Jill A. Osborn

Fetal ethanol exposure alters pituitary-adrenal sensitivity to dexamethasone suppression

The present study investigated the hypothesis that a deficit in feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the hormonal hyperresponsiveness seen in fetal ethanol-exposed rats. Male and female Sprague-Dawley rats from prenatal ethanol (E), pair-fed (PF) and ad lib-fed control (C) treatment groups were tested in adulthood. The effects of dexamethasone (DEX) blockade on basal and stress corticosterone (CORT) levels and stress adrenocorticotropin (ACTH) levels were examined over a 36-h period. Stress CORT and ACTH levels after DEX administration at the trough (AM) and peak (PM) of the CORT circadian rhythm were compared. DEX administration significantly suppressed both resting and stress levels of CORT and ACTH in all animals, regardless of prenatal treatment. Importantly, E animals did not differ from PF and C animals in basal CORT. However, E males and females had significantly higher stress levels of CORT and/or ACTH than PF and C animals, and further, showed differential responsiveness following DEX administration depending on the time of day when testing occurred. At the trough of the CORT circadian rhythm. E males did not differ from PF and C males, whereas E females had increased stress levels of CORT compared to PF and C females. In contrast, at the peak of the circadian rhythm, E males showed increased stress levels of CORT but not ACTH, whereas E females showed increased stress levels of both CORT and ACTH compared to males and females in respective control groups. These data support the hypothesis that E animals may exhibit deficits in HPA feedback inhibition compared to controls and suggest a sex-specific difference in sensitivity of the mechanism underlying HPA hyperresponsiveness.

Chronic intermittent stress does not differentially alter brain corticosteroid receptor densities in rats prenatally exposed to ethanol.

Prenatal ethanol exposure produces hypothalamic-pituitary-adrenal (HPA) hyperresponsiveness to stressors. The present study tested the hypothesis that decreased corticosteroid receptor densities at HPA feedback sites may play a role in deficient feedback inhibition and the resultant HPA hyperresponsiveness that is observed following prenatal ethanol exposure. Brains of adult Sprague-Dawley rats from prenatal ethanol (E), pair-fed (PF) and ad libitum-fed control (C) treatment groups were examined for both mineralocorticoid receptor (MR; Type I) and glucocorticoid receptor (GR; Type II) densities using a cytosolic binding assay. Experiment 1 compared the effects of chronic intermittent stress (Stress Regimen I) and corticosterone (CORT) pellet implants on hippocampal corticosteroid receptor densities in control rats. Experiment 2 determined whether exposure to Stress Regimen I would differentially downregulate and whether adrenalectomy (ADX) would differentially upregulate hippocampal corticosteroid receptors in E compared with PF and C animals. Experiment 3 examined the effects of a modified chronic intermittent stress regimen (Stress Regimen II) on corticosteroid receptor densities at several HPA feedback sites (hippocampus, prefrontal cortex, hypothalamus, and anterior pituitary) in E compared with PF and C animals. CORT pellet implants significantly downregulated hippocampal GR and MR densities in control males and females. Exposure to Stress Regimen I produced downregulation of hippocampal GRs and MRs in males comparable with that produced with CORT pellet implants, and significant downregulation of hippocampal GRs in females across all prenatal treatment groups. This stress regimen also elevated basal plasma CORT levels without concurrent changes in plasma CBG levels, and increased relative adrenal weights in both males and females. In addition, upregulation of hippocampal GRs occurred at 7 days compared with 24 h following ADX in females that had previously been exposed to this stress regimen. Following exposure to Stress Regimen II, both the downregulation of hippocampal corticosteroid receptors and the increase in basal CORT levels in males and females appear to have been abolished by the changes in housing condition during the period of chronic stress. Importantly, prenatal ethanol exposure did not differentially alter GR or MR densities at any feedback site under non-stressed conditions. Exposure to Stress Regimen II, revealed subtle effects of prenatal treatments on hippocampal GRs however it is unlikely that these changes in corticosteroid receptor densities mediated the feedback inhibition deficits observed in E animals. Together, these data demonstrate that: (1) a relatively mild intermittent stress regimen can increase basal CORT levels and downregulate hippocampal corticosteroid receptor densities (2) a seemingly small change in housing conditions during stress appears to eliminate both receptor downregulation and increase in basal CORT levels and (3) decreased corticosteroid receptor densities at HPA feedback sites in the brain do not appear to underlie the HPA hyperresponsiveness observed in E animals.

