )-≈(2 S ,3 E )-≈(2 R )-≈(2 S )-derivative. Qualitative analysis of DNA fragmentation caused by these compounds was conducted using agarose gel electrophoresis, and typical DNA fragmentation was found in the cases of (2 R ,3 Z )- and (2 S ,3 Z )-isomers such as C2-Cer, but not trans and saturated isomers. The morphological features of the cells, the proteolytic processing of pro-caspase-3, and the cleavage of PARP as a result of exogenous treatment with (2 R ,3 Z )- and (2 S ,3 Z )-isomers indicated that cell death induced by these compounds was apoptosis. These observations suggest that these newly synthesized compounds, ( 3Z )-2-Acetylamino-3-octadecen-1-ol, have similar characteristics and apoptosis-inducing activities against HL-60 cells with C2-Cer.

Naturally occurring symbioramide, (2S,3R,2'R,3'E)-N-(2'-hydroxy-3'-octadecenoyl)-dihydrosphingosine 1a, was synthesized from d-erythro-dihydrosphingosine (amino part, 2) and (2R,3E)-2-hydroxy-3-octadecenoic acid (acid part, 3a), both of which were prepared from l-serine. Its diastereomer, (2S,3R,2'S,3'E)-1b, having an enantiomer of the unnatural-type acid part that was prepared from d-mannitol, and its corresponding (Z)-isomers, (2S,3R,2'R,3'Z)-1c and (2S,3R,2'S,3'Z)-1d, were also prepared. The antileukemic activities of 1a-d against HL-60 and L-1210 cells were appreciated by a MTT assay. None of the four symbioramide derivatives showed antileukemic activities in HL-60 cells. In L-1210 cells, all the symbioramide derivatives showed moderate antileukemic activities. Compound 1d had the most effective activity against L-1210 cells among the four derivatives. The data suggest that unnatural types of (2'S)-isomers of acid parts are more active than those of (2'R)-isomers.

Non-natural ceramide analogues, C2-homo-ceramide and C2-homo-dihydroceramide, were prepared from L-aspartic acid via L-homo-serine. The apoptotic activities of the synthesized ceramide analogues were examined in HL-60 human leukemia cells. C2-homo- and C2-bishomo-ceramide indicate low but considerable apoptotic activities in comparison with C2-ceramide.

Novel and non-natural ceramide analogues, having a different methylene spacer between the primary hydroxymethyl group and aminomethane of sphingosine backbone, have been prepared from l -glutamic acid. The key step in the preparation is the diastereoselective reduction of an enone adjacent to a Boc protected amino group by reducing agents.

Systematic investigations on the emotional impacts of repeated spontaneous abortions have been few. We mounted a prospective study of a cohort of couples who had experienced two consecutive first trimester spontaneous abortions and for whom no clearly identifiable causes were found. The present report is based on the first part of the study and examines: (1) emotional distress reported by the miscarrying women at six months (median, range 1-12 months) after two abortions; and (2) psychosocial predictors influencing such distress. The mean score of the women on the Symptom Checklist 90-Revised--one of the most popular self-report scales for psychopathology--was 0.38, whereas that for the general population is reported to be 0.26 (the higher the score, the more psychopathology). Fourteen percent of the cohort scored above the cutoff point for mental disorders screening. Factors examined and found non-influential upon the level of emotional distress include: the maternal age; whether the last pregnancy was planned and wished for or not; and coping styles of the women after the abortions. Control by the husbands over the marital relationship and neurotic personality traits of the women increased the emotional distress, whereas the social support the women perceive decreased it. These findings suggest that martial and social support are important in determining the level of psychiatric morbidity after repeated abortions.

A time series analysis of electroconvulsive (ECT) seizures was performed in patients with depression, examining ictal electroencephalography (EEG), electromyography (EMG), and heart rate (HR) over time, particularly with respect to the physiological interrelations of the ECT seizures. A total of 200 seizures from 21 consecutive patients were analyzed. EEG and EMG data were analyzed by discrete Fourier transform-based continuous wavelet analysis using Morlet wavelet. The time to peak value was investigated for each of these physiological measures. The first group of peaks was the EMG power and the first point of peak HR; the second was EEG power and the last point of peak HR; the third was EMG duration; the fourth was EEG duration; and the fifth was the time of the lowest HR. The time to peak in the central EEG power was associated with that in the low frequency EMG power, the time to peak HR and the time to peak in the frontal pole EEG power. The time to peak in the frontal pole EEG power was associated with that in the central EEG power. The central EEG was considered to be more relevant for seizure generalization than the frontal pole EEG.

