Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis.

Temperament involves stable behavioral and emotional tendencies that differ between individuals, which can be first observed in infancy or early childhood and relate to behavior in many contexts and over many years.1 One of the most rigorously characterized temperament classifications relates to the tendency of individuals to avoid the unfamiliar and to withdraw from unfamiliar people, objects, and unexpected events. This temperament is referred to as behavioral inhibition or inhibited temperament (IT).2 IT is a moderately heritable trait1 that can be measured in multiple species.3 In humans, levels of IT can be quantified from the first year of life through direct behavioral observations or reports by caregivers or teachers. Similar approaches as well as self-report questionnaires on current and/or retrospective levels of IT1 can be used later in life.

Long-term survival after use of internal thoracic artery in octogenarians is gender related.

OBJECTIVE: The goal of this study is to assess the benefits of a left internal thoracic artery as a bypass conduit in octogenarians undergoing elective coronary artery bypass grafting. We hypothesize that there is no survival advantage and that outcome may be gender related. METHODS: In a retrospective analysis of 1141 octogenarians (aged >80 years) undergoing isolated coronary artery bypass grafting from 1996 to 2012, patients were divided into 2 groups: Group I (coronary artery bypass grafting-left internal thoracic artery) included 870 patients (339 female/531 male), and group II (coronary artery bypass grafting-saphenous vein graft) included 271 patients (131 female/140 male). RESULTS: The overall 30-day mortality was 5.7%: 4.3% in group I and 7.0% in group II (P = .1). Group II had a lower trend of any postoperative complication (P = .05) and pneumonia (P = .05). When analyzed by gender, there were no discernable differences in long-term survival for male patients in group I (65% at 5 years and 29% at 10 years) versus male patients in group II (65% at 5 years and 31% at 10 years) (P = .2). However, survival was significantly greater for female patients in group I (70% at 5 years and 35% at 10 years) versus female patients in group II (63% at 5 years and 21% at 19 years) (P = .01). Multiple logistic and Cox regression analysis showed that left internal thoracic artery use is associated with improved survival in female patients (hazard ratio [HR], 0.72; confidence interval [CI], 0.56-0.93) but not in male patients (HR, 1.14; CI, 0.9-1.4). Advanced age was associated with an increased risk of mortality (HR, 1.08 per year; CI, 1.05-1.1). Both patient age (P = .01) and Society of Thoracic Surgeons-predicted 30-day mortality (P = .03) remain in the final model for 30-day mortality. The benefit of the left internal thoracic artery after coronary artery bypass grafting in octogenarians may be gender related. CONCLUSIONS: This study shows that the benefit of the left internal thoracic artery in the octogenarian population undergoing coronary artery bypass grafting may be gender related. For elderly female patients, the use of the left internal thoracic artery as a bypass conduit was associated with better long-term survival, whereas no significant difference was found among the male population. The use of the left internal thoracic artery was associated with a greater postoperative pulmonary morbidity for the study population as a whole. The present study does not refute the benefit of the left internal thoracic artery-left anterior descending graft, but instead distinguishes a subset who might benefit more.

Neural mechanisms of symptom improvements in generalized anxiety disorder following mindfulness training.

Mindfulness training aims to impact emotion regulation. Generalized anxiety disorder (GAD) symptoms can be successfully addressed through mindfulness-based interventions. This preliminary study is the first to investigate neural mechanisms of symptom improvements in GAD following mindfulness training. Furthermore, we compared brain activation between GAD patients and healthy participants at baseline. 26 patients with a current DSM-IV GAD diagnosis were randomized to an 8-week Mindfulness Based Stress Reduction (MBSR, N = 15) or a stress management education (SME, N = 11) active control program. 26 healthy participants were included for baseline comparisons. BOLD response was assessed with fMRI during affect labeling of angry and neutral facial expressions. At baseline, GAD patients showed higher amygdala activation than healthy participants in response to neutral, but not angry faces, suggesting that ambiguous stimuli reveal stronger reactivity in GAD patients. In patients, amygdala activation in response to neutral faces decreased following both interventions. BOLD response in ventrolateral prefrontal regions (VLPFC) showed greater increase in MBSR than SME participants. Functional connectivity between amygdala and PFC regions increased significantly pre- to post-intervention within the MBSR, but not SME group. Both, change in VLPFC activation and amygdala-prefrontal connectivity were correlated with change in Beck Anxiety Inventory (BAI) scores, suggesting clinical relevance of these changes. Amygdala-prefrontal connectivity turned from negative coupling (typically seen in down-regulation of emotions), to positive coupling; potentially suggesting a unique mechanism of mindfulness. Findings suggest that in GAD, mindfulness training leads to changes in fronto-limbic areas crucial for the regulation of emotion; these changes correspond with reported symptom improvements.

