GLUT2 expression by glial fibrillary acidic protein-positive tanycytes is required for promoting feeding-response to fasting.

Feeding behavior is a complex process that depends on the ability of the brain to integrate hormonal and nutritional signals, such as glucose. One glucosensing mechanism relies on the glucose transporter 2 (GLUT2) in the hypothalamus, especially in radial glia-like cells called tanycytes. Here, we analyzed whether a GLUT2-dependent glucosensing mechanism is required for the normal regulation of feeding behavior in GFAP-positive tanycytes. Genetic inactivation of Glut2 in GFAP-expressing tanycytes was performed using Cre/Lox technology. The efficiency of GFAP-tanycyte targeting was analyzed in the anteroposterior and dorsoventral axes by evaluating GFP fluorescence. Feeding behavior, hormonal levels, neuronal activity using c-Fos, and neuropeptide expression were also analyzed in the fasting-to-refeeding transition. In basal conditions, Glut2-inactivated mice had normal food intake and meal patterns. Implementation of a preceeding fasting period led to decreased total food intake and a delay in meal initiation during refeeding. Additionally, Glut2 inactivation increased the number of c-Fos-positive cells in the ventromedial nucleus in response to fasting and a deregulation of Pomc expression in the fasting-to-refeeding transition. Thus, a GLUT2-dependent glucose-sensing mechanism in GFAP-tanycytes is required to control food consumption and promote meal initiation after a fasting period.

Tanycytes: a gateway to the metabolic hypothalamus.

The central regulation of energy balance relies on the ability of the brain to promptly and efficiently sense variations of metabolic state. To achieve this, circulating hormonal and metabolic signals have to cross the blood-brain interface, where unusual glial cells named tanycytes have been described to play a key role in this process. Tanycytes are specialised polarised ependymoglial cells that line the floor of the third ventricle and send a single process to contact hypothalamic neurones and blood vessels. Although their role in the regulation of energy balance via the modulation of neuronal activity or their chemosensitivity has been already described, recent studies ascribe a new function to tanycytes in the regulation of energy homeostasis as a result of their capacity to regulate the access of metabolic signals to the hypothalamus. This review discusses the peculiar place of tanycytes within the blood-hypothalamus interface, as well as a striking capacity to remodel their own interface to ensure an adaptive metabolic response to energy imbalances.

Different effects of epoprostenol on ischemia-induced ventricular arrhythmias in dogs.

In 60 randomized dogs the effects of epoprostenol infusion (100 ng/kg/min) on ischemia-induced premature ventricular contractions (PVCs), ventricular tachycardia (VT), ventricular flutters and ventricular fibrillation were studied. The circumflex coronary artery occlusion canine model of sudden death was used. The results demonstrate different effects of epoprostenol on ischemia-induced ventricular arrhythmias: 1) both postischemic (7 of 30 vs 15 of 30, p = 0.0298) and postreperfusion (5 of 23 vs 8 of 15, p = 0.0492) ventricular fibrillations were prevented in epoprostenol dogs with an improvement of the global survival rate (18 of 30 vs 7 of 30, p = 0.0019) as compared to controls; 2) in epoprostenol treated dogs a significantly increased incidence of non lethal arrhythmias-including ventricular flutters that occurred in 12 of 30 dogs vs 4 of 30 in controls (p = 0.0195)--was observed; 3) a positive correlation between the percent diastolic pressure fall 10 min after the start of epoprostenol infusion and the number of non lethal arrhythmias was noted. However, hemodynamic effects of the compound, suggesting an oxygen sparing action, did not preclude the antifibrillatory effectiveness. Thus, the antifibrillatory and antiarrhythmic effects of epoprostenol after circumflex coronary artery occlusion and reperfusion in dogs seem independent from one another.

Effect of concurrent medical illness on dexamethasone suppression test results in depressed inpatients.

