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2.  Effects of Brilliant Blue G on Serum Tumor Necrosis Factor-α Levels and Depression-like Behavior in Mice after Lipopolysaccharide Administration 
Objective
Accumulating evidence suggests that inflammation plays a role in the pathophysiology of major depression. The adenosine triphosphate (ATP)-sensitive P2X7 receptor (P2X7R) plays a crucial role in microglial activation caused by inflammation. The dye brilliant blue G (BBG) is a P2X7R antagonist. This study examined whether BBG shows antidepressant effects in an inflammation-induced model of depression.
Methods
We examined the effects of BBG (12.5, 25, or 50 mg/kg) on serum tumor necrosis factor-α (TNF-α) levels after administering the bacterial endotoxin lipopolysaccharide (LPS; 0.5 mg/kg) and the effects of BBG (50 mg/kg) on depression-like behavior in the tail-suspension test (TST) and forced swimming test (FST).
Results
Pretreatment with BBG (12.5, 25, or 50 mg/kg) significantly blocked the increase in serum TNF-α levels after a single dose of LPS (0.5 mg/kg). Furthermore, BBG (50 mg/kg) significantly attenuated the increase in immobility time in the TST and FST after LPS (0.5 mg/kg) administration.
Conclusion
The results suggest that BBG has anti-inflammatory and antidepressant effects in mice after LPS administration. Therefore, P2X7R antagonists are potential therapeutic drugs for inflammation-related major depression.
doi:10.9758/cpn.2014.12.1.31
PMCID: PMC4022763  PMID: 24851118
Coomassie Brilliant Blue; Cytokine; Depression; Inflammation; Purinergic P2X7 receptors; Tumor necrosis factor-alpha
4.  Systemic IgG4-related disease with extensive peripheral nerve involvement that progressed from localized IgG4-related lymphadenopathy: an autopsy case 
Diagnostic Pathology  2014;9:41.
A 77-year-old man, with a lengthy medical history of chronic dysuria, constipation, hypertension, myocardial infarction, and a submandibular lymphadenopathy that was excised 3 years ago, was hospitalized due to elevated liver enzyme levels. He demonstrated hypergammaglobulinemia, hyperproteinemia, high levels of IgG and IgG4, eosinophilia, sclerosing cholangitis, and retroperitoneal fibrosis. He was diagnosed with IgG4-related disease (IgG4-RD). While hospitalized, he had several episodes of syncope while standing and was diagnosed with autonomic nerve dysfunction. Thirty days after hospitalization, he died of nonocclusive mesenteric ischemia (NOMI). Post-mortem, his submandibular lymphadenopathy lesion was diagnosed with progressively transformed germinal center (PTGC)-type IgG4-related lymphadenopathy. At autopsy, small and large intestines showed mucosal necrosis and the wall muscles of the transverse to sigmoid colon were necrotic. The sigmoid colon was fibrotic and infiltrated with numerous IgG4+ plasma cells and eosinophils; infiltration into Auerbach’s plexus was also observed. The IgG4-RD lesions were also detected in the mesentery of the sigmoid colon, retroperitoneal soft tissue, abdominal aorta, liver, extrahepatic bile duct, bilateral lungs, bilateral kidneys, urinary bladder, prostate, epicardium, bilateral coronary arteries, and lymph nodes. Interestingly, infiltration into the lesions was most notable around the peripheral nerves in every organ. Thus, this case describes an IgG4-RD that progressed from PTGC-type IgG4-related lymphadenopathy to systemic IgG4-RD, suggesting that IgG4-RD may affect many organs through peripheral nerve involvement.
Virtual slide
The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9995992971155224.