Redo sternotomy for cardiac reoperations using peripheral heparin-bonded cardiopulmonary bypass circuits without systemic heparinization: technique and results.

OBJECTIVE: Cardiac reoperations are challenging and time-consuming and incur a high incidence of perioperative complications because of injuries to cardiac structures, bleeding, and hemodynamic instability. Some centers are using extracorporeal circulation with heparinization at the time of resternotomy, but it leads to prolonged anticoagulation, platelet dysfunction, fibrinolysis, coagulopathy, and morbidity. The authors routinely perform resternotomy in complex surgery with the support of heparinless cardiopulmonary bypass with heparin-bonded circuits (HBCs). The authors describe their technique, indication, and results. METHODS: The femoral artery or axillary artery and femoral veins are cannulated before sternotomy, and cardiopulmonary bypass is instituted using an HBC without systemic heparinization. Systemic heparin (200-300 U/kg) is administered when all structures are isolated before aortic cross-clamping (activated coagulation time >400 seconds). RESULTS: Between 1996 and 2008, 336 patients underwent redo sternotomy using the HBC for complex cardiac procedures, with 29 deaths (8.6% deaths within 30 days). Only 5 (1.5%) of 336 patients sustained injury to the right ventricle, aorta, bypass grafts, or ventricular fibrillation during re-entry without hemodynamic deterioration; and underwent uneventful repair and outcomes. There was no online HBC thrombosis. CONCLUSIONS: This study shows that HBC without systemic heparinization during resternotomy can be used safely in complex redo cardiac surgery. The heart is completely decompressed during the resternotomy, allowing easy dissection, less likely injury to vital structures, and less bleeding without compromising the hemodynamics.

Resolvin E1 improves tear production and decreases inflammation in a dry eye mouse model.

PURPOSE: Dry eye (DE) is a common ocular surface disease, particularly among women and the elderly, with chronic symptoms of eye irritation and, in severe cases, blurred vision. Several studies have shown that there is an inflammatory component in DE, although the pathogenesis is not thoroughly understood. Resolvin E1 (RvE1; RX-10001) is an endogenous mediator derived from the omega-3 polyunsaturated fatty acid eicosapentaenoic acid and is involved in inflammation resolution and tissue protection. Here we investigated the role of RvE1 in a DE mouse model. METHODS: Thirteen- to 14-week-old female BALB/C mice were exposed to desiccating conditions. One week after DE exposure, animals were treated topically with drug or vehicle 4 times per day for an additional week. Controls were nontreated animals placed in a normal environment. Schirmer's test was performed before treatment initiation and at days 2 and 4 after treatment. Density of corneal epithelial cells was analyzed in vivo using the Rostock Cornea Module of the Heidelberg Retina Tomograph (HRT-II). Corneas were processed using Western blot analysis and immunofluorescence examination. RESULTS: Schirmer's test showed a significant decrease in tear production in DE compared with controls. There was no change at 2 and 4 days after treatment with the vehicle, but a significant increase was observed at 2 and 4 days in the RvE1-treated group. The density of the superficial epithelial cells showed a significant decrease after DE compared with controls, which increased after 7 days of RvE1 treatment. Western blot analysis showed that α-smooth muscle actin and cyclooxygenase-2 (COX-2) expression were strongly upregulated after DE and decreased after 7 days of RvE1 treatment. Immunofluorescence confirmed strong positive staining of α-smooth muscle actin and COX-2 in stroma and/or in epithelia after DE, which decreased with RvE1 treatment. The percentage of infiltrating CD4+ T cells and CD11b+ cells decreased after RvE1 treatment when compared with DE. CONCLUSION: RvE1 promotes tear production, corneal epithelial integrity, and a decrease in inflammatory inducible COX-2. In the stroma, RvE1 inhibits keratocyte transformation to myofibroblasts and lowers the number of monocytes/macrophages in this DE mouse model. These results suggest that RvE1 and similar resolvin analogs have therapeutic potential in the treatment of DE.

