Sex differences in HIV effects on visual memory among substance-dependent individuals.

HIV's effects on episodic memory have not been compared systematically between male and female substance-dependent individuals. We administered the Brief Visuospatial Memory Test-Revised (BVMT-R) to 280 substance-dependent HIV+ and HIV- men and women. Groups were comparable on demographic, substance use, and comorbid characteristics. There were no significant main effects of sex or HIV serostatus on BVMT-R performance, but HIV+ women performed significantly more poorly on delayed recall. This effect was most prominent among cocaine-dependent HIV+ women. Our findings are consistent with recent speculation that memory impairment may be more common among HIV+ women, particularly those with a history of cocaine dependence.

Generating an item pool for translational social cognition research: methodology and initial validation.

Existing sets of social and emotional stimuli suitable for social cognition research are limited in many ways, including size, unimodal stimulus delivery, and restriction to major universal emotions. Existing measures of social cognition could be improved by taking advantage of item response theory and adaptive testing technology to develop instruments that obtain more efficient measures of multimodal social cognition. However, for this to be possible, large pools of emotional stimuli must be obtained and validated. We present the development of a large, high-quality multimedia stimulus set produced by professional adult and child actors (ages 5 to 74) containing both visual and vocal emotional expressions. We obtained over 74,000 audiovisual recordings of a wide array of emotional and social behaviors, including the main universal emotions (happiness, sadness, anger, fear, disgust, and surprise), as well as more complex social expressions (pride, affection, sarcasm, jealousy, and shame). The actors generated a high quantity of technically superior, ecologically valid stimuli that were digitized, archived, and rated for accuracy and intensity of expressions. A subset of these facial and vocal expressions of emotion and social behavior were submitted for quantitative ratings to generate parameters for validity and discriminability. These stimuli are suitable for affective neuroscience-based psychometric tests, functional neuroimaging, and social cognitive rehabilitation programs. The purposes of this report are to describe the method of obtaining and validating this database and to make it accessible to the scientific community. We invite all those interested in participating in the use and validation of these stimuli to access them at www.med.upenn.edu/bbl/actors/index.shtml .

Resting state amygdala-prefrontal connectivity predicts symptom change after cognitive behavioral therapy in generalized social anxiety disorder.

BACKGROUND: Aberrant amygdala-prefrontal interactions at rest and during emotion processing are implicated in the pathophysiology of generalized social anxiety disorder (gSAD), a common disorder characterized by fears of potential scrutiny. Cognitive behavioral therapy (CBT) is first-line psychotherapy for gSAD and other anxiety disorders. While CBT is generally effective, there is a great deal of heterogeneity in treatment response. To date, predictors of success in CBT for gSAD include reduced amygdala reactivity and increased activity in prefrontal regulatory regions (e.g., anterior cingulate cortex, "ACC") during emotion processing. However, studies have not examined whether tonic (i.e., at rest) coupling of amygdala and these prefrontal regions also predict response to CBT. RESULTS: Twenty-one patients with gSAD participated in resting-state functional magnetic resonance imaging (fMRI) before 12 weeks of CBT. Overall, symptom severity was significantly reduced after completing CBT; however, the patients varied considerably in degree of symptom change. Whole-brain voxel-wise findings showed symptom improvement after CBT was predicted by greater right amygdala-pregenual ACC ("pgACC") connectivity and greater left amygdala-pgACC coupling encompassing medial prefrontal cortex. In support of their predictive value, area under receiver operating characteristic curve was significant for the left and right amygdala-pgACC in relation to treatment responders. CONCLUSIONS: Improvement after CBT was predicted by enhanced resting-state bilateral amygdala-prefrontal coupling in gSAD. Preliminary results suggest baseline individual differences in a fundamental circuitry that may underlie emotion regulation contributed to variation in symptom change after CBT. Findings offer a new approach towards using a biological measure to foretell who will most likely benefit from CBT. In particular, the departure from neural predictors based on illness-relevant stimuli (e.g., socio-emotional stimuli in gSAD) permits the development of biomarkers that reflect commonalities in the neurobiology of anxiety and mood disorders.