doi:10.1186/1746-1596-9-41
PMCID: PMC3942268  PMID: 24559103
IgG4; IgG4-related disease; IgG4-related lymphadenopathy; IgG4-related perineural disease; Systemic progression; Peripheral nerve involvement
5.  An Increased Ratio of Glycated Albumin to HbA1c Is Associated with the Degree of Liver Fibrosis in Hepatitis B Virus-Positive Patients 
Background. In hepatitis B virus- (HBV-) positive patients, the relationship between the metabolic variables and histological degree of liver fibrosis has been poorly investigated. Methods. A total of 176 HBV-positive patients were assessed in whom the ratios of glycated albumin-to-glycated hemoglobin (GA/HbA1c) were calculated in order to investigate the relationship with the degree of liver fibrosis. Results. The GA/HbA1c ratio increased in association with the severity of fibrosis (METAVIR scores: F0-1: 2.61 ± 0.24, F2: 2.65 ± 0.24, F3: 2.74 ± 0.38, and F4: 2.91 ± 0.63). The GA/HbA1c ratios were inversely correlated with four variables of liver function: the prothrombin time (PT) percentage (P < 0.0001), platelet count (P < 0.0001), albumin value (P < 0.0001), and cholinesterase value (P < 0.0001). The GA/HbA1c ratio was positively correlated with two well-known markers of liver fibrosis, FIB-4 (P < 0.0001) and the AST-to-platelet ratio index (APRI) (P < 0.0001). Furthermore, the GA/HbA1c showed better correlations with two variables of liver function (PT percentage and cholinesterase value) than did FIB-4 and with all four variables than did the APRI. Conclusion. The GA/HbA1c ratio is associated with the degree of liver fibrosis in HBV-positive patients.
doi:10.1155/2014/351396
PMCID: PMC3947677  PMID: 24693282
6.  Foot Placement Modification for a Biped Humanoid Robot with Narrow Feet 
The Scientific World Journal  2014;2014:259570.
This paper describes a walking stabilization control for a biped humanoid robot with narrow feet. Most humanoid robots have larger feet than human beings to maintain their stability during walking. If robot's feet are as narrow as humans, it is difficult to realize a stable walk by using conventional stabilization controls. The proposed control modifies a foot placement according to the robot's attitude angle. If a robot tends to fall down, a foot angle is modified about the roll axis so that a swing foot contacts the ground horizontally. And a foot-landing point is also changed laterally to inhibit the robot from falling to the outside. To reduce a foot-landing impact, a virtual compliance control is applied to the vertical axis and the roll and pitch axes of the foot. Verification of the proposed method is conducted through experiments with a biped humanoid robot WABIAN-2R. WABIAN-2R realized a knee-bended walking with 30 mm breadth feet. Moreover, WABIAN-2R mounted on a human-like foot mechanism mimicking a human's foot arch structure realized a stable walking with the knee-stretched, heel-contact, and toe-off motion.
doi:10.1155/2014/259570
PMCID: PMC3926377  PMID: 24592154
7.  Tipepidine in children with attention deficit/hyperactivity disorder: a 4-week, open-label, preliminary study 
Background
Tipepidine (3-[di-2-thienylmethylene]-1-methylpiperidine) has been used solely as a nonnarcotic antitussive in Japan since 1959. The safety of tipepidine in children and adults has already been established. It is reported that tipepidine inhibits G-protein-coupled inwardly rectifying potassium (GIRK)-channel currents. The inhibition of GIRK channels by tipepidine is expected to modulate the level of monoamines in the brain. We put forward the hypothesis that tipepidine can improve attention deficit/hyperactivity disorder (ADHD) symptoms by modulating monoaminergic neurotransmission through the inhibition of GIRK channels. The purpose of this open-label trial was to confirm whether treatment with tipepidine can improve symptoms in pediatric patients with ADHD.
Subjects and methods
This was a 4-week, open-label, proof-of-efficacy pilot study for pediatric subjects with ADHD. Ten pediatric ADHD subjects (70% male; mean age, 9.9 years; combined [inattentive and hyperactive/impulsive] subtype, n=7; inattentive subtype, n=3; hyperimpulsive subtype, n=0) received tipepidine hibenzate taken orally at 30 mg/day for 4 weeks. All subjects were assessed using the ADHD Rating Scale IV (ADHD-RS), Japanese version, and the Das–Naglieri Cognitive Assessment System (DN-CAS), Japanese version.
Results
A comparison of baseline scores and 4-week end-point scores showed that all the ADHD-RS scores (total scores, hyperimpulsive subscores, and inattentive subscores) improved significantly (P<0.001). Furthermore, a comparison of baseline DN-CAS total scores and 4-week end-point scores showed a mild trend of improvement (P=0.093). Tipepidine was well tolerated, with no patients discontinuing medication because of side effects.
Conclusion
Our pilot study suggests that tipepidine therapy may prove to be an effective alternative treatment for pediatric patients with ADHD. Nonetheless, more detailed randomized, double-blind trials are needed to confirm tipepidine’s efficacy.
doi:10.2147/NDT.S58480
PMCID: PMC3908907  PMID: 24493927
attention deficit/hyperactivity disorder; tipepidine; GIRK channel; pediatric; antitussive; nucleus accumbens
8.  Benefical Effects of Sigma-1 Agonist Fluvoxamine for Tardive Dyskinesia and Tardive Akathisia in Patients with Schizophrenia: Report of Three Cases 
Psychiatry Investigation  2013;10(4):417-420.
