The development of an fMRI protocol to investigate vmPFC network topology underlying the generalization of behavioral control

Description: Experiencing behavioral control over stress can have long lasting and generalizing effects. The controllability of a physical threat, for example, affects the processing of subsequent social stress. Animal research has shown that the vmPFC plays a critical role in behavioral control and orchestrating subcortical responses. However, translational research on these neural systems in humans is sparse and we therefore aimed to develop a paradigm to test the generalization effect of behavioral control on vmPFC functioning. A pilot study was performed in which subjects (n=18) were first randomly assigned to one of two versions of a signal detection task, where feedback was either paired with a controllable or an uncontrollable mild shock. Subsequently, subjects underwent a social evaluative threat fMRI paradigm to measure their response to the anticipation of speaking in public. The analyses tested whether the controllability manipulation influenced behavioral and physiological responses and vmPFC network topology. Results showed that overall subjects were faster to respond to potential shock trials in the signal detection task, and there was a trend significant difference between the controllable or uncontrollable group. No significant differences between the two groups were observed on other behavioral or physiological responses. fMRI results showed higher vmPFC efficiency in the controllable threat group at baseline and recovery but similar to the uncontrollable group during speech anticipation. The current report establishes the feasibility of the protocol and adequately-powered follow-up research is needed to further evaluate the generalization effect on the behavioral, physiological and neural level

Top-down control of visual sensory processing during an ocular motor response inhibition task

The study addressed whether top-down control of visual cortex supports volitional behavioral control in a novel antisaccade task. The hypothesis was that anticipatory modulations of visual cortex activity would differentiate trials on which subjects knew an anti- versus a pro-saccade response was required. Trials consisted of flickering checkerboards in both peripheral visual fields, followed by brightening of one checkerboard (target) while both kept flickering. Neural activation related to checkerboards before target onset (bias signal) was assessed using electroencephalography. Pretarget visual cortex responses to checkerboards were strongly modulated by task demands (significantly lower on antisaccade trials), an effect that may reduce the predisposition to saccade generation instigated by visual capture. The results illustrate how top-down sensory regulation can complement motor preparation to facilitate adaptive voluntary behavioral control

Characterization of childhood trauma, hippocampal mediation and Cannabis use in a large dataset of psychosis and non-psychosis individuals

Background Cannabis use (CA) and childhood trauma (CT) independently increase the risk of earlier psychosis onset; but their interaction in relation to psychosis risk and association with endocannabinoid-receptor rich brain regions, i.e. the hippocampus (HP), remains unclear. The objective was to determine whether lower age of psychosis onset (AgePsyOnset) is associated with CA and CT through mediation by the HP volumes, and genetic risk, as measured by schizophrenia polygene scores (SZ-PGRS). Methods Cross-sectional, case-control, multicenter sample from 5 metropolitan US regions. Participants (n = 1185) included 397 controls not affected by psychosis (HC); 209 participants with bipolar disorder type-1; 279 with schizoaffective disorder; and 300 with schizophrenia (DSM IV-TR). CT was assessed using the Childhood Trauma Questionnaire (CTQ); CA was assessed by self-reports and trained clinical interviewers. Assessment included neuroimaging, symptomatology, cognition and calculation of the SZ polygenic risk score (SZ-PGRS). Results In survival analysis, CT and CA exposure interact to be associated with lower AgePsyOnset. At high CT or CA, CT or CA are individually sufficient to affect AgePsyOnset. CT relation with AgePsyOnset is mediated in part by the HP in CA users before AgePsyOnset. CA before AgePsyOnset is associated with higher SZ-PGRS and correlated with younger age at CA usage. Discussion CA and CT interact to increase risk when moderate; while severe CT and/or CA abuse/dependence are each sufficient to affect AgePsyOnset, indicating a ceiling effect. Probands with/out CA before AgePsyOnset differ on biological variables, suggesting divergent pathways to psychosis

Visuomotor brain network activation and functional connectivity among individuals with autism spectrum disorder