A retrospective evaluation of the clinical records of 138 depressed patients, who received the dexamethasone suppression test (DST) as part of a standardized physical and psychiatric assessment protocol, revealed that 60 had acute, chronic (mild or severe), stable or remitted medical conditions. The proportion of DST nonsuppressors did not differ between depressed subjects with medical conditions (45% nonsuppressors) and those without (34.6% nonsuppressors; p greater than 0.2). However, all of the six subjects with acute or chronic-severe medical conditions were found to be nonsuppressors (p = 0.003). These results may help clarify the medical exclusion criteria for the clinical application of the DST.

Age-specific prevalence of Epstein-Barr virus antibodies in adult patients with affective disorders.

It has been suggested that prior Epstein-Barr virus (EBV) infection is a necessary condition for the development of affective disorders. To address this issue, the authors performed serologic screening for the presence of EBV antibodies in 60 adult patients seen at an affective disorders investigational unit. Six patients with clinically significant mood disorders, all aged 32 years or younger, had no detectable EBV antibodies. The authors conclude that the onset of clinical mood disorders can occur before primary EBV infection; thus, EBV infection is not a necessary condition for the development of mood disorders.

Prevention of postischemic ventricular fibrillation late after right or left stellate ganglionectomy in dogs.

To gain insight into the differences in antiarrhythmic potential of right vs left stellate ganglionectomy, 72 dogs were randomized to either unilateral stellectomy or second intercostal space thoracotomy and left circumflex coronary arteriovenous pedicle occlusion was performed, without vagotomy, a mean of 8 weeks later under anesthesia. The type and timing of ventricular ectopic beats, including both nonsustained and sustained ventricular tachycardia and ventricular fibrillation, were investigated. Several covariates, including postischemic electrocardiographic changes, were considered. Both right and left stellate ganglionectomy reduced the incidence of early (0 to 10 min) (p = .004 and p = .001, respectively) and total (0 to 60 min) (p = .009 and p = .008, respectively) ischemia-induced ventricular fibrillation, and improved outcome (p = .0013 and p = .0012, respectively). Early sustained ventricular tachycardia was similarly reduced (p = .02) in both stellectomized groups. By contrast, neither the type nor the time distribution of the other forms of ventricular arrhythmias differed significantly among the randomized groups. The multivariate Cox's regression model showed that ST segment elevation at 3 min postocclusion, unilateral stellate ganglionectomy (either right or left), sex, and weight were significant independent predictors of the incidence of ventricular fibrillation during the occlusion period. Lower ST segment elevation and reduced incidence of sustained ventricular tachycardia in the early postischemic period might explain improved outcome in stellectomized dogs by Cox analysis. The side of intervention (either stellectomy or sham operation) did not influence survival; however, left-sided interventions were more effective than right-sided ones. These results confirm the previously reported antifibrillatory effect of left and indicate like effects of right stellate ganglionectomy in a randomized experimental study.

Effects of cicletanine in the left circumflex coronary artery occlusion-reperfusion canine model of sudden death: analysis of 107 experiments using Cox's proportional hazards model.

Multivariate analysis of survival using Cox's proportional hazards model demonstrates that several clinically measurable covariates are determinants of life-threatening arrhythmias following left circumflex coronary artery occlusion-reperfusion in 107 dogs. These are heart rate, ST segment elevation and mean aortic pressure immediately (3 min) following occlusion, and the presence of early (0-10 min) post-occlusion sustained ventricular tachycardia. The risk of occlusion-reperfusion ventricular fibrillation was determined according to Cox's solution based on ST segment elevation, thus enabling quantification of the role of cicletanine. Since cicletanine-treated dogs had reduced mean ST segment elevation at 3 min post-occlusion, lower incidence of early post-occlusion (0-10 min) sustained ventricular tachycardia, and increased endogenous production of prostacyclin, and the latter was inversely correlated with the level of ST segment elevation, it is concluded that such favourable effects on the ischaemic myocardium were contributory to the improved outcome in these experiments. These effects on the ischaemic myocardium obtained in spite of a hypotensive action in the experimental setting might be regarded as desirable and it is therefore suggested that they should be further investigated by pharmacodynamic studies in human subjects.