Fluvoxamine is a selective serotonin reuptake inhibitor that is approved for psychiatric disorders such as major depressive episodes and obsessive-compulsive disorder. Beside inhibition of serotonin reuptake, fluvoxamine is also a potent agonist of endoplasmic reticulum (ER) protein sigma-1 receptors, which play a role in the pathophysiology of a number of psychiatric and neurodegenerative disorders. This report presents beneficial effects of sigma-1 agonist fluvoxamine on hyperkinetic movement disorders such as tardive dyskinesia and tardive akathisia. Fluvoxamine might be a novel treatmet approach in the treatment of hyperkinetic movement disorders.
doi:10.4306/pi.2013.10.4.417
PMCID: PMC3902161  PMID: 24474992
Sigma receptor; Fluvoxamine; Akathisia; Dyskinesia
9.  Synthesis and SAR of 1-hydroxy-1H-benzo[d]imidazol-2(3H)-ones as Inhibitors of D-Amino Acid Oxidase 
ACS medicinal chemistry letters  2012;3(10):839-843.
A series of 1-hydroxy-1H-benzo[d]imidazol-2(3H)-ones were synthesized and evaluated for their ability to inhibit human and porcine forms of D-amino acid oxidase (DAAO). Inhibitory potency is largely dependent on the size and position of substituents on the benzene ring with IC50 values of the compounds ranging from 70 nM to greater than 100 µM. Structure-activity relationships of this new class of DAAO inhibitors will be presented in detail along with comparisons to previously published SAR data from other classes of DAAO inhibitors. Some of these compounds were given to mice orally together with D-serine to assess their effects on plasma D-serine pharmacokinetics.
doi:10.1021/ml300212a
PMCID: PMC3519437  PMID: 23243487
D-amino acid oxidase (DAAO); D-serine; NMDA receptors; Glucuronidation
10.  Reduced serum paraoxonase 1 (PON1) activity in patients with schizophrenia treated with olanzapine but not quetiapine 
Background
Second generation antipsychotics (SGAs) are currently the most prescribed drugs in the treatment of schizophrenia. Despite their advantages, which include greater improvement in negative symptoms, cognitive function, prevention of deterioration, quality of life, and fewer extrapyramidal symptoms, the concern regarding metabolic abnormalities which might cause cardiovascular diseases during treatment with SGAs have been rising. Paraoxonase 1 (PON1) is an enzyme mostly located on high-density lipoprotein particles, and has been shown to protect or inhibit lipoprotein oxidation. Growing evidence suggests that PON1 plays a key role in the pathophysiology of atherosclerosis.
Methods
In the present study, we measured serum PON1 activity and serum levels of total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in patients with schizophrenia, who had been treated with either olanzapine or quetiapine, and in healthy controls. Thirty five patients who had been treated with olanzapine, 29 patients who had been treated with quetiapine, and 32 age, sex, and smoking status-matched healthy control (HC) participants were enrolled. Serum PON1 activity and serum levels of TC, triglyceride, HDL-C, and LDL-C were measured.
Results
Serum PON1 activity in the olanzapine group was significantly lower than that of HC and quetiapine groups. Furthermore, serum levels of TC and LDL-C in the olanzapine group were significantly higher than those of quetiapine and HC groups. Interestingly, there was a positive correlation between PON1 activity and HDL-C levels in the olanzapine group.
Conclusion
These findings suggest that serum PON1 activity in patients treated with olanzapine was lower than that of HC and quetiapine groups, and that PON1 may play a role in the metabolic side effects associated with olanzapine treatment. A further study to examine the relationship between serum PON1 activity and cardiovascular and metabolic side effects during treatment with SGAs will be of great interest.
doi:10.2147/NDT.S52463
PMCID: PMC3798239  PMID: 24143103
second generation antipsychotics; SGA; atherosclerosis; metabolic; dyslipidemia; LDL-C
11.  Synthesis and SAR of 1-Hydroxy-1H-benzo[d]imidazol-2(3H)-ones as Inhibitors of d-Amino Acid Oxidase 
ACS Medicinal Chemistry Letters  2012;3(10):839-843.
