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Neurofeedback (NF) aptitude, which refers to an individual's ability to change brain activity through NF training, has been reported to vary significantly from person to person. The prediction of individual NF aptitudes is critical in clinical applications to screen patients suitable for NF treatment. In the present study, we extracted the resting-state functional brain connectivity (FC) markers of NF aptitude, independent of NF-targeting brain regions. We combined the data from fMRI-NF studies targeting four different brain regions at two independent sites (obtained from 59 healthy adults and six patients with major depressive disorder) to collect resting-state fMRI data associated with aptitude scores in subsequent fMRI-NF training. We then trained the multiple regression models to predict the individual NF aptitude scores from the resting-state fMRI data using a discovery dataset from one site and identified six resting-state FCs that predicted NF aptitude. Subsequently, the reproducibility of the prediction model was validated using independent test data from another site. The identified FC model revealed that the posterior cingulate cortex was the functional hub among the brain regions and formed predictive resting-state FCs, suggesting that NF aptitude may be involved in the attentional mode-orientation modulation system's characteristics in task-free resting-state brain activity.

The tendency to avoid punishment, called behavioral inhibition system, is an essential aspect of motivational behavior. Behavioral inhibition system is related to negative affect, such as anxiety, depression and pain, but its neural basis has not yet been clarified. To clarify the association between individual variations in behavioral inhibition system and brain 5-HT

For becoming a talented pharmacist at a health support pharmacy, the practitioner must obtain ability in two significant skill sets: "Technical skill" and "Non-technical skill". Technical skills are that required for a pharmacist's specialty/expertise, such as a wide variety of specialized knowledge and techniques. Non-technical skills are those required for effective communication and cooperation with patients, as well as with professionals from multiple fields, and also leadership/problem-solving ability within a team. Therefore, technical skill and non-technical skill go hand-in-hand like the two wheels on an axle. In a community-based integrated care system, medical professionals are expected to support a patient's overall health more effectively, even extending into his/her private life. In order to enable pharmacists to expand their scope of activity and fully execute their expertise, Yakugaku Seminar Lifelong Learning Center supports pharmacists from the standpoint of education with various themes, for example: the simulated experience of doctor conducting patient education and formulation on a daily basis, learning a basic way of thinking when clinical decisions are made for a patient nearby, mature decision making by combining vital signs, communication that takes into consideration a patient's background, and improved communication or problem-solving abilities within a broader team.

Histamine HTo measure the histamine HAdministration of enerisant hydrochloride decreased the radioligand binding in a dose-dependent manner. The estimated receptor occupancy values at 2 h varied as a function of its dose or plasma concentration. The time course of the occupancy showed persistently high levels ( 85%) in the two subjects with higher doses (25 and 12.5 mg). The occupancy was also initially high at 2 h and 6 h with the lower dose of 5 mg, but it decreased to 69.7% at 26 h.The target engagement of enerisant was demonstrated in the brains of living human subjects. The occupancy of histamine HThis study was retrospectively registered with ClinicalTrials.gov (NCT04631276) on November 17, 2020.

Esaxerenone is a novel non-steroidal mineralocorticoid receptor antagonisit (MR blocker), whose unique binding to the MR-ligand domain yields a stronger MR antagonistic effect and higher selectivity than existing MR antagonisits. Esaxerenone was approved for the treatment of hypertension in Japan in January 2019. Esaxerenone suppresses the reduction of urinary Na+/K+ ratio in adrenalectomized rats and blood pressure increase, proteinuria, and renal tissue lesions in salt-sensitive hypertensive rats-all in a dose-dependent manner. Esaxerenone is rapidly absorbed and reaches intracellular targets because of its high membrane permeability, exhibits high bioavailability with small interindividual exposure variation, and is metabolized via several pathways (e.g., oxidation, glucuronidation, and hydrolysis), which is associated with low drug-drug interaction risk. As esaxerenone is slightly excreted into urine, its exposure is similar between elderly and non-elderly patients, and between patients with normal and moderately deteriorated renal function. Given its 19-hour half-life, once-daily administration would have a sustainable antihypertensive effect. The ESAX-HTN phase 3 study demonstrated the non-inferiority of esaxerenone's antihypertensive effect versus that of eplerenone in essential hypertension. Another study showed a stable antihypertensive effect for 52 weeks as monotherapy or combination therapy. In hypertensive patients with moderate impairment or both type 2 diabetes and albuminuria treated with a renin-angiotensin system inhibitor, esaxerenone elicited a stable antihypertensive effect and manageable hyperkalemia incidence with titration from a low dose and monitoring including serum potassium. Thus, with careful monitoring of serum potassium, esaxerenone can be administered to patients with moderate renal impairment or both diabetes and albuminuria.

Esaxerenone (CS-3150) is a novel, oral, nonsteroidal, selective mineralocorticoid receptor blocker approved for the treatment of hypertension in Japan. Here, the drug-drug interaction (DDI) potential of esaxerenone was evaluated in vitro, and its impact in clinical practice was estimated. Esaxerenone exhibited time-dependent inhibition and induction of CYP3A. When the clinical impacts of esaxerenone on the inhibition and induction of CYP3A were estimated separately by using a mechanistic static model, the predicted area under the curve ratios (AUCRs) of midazolam, a typical CYP3A substrate, were 1.80 and 0.31, respectively, suggesting that the DDI potential of esaxerenone cannot be neglected. Because it was suggested that DDIs mainly occur in the intestine, predictions using concentration-time profiles in each segment of the gastrointestinal tract were performed with GastroPlus, a physiologically based pharmacokinetic (PBPK) modeling software. The predicted AUCR of midazolam was approximately 1.2, which is close to that in a clinical study, despite the difficulty of predicting DDIs for compounds with both inhibition and induction effects. When only inhibition or induction was incorporated into a model, the AUCR of midazolam changed depending on the dosing period and dose level of esaxerenone and the timing of midazolam administration. However, the AUCR calculated by incorporating both effects remained almost constant. This study shows the ability of PBPK models to simulate weak DDIs via intestinal CYP3A and that esaxerenone has low DDI potential as a perpetrator because of the offset of inhibition and induction. SIGNIFICANCE STATEMENT: Weak CYP3A inhibition and/or induction sometimes cause DDIs in the intestine but not the liver. Because strong inhibitors maximally inhibit intestinal CYP3A, the predictability of weak DDIs in the intestine should be evaluated further. Here, we simulate the DDIs of esaxerenone as a perpetrator by using physiologically based pharmacokinetic modeling focusing on the intestine and offset of inhibition and induction.

