Characterization of the discriminative stimulus effects of the neuroactive steroid pregnanolone in DBA/2J and C57BL/6J inbred mice

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as GABA(A). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. This study aimed to examine the effects of strain and sex on the discriminative stimulus effects of pregnanolone. Twelve male and female DBA/2J mice and 12 male and female C57BL/6J mice were trained to discriminate 10 mg/kg pregnanolone from saline. The male C57BL/6J mice had to be removed from the study due to increased seizures apparently associated with the chronic intermittent pregnanolone administration used in drug discrimination. GABA(A)-positive modulators, neuroactive steroids, N-methyl-d-aspartate (NMDA) antagonists, and 5-hydroxytryptamine (5-HT)(3) agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice, a benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for the stimulus effects of pregnanolone. NMDA antagonists, 5-HT(3) agonists, and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either sex or strain. Pentobarbital and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. Differences in sensitivities to neurosteroids between the two strains were not evident. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest that many of the previously documented neurosteroid-induced behavioral differences between the DBA/2J and C57BL/6J are acute effects and are not apparent in a drug discrimination procedure.     

Attention alters neural responses to evocative faces in behaviorally inhibited adolescents

Behavioral inhibition (BI) is a risk factor for anxiety disorders. While the two constructs bear behavioral similarities, previous work has not extended these parallels to the neural level. This study examined amygdala reactivity during a task previously used with clinically anxious adolescents. Adolescents were selected for enduring patterns of BI or non-inhibition (BN). We examined amygdala response to evocative emotion faces in BI (N=10, mean 12.8 years) and BN (N=17, mean 12.5 years) adolescents while systematically manipulating attention. Analyses focused on amygdala response during subjective ratings of internal fear (constrained attention) and passive viewing (unconstrained attention) during the presentation of emotion faces (Happy, Angry, Fearful, and Neutral). BI adolescents, relative to BN adolescents, showed exaggerated amygdala response during subjective fear ratings and deactivation during passive viewing, across all emotion faces. In addition, the BI group showed an abnormally high amygdala response to a task condition marked by novelty and uncertainty (i.e., rating fear state to a Happy face). Perturbations in amygdala function are evident in adolescents temperamentally at risk for anxiety. Attention state alters the underlying pattern of neural processing, potentially mediating the observed behavioral patterns across development. BI adolescents also show a heightened sensitivity to novelty and uncertainty, which has been linked to anxiety. These patterns of reactivity may help sustain early temperamental biases over time and contribute to the observed relation between BI and anxiety.     

Routine versus difficult cholecystectomy: using predictive analytics to assess patient outcomes

Background

The American College of Surgeons National Surgical Quality Improvement Program^® (NSQIP) Surgical Risk. Calculator (SRC) estimates postoperative outcomes. The aim of this study was to develop and validate a specific predictive outcomes model for cholecystectomy procedures.

Risk factors for mortality in patients with alcoholic hepatitis and assessment of prognostic models: A population-based study

BACKGROUND:

Severe alcoholic hepatitis (AH) is associated with a substantial risk for short-term mortality.

OBJECTIVES:

To identify prognostic factors and validate well-known prognostic models in a Canadian population of patients hospitalized for AH.

METHODS:

In the present retrospective study, patients hospitalized for AH in Calgary, Alberta, between January 2008 and August 2012 were included. Stepwise logistic regression models identified independent risk factors for 90-day mortality, and the discrimination of prognostic models (Model for End-stage Liver Disease [MELD] and Maddrey discriminant function [DF]) were examined using areas under the ROC curves.

RESULTS:

A total of 122 patients with AH were hospitalized during the study period; the median age was 49 years (interquartile range [IQR] 42 to 55 years) and 60% were men. Median MELD score and Maddrey DF on admission were 21 (IQR 18 to 24) and 45 (IQR 26 to 62), respectively. Seventy-three percent of patients received corticosteroids and/or pentoxifylline, and the 90-day mortality was 17%. Independent predictors of mortality included older age, female sex, international normalized ratio, MELD score and Maddrey DF (all P<0.05). For discrimination of 90-day mortality, the areas under the ROC curves of the prognostic models (MELD 0.64; Maddrey DF 0.68) were similar (P>0.05). At optimal cut-offs of ≥22 for MELD score and ≥37 for Maddrey DF, both models excluded death with high certainty (negative predictive values 90% and 96%, respectively).

CONCLUSIONS:

In patients hospitalized for AH, well-known prognostic models can be used to predict 90-day mortality, particularly to identify patients with a low risk for death.     

Specificity of the Relationships Between Dysphoria and Related Constructs in an Outpatient Sample

Dysphoria has recently been conceptualized as a complex emotional state that consists of discontent and/or unhappiness and a predominantly externalizing mode of coping with these feelings. The Nepean Dysphoria Scale (NDS) was developed on the basis of this model of dysphoria and used in this clinical study to ascertain the specificity of the relationships between dysphoria and relevant domains of psychopathology. Ninety-six outpatients completed the NDS, Symptom Checklist 90-Revised (SCL-90R) and Depression, Anxiety, Stress Scales, 21-item version (DASS-21). The scores on the NDS subscales (Discontent, Surrender, Irritability and Interpersonal Resentment) and total NDS scores correlated significantly with scores on the DASS-21 scales and relevant SCL-90R subscales. Multiple regression analyses demonstrated the following: DASS-21 Depression and Stress each had unique relationships with NDS Discontent and Surrender; DASS-21 Anxiety had a unique relationship with NDS Discontent; SCL-90R Hostility and Paranoid Ideation and DASS-21 Stress each had unique relationships with NDS Irritability; and SCL-90R Paranoid Ideation and DASS-21 Stress, Depression and Anxiety each had unique relationships with NDS Interpersonal Resentment. These findings support the notion that dysphoria is a complex emotional state, with both non-specific and specific relationships with irritability, tension, depression, paranoid tendencies, anxiety, hostility and interpersonal sensitivity. Conceptual rigor when referring to dysphoria should be promoted in both clinical practice and further research.     

Interleukin-1β transfer across the blood–brain barrier in the ovine fetus

Pro-inflammatory cytokines contribute to hypoxic–ischemic brain injury. Blood–brain barrier (BBB) dysfunction represents an important component of hypoxic–ischemic brain injury in the fetus. Hypoxic–ischemic injury could accentuate systemic cytokine transfer across the fetal BBB. There has been considerable conjecture suggesting that systemic cytokines could cross the BBB during the perinatal period. Nonetheless, evidence to support this contention is sparse. We hypothesized that ischemia–reperfusion increases the transfer of systemic interleukin-1β (IL-1β) across the BBB in the fetus. Ovine fetuses at 127 days of gestation were studied 4 hours after 30 minutes of bilateral carotid artery occlusion and compared with a nonischemic group. Recombinant ovine IL-1β protein was expressed from an IL-1β pGEX-2 T vector in E. coli BL-21 cells and purified. The BBB function was quantified in 12 brain regions using a blood-to-brain transfer constant with intravenous ¹²⁵I-radiolabeled IL-1β (¹²⁵I-IL-1β). Interleukin-1β crossed the intact BBB in nonischemic fetuses. Blood-to-brain transport of ¹²⁵I-IL-1β was higher (P<0.05) across brain regions in fetuses exposed to ischemia–reperfusion than nonischemic fetuses. We conclude that systemic IL-1β crosses the intact fetal BBB, and that ischemia–reperfusion increases transfer of this cytokine across the fetal BBB. Therefore, altered BBB function after hypoxia–ischemia facilitates entry of systemic cytokines into the brain of the fetus.