Structural differences in adult orbital and ventromedial prefrontal cortex predicted by infant temperament at 4 months of age.

CONTEXT: The term temperament refers to a biologically based predilection for a distinctive pattern of emotions, cognitions, and behaviors first observed in infancy or early childhood. High-reactive infants are characterized at age 4 months by vigorous motor activity and crying in response to unfamiliar visual, auditory, and olfactory stimuli, whereas low-reactive infants show low motor activity and low vocal distress to the same stimuli. High-reactive infants are biased to become behaviorally inhibited in the second year of life, defined by timidity with unfamiliar people, objects, and situations. In contrast, low-reactive infants are biased to develop into uninhibited children who spontaneously approach novel situations. OBJECTIVE: To examine whether differences in the structure of the ventromedial or orbitofrontal cerebral cortex at age 18 years are associated with high or low reactivity at 4 months of age. DESIGN: Structural magnetic resonance imaging in a cohort of 18-year-olds enrolled in a longitudinal study. Temperament was determined at 4 months of age by direct observation in the laboratory. SETTING: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital. PARTICIPANTS: Seventy-six subjects who were high-reactive or low-reactive infants at 4 months of age. MAIN OUTCOME MEASURE: Cortical thickness. RESULTS: Adults with a low-reactive infant temperament, compared with those categorized as high reactive, showed greater thickness in the left orbitofrontal cortex. Subjects categorized as high reactive in infancy, compared with those previously categorized as low reactive, showed greater thickness in the right ventromedial prefrontal cortex. CONCLUSIONS: To our knowledge, this is the first demonstration that temperamental differences measured at 4 months of age have implications for the architecture of human cerebral cortex lasting into adulthood. Understanding the developmental mechanisms that shape these differences may offer new ways to understand mood and anxiety disorders as well as the formation of adult personality.

Aortic valve replacement with or without coronary artery bypass graft surgery: the risk of surgery in patients > or =80 years old.

OBJECTIVE: The purpose of this study was to evaluate the outcomes for elderly (> or =80 years) patients undergoing aortic valve replacement (AVR) with or without coronary artery bypass graft surgery (AVR/CABG). The authors hypothesized that the mortalities of AVR and AVR/CABG are lower than that predicted by published risk scores. DESIGN: A retrospective analysis of data from a single-hospital database. SETTING: Single tertiary care, private practice. PARTICIPANTS: Consecutive patients undergoing AVR or AVR/CABG. MEASUREMENTS: Two hundred sixty-one elderly (> or =80 years) patients undergoing isolated AVR (145) or AVR/CABG (116) were evaluated. The majority (94.6%) underwent AVR for aortic valve stenosis. Outcomes were recorded and compared between the 2 surgical procedures with predicted mortalities based on published risk assessment scoring systems. RESULTS: The overall short-term mortality for the elderly group was 6.1% (AVR 5.5% and AVR/CABG 6.9%). The median long-term survival was 6.8 years. There were no significant differences in either morbidity or mortality between the AVR and AVR/CABG groups. Although predicted mortalities were similar for each surgical procedure, they overestimated observed outcome by up to 4-fold. CONCLUSIONS: Short- and long-term mortality was low for this group of elderly patients undergoing AVR or AVR/CABG and not significantly different between the 2 surgical groups. Predicted outcomes were worse than that observed, consistent with the hypothesis, and supportive of a more aggressive surgical treatment for aortic valve disease in the elderly patient.

Case report: paradoxical ventricular septal motion in the setting of primary right ventricular myocardial failure.

PURPOSE: In this report, a case of right ventricular (RV) failure, hemodynamic instability, and systemic organ failure is described to highlight how paradoxical ventricular systolic septal motion (PVSM), or a rightward systolic displacement of the interventricular septum, may contribute to RV ejection. CLINICAL FEATURES: Multiple inotropic medications and vasopressors were administered to treat right heart failure and systemic hypotension in a patient following combined aortic and mitral valve replacement. In the early postoperative period, echocardiographic evaluation revealed adequate left ventricular systolic function, akinesis of the RV myocardial tissues, and PVSM. In the presence of PVSM, RV fractional area of contraction was > or =35% despite akinesis of the primary RV myocardial walls. The PVSM appeared to contribute toward RV ejection. As a result, the need for multiple inotropes was re-evaluated, in considering that end-organ dysfunction was the result of systemic hypotension and prolonged vasopressor administration. After discontinuation of phosphodiesterase inhibitors, native vascular tone returned and the need for vasopressors declined. This was followed by recovery of systemic organ function. Echocardiographic re-evaluation two years later, revealed persistent akinesis of the RV myocardial tissues and PVSM, the latter appearing to contribute toward RV ejection. CONCLUSIONS: This case highlights the importance of left to RV interactions, and how PVSM may mediate these hemodynamic interactions.