Prevention of postischaemic ventricular fibrillation by long term beta adrenoceptor blockade with acebutolol in the anaesthetised dog.

Acute occlusions of the proximal left circumflex coronary arteriovenous pedicle were performed in open chest anaesthetised dogs. Twenty eight dogs were randomly allocated to receive acebutolol (3 mg X kg-1 twice daily) or placebo given blindly by mouth for five days; a control group of 14 dogs without any pretreatment underwent the same procedure. Coronary ligations in the randomised study were performed during seven consecutive days, and four dogs were operated on each day. This schedule was chosen in order to measure acebutolol plasma concentrations just before ligation from 60 to 540 min after the last dose of the drug. Long term oral treatment with acebutolol protected against postischaemic ventricular fibrillation and significantly reduced the incidence of both early phase (0-10 min postocclusion) ventricular arrhythmias and ventricular fibrillation. As a result the outcome was significantly improved after 60 min of ischaemia in acebutolol compared with placebo treated animals. The results in the control animals were similar to those in the placebo treated dogs. The protective effect of long term oral treatment with acebutolol lasted for nine hours and was apparently independent of the plasma concentrations of the drug. These data show that improved outcome in this canine model is due to the prevention of ischaemia induced ventricular fibrillation by long term beta adrenoceptor blockade, which is able to overcome the effect, if any, of partial agonist activity of acebutolol. A direct myocardial anti-ischaemic effect might explain the effectiveness of long term oral treatment, which is independent of plasma concentrations of the drug.

Molsidomine prevents post-ischaemic ventricular fibrillation in dogs.

Forty anaesthetized dogs were subjected to left circumflex coronary artery ligation followed by reperfusion. Molsidomine was randomly administered to 20 dogs (50 micrograms kg-1 as an i.v. bolus - 15 min prior to coronary occlusion - followed by an infusion of 0.05 micrograms kg-1 min-1. Standard electrocardiographic leads 2 and 3 were continuously recorded to measure ST segment and delta R% changes and to document both the number of ventricular premature beats and the onset of ventricular fibrillation; aortic pressure and cardiac output were measured; thromboxane B2 plasma levels, platelet aggregation produced by ADP, and molsidomine plasma levels were determined before and at 10, 30 and 75 min after the start of the drug protocol. Molsidomine protected the treated animals from early (10 min) post-ischaemic ventricular fibrillation (0 of 20 vs 6 of 20, P = 0.0202), reduced the incidence of overall post-occlusion ventricular fibrillation (3 of 20 vs 10 of 20, P = 0.0407) and improved the total survival rate (P = 0.0067). In molsidomine treated dogs: mean aortic pressure and the rate-pressure product were lowered 10 min after the start of the drug; immediate post-occlusion (3 min) ST segment changes (0.82 +/- 0.52 vs 1.52 +/- 0.78 mV, P less than 0.025) and delta R% changes (37 +/- 50 vs 90 +/- 84%, P less than 0.025) were less marked; the number of ventricular premature beats was lowered and finally, a progressive decline of platelet aggregation produced by ADP was achieved after 75 min of drug infusion. These results were obtained in the presence of mean plasma levels of molsidomine ranging from 20 to 28 ng ml-1. The time-action curve of the antifibrillatory effect of molsidomine parallels those at the level of post-ischaemic electrocardiographic changes.

[Use of elastic laces with attached needle in coronary surgery]. / Utilisation de lacs élastiques sertis en chirurgie coronaire.

Using elastic laces with attached needle for surgery of the coronary arteries ensures adequate exposure, presentation and drying up of these vessels during distal anastomosis.

The circumflex coronary artery occlusion canine model of sudden death: methodology and electrocardiographic observations.