CREMA-D: Crowd-sourced Emotional Multimodal Actors Dataset.

People convey their emotional state in their face and voice. We present an audio-visual data set uniquely suited for the study of multi-modal emotion expression and perception. The data set consists of facial and vocal emotional expressions in sentences spoken in a range of basic emotional states (happy, sad, anger, fear, disgust, and neutral). 7,442 clips of 91 actors with diverse ethnic backgrounds were rated by multiple raters in three modalities: audio, visual, and audio-visual. Categorical emotion labels and real-value intensity values for the perceived emotion were collected using crowd-sourcing from 2,443 raters. The human recognition of intended emotion for the audio-only, visual-only, and audio-visual data are 40.9%, 58.2% and 63.6% respectively. Recognition rates are highest for neutral, followed by happy, anger, disgust, fear, and sad. Average intensity levels of emotion are rated highest for visual-only perception. The accurate recognition of disgust and fear requires simultaneous audio-visual cues, while anger and happiness can be well recognized based on evidence from a single modality. The large dataset we introduce can be used to probe other questions concerning the audio-visual perception of emotion.

Inter-rater reliability of historical data collected by non-medical research assistants and physicians in patients with acute abdominal pain.

OBJECTIVES: In many academic emergency departments (ED), physicians are asked to record clinical data for research that may be time consuming and distracting from patient care. We hypothesized that non-medical research assistants (RAs) could obtain historical information from patients with acute abdominal pain as accurately as physicians. METHODS: Prospective comparative study conducted in an academic ED of 29 RAs to 32 resident physicians (RPs) to assess inter-rater reliability in obtaining historical information in abdominal pain patients. Historical features were independently recorded on standardized data forms by a RA and RP blinded to each others' answers. Discrepancies were resolved by a third person (RA) who asked the patient to state the correct answer on a third questionnaire, constituting the "criterion standard." Inter-rater reliability was assessed using kappa statistics (kappa) and percent crude agreement (CrA). RESULTS: Sixty-five patients were enrolled (mean age 43). Of 43 historical variables assessed, the median agreement was moderate (kappa 0.59 [Interquartile range 0.37-0.69]; CrA 85.9%) and varied across data categories: initial pain location (kappa 0.61 [0.59-0.73]; CrA 87.7%), current pain location (kappa 0.60 [0.47-0.67]; CrA 82.8%), past medical history (kappa 0.60 [0.48-0.74]; CrA 93.8%), associated symptoms (kappa 0.38 [0.37-0.74]; CrA 87.7%), and aggravating/alleviating factors (kappa 0.09 [-0.01-0.21]; CrA 61.5%). When there was disagreement between the RP and the RA, the RA more often agreed with the criterion standard (64% [55-71%]) than the RP (36% [29-45%]). CONCLUSION: Non-medical research assistants who focus on clinical research are often more accurate than physicians, who may be distracted by patient care responsibilities, at obtaining historical information from ED patients with abdominal pain.

Resuscitation of hypotensive head-injured patients: is hypertonic saline the answer?