Individual differences in positive memory recollection are of interest in mental health, as positive memories can help protect people against stress and depression. However, it is unclear how individual differences in positive memory recollection are reflected in brain activity in the resting state. Here, we investigate the resting-state functional connectivity (FC) associated with interindividual variations in positive memory by employing cluster-level inferences based on randomization/permutation region of interest (ROI)-to-ROI analyses. We identified a cluster of FCs that was positively associated with positive memory performance, including the frontal operculum, central operculum, parietal operculum, Heschl's gyrus, and planum temporale. The current results suggest that positive memory is innervated by frontotemporal network connectivity, which may have implications for future investigations of vulnerability to stress and depression.

Although the benzodiazepine class of drugs has proven useful in treating anxiety symptoms, recent studies yield no consistent empirical support for their use in treating psychiatric disorders. However, animal studies using a fear conditioning paradigm have suggested that benzodiazepines facilitate fear memory extinction, dependent on treatment timing and subject conditions. However, we have no data on the effect of subject conditions. The purpose of this study was to investigate whether the effect of benzodiazepines depends on hypersensitivity to fear-memory processing. We examined the effect of diazepam, a benzodiazepine, on the extracellular dopamine level in the left amygdala of methamphetamine-sensitized, fear-conditioned model rats, using microdialysis and high-performance liquid chromatography. In this model, the dopamine level in the amygdala excessively increases in response to a fear-conditioned stimulus; the phenomenon has been proposed as a biological marker for hypersensitivity to fear-memory processing. Diazepam inhibited this excessive increase. The extent of the inhibitory effect was greater in the sensitized condition. Diazepam alone increased amygdalar dopamine levels under physiological conditions but not under sensitized conditions. Diazepam did not shorten freezing time in any group. These results suggest that diazepam modulates amygdala dopamine with state dependence and that amygdalar dopamine fine-tuning accounts for part of the therapeutic effect of benzodiazepines on fear memory processing. Further investigation is required to identify patients suitable for treatment with benzodiazepines. This is the first report on the pharmacodynamic effects of benzodiazepine on the amygdalar dopamine basal level and on fear memory processing.

A great deal of effort has been being made to improve the accuracy of the prediction of drug-drug interactions (DDIs). In this study, we addressed CYP3A-mediated weak DDIs, in which a relatively high false prediction rate was pointed out. We selected 17 orally administered drugs that have been reported to alter area under the curve (AUC) of midazolam, a typical CYP3A substrate, 0.84-1.47 times. For weak CYP3A perpetrators, the predicted AUC ratio mainly depends on intestinal DDIs rather than hepatic DDIs because the drug concentration in the enterocytes is higher. Thus, DDI prediction using simulated concentration-time profiles in each segment of the digestive tract was made by physiologically based pharmacokinetic (PBPK) modeling software GastroPlus. Although mechanistic static models tend to overestimate the risk to ensure the safety of patients, some underestimation is reported about PBPK modeling. Our in vitro studies revealed that 16 out of 17 tested drugs exhibited time-dependent inhibition (TDI) of CYP3A, and the subsequent DDI simulation that ignored these TDIs provided false-negative results. This is considered to be the cause of past underestimation. Inclusion of the DDI parameters of all the known DDI mechanisms, reversible inhibition, TDI, and induction, which have opposite effects on midazolam AUC, to PBPK model was successful in improving predictability of the DDI without increasing false-negative prediction as trade-off. This comprehensive model-based analysis suggests the importance of the intestine in assessing weak DDIs via CYP3A and the usefulness of PBPK in predicting intestinal DDIs. SIGNIFICANCE STATEMENT: Although drug-drug interaction (DDI) prediction has been extensively performed previously, the accuracy of prediction for weak interactions via CYP3A has not been thoroughly investigated. In this study, we simulate DDIs considering drug concentration-time profile in the enterocytes and discuss the importance and the predictability of intestinal DDIs about weak CYP3A perpetrators.

Positron emission tomography (PET) scans of imaging receptors require 60-90-min dynamic acquisition for quantitative analysis. Head movement is often observed during scanning, which hampers the reliable estimation of quantitative parameters. This study evaluated image-based motion correction by frame-to-frame realignment for PET studies with [First, an optimal method for estimating motion parameters was evaluated by computer simulation. Simulated emission sinograms were reconstructed to the PET images with or without attenuation correction using a µ-map of the transmission scan. Six motion parameters were estimated frame-by-frame by registering each frame of the PET images to several types of reference images and the reliability of registration was compared. Next, in [In the simulations, the motion parameters could be reliably estimated by registering each frame of the non-attenuation-corrected PET images to their early-phase frame. The motion parameters in the human studies were also obtained using the same method. After correction, a discontinuity of TACs in the striatum and cerebral cortex was remarkably improved and the BPIn PET receptor imaging, head movement during dynamic scans can be corrected by frame-to-frame realignment. This method is easily applicable to clinical studies and provides reliable TACs and BP

The beneficial effects of psychostimulant drugs in the treatment of psychiatric disorders occur because they increase the extracellular dopamine concentration by inhibiting re-uptake of extracellular dopamine at dopamine transporters. However, the psychological effects at low dopamine transporter occupancy have not been well demonstrated. The purpose of the study was to evaluate the psychological effects, dopamine transporter occupancy, and dopamine release induced by a single oral administration of a clinical dose of mazindol. Ten healthy male volunteers were orally administered a placebo and a clinical dose of mazindol (1.5 mg) on separate days. The psychological effects of mazindol were assessed using a visual analogue scale to detect alterations in the state of consciousness. The amount of blockade of dopamine transporters was assessed using positron emission tomography with [18F]FE-PE2I and extracellular dopamine release was measured as the amount of change in [11C]raclopride binding. Following administration of a clinical dose of mazindol, the dopamine transporters were blocked by 24–25 %, and the binding potential of [11C]raclopride was reduced by 2.8–4.6 %. The differences of a score measuring derealisation and depersonalization associated with a positive basic mood were significantly correlated with the change in the [11C]raclopride binding in the limbic striatum. A subtle alteration in the state of consciousness was detected with a correlation to the changes in the [11C]raclopride binding, which implies that a subtle alteration in extracellular dopamine concentration in the limbic striatum by a small amount of dopamine transporter occupancy can affect the state of consciousness. UMIN000008232