A series of 1-hydroxy-1H-benzo[d]imidazol-2(3H)-ones were synthesized and evaluated for their ability to inhibit human and porcine forms of d-amino acid oxidase (DAAO). The inhibitory potency is largely dependent on the size and position of substituents on the benzene ring with IC50 values of the compounds ranging from 70 nM to greater than 100 μM. Structure–activity relationships of this new class of DAAO inhibitors will be presented in detail along with comparisons to previously published SAR data from other classes of DAAO inhibitors. Two of these compounds were given to mice orally together with d-serine to assess their effects on plasma d-serine pharmacokinetics.
doi:10.1021/ml300212a
PMCID: PMC3519437  PMID: 23243487
d-amino acid oxidase (DAAO); d-serine; NMDA receptors; glucuronidation
12.  Low Openness on the Revised NEO Personality Inventory as a Risk Factor for Treatment-Resistant Depression 
PLoS ONE  2013;8(9):e71964.
Background
Recently, we reported that low reward dependence, and to a lesser extent, low cooperativeness in the Temperature and Character Inventory (TCI) may be risk factors for treatment-resistant depression. Here, we analyzed additional psychological traits in these patients.
Methods
We administered Costa and McCrae's five-factor model personality inventory, NEO Personality Inventory-Revised (NEO-PI-R), to antidepressant-treatment resistant depressed patients (n = 35), remitted depressed patients (n = 27), and healthy controls (n = 66). We also evaluated the relationships between scores on NEO and TCI, using the same cohort of patients with treatment-resistant depression, as our previous study.
Results
Patients with treatment-resistant depression showed high scores for neuroticism, low scores for extraversion, openness and conscientiousness, without changes in agreeableness, on the NEO. However, patients in remitted depression showed no significant scores on NEO. Patients with treatment-resistant depression and low openness on NEO showed positive relationships with reward dependence and cooperativeness on the TCI.
Conclusions
Many studies have reported that depressed patients show high neuroticism, low extraversion and low conscientiousness on the NEO. Our study highlights low openness on the NEO, as a risk mediator in treatment-resistant depression. This newly identified trait should be included as a risk factor in treatment-resistant depression.
doi:10.1371/journal.pone.0071964
PMCID: PMC3760870  PMID: 24019864
13.  Reliability and Validity of the CogState Battery Chinese Language Version in Schizophrenia 
PLoS ONE  2013;8(9):e74258.
Background
Cognitive impairment in patients with schizophrenia is a core symptom of this disease. The computerized CogState Battery (CSB) has been used to detect seven of the most common cognitive domains in schizophrenia. The aim of this study was to examine the reliability and validity of the Chinese version of the CSB (CSB-C), in Chinese patients with schizophrenia.
Methodology/Principal Findings
Sixty Chinese patients with schizophrenia and 58 age, sex, and education matched healthy controls were enrolled. All subjects completed the CSB-C and the Repeated Battery for the Assessment of Neuropsychological Status (RBANS). To examine the test-retest reliability of CSB-C, we tested 33 healthy controls twice, at a one month interval. The Cronbach α value of CSB-C in patients was 0.81. The test-retest correlation coefficients of the Two Back Task, Gronton Maze Learning Task, Social Emotional Cognition Task, and Continuous Paired Association Learning Task were between 0.39 and 0.62 (p<0.01) in healthy controls. The composite scores and all subscores for the CSB-C in patients were significantly (p<0.01) lower than those of healthy controls. Furthermore, composite scores for patients on the RBANS were also significantly lower than those of healthy controls. Interestingly, there was a positive correlation (r  =  0.544, p<0.001) between the composite scores on CSB-C and RBANS for patients. Additionally, in the attention and memory cognitive domains, corresponding subsets from the two batteries correlated significantly (p<0.05). Moreover, factor analysis showed a two-factor model, consisting of speed, memory and reasoning.
Conclusions/Significance
The CSB-C shows good reliability and validity in measuring the broad cognitive domains of schizophrenia in affected Chinese patients. Therefore, the CSB-C can be used as a cognitive battery, to assess the therapeutic effects of potential cognitive-enhancing agents in this cohort.
doi:10.1371/journal.pone.0074258
PMCID: PMC3759436  PMID: 24023931
14.  Personality Traits as Risk Factors for Treatment-Resistant Depression 
PLoS ONE  2013;8(5):e63756.