This study deals with a left circumflex coronary artery occlusion-reperfusion canine model of sudden death using multiple electrocardiographic leads to define a subgroup of animals at high risk of ventricular fibrillation. Occlusion was followed by ventricular fibrillation in 15 of 30 animals (50%). In the 15 dogs surviving 60 min postocclusion, reperfusion gave rise to ten cases of ventricular fibrillation (66.7%). Thus, the total incidence of occlusion-reperfusion ventricular fibrillation was 25 of 30 (83.3%). Electrocardiographic delta R% changes greater than or equal to 25% in leads 2 and 3 at both 3 and 5 min postocclusion predicted the occurrence of postocclusion ventricular fibrillation with 80% specificity and 56% sensitivity. However, ST segment elevation greater than or equal to 0.5 mV in the same leads at the same times predicted postocclusion ventricular fibrillation with 67% specificity and 100% sensitivity. When only dogs with ST segment elevation greater than or equal to 0.5 mV in leads 2 and 3 at both 3 and 5 min postocclusion were considered, ventricular fibrillation postocclusion was seen in 15 of 20 dogs (75%) and ventricular fibrillation after reperfusion occurred in four of the remaining five animals (80%). Thus, in the subgroup of animals presenting with ST segment elevation greater than or equal to 0.5 mV in leads 2 and 3 at both 3 and 5 min postocclusion, the overall incidence of occlusion-reperfusion ventricular fibrillation was 19 of 20 (95%). These data may be useful in studies aimed at testing the effectiveness of drugs or other interventions in a canine model of sudden death.

Cicletanide improves outcome after left circumflex coronary artery occlusion-reperfusion in the dog.

The possible antifibrillatory effect of cicletanide, a new diuretic antihypertensive drug, was investigated at random in 50 anesthetized dogs subjected to left circumflex coronary artery ligation for 60 min and later reperfused. In this model, standard electrocardiographic leads 2 and 3 were continuously registered to measure delta R wave percent changes, to count the number of ventricular premature beats, and to document the onset of ventricular fibrillation; aortic pressure was recorded; 6-keto PGF1 alpha and TXB2 plasma levels were determined. Cicletanide significantly reduced early (Phase 1a) postischemic ventricular fibrillation (5 of 25 vs. 12 of 25, p = 0.036) but failed to reduce the incidence of global ischemia-induced ventricular fibrillation. On the other hand, the incidence of postreperfusion ventricular fibrillation was lower in the cicletanide group (1 of 14 vs. 5 of 9, p = 0.04). In addition, the total survival rate was improved in cicletanide treated dogs (p = 0.0257). While the rate-pressure product was lowered by the drug independent of the presence of ischemia, delta R% changes after occlusion were less in treated dogs than in controls. Moreover, the drug reduced significantly the number of ventricular premature beats in the early (Phase 1a) postischemic period. Finally, the drug increased (mean two-fold) the plasma levels of 6-keto PGF1 alpha as compared with controls; however, this increase was less than that achieved (mean 20-fold) after 100 ng/kg/min epoprostenol (prostacyclin) given in a further series of animals. Thus, improved outcome follows 10 mg/kg i.v. cicletanide administration in this model.

Epoprostenol (PGI2) prevents postischemic ventricular fibrillation and improves outcome in a canine model of sudden death.