Ictal heart rate (HR) and postictal suppression in ictal EEG are believed to be predictive of the therapeutic efficacy of eletroconvulsive therapy (ECT) for depression. However, regarding ictal peak HR, previous studies investigated ictal HR on only one or two occasions during the course of ECT. We prospectively examined whether two physiological parameters, ictal peak HR and postictal suppression in ictal EEG, during every session, including those with abortive seizure, predicted ECT efficacy. Ictal peak HR and postictal suppression index were analyzed in 53 consecutive inpatients with depression using generalized estimating equations analysis, which corrects for the repeated nature of the observations. The peak HR and postictal suppression index were associated with therapeutic efficacy in remitters during sessions with adequate seizure. The physiological characteristics of the remitters included lower peak HR, lower stimulus energy, and higher postictal suppression index. However, these results could not be generalized, and are limited to non-atropine conditions and bilateral ECT.

S-allyl cysteine (SAC) is the most abundant compound in aged garlic extracts (AGEs). AGE has been reported to ameliorate the oxidative damage implicated in a variety of diseases. However, the effects of SAC have not been established in liver cirrhosis. The aim of this study was to examine the effect of therapeutic administration of SAC in liver cirrhosis by chronic carbon tetrachloride (CCl4) administration in rats. SAC or other cysteine compounds were administered from 4 weeks when liver fibrosis was confirmed to be in process. CCl4 administration elevated plasma alanine aminotransferase, plasma lipid peroxidation, liver hydroxyproline, and liver transforming growth factor (TGF)-β at 12 weeks. SAC prevented these changes induced by CCl4. Furthermore, SAC improved survival in a dose-dependent manner following consecutive CCl4 administration. The inhibitory mechanisms may be associated with a decrease in the profibrogenic cytokine, TGF-β as well as the antioxidative properties of SAC.

This study aimed to investigate the quality of life (QOL) in patients with epilepsy and its correlation with psychosocial impact, depression, seizure-related items, and living circumstances. One hundred two patients who visited the epilepsy clinic at Nagoya City University Hospital participated in this study. We used the Quality of Life in Epilepsy Inventory-31-P (QOLIE-31-P) as a measure of QOL, the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) as the screening instrument for rapid detection of major depression, and the Side Effects and Life Satisfaction Inventory (SEALS) to evaluate psychosocial functioning, seizure-related items, and living circumstances. Significant correlations of the QOLIE-31-P overall score with these questionnaires and seizure-related or demographic variables were identified and analyzed by stepwise linear regression. The QOLIE-31-P overall score correlated significantly with the NDDI-E, SEALS overall score, number of anticonvulsants, frequency of focal seizure with impairment of consciousness or awareness (focal seizure), sheltered work, and employment. The stepwise linear regression showed that the QOLIE-31-P overall score was explained by the effects of psychosocial functioning, depression, frequency of focal seizure, and employment, in that order, with these factors explaining 74% of the variance. Thus, using both the SEALS and NDDI-E may be useful to detect some aspects of QOL in clinical settings.

N-(R)- and N-(S)-lactylsphingosine and their corresponding dihydrosphingosine derivatives were synthesized. The antileukemic activities of these compounds were measured by MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay in human leukemia HL-60 cells. N-(R)- and N-(S)-Lactylsphingosine displayed higher activities than N-acetylsphingosine (C2-ceramide, a well-known apoptosis inducer), and their dihydrosphingosine derivatives had slight activities.

In order to enhance the nuclear import of the transgene, we prepared plasmid DNA/importin-β conjugates consisting of biotinylated poly(ethylenimine)s and recombinant streptavidin-fused importin-β. Hemagglutinating virus of Japan-envelope vector containing the PEI polyplex/importin-β conjugate showed high transfection efficiency not only in vitro but also in vivo. We showed that novel HVJ-E/importin-β-conjugated PEI polyplex hybrid vector could overcome plasma and nuclear membrane barriers to achieve effective transfection.

