Entacapone augmentation of antipsychotic treatment in schizophrenic patients with negative symptoms; a double-blind placebo-controlled study.

Negative symptoms in schizophrenia are associated with decreased dopaminergic activity in the prefrontal cortex (PFC). It is hypothesized that increasing dopamine levels would alleviate negative symptoms. Termination of dopamine activity in the PFC is mainly via catechol-O-methyl tranferase (COMT) activity. Hence, inhibition of COMT activity with entacapone should reverse PFC dopaminergic transmission. To assess the efficacy of entacapone addition to antipsychotic treatment in patients with residual schizophrenia, we conducted a double-blind, randomised, placebo-controlled study for 12 wk of treatment with entacapone or placebo. Clinical measures (PANSS, CGI and QLS) were obtained at baseline and at weeks 4, 8 and 12 and cognitive functions were assessed by the RBANSS. Significant improvement over time in PANSS and QLS scores was observed in both groups. However, entacapone did not demonstrate a beneficial effect compared to placebo. Therefore, this study does not support a therapeutic role for entacapone in residual schizophrenia.

Dexamethasone in the presence of desipramine enhances MAPK/ERK1/2 signaling possibly via its interference with ß-arrestin.

Antidepressant medication is the standard treatment for major depression disorder (MDD). However, the response to these treatments is often incomplete and many patients remain refractory. In the present study, we show that the glucocorticoid receptor (GR) agonist dexamethasone (DEX) increased MAPK/ERK1/2 signaling in the presence of the noradrenergic antidepressant, desipramine (DMI), while no such effect was induced by DEX or DMI alone in human neuroblastoma SH-SY5Y cells. This enhancement was dependent on the activation of both α(2) adrenergic receptors (AR) and GR. The timing of MAPK/ERK1/2 activation as well as DEX-induced reduction in membranous α(2) AR suggests the involvement of a ß-arrestin-dependent mechanism. In line with the latter, DEX increased cytosolic and decreased membranous levels of ß-arrestin. Concomitantly, DEX induced a time-dependent increase in cytosolic α(2) AR-ß-arrestin interaction and a decrease in ß-arrestin interaction with Mdm2 E3 ubiquitin ligase. All of these effects of DEX were prevented by the GR antagonist RU486. Our data suggest an additional intracellular role for DEX, in which activation of GR interferes with the trafficking and degradation of ß-arrestin-α2c-AR complex. We suggest that such an interaction in the presence of DMI can enhance MAPK/ERK1/2 signaling, a key player in neural plasticity and neurogenesis processes, which is impaired in MDD, while stimulated by antidepressants.

Resource loss and posttraumatic responses in Bedouin members of the Israeli Defense Forces.

This study examined the impact of exposure to traumatizing events in an ethnic minority group of Bedouin members of the Israel Defense Forces (N = 317). Guided by the conservation of resources (COR) theory (Hobfoll, 1988), the authors hypothesized that loss of resources would mediate the relationship between trauma and posttraumatic responses. We found that loss of personal resources (e.g., self-esteem, self-mastery) was the best predictor of psychological distress among traumatized Bedouin servicemen. Our findings suggest the significance of personal resources within collectivist communities in coping with trauma and maintaining resilience. This study contributes to the understanding of the ethnocultural aspects of trauma and the potential interventions that may be tailored for minority groups.

Hypercoagulation in chronic post-traumatic stress disorder.

BACKGROUND: Whereas procoagulation abnormalities in acute stress are well established, little is known about the mechanism of hypercoagulation in chronic stress, such as post-traumatic stress disorder (PTSD). This is crucial, given the fact that chronic coagulation disturbances have been associated with increased morbidity and premature mortality due to thromboembolism and cardiovascular disorders, complications recently described in PTSD patients. OBJECTIVES: To explore the mechanisms of hypercoagulation in chronic PTSD. METHODS: Thirty patients diagnosed with chronic PTSD were enrolled and compared with a control group matched for age, gender and ethnicity. Hypercoagulation state was evaluated by levels of fibrinogen, D-dimer, prothrombin fragment F 1+2, von Willebrand factor (vWF) antigen, factor VIII activity, activated protein C resistance, ProC Global assay, and tissue factor antigen. Psychiatric evaluation was performed using the Mini-International Neuropsychiatric Interview and Clinician Administered PTSD Scale (CAPS). RESULTS: vWF antigen levels were significantly higher in patients with chronic PTSD compared with the controls (121.3 +/- 42 vs. 99.7 +/- 23, respectively, P = 0.034). Higher levels of vWF antigen and factor VIII activity were found in patients with severe chronic PTSD (CAPS > 80), compared to controls and patients with chronic PTSD and less severe symptoms (CAPS < or = 80). However, no differences were observed in any other studied coagulation parameters between patients and controls. CONCLUSIONS: Increased levels of vWF antigen and factor VIII activity were documented in severe chronic PTSD. These findings suggest that the higher risk of arterial and venous thromboembolic events in PTSD patients could be related to endothelial damage or endothelial activation.