Fetal Ethanol Effects on Benzodiazepine Sensitivity Measured by Behavior on the Elevated Plus-Maze

Rodents prenatally exposed to ethanol demonstrate altered behavioral and hormonal responses to stressful environments. Prenatal ethanol exposure may also have long-term effects on the offsprings GABAergic system. Using the elevated plus-maze, the present study examined the sensitivity of adult Sprague-Dawley rat offspring from prenatal ethanol (E), pair-fed (PF) and ad lib-fed control (C) conditions to the effects of benzodiazepine (BZD) on plus-maze behavior and corticosterone (CORT) responses. At 60-90 days of age, E, PF, and C males and females were injected subcutaneously with either BZD or saline. Twenty minutes later animals were placed in an open field (OF) for a 5-min test and then on the plus-maze for a 5 min test; behaviors were recorded during testing and blood samples collected at the end of testing for CORT determinations. Overall, sex differences were observed in both OF and plus-maze behaviors. Females showed more ambulation and rearing in the OF than males, and exhibited increased exploratory behaviors and decreased fear-related behaviors compared to males on the plus-maze. Following BZD treatment, both males and females exhibited increased time on open arms, increased open arm entries, and decreased time on closed arms compared to saline-treated males and females, regardless of prenatal treatment. These differences did not appear to be due to altered activity levels, as BZD treatment had no effect on total ambulation in the OF. Importantly, although no significant differences in plus-maze behaviors were found among saline-injected E, PF, and C males or females. BZD treatment differentially affected E males and females compared to their PF and C counterparts. Both E males and females treated with BZD spent increased time on open arms and decreased time on closed arms compared to their PF and C counterparts, suggesting decreased fear. Further, BZD-treated E males exhibited decreased open and closed arm entries, spent significantly more time in the central area, and had lower CORT levels, another index of fear or stress, compared to BZD-treated PF and C males. These data support and extend previous work demonstrating that the plus-maze provides a reliable measure of anxiety/fear, and that plus-maze behavior is sensitive to anxiolytic agents such as BZD. Furthermore, these data suggest that prenatal ethanol exposure may alter sensitivity to the effects of BZD on plus-maze behavior and CORT responsiveness, and may do so differentially in male and females offspring.

Prenatal ethanol exposure alters sensitivity to the effects of corticotropin-releasing factor (CRF) on behavior in the elevated plus-maze

Animals prenatally exposed to ethanol (E) exhibit behavioral alterations in a wide variety of stressful or challenging tasks. The hypothalamic peptide corticotropin-releasing factor (CRF) is known to play a crucial role in integrating an organisms behavioral responses to environmental stressors or challenges. Previous research indicates that E animals exhibit increased hypothalamic-pituitary-adrenal (HPA) reactivity, including increased hypothalamic CRF expression under both basal and stress conditions. However, the possible role of CRF in mediating the behavioral changes observed in E animals remains to be determined. The current study investigated the hypothesis that E animals may be differentially sensitive to the effects of CRF on behavior in the elevated plus-maze, a task widely used to assess anxiety-like behavior in rodents. Sprague-Dawley offspring from prenatal E, pair-fed (PF), and ad lib-fed control (C) groups were tested at 60-90 days of age. Thirty minutes prior to a 5 min test on the elevated plus-maze, animals received an icv infusion of vehicle (VEH) or CRF (males: 0.75 microg or 1.5 microg ; females: 1.0 microg or 2.0 microg ). Under VEH conditions, E males showed greater activity (more total arm entries) than PF and C males and both E males and E and PF females showed less anxiety-like behavior (more open arm entries) than their PF and/or C counterparts. As expected, CRF treatment resulted in fewer open arm, closed arm and total arm entries, and total rears in both males and females in all prenatal groups, and increased time in the closed arms in males compared to that in their VEH-treated counterparts. Importantly, the effects of CRF were most pronounced in E animals. That is, when normalized for prenatal group differences following VEH treatment, CRF-treated E males showed fewer total arm entries and total rears than PF and C males, and CRF-treated E and PF females showed fewer open arm entries than C females. These results support and extend previous findings demonstrating that E animals show altered behavior in aversive or stressful situations. While some effects of CRF in females may be mediated partially by nutritional effects of ethanol, the data overall suggest that the behavioral alterations observed in E animals may be due, at least in part, to increased sensitivity to CRF.

