The cooperative induction of hypoxia-inducible factor-1 alpha and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis.

Hypoxia is an essential component of tumor microenvironment. In this study, we investigated the influence of hypoxia (1% PO(2)) on CTL-mediated tumor cell lysis. We demonstrate that exposure of target tumor cells to hypoxia has an inhibitory effect on the CTL clone (Heu171)-induced autologous target cell lysis. Such inhibition correlates with hypoxia-inducible factor-1alpha (HIF-1alpha) induction but is not associated with an alteration of CTL reactivity as revealed by granzyme B polarization or morphological change. Western blot analysis indicates that although hypoxia had no effect on p53 accumulation, it induced the phosphorylation of STAT3 in tumor cells by a mechanism at least in part involving vascular endothelial growth factor secretion. We additionally show that a simultaneous nuclear translocation of HIF-1alpha and phospho-STAT3 was observed. Interestingly, gene silencing of STAT3 by small interfering RNA resulted in HIF-1alpha inhibition and a significant restoration of target cell susceptibility to CTL-induced killing under hypoxic conditions by a mechanism involving at least in part down-regulation of AKT phosphorylation. Moreover, knockdown of HIF-1alpha resulted in the restoration of target cell lysis under hypoxic conditions. This was further supported by DNA microarray analysis where STAT3 inhibition resulted in a partly reversal of the hypoxia-induced gene expression profile. The present study demonstrates that the concomitant hypoxic induction of phospho-STAT3 and HIF-1alpha are functionally linked to the alteration of non-small cell lung carcinoma target susceptibility to CTL-mediated killing. Considering the eminent functions of STAT3 and HIF-1alpha in the tumor microenvironment, their targeting may represent novel strategies for immunotherapeutic intervention.

Thrombolyse intracoronarienne comme traitement de l'infarctus en constitution [Intracoronary thrombolysis as a treatment for evolving myocardial infarction].

Myocardial infarction is almost always the consequence of a thrombotic obstruction of one or more coronary arteries. We report our experience with the first 24 cases of intracoronary thrombolysis for recanalization of obstructed coronary arteries. 19 cases were successful, 1 case was partially successful and in 4 instances no reopening was observed. The amount of streptokinase used was 206 000 +/- 107 000 units, and reperfusion was achieved after 37 +/- 27.5 minutes. Recanalization of the vessel was accompanied by cessation of precordial pain and partial or complete normalization of the electrocardiogram. In one case bypass surgery was necessary because of reocclusion. Left ventricular function improvement after thrombolysis was dependent on the time-lag between occlusion and recanalization. These observations confirm others' experience that intracoronary thrombolysis appears to have favorable effects in patients with evolving myocardial infarction.

Training in hypoxia fails to further enhance endurance performance and lactate clearance in well-trained men and impairs glucose metabolism during prolonged exercise.

The aim of this study was to investigate the synergistic effects of endurance training and hypoxia on endurance performance in normoxic and hypoxic conditions (approximately 3000 m above sea level) as well as on lactate and glucose metabolism during prolonged exercise. For this purpose, 14 well-trained cyclists performed 12 training sessions in conditions of normobaric hypoxia (HYP group, n = 7) or normoxia (NOR group, n = 7) over 4 weeks. Before and after training, lactate and glucose turnover rates were measured by infusion of exogenous lactate and stable isotope tracers. Endurance performance was assessed during incremental tests performed in normoxia and hypoxia and a 40 km time trial performed in normoxia. After training, performance was similarly and significantly improved in the NOR and HYP groups (training, P < 0.001) in normoxic conditions. No further effect of hypoxic training was found on markers of endurance performance in hypoxia (training x hypoxia interaction, n.s.). In addition, training and hypoxia had no significant effect on lactate turnover rate. In contrast, there was a significant interaction of training and hypoxia (P < 0.05) on glucose metabolism, as follows: plasma insulin and glucose concentrations were significantly increased; glucose metabolic clearance rate was decreased; and the insulin to glucagon ratio was increased after training in the HYP group. In conclusion, our results show that, compared with training in normoxia, training in hypoxia has no further effect on endurance performance in both normoxic and hypoxic conditions or on lactate metabolic clearance rate. Additionally, these findings suggest that training in hypoxia impairs blood glucose regulation in endurance-trained subjects during exercise.