Perioperative renal outcome in cardiac surgical patients with preoperative renal dysfunction: aprotinin versus epsilon aminocaproic acid.

OBJECTIVE: The administration of aprotinin to patients with pre-existing renal dysfunction who are undergoing cardiac surgery is controversial. Therefore, the authors present their experience with the use of aprotinin for patients with preoperative renal dysfunction who underwent elective cardiac surgery requiring cardiopulmonary bypass (CPB). DESIGN: Retrospective analysis. SETTING: University hospital. PARTICIPANTS: Consecutive cardiac surgical patients with preoperative serum creatinine (SCr) > or =1.8 mg/dL undergoing nonemergent cardiac surgery requiring CPB. INTERVENTIONS: None. METHODS: One hundred twenty-three patients either received epsilon aminocaproic acid (EACA, n = 82) or aprotinin (n = 41) as decided by the attending anesthesiologist and surgeon. Data were collected from the Society of Thoracic Surgeons database and from automated intraoperative anesthesia records. Renal function was assessed from measured serum creatinine (SCr) and calculated creatinine clearances (CrCls). Acute perioperative renal dysfunction was defined as a worsening of perioperative renal function by > or =25% and/or the need for hemodialysis (HD). ANALYSIS: Data were recorded as mean and standard deviation or percentage of population depending on whether the data were continuous or not. Data were compared by using an analysis of variance, chi-square analysis, Student paired and unpaired t tests, Fisher exact test, Wilcoxon rank sum test, and Mann-Whitney U test. A p value <0.05 was considered significant. RESULTS: Overall, 32% and 41% of patients had acute perioperative renal dysfunction measured by CrCl and SCr, respectively. Seven patients required HD (5.7%). Six of these 7 had complicated postoperative courses. Of all the variables measured, only the duration of the aortic crossclamp (AoXCl) and CPB were significantly associated with acute perioperative renal dysfunction. Acute perioperative renal dysfunction was associated with increased intensive care unit and hospital stays, postoperative blood transfusion, dialysis, and major infection. Aprotinin patients were significantly older (75.2 v 70.2 years, p < 0.05), had lower left ventricular ejection fraction (44.4% v 49.2%, p < 0.05), a greater preoperative history of congestive heart failure (63 v 44%, p < 0.05), a greater renal risk score (5.8 v 4.9, p < 0.05), and underwent more nonisolated coronary artery bypass graft surgeries (77% v 29%, p < 0.0001). CPB time (126.0 v 96.5 minutes, p < 0.001) and AoXCl duration (100.9 v 78.0 minutes, p < 0.005) were longer in the aprotinin group. Diabetes (60.5% v 41.5%, p < 0.05) and hypertension (90.1% v 73.2%, p < 0.05) were more prevalent in the EACA group. Baseline renal function and renal outcomes were not significantly different between the aprotinin and EACA groups. Six of the 7 patients who required HD received EACA (p = 0.1). The earliest SCr recorded > or =3 months after surgery was significantly lower in the aprotinin group compared with the EACA group (1.8 v 2.2 mg/dL, p < 0.05). CONCLUSION: Acute perioperative renal dysfunction was associated with worse patient outcome and longer CPB and AoXCl times. Demographic and surgical variables indicated that the sicker patients undergoing more complex surgeries were more likely to be treated with aprotinin. Although aprotinin patients had a higher renal risk score, the administration of aprotinin did not negatively impact renal outcome.

Stroke after cardiac surgery in a patient with Smith-Magenis syndrome.

Patients with Smith-Magenis syndrome have a high incidence of congenital heart disease that requires open-heart surgery. These patients may have gene deletions that affect cholesterol homeostasis, although no previous association has been made with premature atherosclerosis. Herein, we report a case of such a patient, who experienced a stroke after cardiac surgery because of what we believe to be premature intracerebral atherosclerosis.

The hemodynamic effects of methylene blue when administered at the onset of cardiopulmonary bypass.