Pharmacological Risk Factors for Delirium after Cardiac Surgery: A Review

Purpose: The objective of this review is to evaluate the literature on medications associated with delirium after cardiac surgery and potential prophylactic agents for preventing it. Source: Articles were searched in MEDLINE, Cumulative Index to Nursing and Allied Health, and EMBASE with the MeSH headings: delirium, cardiac surgical procedures, and risk factors, and the keywords: delirium, cardiac surgery, risk factors, and drugs. Principle inclusion criteria include having patient samples receiving cardiac procedures on cardiopulmonary bypass, and using DSM-IV-TR criteria or a standardized tool for the diagnosis of delirium. Principal Findings: Fifteen studies were reviewed. Two single drugs (intraoperative fentanyl and ketamine), and two classes of drugs (preoperative antipsychotics and postoperative inotropes) were identified in the literature as being independently associated with delirium after cardiac surgery. Another seven classes of drugs (preoperative antihypertensives, anticholinergics, antidepressants, benzodiazepines, opioids, and statins, and postoperative opioids) and three single drugs (intraoperative diazepam, and postoperative dexmedetomidine and rivastigmine) have mixed findings. One drug (risperidone) has been shown to prevent delirium when taken immediately upon awakening from cardiac surgery. None of these findings was replicated in the studies reviewed. Conclusion: These studies have shown that drugs taken perioperatively by cardiac surgery patients need to be considered in delirium risk management strategies. While medications with direct neurological actions are clearly important, this review has shown that specific cardiovascular drugs may also require attention. Future studies that are methodologically consistent are required to further validate these findings and improve their utility.

Regional Versus General Anesthesia and the Incidence of Unplanned Health Care Resource Utilization for Postoperative Pain After Wrist Fracture Surgery: Results From a Retrospective Quality Improvement Project.

Background and Objectives The establishment at our center of a dedicated regional anesthesia service in 2008–2009 has resulted in a marked increase in single-shot brachial plexus blocks (sBPBs) for ambulatory wrist fracture surgery. Despite the documented benefits of regional over general anesthesia (GA), there has been a perceived increase among sBPB patients in postoperative return rates for pain at our institution. We conducted a retrospective quality improvement project to examine this. Methods After exemption from human ethics board review, we sought to identify and contact all wrist fracture surgery patients treated at our center between 2003 and 2012. Our primary outcome was the incidence of unplanned physician visits (office/clinic or emergency department) for pain in the first 48 hours after surgery. Other main outcomes included the incidence of seeking any form of medical attention for pain and self-reporting of severe pain in the first 48 hours. Results Of 1008 identified patients, 419 could be contacted; 195 qualified for analysis. The incidence of unplanned physician visits in the first 48 hours was 12% (13 of 118) among sBPB patients versus 4% (3 of 77) in GA patients (odds ratio [OR], 3.1; 95% confidence interval [95% CI], 0.8–11.1; P = 0.11). More sBPB versus GA patients sought any form of medical attention for pain (20% vs 5%; OR, 4.7; 95% CI, 1.4–10.9; P = 0.003). Similarly, more sBPB patients reported severe postoperative pain (41% vs 10%; OR, 5.9; 95% CI, 2.6–13.4; P < 0.0001). Conclusions Patients who received sBPBs for ambulatory wrist fracture surgery had a higher rate of unplanned health care resource utilization caused by pain after hospital discharge than those undergoing GA. These findings warrant confirmation in a prospective trial and emphasize the need for a defined postdischarge analgesic pathway as well as the potential merits of perineural home catheters.

Gevolgen van prenatale blootstelling aan alcohol voor de neuromotorische en cognitieve ontwikkeling van jonge kinderen

Het foetale-alcoholsyndroom (fas) werd voor het eerst beschreven in 1973, maar er bestaan in de literatuur geen vermeldingen over evaluatie en behandeling van fas. Kenmerkend voor de diagnose zijn afwijkingen op drie gebieden