The histamine H3 receptors are presynaptic neuroreceptors that inhibit the release of histamine and other neurotransmitters. The receptors are considered a drug target for sleep disorders and neuropsychiatric disorders with cognitive decline. We developed a novel PET ligand for the H3 receptors, [11C]TASP0410457 ([11C]TASP457), with high affinity, selectivity and favorable kinetic properties in the monkey, and evaluated its kinetics and radiation safety profile for quantifying the H3 receptors in human brain. Ten healthy men were scanned for 120 min with a PET scanner for brain quantification and three healthy men were scanned for radiation dosimetry after injection of 386 ± 6.2 MBq and 190 ± 7.5 MBq of [11C]TASP457, respectively. For brain quantification, arterial blood sampling and metabolite analysis were performed using high-performance liquid chromatography. Distribution volumes (V T) in brain regions were determined by compartment and graphical analyses using the Logan plot and Ichise multilinear analysis (MA1). For dosimetry, radiation absorbed doses were estimated using the Medical Internal Radiation Dose scheme. [11C]TASP457 PET showed high uptake (standardized uptake values in the range of about 3 – 6) in the brain and fast washout in cortical regions and slow washout in the pallidum. The two-tissue compartment model and graphical analyses estimated V T with excellent identification using 60-min scan data (about 16 mL/cm3 in the pallidum, 9 – 14 in the basal ganglia, 6 – 9 in cortical regions, and 5 in the pons), which represents the known distribution of histamine H3 receptors. For parametric imaging, MA1 is recommended because of minimal underestimation with small intersubject variability. The organs with the highest radiation doses were the pancreas, kidneys, and liver. The effective dose delivered by [11C]TASP457 was 6.9 μSv/MBq. [11C]TASP457 is a useful novel PET ligand for the investigation of the density of histamine H3 receptors in human brain.

Esaxerenone (CS-3150) is a novel, nonsteroidal, selective mineralocorticoid receptor blocker. The absorption, metabolism, distribution, and excretion of esaxerenone were assessed in in vitro studies and in a clinical study, where [

Sunitinib is an orally administered tyrosine kinase inhibitor. Therapeutic drug monitoring is an important component of the follow-up of patients because of high interpatient variability in the pharmacokinetics of sunitinib and large variabilities in its efficacy and toxicity. The aim of the present study was to examine the light stability of sunitinib and confirm the effects of light exposure on sunitinib measurements by LC-MS/MS. Sunitinib and its active metabolite, SU12662, convert Z isomers to E isomers with exposure to light. The Z-E photoisomerization ratio reached a plateau at 35% for both E isomers in methanol within 15 min of normal light exposure (700 lx). However, the Z isomer of the sunitinib and SU12662 peak area ratios in plasma decreased by 10% within 15 min. These results suggest that sunitinib samples need to be handled without light exposure in all sample preparation steps. Alternatively, it should be measured sunitinib and SU12662 after the sample has reached photoisomerical equilibrium. These results suggest that the sunitinib therapeutic range changes depending on light conditions during sample handling in sunitinib and SU12662 measurements.

DS-2969b is a novel GyrB inhibitor in development for the treatment of Clostridium difficile infection. The aim of this study was to assess the safety, tolerability, pharmacokinetics, and effects on normal gastrointestinal microbiota groups of single daily oral ascending doses of DS-2969b in healthy subjects. The study enrolled 6 sequential ascending dose cohorts (6 mg, 20 mg, 60 mg, 200 mg, 400 mg, and 600 mg). In each cohort, 6 subjects were administered DS-2969b and 2 subjects were administered matching placebo. DS-2969b was safe and well tolerated at all dose levels examined. All adverse events related to DS-2969b were mild to moderate in severity and predominantly related to the gastrointestinal tract. DS-2969a (free form of DS-2969b) plasma concentrations increased with increasing doses; however, both the maximum serum concentration and area under the plasma concentration-time curve generally increased less than dose proportionally. DS-2969a was predominantly eliminated in the urine, with feces as a minor route of elimination. While the overall proportion of DS-2969a eliminated in the feces was low, target fecal levels sufficient for C. difficile eradication were achieved within 24 hours of administration with doses of 60 mg or higher. In exploratory analyses, DS-2969b appeared to reduce bacterial counts in 8 of the 25 groups of normal intestinal microbiota examined, suggesting that DS-2969b has only a mild effect on intestinal microbiota. Data from this study support and encourage further development of DS-2969b as a novel treatment for C. difficile infection.

Perceptual changes in shape, size, or color are observed in patients with derealization symptoms; however, the underlying neural and molecular mechanisms are not well understood. The current study explored the relationship between neural activity associated with altered colorfulness perception assessed by fMRI and striatal dopamine D2 receptor availability measured by [11C]raclopride PET in healthy participants. Inside an fMRI scanner, participants performed the saturation adaptation task, where they rated how much vivid/faded visual objects looked like real/unreal ones using a visual analog scale. We found that participants experienced greater unreality when they perceived fadedness than vividness despite physically identical saturation. The combined fMRI and PET analyses revealed that the faded perception-related activities of the dorsolateral prefrontal and parietal cortex were positively correlated with striatal D2 receptor availability. This finding may help to understand the neuromolecular mechanisms of faded perception associated with feeling unreal in derealization symptoms.

Negativity bias, which describes the tendency to interpret ambiguous stimuli or events as negative, is often observed in patients with depression and may prevent psychological well-being. Here, we used ambiguous facial stimuli, with negative (sad) and positive (happy) emotions simultaneously accessible, to examine neural activation during perceptual decision-making in healthy participants. The negativity bias was positively correlated with the activity of the bilateral pregenual anterior cingulate cortex (pgACC) when ambiguous faces were perceived as sad versus happy. Additionally, the strength of the functional connectivity between the bilateral pgACC and the right dorsal ACC (dACC)/right thalamus was positively correlated with hopelessness, one of the core characteristics of depression. Given the role of the pgACC as a major site of depressive affect and the roles of the dACC and thalamus in conflict monitoring and vigilance, respectively, our results reveal valid and important neuroanatomical correlates of the association between negativity bias and hopelessness in the healthy individuals.

Over the last two decades, evidence of enhancement of drawing and painting skills due to focal prefrontal damage has accumulated. It is of special interest that most artworks created by such patients were highly realistic ones, but the mechanism underlying this phenomenon remains to be understood. Our hypothesis is that enhanced tendency of realism was associated with accuracy of visual numerosity representation, which has been shown to be mediated predominantly by right parietal functions. Here, we report a case of left prefrontal stroke, where the patient showed enhancement of artistic skills of realistic painting after the onset of brain damage. We investigated cognitive, functional and esthetic characteristics of the patient׳s visual artistry and visual numerosity representation. Neuropsychological tests revealed impaired executive function after the stroke. Despite that, the patient׳s visual artistry related to realism was rather promoted across the onset of brain damage as demonstrated by blind evaluation of the paintings by professional art reviewers. On visual numerical cognition tasks, the patient showed higher performance in comparison with age-matched healthy controls. These results paralleled increased perfusion in the right parietal cortex including the precuneus and intraparietal sulcus. Our data provide new insight into mechanisms underlying change in artistic style due to focal prefrontal lesion.