Hypotension occurs during cardiopulmonary bypass (CPB), in part because of induction of the inflammatory response, for which nitric oxide and guanylate cyclase play a central role. In this study we examined the hemodynamic effects of methylene blue (MB), an inhibitor of guanylate cyclase, administered during cardiopulmonary bypass (CPB) to patients taking angiotensin-converting enzyme inhibitors. Thirty patients undergoing cardiac surgery were randomized to receive either MB (3 mg/kg) or saline (S) after institution of CPB and cardioplegic arrest. CPB was managed similarly for all study patients. Hemodynamic data were assessed before, during, and after CPB. The use of vasopressors was recorded. All study patients experienced a similar reduction in mean arterial blood pressure (MAP) and systemic vascular resistance (SVR) with the onset of CPB and cardioplegic arrest. MB increased MAP and SVR and this effect lasted for 40 minutes. The saline group demonstrated a persistently reduced MAP and SVR throughout CPB. The saline group received phenylephrine more frequently during CPB, and more norepinephrine after CPB to maintain a desirable MAP. The MB group recorded significantly lower serum lactate levels despite equal or greater MAP and SVR. In conclusion, administration of MB after institution of CPB for patients taking angiotensin-converting enzyme inhibitors increased MAP and SVR and reduced the need for vasopressors. Furthermore, serum lactate levels were lower in MB patients, suggesting more favorable tissue perfusion.

Endovascular vein harvest: systemic carbon dioxide absorption.

OBJECTIVE: Endovascular vein harvest (EDVH) requires CO(2) insufflation to expand the subcutaneous space, allowing visualization and dissection of the saphenous vein. The purpose of this study was to assess the extent of CO(2) absorption during EDVH. DESIGN: Prospective observational study. SETTING: Single tertiary care hospital. PATIENTS: Sixty patients (30 EDVH and 30 open-vein harvest) undergoing isolated coronary artery bypass graft surgery. METHODS: Hemodynamic, procedural, and laboratory data were collected prior to (baseline), during, and at it the conclusion (final) of vein harvesting. Data were also collected during cardiopulmonary bypass (CPB). Data were compared by using t tests, analysis of variance, and correlation statistics when needed. RESULTS: There were significant increases in arterial CO(2) (PaCO(2), 35%) and decreases in pH (1.35%) during EDVH. These were associated with increases in heart rate, mean blood pressure, and cardiac output. Within the EDVH group, greater elevations (>10 mmHg) in PaCO2 were more likely during difficult harvest procedures, and these patients exhibited greater increase in heart rate. Elevated CO(2) persisted during CPB, requiring higher systemic gas flows and greater use of phenylephrine to maintain desired hemodynamics. CONCLUSION: EDVH was associated with systemic absorption of CO(2). Greater absorption was more likely in difficult procedures and was associated with greater hemodynamic changes requiring medical therapy.

Neuroanatomical correlates of extraversion and neuroticism.

Introversion/extraversion and neuroticism are 2 important and frequently studied dimensions of human personality. These dimensions describe individual differences in emotional responding across a range of situations and may contribute to a predisposition for psychiatric disorders. Recent neuroimaging research has begun to provide evidence that neuroticism and introversion/extraversion have specific functional and structural neural correlates. Previous studies in healthy adults have reported an association between neuroticism, introversion/extraversion, and the activity of the prefrontal cortex and amygdala. Studies of individuals with psychopathological states have also indicated that anatomic variations in these brain areas may relate to extraversion and neuroticism. The purpose of the present study was to examine selected structural correlates of neuroticism and extraversion in healthy subjects (n = 28) using neuroanatomic measures of the cerebral cortex and amygdala. We observed that the thickness of specific prefrontal cortex regions correlates with measures of extraversion and neuroticism. In contrast, no such correlations were observed for the volume of the amygdala. The results suggest that specific aspects of regional prefrontal anatomy are associated with specific personality traits.

Temperament and its implications for neuroimaging of anxiety disorders.

We review the attributes of inhibited and uninhibited infant temperaments, and their developmental trajectories into early adulthood. Inborn individual differences in infants' propensity to respond to novel people and objects are associated with persistent differences in the responsivity of the amygdala to novelty, as measured with functional magnetic resonance imaging, after more than 20 years of development. Because an inhibited temperament is a risk factor for developing later psychiatric disorders, particularly generalized social anxiety disorder, temperamental differences are confounds in neuroimaging and genetic studies. Longitudinal studies are a unique tool for understanding the developmental and temperamental risk factors for psychiatric disorder.