Background
The clinical outcome of antidepressant treatment in patients with major depressive disorder (MDD) is thought to be associated with personality traits. A number of studies suggest that depressed patients show high harm avoidance, low self-directedness and cooperativeness, as measured on the Temperament and Character Inventory (TCI). However, the psychology of these patients is not well documented.
Methods
Psychological evaluation using Cloninger’s TCI, was performed on treatment-resistant MDD patients (n = 35), remission MDD patients (n = 31), and age- and gender-matched healthy controls (n = 174).
Results
Treatment-resistant patients demonstrated high scores for harm avoidance, and low scores for reward dependence, self-directedness, and cooperativeness using the TCI, compared with healthy controls and remission patients. Interestingly, patients in remission continued to show significantly high scores for harm avoidance, but not other traits in the TCI compared with controls. Moreover, there was a significant negative correlation between reward dependence and harm avoidance in the treatment-resistant depression cohort, which was absent in the control and remitted depression groups.
Conclusions
This study suggests that low reward dependence and to a lesser extent, low cooperativeness in the TCI may be risk factors for treatment-resistant depression.
doi:10.1371/journal.pone.0063756
PMCID: PMC3661718  PMID: 23717477
15.  Neonatal Disruption of Serine Racemase Causes Schizophrenia-Like Behavioral Abnormalities in Adulthood: Clinical Rescue by D-Serine 
PLoS ONE  2013;8(4):e62438.
Background
D-Serine, an endogenous co-agonist of the N-methyl-D-aspartate (NMDA) receptor, is synthesized from L-serine by serine racemase (SRR). Given the role of D-serine in both neurodevelopment and the pathophysiology of schizophrenia, we examined whether neonatal disruption of D-serine synthesis by SRR inhibition could induce behavioral abnormalities relevant to schizophrenia, in later life.
Methodology/Principal Findings
Neonatal mice (7–9 days) were injected with vehicle or phenazine methosulfate (Met-Phen: 3 mg/kg/day), an SRR inhibitor. Behavioral evaluations, such as spontaneous locomotion, novel object recognition test (NORT), and prepulse inhibition (PPI) were performed at juvenile (5–6 weeks old) and adult (10–12 weeks old) stages. In addition, we tested the effects of D-serine on PPI deficits in adult mice after neonatal Met-Phen exposure. Finally, we assessed whether D-serine could prevent the onset of schizophrenia-like behavior in these mice. Neonatal Met-Phen treatment reduced D-serine levels in the brain, 24 hours after the final dose. Additionally, this treatment caused behavioral abnormalities relevant to prodromal symptoms in juveniles and to schizophrenia in adults. A single dose of D-serine improved PPI deficits in adult mice. Interestingly, chronic administration of D-serine (900 mg/kg/day from P35 to P70) significantly prevented the onset of PPI deficits after neonatal Met-Phen exposure.
Conclusions/Significance
This study shows that disruption of D-serine synthesis during developmental stages leads to behavioral abnormalities relevant to prodromal symptoms and schizophrenia, in later life. Furthermore, early pharmacological intervention with D-serine may prevent the onset of psychosis in adult.
doi:10.1371/journal.pone.0062438
PMCID: PMC3632541  PMID: 23630632
17.  Enzymes in the glutamate-glutamine cycle in the anterior cingulate cortex in postmortem brain of subjects with autism 
Molecular Autism  2013;4:6.
Background
Accumulating evidence suggests that dysfunction in the glutamatergic system may underlie the pathophysiology of autism. The anterior cingulate cortex (ACC) has been implicated in autism as well as in glutamatergic neurotransmission. We hypothesized that alterations in the glutamate-glutamine cycle in the ACC might play a role in the pathophysiology of autism.
Methods
We performed Western blot analyses for the protein expression levels of enzymes in the glutamate-glutamine cycle, including glutamine synthetase, kidney-type glutaminase, liver-type glutaminase, and glutamate dehydrogenases 1 and 2, in the ACC of postmortem brain of individuals with autism (n = 7) and control subjects (n = 13).
Results
We found that the protein levels of kidney-type glutaminase, but not those of the other enzymes measured, in the ACC were significantly lower in subjects with autism than in controls.
Conclusion
The results suggest that reduced expression of kidney-type glutaminase may account for putative alterations in glutamatergic neurotransmission in the ACC in autism.
doi:10.1186/2040-2392-4-6
PMCID: PMC3621600  PMID: 23531457
Autism; Glutamate; Glutaminase; Glutamate-glutamine cycle; Anterior cingulate cortex
19.  Long-Lasting Antidepressant Action of Ketamine, but Not Glycogen Synthase Kinase-3 Inhibitor SB216763, in the Chronic Mild Stress Model of Mice 
PLoS ONE  2013;8(2):e56053.