Serotonin 2A (5-HT2A) receptors and dopamine D2 receptors are intimately related to the physiology and pathophysiology of neuropsychiatric disorders. A large number of studies have reported the effectiveness of psychotropic agents targeting 5-HT2A and D2 receptors in these disorders. In addition to the individual functions of these receptors, the interaction between the two neurotransmitter systems has been studied in the living brain. However, little is known about their regional relationship in individual human brains. We investigated regional relationships between 5-HT2A and D2 receptors using positron emission tomography (PET) and a bicluster analysis of the correlation matrix of individual variation in the two receptor densities to identify groups of distinctive regional correlations between the two receptors. Methods Seven healthy volunteers underwent PET scans with [18F]altanserin and [11C]FLB 457 for 5-HT2A and D2 receptors, respectively. As a measure of receptor density, a binding potential (BP) was calculated from PET data for 76 cerebral cortical regions. A correlation matrix was calculated between the binding potentials of [18F]altanserin and [11C]FLB 457 for those regions. The regional relationships were investigated using a bicluster analysis of the correlation matrix with an iterative signature algorithm. Results We identified two clusters of regions. The first cluster identified a distinct profile of correlation coefficients between 5-HT2A and D2 receptors, with the former in regions related to sensorimotor integration (supplementary motor area, superior parietal gyrus, and paracentral lobule) and the latter in most cortical regions. The second cluster identified another distinct profile of correlation coefficients between 5-HT2A receptors in the bilateral hippocampi and D2 receptors in most cortical regions. Conclusions The observation of two distinct clusters in the correlation matrix suggests regional interactions between 5-HT2A and D2 receptors in sensorimotor integration and hippocampal function. A bicluster analysis of the correlation matrix of these neuroreceptors may be beneficial in understanding molecular networks in the human brain.

Objective:The norepinephrine transporter has been suggested to play a crucial role in major depressive disorder. However, norepinephrine transporter availability in major depressive disorder and its role with clinical symptoms are not known. The authors tested norepinephrine transporter availability in patients with major depressive disorder with the aim to identify any associations between test results and clinical symptoms.Method:The present research was a cross-sectional study in which 19 patients with major depressive disorder and 19 age- and sex-matched healthy comparison subjects underwent positron emission tomography scanning to evaluate the norepinephrine transporter availability measured by the radioligand (S,S)-[18F]FMeNER-D2. Norepinephrine transporter availability in the thalamus and its subregions was quantified in terms of nondisplaceable binding potential (BPND). The authors also analyzed the association between norepinephrine transporter availability and clinical symptoms.Results:Compared ...

The sunk cost effect, an interesting and well-known maladaptive behavior, is pervasive in real life, and thus has been studied in various disciplines, including economics, psychology, organizational behavior, politics, and biology. However, the neural mechanisms underlying the sunk cost effect have not been clearly established, nor have their association with differences in individual susceptibility to the effect. Using functional magnetic resonance imaging, we investigated neural responses induced by sunk costs along with measures of core human personality. We found that individuals who tend to adhere to social rules and regulations (who are high in measured agreeableness and conscientiousness) are more susceptible to the sunk cost effect. Furthermore, this behavioral observation was strongly mediated by insula activity during sunk cost decision-making. Tight coupling between the insula and lateral prefrontal cortex was also observed during decision-making under sunk costs. Our findings reveal how individual differences can affect decision-making under sunk costs, thereby contributing to a better understanding of the psychological and neural mechanisms of the sunk cost effect.

Norepinephrine transporter (NET) in the brain plays important roles in human cognition and the pathophysiology of psychiatric disorders. Two radioligands, (

How does one deal with unfair behaviors? This subject has long been investigated by various disciplines including philosophy, psychology, economics, and biology. However, our reactions to unfairness differ from one individual to another. Experimental economics studies using the ultimatum game (UG), in which players must decide whether to accept or reject fair or unfair offers, have also shown that there are substantial individual differences in reaction to unfairness. However, little is known about psychological as well as neurobiological mechanisms of this observation. We combined a molecular imaging technique, an economics game, and a personality inventory to elucidate the neurobiological mechanism of heterogeneous reactions to unfairness. Contrary to the common belief that aggressive personalities (impulsivity or hostility) are related to the high rejection rate of unfair offers in UG, we found that individuals with apparently peaceful personalities (straightforwardness and trust) rejected more often and were engaged in personally costly forms of retaliation. Furthermore, individuals with a low level of serotonin transporters in the dorsal raphe nucleus (DRN) are honest and trustful, and thus cannot tolerate unfairness, being candid in expressing their frustrations. In other words, higher central serotonin transmission might allow us to behave adroitly and opportunistically, being good at playing games while pursuing self-interest. We provide unique neurobiological evidence to account for individual differences of reaction to unfairness.

The role of dopamine D1 receptors in prefrontal cortex function, including working memory, is well acknowledged. However, relatively little is known about their role in other cognitive or emotional functions. We measured both D1 and D2 receptors in the brain using positron emission tomography in healthy subjects, with the aim of elucidating how regional D1 and D2 receptors are differentially involved in cognitive and emotional functions beyond working memory. We found an inverted U-shaped relation between prefrontal D1 receptor availability and Wisconsin Card Sorting Test performance, indicating that too little or too much D1 receptor stimulation impairs working memory or set shifting. In addition, variability of D1 receptor availability in the amygdala and striatum was related to individual differences in emotional responses and decision-making processes, respectively. These observations suggest that the variability of available D1 receptors might be associated with individual differences in brain functions that require phasic dopamine release. An interdisciplinary approach combining molecular imaging of dopamine neurotransmission with cognitive neuroscience and clinical psychiatry will provide new perspectives for understanding the neurobiology of neuropsychiatric disorders such as schizophrenia, addiction and Parkinson's disease, as well as novel therapeutics for cognitive impairments observed in them.

Background Oculocutaneous albinism (OCA) type 3 caused by mutations of the TYRP1 gene is an autosomal recessive disorder of pigmentation characterized by reduced biosynthesis of melanin pigment in the skin, hair, and eye. The clinical phenotype has been reported as mild in Caucasian OCA3 patients. Objective We had the opportunity to examine a Japanese girl with OCA3 and investigated activity of TYRP1 protein derived from the mutant allele detected in the patient. Methods Mutation search for OCA responsible genes was done. A mutant allele with a missense mutation was analyzed using melanocyte cultures (b cells) established from a mouse model of OCA3. Results Compound heterozygous mutations, p.C30R and p.367fsX384, were detected in the Japanese girl. Then we revealed that the missense mutation, p.C30R, was functionally incapable of melanin synthesis with in vitro experiments. Conclusion This is the first report of the occurrence of OCA3 in Japanese population.

