A Randomized Sham-controlled Trial of 1-Hz and 10-Hz Repetitive Transcranial Magnetic Stimulation (rTMS) of the Right Dorsolateral Prefrontal Cortex in Civilian Post-traumatic Stress Disorder: Un essai randomisé contrôlé simulé de stimulation magnétique transcrânienne repetitive (SMTr) de 1 Hz et 10 Hz du cortex préfrontal dorsolatéral droit dans le trouble de stress post-traumatique chez des civils.

OBJECTIVE: Despite effective psychological and pharmacological treatments, there is a large unmet burden of illness in post-traumatic stress disorder (PTSD). Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive intervention and a putative treatment strategy for PTSD. The evidence base to date suggests that rTMS targeting the dorsolateral prefrontal cortex (DLPFC), in particular the right DLPFC, leads to improvements in PTSD symptoms. However, optimal stimulation parameters have yet to be determined. In this study, we examine the efficacy of high- and low-frequency rTMS of the right DLPFC using a randomized, double-blind, sham-controlled design in civilian PTSD. METHODS: We conducted a 2-week single-site randomized sham-controlled trial of rTMS targeting the right DLPFC. We recruited civilians aged 19 to 70 with PTSD and randomized subjects with allocation concealment to daily 1-Hz rTMS, 10-Hz rTMS, or sham rTMS. The primary outcome was improvement in Clinician Administered PTSD Scale-IV (CAPS-IV). Secondary outcomes included change in depressive and anxiety symptoms. RESULTS: We recruited 31 civilians with PTSD. One 1-Hz-treated patient developed transient suicidal ideation. Analyses revealed significant improvement in CAPS-IV symptoms in the 1-Hz group relative to sham (Hedges' g = -1.07) but not in the 10-Hz group. This was not attributable to changes in anxious or depressive symptomatology. Ten-Hz stimulation appeared to improve depressive symptoms compared to sham. CONCLUSION: Low-frequency rTMS is efficacious in the treatment of civilian PTSD. Our data suggest that high-frequency rTMS of the right DLPFC is worthy of additional investigation for the treatment of depressive symptoms comorbid with PTSD.

The peptidyl-prolyl isomerase PIN1 relieves cyclin-dependent kinase 2 (CDK2) inhibition by the CDK inhibitor p27.

PIN1 is a peptidyl-prolyl isomerase that catalyzes the cis/trans isomerization of peptide bonds between proline and phosphorylated serine/threonine residues. By changing the conformation of its protein substrates, PIN1 increases the activities of key proteins that promote cell cycle progression and oncogenesis. Moreover, it has been shown that PIN1 stabilizes and increases the level of the cyclin-dependent kinase (CDK) inhibitor p27, which inhibits cell cycle progression by binding cyclin A- and cyclin E-CDK2. Notwithstanding the associated increase in the p27 level, PIN1 expression promotes rather than retards cell proliferation. To explain the paradoxical effects of PIN1 on p27 levels and cell cycle progression, we hypothesized that PIN1 relieves CDK2 inhibition by suppressing the CDK inhibitory activity of p27. Here, we confirmed that PIN1-expressing cells exhibit higher p27 levels but have increased CDK2 activities and higher proliferation rates in the S-phase compared with Pin1-null fibroblasts or PIN1-depleted hepatoma cells. Using co-immunoprecipitation and CDK kinase activity assays, we found that PIN1 binds the phosphorylated Thr187-Pro motif in p27 and reduces p27's interaction with cyclin A- or cyclin E-CDK2, leading to increased CDK2 kinase activity. In conclusion, our results indicate that although PIN1 increases p27 levels, it also attenuates p27's inhibitory activity on CDK2 and thereby contributes to increased G1-S phase transitions and cell proliferation.

miR-874-3p is down-regulated in hepatocellular carcinoma and negatively regulates PIN1 expression.