Background
Clinical studies demonstrate that the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, induces rapid antidepressant effects in patients with refractive major depressive disorder and bipolar depression. This rapid onset of action makes ketamine a highly attractive drug for patients, particularly those who do not typically respond to therapy. A recent study suggested that glycogen synthase kinase (GSK)-3 may underlie the rapid antidepressant action of ketamine, although the precise mechanisms are unclear. In this study, we examined the effects of ketamine and GSK-3 inhibitor SB216763 in the unpredictable, chronic mild stress (CMS) mouse model of mice.
Methodology/Principal Findings
Adult C57/B6 male mice were divided into 2 groups, a non-stressed control group and the unpredictable CMS (35 days) group. Then, either vehicle, ketamine (10 mg/kg), or the established GSK-3 inhibitor, SB216763 (10 mg/kg), were administered into mice in the CMS group, while vehicle was administered to controls. In the open field test, there was no difference between the four groups (control+vehicle, CMS+vehicle, CMS+ketamine, CMS+SB216763). In the sucrose intake test, a 1% sucrose intake drop, seen in CMS mice, was significantly attenuated after a single dose of ketamine, but not SB216763. In the tail suspension test (TST) and forced swimming test (FST), the increased immobility time seen in CMS mice was significantly attenuated by a single dose of ketamine, but not SB216763. Interestingly, the ketamine-induced increase in the sucrose intake test persisted for 8 days after a single dose of ketamine. Furthermore, a single administration of ketamine, but not SB216763, significantly attenuated the immobility time of the TST and FST in the control (non-stressed) mice.
Conclusions/Significance
These findings suggest that a single administration of ketamine, but not GSK-3 inhibitor SB216763, produces a long-lasting antidepressant action in CMS model mice.
doi:10.1371/journal.pone.0056053
PMCID: PMC3563541  PMID: 23390559
20.  Tachikawa project for prevention of posttraumatic stress disorder with polyunsaturated fatty acid (TPOP): study protocol for a randomized controlled trial 
BMC Psychiatry  2013;13:8.
Background
Preclinical and clinical studies suggest that supplementation with omega-3 fatty acids after trauma might reduce subsequent posttraumatic stress disorder (PTSD). To date, we have shown in an open trial that PTSD symptoms in critically injured patients can be reduced by taking omega-3 fatty acids, hypothesized to stimulate hippocampal neurogenesis. The primary aim of the present randomized controlled trial is to examine the efficacy of omega-3 fatty acid supplementation in the secondary prevention of PTSD following accidental injury, as compared with placebo. This paper describes the rationale and protocol of this trial.
Methods/design
The Tachikawa Project for Prevention of Posttraumatic Stress Disorder with Polyunsaturated Fatty Acid (TPOP) is a double-blinded, parallel group, randomized controlled trial to assess whether omega-3 fatty acid supplementation can prevent PTSD symptoms among accident-injured patients consecutively admitted to an intensive care unit. We plan to recruit accident-injured patients and follow them prospectively for 12 weeks. Enrolled patients will be randomized to either the omega-3 fatty acid supplement group (1,470 mg docosahexaenoic acid and 147 mg eicosapentaenoic acid daily) or placebo group. Primary outcome is score on the Clinician-Administered PTSD Scale (CAPS). We will need to randomize 140 injured patients to have 90% power to detect a 10-point difference in mean CAPS scores with omega-3 fatty acid supplementation compared with placebo. Secondary measures are diagnosis of PTSD and major depressive disorder, depressive symptoms, physiologic response in the experiment using script-driven imagery and acoustic stimulation, serum brain-derived neurotrophic factor, health-related quality of life, resilience, and aggression. Analyses will be by intent to treat. The trial was initiated on December 13 2008, with 104 subjects randomized by November 30 2012.
Discussion
This study promises to be the first trial to provide a novel prevention strategy for PTSD among traumatized people.
Trial registration
ClinicalTrials.gov Identifier NCT00671099
doi:10.1186/1471-244X-13-8
PMCID: PMC3598223  PMID: 23289548
Fish oil; Omega-3 fatty acid; Docosahexaenoic acid; Eicosapentaenoic acid; Posttraumatic stress disorder; Accidental injury; Prevention
21.  Decreased Serum Levels of Mature Brain-Derived Neurotrophic Factor (BDNF), but Not Its Precursor proBDNF, in Patients with Major Depressive Disorder 
PLoS ONE  2012;7(8):e42676.