Background The pathology of schizophrenia is thought to involve multiple gray and white matter regions. A number of studies have revealed impaired social cognition in schizophrenia. Some evidence suggests an association of this social cognition deficit with gray matter reductions in ‘social brain’ areas. However, no study has yet revealed the association between social cognition abilities and white matter abnormalities in schizophrenia patients. Methods Twenty-six schizophrenia patients and 27 healthy controls underwent the Perception of Affect Task (PAT), which consisted of four subtasks measuring different aspects of emotion attribution. Voxelwise group comparison of white matter fractional anisotropy (FA) was performed using tract-based spatial statistics (TBSS). The relation between impaired social cognition ability and FA reduction was examined in patients for each subtask, using simple regression analysis within brain areas that showed a significant FA reduction in patients compared with controls. The same correlational analysis was also performed for healthy controls in the whole brain. Results Schizophrenia patients showed reduced emotion attribution ability compared with controls in all four subtasks. The facial emotion perception subtask showed a significant correlation with FA reductions in the left occipital white matter region and left posterior callosal region. The correlational analyses in healthy controls revealed no significant correlation of FA with any of the PAT subtasks. Conclusions Our voxelwise correlational analysis of white matter provided a potential neural basis for the social cognition impairments in schizophrenia, in support of the disconnection hypothesis.

The structural and functional abnormalities of the frontal lobes, the region implicated in social information processing, have been suspected to underlie social cognitive impairments in schizophrenia. However, multiple structures, including the limbic/paralimbic areas that are also important for social cognition, have been reported to be abnormal in schizophrenia. The aim of this study is to investigate the extent to which the frontal lobe dysfunction accounts for social cognitive impairments in schizophrenia by comparing with patients who have focal frontal lobe injuries. Social cognitive abilities, focusing on affective aspects, were examined by an emotion intensity recognition task, which is sensitive to the amygdala function, and the emotion attribution tasks, which rely mainly on the frontal lobe function. Individuals with schizophrenia were impaired on the emotion intensity recognition task as well as on the emotion attribution tasks as compared with healthy subjects. By contrast, the frontal lobe-damaged group was defective in the emotion attribution tasks but not in the emotion intensity recognition task. Our results indicated that social cognitive impairments observed in schizophrenia can be accounted for partly by their frontal lobe pathology. Other aspects of social cognitive impairments could also be associated with the extra-frontal pathology, such as the amygdala.

We report a case of a male patient who showed personality changes and marked social problems after a traumatic brain injury. Although suspected to have lesions in the orbitofrontal cortex because of the typical characteristics of his behavioural change, lesions were not apparent using conventional imaging techniques. However, investigation using high-resolution MRI revealed lesions in the orbitofrontal cortex. Our case suggests that standard MRI scanning techniques may have only limited power. Hence, we stress the important role played by qualitative assessments of emotion, personality, and social behaviour in evaluating sequelae of traumatic orbitofrontal injuries.

Impaired ability to infer the mental states of others (theory of mind; ToM) is considered to be a key contributor to the poor social functioning of patients with schizophrenia. Although neuroimaging and lesion studies have provided empirical evidence for the neural basis of ToM ability, including the involvement of several prefrontal and temporal structures, the association between pathology of these structures and ToM impairment in schizophrenia patients is less well understood. To address this issue, we investigated structural brain abnormalities and ToM impairment in patients with schizophrenia, and examined the relationship between them. Twenty schizophrenia patients and 20 age-, sex- and education-matched healthy participants underwent magnetic resonance imaging (MRI) and were examined for ToM ability based on the revised version of the “Reading the Mind in the Eyes” (or Eyes) test [Baron-Cohen, S., Wheelwright, S., Hill, J., Raste, Y., Plumb, I., 2001. The ‘Reading the Mind in the Eyes’ test revised version: A study with normal adults, and adults with Asperger syndrome or high-functioning autism. J. Child Psychol. Psychiatry 42, 241–251]. Voxel-based morphometry (VBM) was performed to investigate regional brain alterations. Relative to normal controls, schizophrenia patients exhibited gray matter reductions in the dorsomedial prefrontal cortex (DMPFC), left ventrolateral prefrontal cortex (VLPFC), ventromedial prefrontal cortex (VMPFC), anterior cingulate cortex (ACC), right superior temporal gyrus (STG) and right insula. The patients performed poorly on the Eyes test. Importantly, poor performance on the Eyes test was found to be associated with gray matter reduction in the left VLPFC in the patient group. These results suggest that prefrontal cortical reduction, especially in the left VLPFC, is a key pathology underlying the difficulties faced by schizophrenia patients in inferring the mental states of others.

Structural abnormalities of the amygdala and impaired facial emotion recognition have been reported in schizophrenia. Most studies demonstrated reduced amygdalar volumes in schizophrenia patients, and difficulty in recognizing negative facial emotions has also been reported. However, findings on the deficit in facial emotion recognition have been inconsistent, and the relationships between this impairment and amygdalar volume reduction remain unclear. In this study, we investigated these relationships by performing volumetric analysis of the amygdala and evaluation of facial emotion recognition performance in the same subjects with schizophrenia. The sample group comprised 20 schizophrenia patients and 20 matched healthy controls. We measured the volumes of the amygdalae with high-resolution magnetic resonance imaging (MRI) at 3.0 Tesla. Additionally, we included a task that evaluated the subjects' ability to recognize the intensity of basic facial emotions. We found that impaired facial emotion recognition in schizophrenia patients is emotion-specific (sadness, surprise, disgust, and anger). Moreover, the volume of each amygdala on either side of the brain was reduced. Finally, we found a correlation between left amygdalar volume and the recognition of sadness in facial expressions. This study demonstrated that amygdala dysfunction may contribute to impaired facial emotion recognition in schizophrenia.

High-density lipoprotein (HDL) has a protective effect against atherosclerosis. Therefore, a compound that elevates the plasma HDL cholesterol (HDL-C) levels is expected to be a promising anti-atherosclerotic agent. We discovered a novel compound, R-138329, that increased HDL-C by 41% in normolipidemic hamsters at a dose of 100mg/kg. To investigate the mechanism of action of R-138329, we examined the effect of R-138329 on the clearance of [(3)H]cholesterol ether ([(3)H]COE)-labeled and [(125)I]-labeled HDL in mice. R-138329 delayed the clearance of [(3)H]COE-labeled HDL and reduced accumulation of tracer HDL in the liver, whereas the clearance of [(125)I]-labeled HDL particles was unaffected by the compound. In vitro analysis showed that R-154716, a metabolite of R-138329, dramatically inhibited the uptake of [(3)H]COE-labeled HDL in McA-RH 7777 rat hepatoma cells. Furthermore, 100 nM of R-154716 completely inhibited [(3)H]COE-labeled HDL uptake induced by overexpression of scavenger receptor BI (SR-BI) in HEK293 cells. Taken together, these findings suggest that the mechanism by which R-138329 elevates HDL-C in vivo is principally involved in the inhibition of SR-BI-mediated selective lipid uptake in the liver.