DNA methylation in vulnerability to post-traumatic stress in rats: evidence for the role of the post-synaptic density protein Dlgap2.

Post-traumatic stress disorder (PTSD) is unique among psychiatric disorders since there is an explicit requirement for the presence of a well-defined precipitating environmental event. This suggests the participation of adaptable molecular processes such as epigenetic modifications, including acetylation and methylation of histones and DNA methylation. In the present study we investigated whether changes in DNA methylation are associated with the effects of traumatic stressor, using a validated PTSD rat model. Screening of genomic DNA methylation patterns revealed that maladaptation to traumatic stress is associated with numerous changes in the methylation pattern of rat hippocampus. Of the differentially methylated genes revealed by this global screening, Disks Large-Associated Protein (Dlgap2) was of special interest, demonstrating an increase in a specific methylation site which was associated with a reduction in its gene expression in PTSD-like compared to non-PTSD-like rats. The association between the methylation rate and Dlgap2 expression was further substantiated by re-dividing the rats according to their methylation state. A significantly higher expression was observed in the non-methylated compared to methylated rats. In addition, taking all rats as one group revealed a significant correlation between their behavioural stress responses and Dlgap2 transcript levels. These results suggest that alterations in global methylation pattern are involved in behavioural adaptation to environmental stress and pinpoint Dlgap2 as a possible target in PTSD.

Safety, tolerability and preliminary evidence for antidepressant efficacy of theta-burst transcranial magnetic stimulation in patients with major depression.

The aim of this open study was to evaluate the safety and tolerability of theta-burst transcranial magnetic stimulation (TBS) and to assess preliminarily its therapeutic efficacy in patients with major depression. A total of 33 patients were assigned to receive one of four TBS protocols for 10 consecutive work days. TBS consisted of triple-pulse 50-Hz bursts given at a rate of 5 Hz to the left or right dorsolateral prefrontal cortex at different stimulation parameters. Severity of depression was assessed by the Hamilton Depression Rating Scale. Our results indicate that TBS as applied in this study is safe and well tolerated in depressed patients and seems to have antidepressant properties. Increase of stimulation parameters is not associated with more side-effects and adds to its therapeutic effect.

Bedouin wives on the home front: living with men serving in the Israel Defense Forces.

This community-based study examined emotional and somatic symptoms of 129 Bedouin women whose husbands serve in the Israel Defense Forces. Wives of men diagnosed with posttraumatic stress disorder (PTSD) reported more symptoms than wives of men diagnosed with other disorders and wives of men with no diagnosis. Findings indicate that not only was PTSD in Bedouin servicemen positively associated with their wives' symptoms of posttraumatic stress and depression and somatic complaints, but that this relationship was fully mediated by husbands' aggression. Unraveling the special circumstances of women from traditional backgrounds faced with the devastating effects of husbands' combat-related posttraumatic pathology may inform an approach to the concept of vicarious trauma that is more specific to non-Western societies.

Prognostic significance of HER-2/neu expression in patients with ductal carcinoma in situ.