Background
Meta-analyses have identified serum levels of brain-derived neurotrophic factor (BDNF) as a potential biomarker for major depressive disorder (MDD). However, at the time, commercially available human ELISA kits are unable to distinguish between proBDNF (precursor of BDNF) and mature BDNF because of limited BDNF antibody specificity. In this study, we examined whether serum levels of proBDNF, mature BDNF, and matrix metalloproteinase-9 (MMP-9), which converts proBDNF to mature BDNF, are altered in patients with MDD.
Methodology/Principal Findings
Sixty-nine patients with MDD and 78 age- and gender-matched healthy subjects were enrolled. Patients were evaluated using 17 items on the Structured Interview Guide for the Hamilton Depression Rating Scale. Cognitive impairment was evaluated using the CogState battery. Serum levels of proBDNF, mature BDNF, and MMP-9 were measured using ELISA kits. Serum levels of mature BDNF in patients with MDD were significantly lower than those of normal controls. In contrast, there was no difference in the serum levels of proBDNF and MMP-9 between patients and normal controls. While neither proBDNF nor mature BDNF serum levels was associated with clinical variables, there were significant correlations between MMP-9 serum levels and the severity of depression, quality of life scores, and social function scores in patients.
Conclusions/Significance
These findings suggest that mature BDNF may serve as a biomarker for MDD, and that MMP-9 may play a role in the pathophysiology of MDD. Further studies using larger sample sizes will be needed to investigate these results.
doi:10.1371/journal.pone.0042676
PMCID: PMC3411809  PMID: 22880079
22.  Effects of the Antioxidant Sulforaphane on Hyperlocomotion and Prepulse Inhibition Deficits in Mice after Phencyclidine Administration 
Objective
Accumulating evidence suggests that oxidative stress plays a role in the pathophysiology of schizophrenia and that the potent antioxidants may be potential therapeutic drugs for schizophrenia. This study was undertaken to examine the effects of the potent antioxidant sulforaphane (SFN), found in cruciferous vegetables, on behavioral abnormalities (e.g., hyperlocomotion and prepulse inhibition [PPI] deficits) in mice after a single administration of the N-methyl-D-aspartate (NMDA)-receptor antagonist phencyclidine (PCP).
Methods
Effects of SFN (3, 10, and 30 mg/kg, intraperitoneally [i.p.]) on hyperlocomotion and PPI deficits in the adult male ddY mice after administration of PCP (3.0 mg/kg, subcutaneously [s.c.]) were examined.
Results
Administration of SFN (30 mg/kg, intraperitoneally [i.p.]), but not low doses (3 and 10 mg/kg, i.p.), significantly attenuated hyperlocomotion in mice after PCP administration (3.0 mg/kg, subcutaneously [s.c.]). Furthermore, administration of SFN (3, 10, and 30 mg/kg, i.p.) attenuated the PPI deficits in mice after PCP administration (3.0 mg/kg, s.c.) in a dose-dependent manner.
Conclusion
These results suggest that SFN has antipsychotic activity in an animal model of schizophrenia. Therefore, it is likely that SFN may be a potential therapeutic drug for schizophrenia.
doi:10.9758/cpn.2012.10.2.94
PMCID: PMC3569145  PMID: 23430731
Schizophrenia; Phencyclidine; Prepulse inhibition; Sulforaphane; Antioxidants; Nrf2 activator
23.  Prevalence of PTSD and Depression among Junior Middle School Students in a Rural Town Far from the Epicenter of the Wenchuan Earthquake in China 
PLoS ONE  2012;7(7):e41665.
Context
On May12th 2008, a devastating earthquake measuring 8.0 on the Richter scale, struck Wenchuan county and surrounding areas in China. The prevalence of mental illness among children and adolescents in a rural town far from the earthquake epicenter is unknown.
Objective
To assess the prevalence of posttraumatic stress disorder (PTSD) and depression among junior middle school students in a rural town Ningqiang county, 327 km from the earthquake epicenter.
Design, Setting, and Participants
A population-based mental health survey was conducted in March, 2009.