The anterior cingulate gyrus (ACG) is a critical structure for social cognitive processing; the pathology of this structure might be a major source of social dysfunction in schizophrenia. Multiple structural abnormalities of the ACG have been demonstrated in schizophrenia including changes in gray matter volume, white matter microstructures and macroscopic sulcal morphology. However, the interrelationships among these different abnormalities have not been investigated. Thus, the relationship between structural abnormalities in the ACG and social cognition in schizophrenia remains to be elucidated. Magnetic resonance imaging data were acquired at 3.0 T from 26 schizophrenic patients and 20 healthy participants. We performed anterior cingulate cortex (ACC) volumetry, evaluated diffusion tensor imaging of the anterior cingulum, analyzed paracingulate/cingulate sulcus (PCS/CS) morphology and investigated the interrelationships among these measures. We also investigated the association between ACG structural abnormalities and psychopathology, and the social cognition ability of schizophrenic patients as estimated by emotion attribution tasks. Compared with healthy subjects, schizophrenic patients exhibited reduced ACC volume, decreased fractional anisotropy in the anterior cingulum bilaterally and a poorly developed PCS/CS in the left hemisphere. No interrelationship was identified among these measures in the schizophrenic group. Schizophrenic patients performed poorly on emotion attribution tasks. Importantly, clinical symptoms and performance on emotion attribution subtasks were associated with ACC volumes and left PCS/CS variation in different ways. These results suggested that pathology of the ACC, anterior cingulum and PCS/CS is, at least partially, independent and has differential impacts on psychopathology and social cognitive impairment in schizophrenia.

Hypothermia and frostbite are frequently seen in accidents in remote wilderness environment, especially in hypobaric hypoxic conditions. The aim of this study was to clarify how hypobaric hypoxic conditions affects peripheral circulation. Peripheral skin temperature and autonomic nervous functions were assessed in two 1000-m ascent exercises. Subjects (n = 15) ascended from 1000 m above sea level in Study 1, and ascended from 2400 m in Study 2. Conditions other than environmental oxygen pressure were mostly identical in both studies. The autonomic nervous activities were decreased solely in Study 2. The relative sympathetic activity was significantly increased in the lower barometric pressure in Study 2 (p0.01). Peripheral skin temperature was significantly decreased after the exercise in Study 2 (p0.01). In conclusion, hypobaric hypoxia itself induced peripheral low temperature during exercise at high altitudes. Relative sympathetic hyperactivity may be responsible for the compromised peripheral circulation.

Cognitive restructuring is a fundamental method within cognitive behavioural therapy of changing dysfunctional beliefs into flexible beliefs and learning to react appropriately to the reality of an anxiety-causing situation. To clarify the neural mechanisms of cognitive restructuring, we designed a unique task that replicated psychotherapy during a brain scan. The brain activities of healthy male participants were analysed using functional magnetic resonance imaging. During the brain scan, participants underwent Socratic questioning aimed at cognitive restructuring regarding the necessity of handwashing after using the restroom. The behavioural result indicated that the Socratic questioning effectively decreased the participants' degree of belief (DOB) that they must wash their hands. Alterations in the DOB showed a positive correlation with activity in the left posterior parietal cortex (PPC) while the subject thought about and rated own belief. The involvement of the left PPC not only in planning and decision-making but also in conceptualization may play a pivotal role in cognitive restructuring.

Three mycobacterium strains isolated from clinical specimens in Japan were provisionally assigned to the genus Mycobacterium based on their phenotypical characteristics. These isolates were further investigated to determine their specific taxonomic statuses. Mycolic acid analysis and 16S rRNA gene, rpoB, and hsp65 sequence data for the isolates showed that they are most similar to M. terrae complex. DNA-DNA hybridization studies indicated that the three strains were of two species and were distinguishable from M. terrae, M. nonchromogenicum, and M. hiberniae. Therefore, these strains represent two novel species within the genus Mycobacterium. However, one potential new species should have been considered as M. arupense with the 16S rRNA gene and hsp65 sequences similarities of 99.8% and 100% respectively; it was isolated from human specimens in the United States and was proposed in June 2006 as a new species. This report describes the first isolation of M. arupense in Japan, suggesting that the organism is clinically relevant. In addition, we propose the novel species designation Mycobacterium kumamotonense sp. nov. The type strain is CST 7247(T) (=GTC 2729(T), =JCM 13453(T), =CCUG 51961(T)).

Autonomic nervous systems have important roles for survival of victims under hypobaric hypoxic condition. In the present study, we assessed the correlation between arterial oxygen saturation (Sp O 2 ) and heart rate variability (HRV) to identify the autonomic nervous responsiveness among trekkers at high altitude (n = 21). HRV was analyzed by the maximum entropy method. Sp O 2 among subjects at 3456 m (495 mm Hg) was 80% +/- 5% (mean +/- SD; range, 69%-93%). Sp O 2 and percentile entropy, and Sp O 2 and low-frequency variability, had positive correlation ( r = 0.455 and 0.518, respectively). Sp O 2 value among subjects with mountain sickness symptoms was not different from that among subjects without the symptoms. In conclusion, autonomic responses among high-altitude trekkers may be blunted under hypobaric hypoxic conditions. Deterioration of autonomic function measured by HRV might be more sensitive to hypoxia than clinical symptoms at high altitudes.

Pyroglutamyl aminopeptidase I (PAP-I) is known for specifically removing the L-pyroglutamate (L-pGlu) residue from the amino terminus of L-pGlu proteins and peptides. In general, substrate recognition of PAP-I as to L-pGlu moiety is tightly regulated. However, we recently identified PAP-I as a metabolic enzyme of an organic nitrate compound, RS-7897, which contains L-2-oxothiazolidine-4-carboxylic acid (L-OTCA). L-OTCA is a latent sulfhydryl group, which has moiety structurally related to L-pGlu. In this study, we investigated the substrate specificity of PAP-I toward modified L-pGlu-containing substrates using recombinant rat, mouse and human PAP-Is. PAP-I was tolerant of replacement of a carbon atom at the 4-position of the L-pGlu moiety by a sulfur atom (L-OTCA), an oxygen atom (L-2-oxooxazolidine-4-carboxylic acid, L-OOCA) and an NH group (L-2-oxoimidazolidine-4-carboxylic acid, L-OICA). The K(m) values for rat PAP-I in hydrolyzing L-pGlu-L-Ala, L-OTCA-L-Ala, L-OOCA-L-Ala and L-OICA-L-Ala were 0.057, 0.43, 0.71 and 0.42 mM, respectively. Similar results were observed in mouse and human PAP-Is as well. Moreover, the hydrolysis of RS-7897 in rat and mouse liver cytosols were both completely inhibited by an antibody against rat PAP-I, strongly suggesting that PAP-I is solely involved in the hydrolysis of L-OTCA-containing compounds in rat and mouse liver cytosols.