Hypertonic saline (HTS) may decrease intracranial pressure (ICP) in severe traumatic brain injury (STBI) and effectively resuscitates hypotensive patients. No data exist on institutional standardization of HTS for hypotensive patients with STBI. It remains unclear how HTS affects brain tissue oxygenation (PbtO2) in STBI. We hypothesized HTS could be safely standardized in patients with STBI and would lower ICP while improving cerebral perfusion pressure (CPP) and PbtO2. Under institutional guidelines in a Level I trauma center, 12 hypotensive STBI intensive care unit subjects received HTS. Inclusion criteria included mean arterial pressure (MAP) < or = 90 mmHg, Glasgow Coma Scale (GCS) < or = 8, ICP > or = 20 mmHg, and serum [Na+] <155 mEq/L. All patients underwent ICP monitoring. Hemodynamics, CPP, ICP, and PbtO2 data were collected before and hourly for 6 hours after HTS infusion. Guideline criteria compliance was greater than 95 per cent. No major complications occurred. Mean ICP levels dropped by 45 per cent (P < 0.01) and this drop persisted for 6 hours. CPP levels increased by 20 per cent (P < 0.05). PbtO2 remained persistently elevated for all time points after HTS infusion. Institutional use of HTS in STBI can be safely implemented in a center caring for neurotrauma patients. HTS infusion in hypotensive STBI reduces ICP and raises CPP. Brain tissue oxygenation tends to improve after HTS infusion.

Mitotic spindle checkpoint inactivation by trichostatin a defines a mechanism for increasing cancer cell killing by microtubule-disrupting agents.

Microtubule-disrupting agents such as the taxanes comprise some of the most clinically useful chemotherapeutic agents and invoke the spindle checkpoint in proliferating cells. A robust spindle checkpoint in turn may forestall mitotic catastrophe, potentially providing a mechanism that permits cancer cells to survive transient exposure to these drugs. Previous reports on G2-M cell cycle progression by histone deacetylase inhibitors suggested a potential role in modulating the therapeutic efficacy of microtubule-disrupting agents. As both classes of agents are generally administered in clinical trials as pulse treatments, we investigated in human cancer cells the effects of brief treatments with the histone deacetylase inhibitor trichostatin A (TSA) alone or with nocodazole or paclitaxel (Taxol) on cell cycle progression and the spindle checkpoint. Treatment of synchronized cells with 200 ng/ml of TSA alone for eight hours to completely block class I and II HDACs did not interfere with progression into mitosis with chromosomal condensation as confirmed by MPM-2 expression. TSA treatment at this concentration surprisingly did not interfere with formation of the mitotic spindle or centrosomal separation, but instead led to missegregation of chromosomes, suggesting effects on the spindle checkpoint. Consistent with this hypothesis, TSA abrogated the phosphorylation and kinetochore localization of the mitotic checkpoint protein BubR1 and the phosphorylation of histone H3 after paclitaxel and nocodazole treatment. These effects in turn led to rapid cell death and considerably reduced clonogenic survival. These results together suggest that by inactivating the spindle checkpoint, TSA can potentiate the lethal effects of microtubule-disrupting drugs, a strategy that might be usefully exploited for optimizing anticancer therapy.

Inactivation of the mitotic checkpoint as a determinant of the efficacy of microtubule-targeted drugs in killing human cancer cells.

Drugs that disrupt microtubule dynamics include some of the most important of cancer chemotherapies. While these drugs, which include paclitaxel (Taxol), are known to invoke the mitotic checkpoint, the factors that determine cancer cell killing remain incompletely characterized. Cells that are relatively resistant to killing by these drugs block robustly in mitosis, whereas cells sensitive to killing block only transiently in mitosis before undergoing nuclear fragmentation and death. Passage through mitosis was an absolute requirement of drug-induced death, because death was markedly reduced in cells blocked at both G(1)-S and G(2). Cell killing was at least in part linked to the absence or inactivation of BubR1, a kinetochore-associated phosphoprotein that mediates the mitotic checkpoint. Sensitivity to paclitaxel correlated with decreased BubR1 protein expression in human cancer cell lines, including those derived from breast and ovarian cancers. Silencing of BubR1 via RNA interference inactivated the mitotic checkpoint in drug-resistant cells, and reversed resistance to paclitaxel and nocodazole. Together, these results suggest that the mitotic checkpoint is an important determinant of the efficacy of microtubule-targeting drugs in killing cancer cells, potentially providing novel targets for increasing treatment efficacy.