Sensorimotor abnormalities are common in autism spectrum disorder (ASD) and predictive of functional outcomes, though their neural underpinnings remain poorly understood. Using functional magnetic resonance imaging, we examined both brain activation and functional connectivity during visuomotor behavior in 27 individuals with ASD and 30 typically developing (TD) controls (ages 9–35 years). Participants maintained a constant grip force while receiving visual feedback at three different visual gain levels. Relative to controls, ASD participants showed increased force variability, especially at high gain, and reduced entropy. Brain activation was greater in individuals with ASD than controls in supplementary motor area, bilateral superior parietal lobules, and contralateral middle frontal gyrus at high gain. During motor action, functional connectivity was reduced between parietal-premotor and parietal-putamen in individuals with ASD compared to controls. Individuals with ASD also showed greater age-associated increases in functional connectivity between cerebellum and visual, motor, and prefrontal cortical areas relative to controls. These results indicate that visuomotor deficits in ASD are associated with atypical activation and functional connectivity of posterior parietal, premotor, and striatal circuits involved in translating sensory feedback information into precision motor behaviors, and that functional connectivity of cerebellar–cortical sensorimotor and nonsensorimotor networks show delayed maturation

A Randomized Phase II Study of Carboplatin With Weekly or Every-3-Week Nanoparticle Albumin-Bound Paclitaxel (Abraxane) in Patients With Extensive-Stage Small Cell Lung Cancer

Platinum plus etoposide is the standard therapy for extensive-stage small cell lung cancer (ES-SCLC) and is associated with significant myelosuppression. We hypothesized that the combination of carboplatin and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) would be better tolerated. We investigated carboplatin with nab-paclitaxel on every-3-week and weekly schedules

Symptom dimensions of the psychotic symptom rating scales in psychosis: a multisite study

The Psychotic Symptom Rating Scales (PSYRATS) is an instrument designed to quantify the severity of delusions and hallucinations and is typically used in research studies and clinical settings focusing on people with psychosis and schizophrenia. It is comprised of the auditory hallucinations (AHS) and delusions subscales (DS), but these subscales do not necessarily reflect the psychological constructs causing intercorrelation between clusters of scale items. Identification of these constructs is important in some clinical and research contexts because item clustering may be caused by underlying etiological processes of interest. Previous attempts to identify these constructs have produced conflicting results. In this study, we compiled PSYRATS data from 12 sites in 7 countries, comprising 711 participants for AHS and 520 for DS. We compared previously proposed and novel models of underlying constructs using structural equation modeling. For the AHS, a novel 4-dimensional model provided the best fit, with latent variables labeled Distress (negative content, distress, and control), Frequency (frequency, duration, and disruption), Attribution (location and origin of voices), and Loudness (loudness item only). For the DS, a 2-dimensional solution was confirmed, with latent variables labeled Distress (amount/intensity) and Frequency (preoccupation, conviction, and disruption). The within-AHS and within-DS dimension intercorrelations were higher than those between subscales, with the exception of the AHS and DS Distress dimensions, which produced a correlation that approached the range of the within-scale correlations. Recommendations are provided for integrating these underlying constructs into research and clinical applications of the PSYRATS

Construction of uricase-overproducing strains of Hansenula polymorpha and its application as biological recognition element in microbial urate biosensor

<p>Abstract</p> <p>Background</p> <p>The detection and quantification of uric acid in human physiological fluids is of great importance in the diagnosis and therapy of patients suffering from a range of disorders associated with altered purine metabolism, most notably gout and hyperuricaemia. The fabrication of cheap and reliable urate-selective amperometric biosensors is a challenging task.</p> <p>Results</p> <p>A urate-selective microbial biosensor was developed using cells of the recombinant thermotolerant methylotrophic yeast <it>Hansenula polymorpha </it>as biorecognition element. The construction of uricase (UOX) producing yeast by over-expression of the uricase gene of <it>H. polymorpha </it>is described. Following a preliminary screening of the transformants with increased UOX activity in permeabilized yeast cells the optimal cultivation conditions for maximal UOX yield namely a 40-fold increase in UOX activity were determined.</p> <p>The UOX producing cells were coupled to horseradish peroxidase and immobilized on graphite electrodes by physical entrapment behind a dialysis membrane. A high urate selectivity with a detection limit of about 8 μM was found.</p> <p>Conclusion</p> <p>A strain of <it>H. polymorpha </it>overproducing UOX was constructed. A cheap urate selective microbial biosensor was developed.</p