A 65-year-old female patient underwent surgery to clip a giant basilar artery aneurysm with closed-chest extracorporeal circulation using femorofemoral bypass. Moderate hypothermia (27 degrees C-30 degrees C), retention of spontaneous circulation, and propofol infusion (3-5 mg. kg(-1). h(-1)) were used under general anesthesia. Blood outflow via femoral vein was sufficient to maintain cardiopulmonary bypass and to induce hypothermia. Hemodynamics were controlled with dopamine and noradrenaline. In this case, extracorporeal circulation under moderate hypothermia was used to assist rather than substitute for spontaneous circulation, and spontaneous circulation was maintained at all times. We think that this method had advantages over deep hypothermic circulatory arrest with regard to intraoperative risks and postoperative complications.

Salmonella enterica subsp. enterica serotype Infantis isolates from retail raw chicken meat (n = 98) and broiler chickens on farms (n = 70) were examined for antimicrobial susceptibility and antimicrobial resistance genes. A total of 15 antimicrobial resistance types, 14 in meat and 10 in broiler isolates, were identified, and 9 of the 15 types were indistinguishable between meat and broiler isolates. Resistance to both oxytetracycline and dihydrostreptomycin accounted for 94.0% of the resistance types in meat and broiler isolates, and each type harbored aadA1 within 1.0 kb of class 1 integron and tetA. Of nalidixic acid resistance types, point mutations at 87Asp (GAC) to Tyr (TAC) in the quinolone resistance-determining region of gyrA was detected in 10 of 13 meat isolates and at 87Asp to Asn (AAC) in four of seven broiler isolates. These findings suggest that the antimicrobial resistance of Salmonella Infantis in retail chicken meat predominantly originates from broiler chickens.

Romano-Ward (R-W) syndrome is an autosomal dominant hereditary disorder and is characterized by a prolonged QT interval on the electrocardiogram (ECG), syncope, and sudden death. We report here a case of cesarian section in a patient with R-W syndrome whose QT prolongation was successfully managed with landiolol, a selective beta1 receptor blocker. A 25-year-old woman with R-W syndrome was scheduled for cesarean section. In the operating room, the patient's ECG showed tachycardia (102 beats x min(-1)) and marked QT prolongation (QTc = 0.56 s). After spinal anesthesia, the patient's heart rate (HR) increased to 130 beats/min accompanied by a slight decrease in arterial blood pressure to 97/57 mmHg and the QTc was prolonged to 0.57 s. Landiolol was continuously infused at a rate of 0.04 mg.kg(-1) x min(-1) and the HR gradually decreased to 80-90 beats x min(-1) accompanied by the normalization of QTc to 0.48 s. We thought that the use of landiolol was more rational and was preferable to a nonselective beta receptor blocker for a term-pregnant woman because blockade of the beta2 receptor might cause uterine contraction. After the use of landiolol, intraoperative and postoperative courses in both the patient and the baby were uneventful.

The majority of individuals evaluate themselves as above average. This is a cognitive bias called "the superiority illusion". This illusory self-evaluation helps us to have hopes for the future, and has been central to the process of human evolution. Possessing this illusion is also important for mental health, as depressed people appear to have a more realistic perception of themselves, dubbed "depressive realism". Our recent study revealed the spontaneous brain activity and central dopaminergic neurotransmission that generate this illusion, using resting-state fMRI and PET. A functional connectivity between the frontal cortex and striatum, regulated by inhibitory dopaminergic neurotransmission, determines individual levels of the superiority illusion. We further revealed that blocking the dopamine transporter, which enhanced the level of dopamine, increased the degree of the superiority illusion. These findings suggest that dopamine acts on striatal dopamine receptors to suppress fronto-striatal functional connectivity, leading to disinhibited, heuristic, approaches to positive self-evaluation. These findings help us to understand how this key aspect of the human mind is biologically determined, and will suggest treatments for depressive symptoms by targeting specific molecules and neural circuits.

Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[18¹⁸F]FMeNER-D₂ to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200 mg/d of nortriptyline. The estimated effective dose (ED₅₀) and concentration (EC₅₀) required to induce 50% occupancy was 65.9 mg/d and 79.8 ng/ml, respectively. Furthermore, as the minimum therapeutic level of plasma nortriptyline for the treatment of depression has been reported to be 70 ng/ml, our data indicate that this plasma nortriptyline concentration corresponds to approximately 50% NET occupancy measured with PET, suggesting that more than 50% of central NET occupancy would be appropriate for the nortriptyline treatment of patients with depression.

Objective Neuropsychiatric symptoms affect many patients with Alzheimer9s disease (AD). ( 11 C)Pittsburgh Compound-B (PIB) positron emission tomography (PET) has enabled the in vivo visualisation of brain amyloid-β (Aβ) deposition. This study exploratively investigated the correlation between brain Aβ deposition measured by ( 11 C)PIB PET and neuropsychiatric symptoms in AD. Methods Participants were 28 patients (15 women, 13 men) with PIB-positive AD. Clinical assessments included Mini-Mental State Examination, Clinical Dementia Rating scale, neuropsychiatry inventory (NPI) and frontal assessment battery. All patients underwent three-dimensional T1-weighted MRI and ( 11 C)PIB PET. The distribution volume ratio (DVR), an index of ( 11 C)PIB retention and, thus, Aβ deposition, was estimated voxel by voxel from ( 11 C)PIB PET data with partial volume correction. Voxel-based correlation analysis was performed to assess the relationships between DVR and each NPI subscale. Additionally, voxel-based analysis of covariance (ANCOVA) of the DVR images was performed between Patients with AD with and without each neuropsychiatric symptom. Voxel-based morphometry analysis of MRI was also performed. Results Apathy subscale was correlated with ( 11 C)PIB retention in the bilateral frontal and right anterior cingulate. ( 11 C)PIB retention was greater in the bilateral frontal cortex of patients with AD with apathy than those of without apathy. Overlapping areas between the two analyses were the bilateral orbitofrontal gyrus and left superior frontal gyrus. Other NPI subscales were not correlated with ( 11 C)PIB retention. Voxel-based morphometry analysis of MRI showed no significant cluster of correlation between grey matter volume and NPI subscales. Conclusions This study revealed that prefrontal Aβ deposition correlates with apathy.