PIN1 is a peptidyl-prolyl cis/trans isomerase (PPIase) that regulates multiple signaling pathways to control cell fate and is found to be over-expressed in cancers, including hepatocellular carcinoma (HCC). However, the regulation of PIN1 in HCC remains poorly defined. Micro-RNAs (miRNAs) have been reported to play a pivotal role in oncogenesis by targeting the 3'-untranslated region (UTR) of mRNAs encoded by oncogenes and tumour suppressor genes, thereby suppressing the levels of both oncoproteins and tumour suppressors. In this report, we aimed to identify miRNAs that suppress PIN1 expression and to determine their role in HCC. By searching the TargetScan database, miR-874-3p was identified as a potential negative regulator of PIN1. miR-874-3p was demonstrated to bind the 3'UTR of PIN1 mRNA directly to suppress expression of PIN1. Functionally, over-expression of miR-874-3p in HCC cell line PLC/PRF/5 inhibited cell growth and colony formation in-vitro, and promoted cellular apoptosis. Furthermore, these tumour suppressive functions conferred by miR-874-3p were abrogated by over-expression of PIN1. Similarly, expression of miR-874-3p in PLC/PRF/5 with PIN1 knocked-down did not further suppress cellular proliferation, suggesting that PIN1 was a major target of miR-874-3p. More importantly, miR-874-3p was found to be down-regulated in HCC tissues and its expression was negatively correlated with that of PIN1. Down-regulation of miR-874-3p was also associated with poorly differentiated tumour cells, more advanced staging, and inferior patient outcomes. In addition, over-expression of miR-874-3p suppressed tumour growth in vivo. Taken together, our data suggested that miR-874-3p plays a tumour suppressive role in HCC through down-regulation of PIN1.

Understanding the role of PIN1 in hepatocellular carcinoma.

PIN1 is a peptidyl-prolyl cis/trans isomerase that binds and catalyses isomerization of the specific motif comprising a phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) in proteins. PIN1 can therefore induce conformational and functional changes of its interacting proteins that are regulated by proline-directed serine/threonine phosphorylation. Through this phosphorylation-dependent prolyl isomerization, PIN1 fine-tunes the functions of key phosphoproteins (e.g., cyclin D1, survivin, ß-catenin and x-protein of hepatitis B virus) that are involved in the regulation of cell cycle progression, apoptosis, proliferation and oncogenic transformation. PIN1 has been found to be over-expressed in many cancers, including human hepatocellular carcinoma (HCC). It has been shown previously that overexpression of PIN1 contributes to the development of HCC in-vitro and in xenograft mouse model. In this review, we first discussed the aberrant transcription factor expression, miRNAs dysregulation, PIN1 gene promoter polymorphisms and phosphorylation of PIN1 as potential mechanisms underlying PIN1 overexpression in cancers. Furthermore, we also examined the role of PIN1 in HCC tumourigenesis by reviewing the interactions between PIN1 and various cellular and viral proteins that are involved in ß-catenin, NOTCH, and PI3K/Akt/mTOR pathways, apoptosis, angiogenesis and epithelial-mesenchymal transition. Finally, the potential of PIN1 inhibitors as an anti-cancer therapy was explored and discussed.

Altered balance of functional brain networks in Schizophrenia.

Activity in dorsal attention (DAN) and frontoparietal (FPN) functional brain networks is linked to allocation of attention to external stimuli, and activity in the default-mode network (DMN) is linked to allocation of attention to internal representations. Tasks requiring attention to external stimuli shift activity to the DAN/FPN and away from the DMN, and optimal task performance depends on balancing DAN/FPN against DMN activity. The current functional magnetic resonance imaging (fMRI) study assessed the balance of DAN/FPN and DMN activity in 13 schizophrenia patients and 13 healthy controls while they were engaged in a task switching Stroop paradigm which demanded internally directed attention to task instructions. The typical pattern of reciprocity between the DAN/FPN and DMN was observed for healthy controls but not for patients, suggesting a reduction in the internally focussed thought important for maintenance of instructions and strategies in schizophrenia. The observed alteration in the balance between DAN/FPN and DMN in patients may reflect a general mechanism underlying multiple forms of cognitive impairment in schizophrenia, including global processing deficits such as cognitive inefficiency and impaired context processing.

Electroconvulsive therapy treatment in patients with somatic symptom and related disorders.