Main Outcome Measure
Survey Self-designed General Condition Survey Scale, Children's Revised Impact of Event Scale (CRIES-13), and the Depression Self-rating Scale for Children (DSRSC) were used to sample 1,841 junior middle school students in Ningqiang county, ten months after the Wenchuan earthquake.
Results
The prevalence rate of a high-risk for PTSD was 28.4%, with 32.7% among females, 23.8% among males (female vs. male, p<0.001), 38.6% in the severe exposure group and 24.3% in the mild exposure group (severe vs. mild exposure, p<0.001). For depressive symptoms, the overall prevalence was 19.5%, with 24.0% among females, 14.7% among males, 24.5% in the severe exposure group and 17.5% in the mild exposure group (female vs. male, p<0.001; severe vs. mild exposure, p<0.001, respectively). In multivariate analysis, factors such as “having felt despair”, or “danger” and “having own house destroyed or damaged” were significantly associated with PTSD symptoms. Female gender and delayed evacuation in females, and earthquake related experiences in males were significantly associated with depression.
Conclusion
Traumatic events experienced during the earthquake were significantly associated with symptoms of PTSD and depression in children and adolescents, ten months after the Wenchuan earthquake. These data highlight a need for mental health services for children and adolescents in rural areas, far from earthquake epicenters.
doi:10.1371/journal.pone.0041665
PMCID: PMC3402444  PMID: 22911838
24.  Calcium-dependent modulation and plasma membrane targeting of the AKT2 potassium channel by the CBL4/CIPK6 calcium sensor/protein kinase complex 
Cell Research  2011;21(7):1116-1130.
Potassium (K+) channel function is fundamental to many physiological processes. However, components and mechanisms regulating the activity of plant K+ channels remain poorly understood. Here, we show that the calcium (Ca2+) sensor CBL4 together with the interacting protein kinase CIPK6 modulates the activity and plasma membrane (PM) targeting of the K+ channel AKT2 from Arabidopsis thaliana by mediating translocation of AKT2 to the PM in plant cells and enhancing AKT2 activity in oocytes. Accordingly, akt2, cbl4 and cipk6 mutants share similar developmental and delayed flowering phenotypes. Moreover, the isolated regulatory C-terminal domain of CIPK6 is sufficient for mediating CBL4- and Ca2+-dependent channel translocation from the endoplasmic reticulum membrane to the PM by a novel targeting pathway that is dependent on dual lipid modifications of CBL4 by myristoylation and palmitoylation. Thus, we describe a critical mechanism of ion-channel regulation where a Ca2+ sensor modulates K+ channel activity by promoting a kinase interaction-dependent but phosphorylation-independent translocation of the channel to the PM.
doi:10.1038/cr.2011.50
PMCID: PMC3193494  PMID: 21445098
calcium sensor; protein kinase; potassium channel; signal transduction
25.  Potentiation of Nerve Growth Factor-Induced Neurite Outgrowth in PC12 Cells by Ifenprodil: The Role of Sigma-1 and IP3 Receptors 
PLoS ONE  2012;7(5):e37989.
In addition to both the α1 adrenergic receptor and N-methyl-D-aspartate (NMDA) receptor antagonists, ifenprodil binds to the sigma receptor subtypes 1 and 2. In this study, we examined the effects of ifenprodil on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Ifenprodil significantly potentiated NGF-induced neurite outgrowth, in a concentration-dependent manner. In contrast, the α1 adrenergic receptor antagonist, prazosin and the NMDA receptor NR2B antagonist, Ro 25-6981 did not alter NGF-induced neurite outgrowth. Potentiation of NGF-induced neurite outgrowth mediated by ifenprodil was significantly antagonized by co-administration of the selective sigma-1 receptor antagonist, NE-100, but not the sigma-2 receptor antagonist, SM-21. Similarly, ifenprodil enhanced NGF-induced neurite outgrowth was again significantly reduced by the inositol 1,4,5-triphosphate (IP3) receptor antagonists, xestospongin C and 2-aminoethoxydiphenyl borate (2-APB) treatment. Furthermore, BAPTA-AM, a chelator of intracellular Ca2+, blocked the effects of ifenprodil on NGF-induced neurite outgrowth, indicating the role of intracellular Ca2+ in the neurite outgrowth. These findings suggest that activation at sigma-1 receptors and subsequent interaction with IP3 receptors may mediate the pharmacological effects of ifenprodil on neurite outgrowth.
doi:10.1371/journal.pone.0037989
PMCID: PMC3360021  PMID: 22655093

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