Neurons are anatomically and physiologically connected to each other, and these connections are involved in various neuronal functions. Multiple important neural networks involved in neurodegenerative diseases can be detected using network analyses in functional neuroimaging. First, the basic methods and theories of voxel-based network analyses, such as principal component analysis, independent component analysis, and seed-based analysis, are described. Disease- and symptom-specific brain networks have been identified using glucose metabolism images in patients with Parkinson's disease. These networks enable us to objectively evaluate individual patients and serve as diagnostic tools as well as biomarkers for therapeutic interventions. Many functional MRI studies have shown that "hub" brain regions, such as the posterior cingulate cortex and medial prefrontal cortex, are deactivated by externally driven cognitive tasks; such brain regions form the "default mode network." Recent studies have shown that this default mode network is disrupted from the preclinical phase of Alzheimer's disease and is associated with amyloid deposition in the brain. Some recent studies have shown that the default mode network is also impaired in Parkinson's disease, whereas other studies have shown inconsistent results. These incongruent results could be due to the heterogeneous pharmacological status, differences in mesocortical dopaminergic impairment status, and concomitant amyloid deposition. Future neuroimaging network analysis studies will reveal novel and interesting findings that will uncover the pathomechanisms of neurological and psychiatric disorders.

The majority of individuals evaluate themselves as superior to average. This is a cognitive bias known as the “superiority illusion.” This illusion helps us to have hope for the future and is deep-rooted in the process of human evolution. In this study, we examined the default states of neural and molecular systems that generate this illusion, using resting-state functional MRI and PET. Resting-state functional connectivity between the frontal cortex and striatum regulated by inhibitory dopaminergic neurotransmission determines individual levels of the superiority illusion. Our findings help elucidate how this key aspect of the human mind is biologically determined, and identify potential molecular and neural targets for treatment for depressive realism.

Matricoma is benign follicular neoplasm with the same constituent cells as pilomatricoma but with a different silhouette. Matricoma consists mostly of solid aggregations of matrical cells, as opposed to pilomatricoma, which is often a cystic lesion. We herein describe a case of agminated pigmented matricoma. A 27-year-old Japanese man visited our hospital complaining of three separate, pigmented, firm and sessile nodules on the back. Histopathologic examination revealed mostly solid aggregations of matrical and supramatrical cells located mainly within the dermis and the upper part of the subcutis. Shadow cells were present mostly within the aggregations. At higher magnifications, occasional indication of inner sheath differentiation, in addition to differentiation toward hair in the form of shadow cells, could be discerned in the center of the aggregations. The matrical and supramatrical cells within the aggregations were relatively uniform in size and shape, and contained several mitotic figures. Heavily pigmented melanocytes were present within the aggregations of matrical and supramatrical cells, and heavily pigmented melanophages were found in adjacent stroma. Pigmentation is a rare event in benign and malignant adnexal tumors, and to our knowledge, no similar case has been reported.

The biological predisposition to resonate emotionally with another person is regarded as a critical aspect of social interaction. There are, however, situations in which the emotional response to others is discordant with their emotional experience. Using event-related potentials, the present study investigated the neural underpinnings of this phenomenon, termed "counterempathy." Participants played a card game under the belief that they were playing jointly with another player who sat in an adjoining room and whose smiles and frowns in response to winning or losing in the game they could observe on a computer screen. Depending upon the experimental setting, the other player's facial expressions conveyed either of two opposing values to the participant. In the empathic setting, his emotional expressions were congruent with the participant's outcome (win or loss), whereas in the counterempathic setting, they indicated incongruent outcomes. Results revealed a reversed pattern of brain responses to facial expressions between congruent and incongruent conditions at ~170 ms (N170) over the temporal cortex. That is, N170 was sensitive to frowns in the congruent condition and to smiles in the incongruent condition, both indicating losses for the participant. Furthermore, frowns in the incongruent condition yielded larger medial frontal negativity (MFN) over the medial prefrontal cortex, which correlated with the subjective pleasantness about one's own winning in the incongruent condition. These findings demonstrate that (1) counterempathic responses are associated with modulation of early sensory processing of emotional cues, (2) that MFN is sensitive to the detection of another person's loss during positive inequity, and (3) that MFN is associated with a pleasant feeling during positive inequity, which is possibly related to "Schadenfreude."

The number of alpine accidents involving older trekkers has increased markedly in developed countries in recent years. More than 76.8% of the trekkers involved in alpine accidents in Japan were older than 40 years, with some experiencing a stroke or myocardial infarction while trekking at altitude. In the present study, we surveyed social trends in trekkers by interview at a popular mountain site, Mt Tanigawa (1963 m in altitude). The total number of trekkers interviewed was 511, and more than 60% of these were older than 40 years. Of trekkers older than 60 years, 42% complained of conditions such as hypertension or diabetes. In 2 volunteer groups (10 younger subjects and 10 older subjects), physical condition was assessed before and after trekking. Significant body weight loss induced by dehydration was observed more often in older subjects than in younger subjects (P < .05). Balance, as measured using the Nintendo WiiFit (Nintendo, Kyoto, Japan), worsened in the older group (P < .05). Local police records for 2009 showed that the total number of alpine accidents was 65. Injuries provoked by stumbling, slipping, and falling accounted for 51% of these, and 82% of casualties were older than 40 years, with 35% being older than 60 years. In conclusion, many older people involved in nonchallenging middle-altitude trekking have problems with regard to overall health and balance. Alpine accidents caused by myocardial infarction, stroke, or hypoglycemia tend to be more common in this population. Alpine rescue teams should be well prepared for this, and older trekkers should be made aware of their increased risk of injury in alpine settings.

Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6 J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6 J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3 mg/kg) in our preliminary analysis.

The continuing investigation of SAR studies of 3-(2-hydroxyethoxy)-N-(5-benzylthiazol-2-yl)-benzamides as stearoyl-CoA desaturase-1 (SCD-1) inhibitors is reported. Our prior hit-to-lead effort resulted in the identification of 1a as a potent and orally efficacious SCD-1 inhibitor. Further optimization of the structural motif resulted in the identification of 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (37c) with sub nano molar IC(50) in both murine and human SCD-1 inhibitory assays. This compound demonstrated a dose-dependent decrease in the plasma desaturation index in C57BL/6J mice on a non-fat diet after 7 days of oral administration.