"Shock and kill" effects of class I-selective histone deacetylase inhibitors in combination with the glutathione synthesis inhibitor buthionine sulfoximine in cell line models for HIV-1 quiescence

Latently infected, resting memory CD4+ T cells and macrophages represent a major obstacle to the eradication of HIV-1. For this purpose, "shock and kill" strategies have been proposed (activation of HIV-1 followed by stimuli leading to cell death). Histone deacetylase inhibitors (HDACIs) induce HIV-1 activation from quiescence, yet class/isoform-selective HDACIs are needed to specifically target HIV-1 latency. We tested 32 small molecule HDACIs for their ability to induce HIV-1 activation in the ACH-2 and U1 cell line models. In general, potent activators of HIV-1 replication were found among non-class selective and class I-selective HDACIs. However, class I selectivity did not reduce the toxicity of most of the molecules for uninfected cells, which is a major concern for possible HDACI-based therapies. To overcome this problem, complementary strategies using lower HDACI concentrations have been explored. We added to class I HDACIs the glutathione-synthesis inhibitor buthionine sulfoximine (BSO), in an attempt to create an intracellular environment that would facilitate HIV-1 activation. The basis for this strategy was that HIV-1 replication decreases the intracellular levels of reduced glutathione, creating a pro-oxidant environment which in turn stimulates HIV-1 transcription. We found that BSO increased the ability of class I HDACIs to activate HIV-1. This interaction allowed the use of both types of drugs at concentrations that were non-toxic for uninfected cells, whereas the infected cell cultures succumbed more readily to the drug combination. These effects were associated with BSO-induced recruitment of HDACI-insensitive cells into the responding cell population, as shown in Jurkat cell models for HIV-1 quiescence. The results of the present study may contribute to the future design of class I HDACIs for treating HIV-1. Moreover, the combined effects of class I-selective HDACIs and the glutathione synthesis inhibitor BSO suggest the existence of an Achilles' heel that could be manipulated in order to facilitate the "kill" phase of experimental HIV-1 eradication strategies

Evaluation of a chemoresponse assay as a predictive marker in the treatment of recurrent ovarian cancer: Further analysis of a prospective study

BACKGROUND: Recently, a prospective study reported improved clinical outcomes for recurrent ovarian cancer patients treated with chemotherapies indicated to be sensitive by a chemoresponse assay, compared with those patients treated with non-sensitive therapies, thereby demonstrating the assay's prognostic properties. Due to cross-drug response over different treatments and possible association of in vitro chemosensitivity of a tumour with its inherent biology, further analysis is required to ascertain whether the assay performs as a predictive marker as well. METHODS: Women with persistent or recurrent epithelial ovarian cancer (n=262) were empirically treated with one of 15 therapies, blinded to assay results. Each patient's tumour was assayed for responsiveness to the 15 therapies. The assay's ability to predict progression-free survival (PFS) was assessed by comparing the association when the assayed therapy matches the administered therapy (match) with the association when the assayed therapy is randomly selected, not necessarily matching the administered therapy (mismatch). RESULTS: Patients treated with assay-sensitive therapies had improved PFS vs patients treated with non-sensitive therapies, with the assay result for match significantly associated with PFS (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.50–0.91, P=0.009). On the basis of 3000 simulations, the mean HR for mismatch was 0.81 (95% range=0.66–0.99), with 3.4% of HRs less than 0.67, indicating that HR for match is lower than for mismatch. While 47% of tumours were non-sensitive to all assayed therapies and 9% were sensitive to all, 44% displayed heterogeneity in assay results. Improved outcome was associated with the administration of an assay-sensitive therapy, regardless of homogeneous or heterogeneous assay responses across all of the assayed therapies. CONCLUSIONS: These analyses provide supportive evidence that this chemoresponse assay is a predictive marker, demonstrating its ability to discern specific therapies that are likely to be more effective among multiple alternatives