Inotropes improve right heart function in patients undergoing aortic valve replacement for aortic stenosis.

UNLABELLED: The administration of inotropes after aortic valve replacement (AVR) for aortic stenosis (AS) is controversial. Issues include the risk of left ventricular (LV) systolic outflow obstruction (LVOTO) and the proper treatment of diastolic dysfunction for patients in whom LV systolic function is often preserved and subsequently improved. In this study, we assessed the hemodynamic benefits of inotropes for patients undergoing AVR for AS. Thirty-four patients were prospectively randomized to one of three groups: epinephrine, milrinone, or placebo. Hemodynamic and echocardiographic data were obtained before and immediately after cardiopulmonary bypass (CPB). Data were also obtained before and after increases in ventricular preload to assess the effects of inotropes on diastolic function. The use of inotropes was associated with significantly larger increases in right ventricular (RV) (placebo, 0.5%; epinephrine, +9%; milrinone, +8%; P < 0.01) and LV (placebo, +7%; epinephrine, +18%; milrinone, +20%; P = 0.07) ejection fractions (EF) and cardiac output after CPB. Changes in cardiac output and index were more strongly correlated with changes in RVEF (r = 0.56, P < 0.01; r = 0.47, P < 0.01, respectively) than with LVEF (r = 0.22, r = 0.08). Of all patients receiving epinephrine or milrinone, only one (1 of 22) had a decrease in RVEF, whereas 6 of 12 patients receiving placebo had a reduction in RVEF from pre-CPB to post-CPB. Correspondingly, for LVEF, 1 of 22 patients receiving inotropes had a decrease in LVEF, whereas 3 of 12 placebo patients had a reduction in LVEF from pre-CPB to post-CPB. No patient had evidence of LVOTO. Inotropes improved hemodynamics after AVR for AS. This was attributable more to improved RV function than to changes in LV function. Although there were no changes in diastolic function, it is possible that this study did not allow significant timing to observe benefits of inotropes on diastolic function in this setting. IMPLICATIONS: Compared with placebo, both epinephrine and milrinone similarly improved biventricular performance after aortic valve replacement, with a greater impact on right ventricular function. Choice of either inotropic drug should be driven by blood pressure and hemodynamic goals in this setting.

Antitussive activity of sigma-1 receptor agonists in the guinea-pig.

1. Current antitussive medications have limited efficacy and often contain the opiate-like agent dextromethorphan (DEX). The mechanism whereby DEX inhibits cough is ill defined. DEX displays affinity at both NMDA and sigma receptors, suggesting that the antitussive activity may involve central or peripheral activity at either of these receptors. This study examined and compared the antitussive activity of DEX and various putative sigma receptor agonists in the guinea-pig citric-acid cough model. 2. Intraperitoneal (i.p.) administration of DEX (30 mg kg(-1)) and the sigma-1 agonists SKF-10,047 (1-5 mg kg(-1)), Pre-084 (5 mg kg(-1)), and carbetapentane (1-5 mg kg(-1)) inhibited citric-acid-induced cough in guinea-pigs. Intraperitoneal administration of a sigma-1 antagonist, BD 1047 (1-5 mg kg(-1)), reversed the inhibition of cough elicited by SKF-10,047. In addition, two structurally dissimilar sigma agonists SKF-10,047 (1 mg ml(-1)) and Pre-084 (1 mg ml(-1)) inhibited cough when administered by aerosol. 3. Aerosolized BD 1047 (1 mg ml(-1), 30 min) prevented the antitussive action of SKF-10,047 (5 mg kg(-1)) or DEX (30 mg kg(-1)) given by i.p. administration and, likewise, i.p. administration of BD 1047 (5 mg kg(-1)) prevented the antitussive action of SKF-10,047 given by aerosol (1 mg ml(-1)). 4. These results therefore support the argument that antitussive effects of DEX may be mediated via sigma receptors, since both systemic and aerosol administration of sigma-1 receptor agonists inhibit citric-acid-induced cough in guinea-pigs. While significant systemic exposure is possible with aerosol administration, the very low doses administered (estimated <0.3 mg kg(-1)) suggest that there may be a peripheral component to the antitussive effect.