We examined the relationship between the structures of hetero-/homoleptic ruthenium(II) tris(bipyridine) metal complexes (Ru(II)(bpy)(3)) and their binding properties for α-chymotrypsin (ChT) and cytochrome c (cyt c). Heteroleptic compound 1a binds to both ChT and cyt c in 1:1 ratio, whereas homoleptic 2 forms 1:2 protein complex with ChT but 1:1 complex with cyt c. These results suggest that the structure of the recognition cavity in Ru(II)(bpy)(3) can be designed for shape complementarity to the targeted proteins. In addition, Ru(II)(bpy)(3) complexes were found to be potent inhibitors of cyt c reduction and to permeate A549 cells.

1'-Acetoxychavicol acetate (ACA), isolated from the rhizomes and the seeds of the Zingiberaceae plant, has a variety of biological activities such as antitumor, antiallergic and repellent effects. However, ACA seems to have some disadvantages which may limit for future possible clinical applications, for example, its poor water solubility. Furthermore, ACA is not stable in aqueous solutions and undergoes hydrolysis and/or isomerization. To improve the solubility and stability of ACA in water, we prepared the inclusion complexes with various β-cyclodextrins (β-CDs).In aqueous solution, the association constants of ACA with various CDs were estimated at 662±95 (β-CD), 336±70 (methyl-β-CD, Meβ-CD), and 322±44M(-1) (hydroxypropyl-β-CD, HPβ-CD), respectively, by a spectrofluorometric displacement method based on competition between a guest and a fluorescent probe for CDs. It was revealed that almost all ACAs existed as a free molecule in the CD-containing aqueous solution. However, in the case of preparing the inclusion complexes of CDs with ACA by a solid phase 'high-speed vibration milling' technique, the average inclusion rates of the obtained water-soluble complexes were calculated as 88±13% (β-CD), 70±1% (Meβ-CD), and 63±2% (HPβ-CD), respectively, by (1)H NMR analysis. To characterize the structures of the CD·ACA complexes, 2,3,6-trimethyl-β-CD (TMeβ-CD)·ACA complex was prepared as a model compound (inclusion rate: 40%). As a result of 2D ROESY experiments, it was considered that the aromatic ring of ACA is located in the narrow side of the hydrophobic cavity of the TMeβ-CD and both 1'- and 4-acetoxy groups of ACA positioned in the vicinity of the secondary and primary methoxy groups of TMeβ-CD, respectively. Furthermore, we examined the apoptogenic activity of CD·ACA complexes to evaluate whether or not the bioactivities of ACA were affected by their inclusion. Although the cytotoxicity of all CD·ACA complexes in human epithelial carcinoma HeLa cells and murine adenocarcinoma colon26 cells were diminished as compared with the ACA alone, only HPβ-CD·ACA maintained high levels of activity. In addition, HPβ-CD·ACA, and Meβ-CD·ACA showed suppressive effect for the transcription factor NF-κB activation on LPS-activated murine macrophage RAW264.7 cells and the former was more active complex. Furthermore, HPβ-CD·ACA inhibited the in vivo tumor growth of tumor-bearing mice, although the activity was slightly weak compared with that of free ACA. These results indicate that HPβ-CD is the best host molecule for ACA to form a water-soluble complex with the similar biological activity of free ACA.

Boron Neutron Capture Therapy (BNCT) is one of the potent cancer radiotherapies using nuclear reaction between 10B atoms and the neutron. Whether BNCT will succeed or not depends on tumor selective delivery of 10B compounds. e-Poly-L-lysine is a naturally occurring polyamine characterized by the peptide linkages between the carboxyl and e-amino groups of L-lysine. Because of high safety e-PLL is applied practically as a food additive due to its strong antimicrobial activity. In this study, we focus on a development of a novel polymeric delivery system for BNCT using biodegradable e-PLL conjugated with 10B-containing clusters (BSH). This polymeric boron carrier will be expected to deliver safely and efficiently into tumor tissues based on Enhanced Permeability and Retention (EPR) effect.