GABA(A) receptors as molecular sites of ethanol action. Direct or indirect actions?

Despite the fact that ethanol is one of the most widely used psychoactive agents, the mechanisms and sites of action by which it modifies brain functions are only now being elucidated. Studies over the last decade have shown that ethanol can specifically alter the function of several ligand-activated ion channels including N-methyl-D-aspartate (NMDA), serotonin (5-HT(3)), glycine and GABA(A) receptors. After several years of extensive research in this field, the resolution of what, where and how ethanol modifies GABA(A) receptors continues to be controversial. For example, after demonstrating that ethanol was able to alter Cl(-) flux in synaptoneurosomes and cultured neurons, several electrophysiological studies were unable to show enhancement of the GABA(A) receptor current in single neurons. The lack of positive results with low ethanol concentrations was interpreted as being due to receptor heterogeneity and differences in intracellular modulation by protein kinases and calcium. The existence of high receptor heterogeneity with respect to ethanol sensitivity has been supported by studies done in a variety of cell types which showed that ethanol potentiated some, but not other neurons. Adding to this complexity, it was shown that while some hippocampal GABA(A) receptors can be affected by ethanol concentrations between 1 and 100 mM, others are only sensitive to concentrations above 200 mM. The curve of the relationship between low ethanol concentrations and current enhancement suggests a high degree of complexity in the molecular interaction because of its steepness and "inverted" U shape. Similarly, the effects of ethanol on GABA(A) receptors seems much more complex than those of benzodiazepines, barbiturates and neurosteroids. The major problem encountered in advancing understanding of the mechanism of ethanol action in native neuronal receptors has been the large variability detected in ethanol sensitivity. For example, several studies have shown that only some groups of neurons are sensitive to pharmacologically relevant concentrations of ethanol (1-100 mM). This receptor sensitivity variability has not been resolved using recombinant expression systems. For example, studies performed in recombinant receptors, although important for elucidating molecular requirements, have shown that they are less sensitive to ethanol suggesting that neuronal substrates are important for ethanol actions. In this review, we discuss the possibility that ethanol's action on the GABA(A) receptor may not be due solely to a direct interaction with the receptor protein, but that its effects could also be modulated by intracellular regulation, and that this latter effect is the more physiologically relevant one. Data in cortical and hippocampal neurons suggest that ethanol action on the receptor is labile, and that it also depends on repetitive stimulation and neuron integrity. In addition, the action of ethanol can be modified by activation of protein kinases and neuronal development. Finally, we discuss that the best approach for studying the interaction between the receptor and ethanol is through the combined use of recombinant receptors and overexpression in neurons.     

Cytokine production by blood mononuclear cells from in-patients with anorexia nervosa

Although protein-energy malnutrition is a common cause of immunodeficiency, the immune function in underweight anorexia nervosa (AN) patients usually seems to be better preserved than would be expected. However, a deranged cytokine production and its consequences are currently being investigated in these patients. This study was aimed at measuring, over time, the capacity of peripheral blood mononuclear cells (PBMC) from AN in-patients to produce several cytokines involved in the regulation of immune responses. The in vitro production of interferon (IFN)-gamma, interleukin (IL)-2, tumour necrosis factor (TNF)-alpha, IL-6 and IL-1 beta by phytohaemagglutinin-stimulated PBMC were assessed on forty female adolescents with AN. These measures were carried out twice, upon hospital admission and at discharge, which occurred on average after 1 month. Thirty-five control subjects were also studied. Cytokines were measured by ELISA kits. The production of TNF-alpha and IL-6 was lower and production of IL-1 beta higher in AN patients than in the control group at both time points of assessment. Refeeding for 1 month was not enough time to reverse these differences and patients still had a low body weight at discharge. IFN-gamma production was lower in the patients than in control subjects only at discharge and no differences were found in IL-2 production between both groups. The results suggest that a mechanism involving modifications in the secretion pattern of proinflammatory cytokines could explain some immune function findings in underweight AN patients.     

Non-anti-Gal alpha1-3Gal antibody mechanisms are sufficient to cause hyperacute lung dysfunction in pulmonary xenotransplantation