BACKGROUND: The prognostic significance of biologic markers in women with ductal carcinoma in situ is not fully understood. HER2/neu is a marker of prognostic significance that is routinely assessed in invasive cancer but its correlation with clinical outcome in DCIS is still obscure. OBJECTIVES: To evaluate the significance of HER-2/neu expression as a prognostic marker in DCIS. METHODS: Clinical and pathologic data from 84 patients treated for DCIS were analyzed. HER-2/neu expression was determined by immunohistochemical staining. Histopathologic parameters (nuclear grade, histologic subtype, necrosis, calcifications, margins) were reviewed by an experienced pathologist. Local recurrence and/or metastatic spread were used as endpoints to determine the prognostic significance of HER-2/neu expression. RESULTS: With a median follow-up of 94.8 months, nine recurrences were reported. Neither univariate nor multivariate analysis showed a significant correlation between HER-2/neu expression and disease recurrence or the time to disease recurrence. Although HER-2/neu expression demonstrated a significant association with high nuclear grade (P < 0.0001) and comedo subtype (P < 0.0001), there was no correlation between these histologic features and recurrence rate. The correlation between high nuclear grade and disease recurrence approached statistical significance (P = 0.07). CONCLUSIONS: No significant association was found between HER-2/neu expression in DCIS and disease recurrence. However, HER-2/neu correlated with negative markers such as nuclear grading and comedo necrosis, and its role should therefore be investigated in larger studies.

Functional connectivity abnormalities during processing of predictive stimuli in patients with major depressive disorder.

The study investigated the underlying mechanisms associated with the ability of patients with major depressive disorder (MDD) to utilize predictive contextual information in order to facilitate detection of predictable versus random targets. To this end we evaluated EEG event-related functional connectivity during the processing of predictive stimuli in MDD and control subjects. A target detection task was used where targets were either preceded by randomized sequences of standards, or by sequences that included a predictive sequence. Functional connectivity was evaluated using synchronization likelihood and graph theory. The cluster coefficient and local efficiency values were greater in MDD compared to controls, during the processing of the three stimuli consisting of the predictive sequence, in the beta frequency band, suggesting an increased structured network organization. These changes were associated with increased functional connectivity within frontal networks in MDD patients compared to controls. However, no significant functional connectivity group-changes were observed for target conditions or randomized standards. These findings suggest that MDD is associated with context-specific functional connectivity abnormalities during the processing of predictive stimuli.

Dopamine modulates mitochondrial function in viable SH-SY5Y cells possibly via its interaction with complex I: relevance to dopamine pathology in schizophrenia.

Deleterious effects of dopamine (DA) involving mitochondrial dysfunction have an important role in DA-associated neuronal disorders, including schizophrenia and Parkinson's disease. DA detrimental effects have been attributed to its ability to be auto-oxidized to toxic reactive oxygen species. Since, unlike Parkinson's disease, schizophrenia does not involve neurodegenerative processes, we suggest a novel mechanism by which DA impairs mitochondrial function without affecting cell viability. DA significantly dissipated mitochondrial membrane potential (delta psi m) in SH-SY5Y cells. Bypassing complex I prevented the DA-induced depolarization. Moreover, DA inhibited complex I but not complex II activity in disrupted mitochondria, suggesting complex I participation in DA-induced mitochondrial dysfunction. We further demonstrated that intact mitochondria can accumulate DA in a saturated manner, with an apparent Km=122.1+/-28.6 nM and Vmax=1.41+/-0.15 pmol/mg protein/min, thereby enabling the interaction between DA and complex I. DA accumulation was an energy and Na+-dependent process. The pharmacological profile of mitochondrial DA uptake differed from that of other characterized DA transporters. Finally, relevance to schizophrenia is demonstrated by an abnormal interaction between DA and complex I in schizophrenic patients. These results suggest a non-lethal interaction between DA and mitochondria possibly via complex I, which can better explain DA-related pathological processes observed in non-degenerative disorders, such as schizophrenia.

Physical stress differs from psychosocial stress in the pattern and time-course of behavioral responses, serum corticosterone and expression of plasticity-related genes in the rat.