OBJECTIVE: Medically unexplained somatic complaints are highly prevalent, and lead to significant impairment and disability. The number of effective treatment modalities for somatic symptom and related disorders (SSDs) or somatoform disorders (SDs) remains limited. To date, there is no formal indication for electroconvulsive therapy (ECT) in SSD or SD. We report on the largest case series to date regarding the effectiveness of ECT in patients with SSD and SD. METHODS: A retrospective chart review of all patients treated with an index course of ECT at the Neuropsychiatric Program at the University of British Columbia Hospital from 2000 to 2010 was conducted. The primary outcomes consisted of changes in pseudoneurologic symptoms, pain symptoms, cardiopulmonary symptoms, and gastrointestinal symptoms. Complaints were examined pre- and post-ECT. RESULTS: Twenty-eight participants were included in this study. Twenty-one participants received right unilateral ECT. Six received bifrontal ECT. One received bitemporal ECT. Eighteen of 21 participants reported improvement in pseudoneurologic symptoms; eleven of 14 participants reported improvement in pain symptoms; one participant reported improvement in cardiopulmonary symptoms; and one of two participants reported improvement in gastrointestinal symptoms. This paper discusses the putative mechanism of action of ECT in the treatment of SD/SSD. CONCLUSION: This retrospective study suggests that ECT could be included as part of the existing treatment for refractory SSD and SD, particularly in refractory cases with comorbid mood disorders.

Research-track programs for residents in psychiatry: a review of literature and a report of 3 Canadian experiences.

OBJECTIVES: Clinician-scientists occupy an interesting position at the interface between science and care, and have a role to play in bridging the 2 valleys between fundamental and clinical research, and between clinical research and clinical practice. However, research training during medical residency for future clinician scientists is an important but challenging process. Our article, written by residents and directors of research-track (RT) programs, aimed at reviewing literature on RT programs for residents, and describing the organization of RT programs at 3 Canadian universities (the University of British Columbia, the University of Toronto, and McGill University). METHODS: A systematic MEDLINE search was conducted for the review section. Psychiatry program directors in Canada were also contacted to provide information about potential RT programs. RESULTS: Twenty articles were related to resident RT programs in medicine, including 6 in psychiatry. Moreover, 5 out of 16 Canadian programs were found to offer a formal RT program, of which 3 are described here. Most reviewed articles described the program organization, while only one provided an outcome assessment with evidence of increased scholarly activity following RT implementation. CONCLUSIONS: Our article sheds light on postgraduate programs aiming at facilitating the dual training of future clinician-scientists, and developed during the last 10 years. It also highlights the lack of outcome assessment, and the paucity of guidelines to organize these programs in relation to the national requirements.

Changes in mindfulness following repetitive transcranial magnetic stimulation for mood disorders.

OBJECTIVE: Mindfulness practices are associated with changes in different cortical regions, including the dorsolateral prefrontal cortices (DLPFCs). Our study sought to examine how an index course of repetitive transcranial magnetic stimulation (rTMS) over the DLPFC improved components of mindfulness as assessed by Baer's Five Facet Mindfulness Questionnaire (FFMQ) and the Experience Questionnaire (EQ). METHOD: Our preliminary study is a retrospective chart review of 32 patients who had undergone an index course of rTMS for major depressive episode between 2009 and 2012. The following information was collected prior to rTMS: patient demographics, diagnosis, and age of onset of primary diagnosis. The following information was collected prior to and after rTMS: 21-item Hamilton Rating Scale for Depression (HRSD) scores, Patient-Health Questionnaire (PHQ-9) scores, Generalized Anxiety Disorder 7-item (GAD-7) scale scores, FFMQ scores, and EQ scores. RESULTS: Following rTMS, results showed statistically significant decreases in HRSD, PHQ-9, and GAD-7 scores. There was significant improvement in the nonreactivity to inner experience subscale of the BFFMQ and in the decentring subscale of the EQ. Subgroup analysis between patients who did not improve on the HRSD by 50% or more following rTMS and those who did revealed no baseline difference in mindfulness. There was significant improvement in the decentring subscale of the EQ in both subgroups. CONCLUSIONS: Our study provides preliminary data that rTMS may be associated with improvement in some components of mindfulness, independently of changes in depression.