BACKGROUND: Hyperacute lung dysfunction, which is always associated with pulmonary pig-to-primate xenotransplantation is not well understood. The mechanisms associated with its occurrence seem to differ from mechanisms involved in hyperacute xenograft rejection seen in porcine hearts or kidneys transplanted into primates. To determine the contribution of anti-Gal alpha1-3Gal antibodies (alphaGAb) in such a process, we performed a set of orthotopic pig lung transplants into baboons depleted of alphaGAb and compared graft function and survival with those receiving only immunosuppression. STUDY DESIGN: Pigs expressing human membrane cofactor protein served as donors. All baboons received triple immunosuppressive therapy. Depletion of alphaGAb in the experimental group (n = 4) was done by way of immunoadsorption using immunoaffinity membranes. Controls (n = 4) did not undergo immunoadsorption. Orthotopic lung transplants were performed through a left thoracotomy. Main pulmonary artery blood flow and pressure, left pulmonary artery blood flow, and left atrial pressure were recorded. RESULTS: At 1 hour after reperfusion, pulmonary artery graft flows and pulmonary vascular resistances (PVR) were better in animals depleted of alphaGAb than in controls (605 +/- 325.2 mL/min versus 230 +/- 21 mL/min; 27.1 +/- 41.3 mmHg/L/min versus 63 +/- 1 mmHg/L/min). But at 3 hours after reperfusion average graft flows in baboons depleted of alphaGAb had decreased to 277.6 +/- 302.2 mL/min and PVRs had increased 58.3 +/- 42.0 mmHg/L/min. On the other hand, controls maintained stable flows and PVRs (223 +/- 23 mL/min; 61 +/- 3 mmHg/L/min). Survival was ultimately better in control baboons when compared with alphaGAb depleted ones (12.2 +/- 3.3 h versus 4.4 +/- 3.2 h). CONCLUSION: Unlike heart and kidney xenograft transplants, hyperacute lung xenograft dysfunction seems to be mediated by factors other than alphaGAb.     

Poor outcome and quality of life in female patients undergoing secondary surgery for recurrent peptic ulcer disease

Secondary peptic ulcer surgery is uncommon given the success of a wide variety of medical therapies, plus the good outcome expected after primary peptic ulcer surgery. Early reports of secondary peptic ulcer surgery in the 1950s and 1960s suggested good long-term outcome in most patients; however, recent data suggest that patients operated in the Helicobacter pylori era have a worse outcome. We have attempted to quantify the poor outcome in these patients and measure the effect of sex, a previously unrecognized risk factor for poor outcome after peptic ulcer surgery. We reviewed the outcomes of 35 patients who underwent secondary peptic ulcer surgery for symptoms of persistent or recurrent peptic ulcer symptoms or complications of the condition. These patients were compared to a "control" group of patients to determine long-term quality of life as measured by the SF-36 and Visick scores (average follow-up 60 months). Visick and SF-36 scores were obtained through telephone interviews. The two groups of patients were age matched to eliminate age as a variable in the SF-36 results. There were more females than males in the secondary peptic ulcer surgery group (4.5/1 female-to-male ratio). Although perioperative mortality was zero for both groups, patients undergoing secondary peptic ulcer surgery had a high number of complications (57% of patients had complications). Patients undergoing secondary peptic ulcer surgery scored lower in seven of the eight subclasses of the SF-36 questionnaire compared to their age-matched cohorts. In contrast, average Visick scores showed slight improvement for three out of four symptoms reported. Immediate postoperative complications were not related to long-term quality of life issues. Secondary peptic ulcer surgery is more prevalent in females than in males. Although secondary peptic ulcer surgery is partially effective in alleviating symptoms, quality of life is poor. Presented at the Forty-Second Annual Meeting of The Society for Surgery of the Alimentary Tract, Atlanta, Georgia, May 20–23, 2001 (poster presentation).     

Rescue therapy with terlipressin by continuous infusion in a child with catecholamine-resistant septic shock

A 2-month-old female infant presented with septic shock, refractory to high doses of catecholamines. Continuous infusion of terlipressin at a rate of 10 mcg/kgh produced a significant increase in the mean arterial pressure that was evident within half and hour, so allowing a reduction in the rate of catecholamine infusion. However, 18 h later, the blood pressure fell again and finally the patient died. This case shows the potential value of terlipressin infusion to restore normal mean arterial pressure in children with vasodilatory shock and hypotension refractory to catecholamines.     

Analysis of head-up tilt test responses in patients suffering from syncope and high blood pressure

We studied the difference in head-up tilt test responses between patients suffering from syncope who had hypertension and those who did not. A total of 338 consecutive patients with syncope underwent head-up tilt testing in our department from January 2003 to October 2004. Of these, 243 did not have hypertension (group A), whereas 95 did (group B). There were significant differences between the groups in age (P=.0001), sex (P=.048), timing of syncope development (P=.0001), and prevalence of diabetes mellitus (P=.0001). The head-up tilt test gave positive results in 168 patients (69.1%) in group A and in 63 (66.3%) in group B (P=.6; NS). There was no significant difference between the groups in the proportion of positive responses that occurred in either the baseline or nitroglycerin-enhanced phase of the test (P=.673; NS), nor in the time to onset of syncope in either phase (P=.69; NS, and P=.28; NS, respectively). However, there was a significant difference in the type of response (vasodepressor response, 33% in group A versus 49% in group B, P=.01). In the multivariate analysis, no independent variable was found to be associated with the result of the head-up tilt test.