Stressors differ in their physiological and behavioral outcomes. One of the major mechanisms by which stressors affect the brain and behavior is alteration in neuronal plasticity. We investigated in the rat the effects of a single exposure to psychophysical (electrical foot shock) vs. psychological (social defeat) stressors on anxiety- and depression-related behaviors, serum levels of corticosterone and the expression of plasticity-related genes CAM-L1, CREB, GAP-43, and laminin in the prefrontal cortex (PFC), the amygdala and the hippocampus. Rats were examined for 24 h or 1 week after the exposure to stress. Footshocks enhanced anxiety-related behaviors, whereas social defeat induced depression-related behaviors at both time points and less pronounced anxiety 1 week post-exposure. Serum corticosterone concentrations were enhanced 24 h after shocks, but only 1 week after exposure to the social stressor. Moreover, the shock-stressed rats exhibited decreased CAM-L1 protein level in the hippocampus 24 h post-exposure and decreased GAP-43 protein level in the PFC 1 week post-exposure. By contrast, the social stressor enhanced expression of the plasticity-related proteins in the amygdala and the hippocampus, mostly 1 week after the exposure. These results indicate stressor-specific time-dependent changes in different neuronal pathways, and suggest consideration of a cause-specific approach to the treatment of stress-related disorders.

Acute stress reactions among medical and non-medical personnel in a general hospital under missile attacks.

BACKGROUND: Recent mass level traumatic events further boosted the growing interest in understanding the effects of primary (direct) and secondary (indirect) traumatic exposure on "helping professionals." The objectives of this study are: (1) to assess the rates and severity of PTSD symptoms (PS) among hospital workers operating under fire while treating war-related injured patients, (2) to explore the effect of PS on level of functioning in real time, and (3) to estimate the added effect of secondary traumatization over and above that of primary traumatization. METHODS: Rates of PS, level of psychological distress, and level of functioning were assessed in 412 medical and non-medical personnel working in a hospital that was under missile attacks during the Second Lebanon War in the summer of 2006. The Posttraumatic Stress Disorder Scale (PSS) was used to assess severity of PS, as well as to estimate probable DSM-IV diagnosis of PTSD. RESULTS: The mean number of reported PS was 8.6 (SD=4.4). Forty-three (10.2%) of the participants met the symptom and severity threshold for a probable diagnosis of PTSD, however only 13 of these 43 reported impaired level of functioning. There were no significant differences between personnel who had direct exposure to injured or traumatized casualties of the war and those who were not on PS severity and frequency of probable PTSD. CONCLUSIONS: These findings suggest that hospital workers operating under prolonged life-threatening conditions are at moderate risk for PTSD. However, they do not support an incremental effect of secondary traumatic exposure.

Laparoscopic colectomy for colonic polyps.

BACKGROUND: Benign colonic polyps not amenable to colonoscopic resection or those containing carcinoma require surgical excision. Traditionally, formal colectomy with clearance of the lymphatic basin has been performed. The aim of this study was to review our experience with the laparoscopic approach for retrieval of colonic polyps with specific emphasis on safety, feasibility, and tumor localization. METHODS: Retrospective chart review of all patients who underwent laparoscopic colectomy for colonic polyps was performed. Initial colonoscopic biopsies were compared with the postoperative pathology report of the resected specimen. RESULTS: Forty-nine patients (22 males, 27 males, mean age 66 years) underwent laparoscopic colectomy for colonic polyps. Indications for surgery were presumably benign polyps in 38 patients, and superficial carcinoma in a polyp, diagnosed by colonoscopy, in 11; twenty-three patients underwent preoperative localization procedures. In 19% of patients who did not have preoperative localization, difficulties locating the polyp were encountered during surgery, requiring intraoperative endoscopy or conversion to laparotomy. In 7 of the 38 patients with presumably benign lesion, colon cancer was diagnosed in the colectomy specimen. None of the 18 patients who had cancerous lesions had any positive lymph nodes. CONCLUSIONS: Laparoscopic surgery for the treatment of colonic polyps seems to be feasible and safe, with a low complication rate. Tumor localization is crucial for adequate resection. Although one-fifth of presumably benign polyps harbored cancer, none of these patients had positive lymph nodes. These preliminary results may question the need for radical lymph node clearance in these patients.

Norepinephrine-glucocorticoids interaction does not annul the opposite effects of the individual treatments on cellular plasticity in neuroblastoma cells.