In a left circumflex coronary artery occlusion-reperfusion canine model of sudden death the hemodynamic, antiplatelet, antiischemic and antifibrillatory activities of 100 ng.kg-1.min-1 infusion of epoprostenol (Prostacyclin, Flolan, Wellcome Foundation, London, UK) were investigated at random in 40 animals. Significant changes were observed on epoprostenol infusion for mean arterial blood pressure (80 +/- 4 vs 93 +/- 7 mmHg, p less than 0.01), systemic vascular resistance (2379 +/- 769 vs 3290 +/- 768 dynes.s.cm-5, p less than 0.01) and rate-pressure product (10800 +/- 1200 vs 13450 +/- 2500 mmHg.beat.min-1, p less than 0.01) while heart rate did not change. In addition platelet aggregation intensity to ADP decreased by 50% (p less than 0.001). On occlusion treated animals presented with lower systemic vascular resistance (3132 +/- 895 vs 4931 +/- 1079 dynes.s.cm-5, p less than 0.05), rate-pressure product (9950 +/- 850 vs 12168 +/- 1980 mmHg.beat.min-1, p less than 0.01) and mean heart rate (145 +/- 10 vs 169 +/- 10 beats.min-1, p less than 0.01) while the anti-platelet activity persisted. A lower D2-3 mean ST segment elevation occurred at 3 min postocclusion in epoprostenol treated dogs (7.7 +/- 5 vs 14 +/- 8.7 mm, p less than 0.02). The incidence of postischemic ventricular fibrillation was significantly reduced (5/20 i.e. 25% vs 12/20 i.e. 60%, p less than 0.05) in the epoprostenol treated dogs. At the end of the occlusion-reperfusion period treated animals showed an improvement of outcome (10/20 i.e. 50% vs 2/20 i.e. 10%, p less than 0.01). It is suggested that the hemodynamic effect of the drug may provide guidelines for the clinical management of patients with acute myocardial ischemia, when a concomitant antiarrhythmic effect is looked for.

[Ventricular arrhythmia following repair of Fallot's tetralogy. Apropos of 59 cases]. / Troubles du rythme ventriculaire après réparation de tétralogie de Fallot. A propos de 59 cas.

Fifty-nine patients operated for Fallot's tetralogy were reviewed over 3 years after surgery. The average age at surgery was 7.4 years (range 6 months to 37 years). The review included ECG, chest X-ray, echocardiography, exercise stress testing and Holter monitoring, completed by cardiac catheterisation in 10 cases and electrophysiological investigation in 4 cases. Forty-eight of the 59 patients (81.3 p. 100) had no signs of ventricular arrhythmia or only benign ventricular extrasystoles (Group I). Four patients (6.8 p. 100) had severe ventricular arrhythmias (Group II). Seven patients (11.9 p. 100) had one or more episodes of ventricular tachycardia (VT) (Group III) and, in 3 of these patients, VT was recorded during Holter monitoring or exercise stress testing. One patient in Group III died after reoperation, but there were no cases of sudden death in this series. The high risk patients Groups II and III) were operated late (after 5 years), had bi- or trifascicular block (7 out of 11 cases), ventricular extrasystoles on resting ECGs (9 out of 11 cases), cardiomegaly (6 out of 7 cases in Group III), echocardiographic dilatation of the infundibulum (6 out of the 8 patients undergoing echocardiography in Groups II and III). They had significant residual malformation but without right ventricular hypertension (as judged mainly by immediate postoperative data). Ventricular arrhythmias occurred over 6 years after surgery. However, none of the patients operated before 2 years of age had ventricular arrhythmias or VT with a mean follow-up period of 7.5 years, perhaps because LV function was protected.(ABSTRACT TRUNCATED AT 250 WORDS)

[An anesthetic technic in dogs for studying the arrhythmogenic effects of acute coronary occlusion]. / Une technique d'anesthésie du chien pour l'étude des effets arythmogènes de l'occlusion coronaire aiguë.

Intramuscular injection of levomepromazine (0.5 mg/kg) 30 min before intravenous injection of 10 mg/kg pentobarbital sodium induces a good surgical anaesthesia in dogs artificially ventilated with 50% N2O and 50% O2 and given 0.01 mg/kg atropine and 0.1 mg/kg pancuronium intravenously before left thoracotomy. This protocol is suitable for the study of the arrhythmogenic effects of acute one-stage coronary artery ligation in anaesthetized dogs. In fact, minor interference with the autonomic nervous system appears to be involved since heart rate is maintained slow and mean aortic pressure is kept within normal limits, as pH, PaO2, anc PaCO2 during subsequent periods. Acute circumflex coronary arterio-venous pedicle ligation close to the left main trunk division resulted in this model in a high incidence of ventricular fibrillation (10 out of 15 dogs) early (7 +/- 4 min) after occlusion. Specific interventions aimed at reducing the incidence of early post-ischemic life-threatening ventricular arrhythmias might be tested in this model.