Objectif : Les pratiques de pleine conscience sont associées à des changements dans différentes régions corticales, notamment les cortex préfrontaux dorsolatéraux (CPFDL). Notre étude cherchait à examiner comment un traitement indiciel de stimulation magnétique transcrânienne répétitive (SMTr) sur le CPFDL améliorait les composantes de la pleine conscience telles qu'évaluées par le questionnaire de pleine conscience en 5 facettes (FFMQ) de Baer et le questionnaire sur l'expérience (EQ). Méthode : Notre étude préliminaire est une revue rétrospective des dossiers de 32 patients qui ont subi un traitement indiciel de SMTr pour un épisode de dépression majeure entre 2009 et 2012. Les renseignements suivants ont été recueillis avant la SMTr : données démographiques des patients, diagnostic et âge à l'apparition du diagnostic primaire. Les renseignements suivants ont été recueillis avant et après la SMTr : les scores à l'échelle de dépression en 21 items d'Hamilton (HRSD), les scores au questionnaire patient-santé (PHQ-9), les scores à l'échelle en 7 items du trouble d'anxiété généralisée (GAD-7), les scores au FFMQ, et les scores au EQ. Résultats : Après la SMTr, les résultats ont montré des diminutions statistiquement significatives des scores à la HRSD, au PHQ-9, et à la GAD-7. Il y a eu une amélioration significative de la non-réactivité à la sous-échelle de l'expérience intérieure du FFMQ et à la sous-échelle de décentration de l'EQ. L'analyse de sous-groupe entre les patients qui ne se sont pas améliorés de 50 % ou plus à la HRSD après la SMTr et ceux qui se sont améliorés n'a révélé aucune différence de pleine conscience au départ. Il y avait une amélioration significative à la sous-échelle de décentration de l'EQ dans les deux sous-groupes. Conclusions : Notre étude propose des données préliminaires selon lesquelles la SMTr peut être associée à une amélioration de certaines composantes de la pleine conscience, indépendamment des changements dans la dépression.

PKCalpha mediated induction of miR-101 in human hepatoma HepG2 cells.

BACKGROUND: Protein Kinase C (PKC) is a serine/threonine kinase that involved in controlling of many cellular processes such as cell proliferation and differentiation. We have observed previously that TPA (12-O-tetradecanoylphorbol 13-acetate) induces cell cycle arrest in G0/G1 phase in human hepatoma HepG2 cells. However, is there any miRNA involved in PKCalpha mediated cell growth arrest is still unknown. METHODS: We first surveyed 270 miRNA expression profiles in 20 pairs of human hepatoma tissues. We identified 11 up-regulated and 23 down-regulated miRNAs (FDR < = 0.01; fold-change > = 2) in human hepatoma tissue after Student's T-test and Mann-Whitney rank test. We then examined miRNAs expression profile in TPA treated HepG2 cells. Two miRNAs, miR-101, and miR-29c, were shown to be significantly down regulated in human hepatoma tissues and induced over 4-fold in HepG2 cells under TPA treatment. RESULTS: In this study, we examined TPA regulated miRNA expression profile in human hepatoma HepG2 cells. We identified two miRNAs, 101 and 29c, were induced by TPA and down regulated in human hepatoma tissues suggest that they might play as tumor suppressor gene and in tumor formation of HCC. Since induction kinetics of miR-101 by TPA was much faster than miR-29c suggests that the induction of miR-101 may be the primary response of TPA treatment. We then further investigated how miR-101 was regulated by TPA. MiR-101 targets two subunits of PRC2 complex, enhancer of zeste homolog 2 (EZH2) and EED, and was shown to play as a tumor suppressor gene in human prostate, breast and liver cancers. The target sequence of miR-101 located in the 3' UTR of both EZH2 and EED's mRNA was identified by bioinformatic analysis and was validated by reporter luciferase activity assay. Then we showed that TPA not only up regulated miR-101 expression, but also reduced protein level of EZH2, EED and H3K27me3 in HepG2 cells. Using lenti-virus-mediated shRNA to knockdown endogenous PKCalpha expression, we observed that TPA induced growth arrest, elevation of miR-101 and reduction of EZH2, EED and H3K27me3 proteins were all PKCalpha dependent. Specific inhibitor of ERK completely blocked TPA induced miR-101 expression. CONCLUSIONS: Therefore, this is the first time to show that PKCalpha and ERK pathway play important role to activate miR-101 expression, reduce PRC2 complex and H3K27me3 level. This epigenetic regulatory pathway may represent a novel mechanism of carcinogenesis and deserve further investigation.