The plasticity hypothesis of major depression states that glucocorticoids may be detrimental to neuronal plasticity while monoamines and antidepressants may reconstitute cellular plasticity. The aim of the present study was to investigate how dexamethasone, a synthetic glucocorticoid, and norepinephrine, both of which are involved in depression, interact to affect aspects of neuronal plasticity. Dexamethasone and norepinephrine administered separately oppositely affected differentiation of human neuroblastoma SH-SY5Y cells, observed by both morphological alterations and gene expression, at the level of mRNA and protein of the differentiation markers Gap-43, L1 and laminin. Norepinephrine increased differentiation, manifested as an increase in neurite length, neurite number, and gene expression, while dexamethasone reduced these parameters. Opposite effects were also observed in the expression of the transcription factor CREB with norepinephrine upregulating phosphorylated CREB (pCREB) levels, while dexamethasone downregulated CREB mRNA and protein levels, as well as pCREB levels. Interestingly, co-administration of dexamethasone and norepinephrine resulted in morphology more differentiated than control and similar to that induced by norepinephrine, albeit to a lesser degree. The alterations in the expression of the differentiation markers induced by norepinephrine or dexamethasone treatments were mostly annulled by the co-treatment. However, pCREB levels were robustly enhanced by co-treatment, as compared to both control and norepinephrine treated cells, providing a possible explanation for the morphological increase in differentiation. These results suggest that in order for cells to combat the deleterious effects of glucocorticoids, a hyperactivation of pCREB may be necessary to restore differentiation and plasticity.

Trauma exposure and posttraumatic reactions in a community sample of Bedouin members of the Israel Defense Forces.

BACKGROUND: Limited available data indicate that minorities in military service face heightened risks for traumatic exposure and more severe posttraumatic reactions. This study explored traumatic exposure and impact on mental and physical health, functioning, and medical services utilization in a previously unstudied ethnic minority group of Bedouins enlisted in the Israeli Defense Forces. METHODS: Participants were 317 community-based Bedouin servicemen recruited through community outreach efforts. Axis I psychiatric diagnoses were determined by the Structured Clinical Interview for DSM-IV Disorders; posttraumatic symptoms were measured with the Screen for Posttraumatic Stress Symptoms; and depression and anxiety symptoms were assessed by the Hopkins Symptom Checklist -25 (HSCL-25) Arabic version. Functional impairment and health service utilization were measured by a self-report questionnaire. RESULTS: Use of a stringent definition of trauma, restricted to experiences involving physical presence at the scene of the event, revealed that 75% of respondents reported potentially traumatizing events. Cap of these nearly 20% were diagnosed with posttraumatic stress disorder (PTSD), which was mostly co-morbid with depression, alcohol abuse, or both. In spite of the widespread trauma exposure in this community, only those trauma-exposed men who developed PTSD experienced extensive impact on their health, as indicated by associations with poor health status, physician-diagnosed medical conditions, health-related impairment in daily functioning, and frequent use of primary or specialty care services. Mental health services were typically not utilized. CONCLUSIONS: Detection of PTSD among Bedouin servicemen necessitates deliberate diagnostic efforts within primary care settings.

Participation of the left inferior frontal gyrus in human originality.

Human creative cognition is commonly described as a twofold cyclic process that involves an idea generation phase and an idea evaluation phase. Although the evaluation phase makes a crucial contribution to originality, its underlying mechanisms have not received sufficient research attention. Here, we suggest that the left inferior frontal gyrus (lIFG) plays a major role in the interplay between the evaluation and generation networks and that inhibiting this region's activity may have an effect on "releasing" the generation neural network, resulting in greater originality. To examine the neural networks that mediate the generation and evaluation of ideas, we conducted an fMRI experiment on a group of healthy human participants (Study 1), in which we compared an idea generation task to an idea evaluation task. We found that evaluating the originality of ideas is indeed associated with a relative increase in lIFG activation, as opposed to generating original ideas. We further showed that temporarily inhibiting the lIFG using continuous theta-burst stimulation (Study 2) results in less strict evaluation on the one hand and increased originality scores on the other. Our findings provide converging evidence from multiple methods to show that the lIFG participates in evaluating the originality of ideas.

Secondary Prevention of Chronic PTSD by Early and Short-Term Administration of Escitalopram: A Prospective Randomized, Placebo-Controlled, Double-Blind Trial.

OBJECTIVE: Prospective studies have not identified a viable pharmacologic strategy for secondary prevention of posttraumatic stress disorder (PTSD). The authors examined whether preventive intervention via early and short-term administration of a selective serotonin reuptake inhibitor (SSRI), within 1 month of exposure to a traumatic event (before diagnosis of PTSD could be made), may reduce the severity of PTSD symptoms according to DSM-IV at 13 months' follow-up. METHODS: Over 25,000 screening calls to patients referred to an emergency department for a traumatic event performed between June 2006 and December 2008 yielded 353 participants who were recruited within the month following a traumatic event . Participants were randomly assigned in a double-blind design to escitalopram (n = 176) or placebo (n = 177). The per-protocol analysis comprised 198 participants (escitalopram, n = 102; placebo, n = 96) who received treatment for 12 to 24 weeks and were available for follow-up at week 56. RESULTS: The primary outcome measure, the Clinician Administered PTSD Scale (CAPS), revealed no prevention effect. However, a secondary outcome, the Pittsburgh Sleep Quality Inventory (PSQI), showed better results for the SSRI group than for the placebo group. For a subset of participants who experienced intentional trauma (missile attacks, rape, or physical assault; n = 50), the prevention effect was found on both primary and secondary measures (CAPS, PSQI and measures of depression and global illness severity). CONCLUSIONS: Early and short-term administration of escitalopram was not shown to prevent PTSD, although it did improve sleep quality. In a subgroup of participants who experienced intentional trauma, however, this early-treatment approach may be effective as secondary prevention. This large study is the first to investigate the preventive effect of early administration of escitalopram on PTSD. It highlights the relevance of the type of trauma (intentional vs unintentional) to the outcome. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00300313​​.

The pro-apoptotic ARTS/Sept4 protein is significantly reduced in post-mortem brains from schizophrenic patients.

Schizophrenic brains exhibit various neuro-pathological changes in size, volume and structure as compared to normal brains. These structural abnormalities could be the result of apoptotic cell death. ARTS/Sept4 protein plays an important role in induction and promotion of apoptosis. Though ARTS is highly expressed in the healthy human brain, most of tested schizophrenic brain samples showed no expression of ARTS protein. Specifically, using Western blot analysis with monoclonal anti-ARTS antibody we found that only 1 out of 14 schizophrenic samples (7%) showed a strong ARTS signal as compared to 10 out of 15 (66.6%) found in the normal controls group. Furthermore, using immunohistochemistry assay only 33.3% (5 of 15) (SE+/-12.5) of the schizophrenic patients samples showed any ARTS immunoreactivity as compared to (13 of 15) 87% (SE+/-9) of bipolar, (11 of 14) 78% (SE+/-11.3) of major depression and (10 of 14) 71% (SE+/-12.5) of normal controls. A four-fold reduction in apoptosis rate was measured in these schizophrenic samples as compared to average apoptosis rate found in all other samples. These data support the linkage between loss of ARTS expression and the loss of sensitivity towards apoptosis. Interestingly, levels of ARTS were significantly lower in male schizophrenic patients as compared to female schizophrenic patients, and males of all other control groups. We propose that ARTS may play an important role in the pathogenesis of schizophrenia and could be used as a marker for this disease.

Cerebral glucose utilization and platelet mitochondrial complex I activity in schizophrenia: A FDG-PET study.

Altered cerebral energy metabolism and mitochondrial dysfunction in periphery and in brain are implicated in the pathophysiology of schizophrenia. This study investigated whether cerebral glucose metabolism (rCGM) abnormalities are linked to altered mitochondrial complex I activity in the periphery, in schizophrenia. Sixteen schizophrenic patients, 8 with total positive PANSS score >or=20 (high positive schizophrenics; HPS), and 8 with total positive score

Specimen length as a perioperative surrogate marker for adequate lymphadenectomy in colon cancer: the surgeon's role.

The objective of this study was to determine whether there is a correlation between the length of the sigmoid colon removed and the number of harvested lymph nodes (LNs). Pathology charts of 137 sigmoid resections that were done over a 5-year period were reviewed. The length of removed sigmoid specimen reported in the pathology reports was correlated with the number of LNs retrieved from the specimen. The mean and median numbers of retrieved LNs were 9 and 10, respectively. There was an increase in the number of retrieved LNs with increasing length of resected sigmoid colon. For Dukes' B patients, the average length of the resected specimen was 15.1 cm for those with < 12 LNs and 20.3 cm for those with > 12 LNs (P = 0.01). Our data suggest that the surgeon may play an important role in determining the extent of LN harvesting during large bowel resection for cancer.