Recommendations on percutaneous coronary intervention for the reperfusion of acute ST elevation myocardial infarction

Little information is currently available from the various societies of cardiology on primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). Since primary PCI is the main method of reperfusion in AMI in many centres, and since of all cardiac emergencies AMI represents the most urgent situation for PCI, recommendations based on scientific evidence and expert experience would be useful for centres practising primary PCI, or those looking to establish a primary PCI programme. To this aim, a task force for primary PCI in AMI was formed to develop a set of recommendations to complement and assist clinical judgment. This paper represents the product of their recommendations.

The impact of fasting on the interpretation of triglyceride levels for predicting myocardial infarction risk in HIV-positive individuals: the D:A:D study.

We assessed whether fasting modifies the prognostic value of these measurements for the risk of myocardial infarction (MI). Analyses used mixed effect models and Poisson regression. After confounders were controlled for, fasting triglyceride levels were, on average, 0.122 mmol/L lower than nonfasting levels. Each 2-fold increase in the latest triglyceride level was associated with a 38% increase in MI risk (relative rate, 1.38; 95% confidence interval, 1.26-1.51); fasting status did not modify this association. Our results suggest that it may not be necessary to restrict analyses to fasting measurements when considering MI risk.

Toward high-resolution myocardial tagging.

Magnetic resonance imaging with preceding tissue tagging is a robust method for assessing cardiac motion of the entire heartbeat cycle with a high degree of accuracy. One limitation of this technique, however, is the low resolution of the obtained displacement map of the labeled points within the myocardium. By a new tagging technique, which is based on the combination of two or more measurements of the same slice but with different grid positions, a highly improved resolution of cardiac motion data can be achieved. In combination with a multi-heart-phase echo-planar imaging sequence, such images with doubled grid frequency can be acquired in two short breath-hold periods.

Alterations in the local myocardial motion pattern in patients suffering from pressure overload due to aortic stenosis.

BACKGROUND: MR tissue tagging allows the noninvasive assessment of the locally and temporally resolved motion pattern of the left ventricle. Alterations in cardiac torsion and diastolic relaxation of the left ventricle were studied in patients with aortic stenosis and were compared with those of healthy control subjects and championship rowers with physiological volume-overload hypertrophy. METHODS AND RESULTS: Twelve aortic stenosis patients, 11 healthy control subjects with normal left ventricular function, and 11 world-championship rowers were investigated for systolic and diastolic heart wall motion on a basal and an apical level of the myocardium. Systolic torsion and untwisting during diastole were examined by use of a novel tagging technique (CSPAMM) that provides access to systolic and diastolic motion data. In the healthy heart, the left ventricle performs a systolic wringing motion, with a counterclockwise rotation at the apex and a clockwise rotation at the base. Apical untwisting precedes diastolic filling. In the athlete's heart, torsion and untwisting remain unchanged compared with those of the control subjects. In aortic stenosis patients, torsion is significantly increased and diastolic apical untwisting is prolonged compared with those of control subjects or athletes. CONCLUSIONS: Torsional behavior as observed in pressure- and volume-overloaded hearts is consistent with current theoretical findings. A delayed diastolic untwisting in the pressure-overloaded hearts of the patients may contribute to a tendency toward diastolic dysfunction.

Circadian Variations of Ischemic Burden Among Patients with Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Introduction Le rythmes circadiens influencent différents paramètres de la physiologie et de la physiopathologie cardiovasculaire. Récemment, une relation entre la taille d'un infarctus et l'heure du jour à laquelle il se produit a été suggérée dans des modèles expérimentaux d'infarctus du myocarde. Le but de cette étude a été de déterminer si les rythmes circadiens pouvaient influencer la gravité d'un infarctus en terme de taille et de mortalité chez les patients hospitalisés pour un infarctus du myocarde avec sus-décalage du segment ST (STEMI) ayant bénéficié d'une intervention coronarienne percutanée primaire (ICPP). Méthode Chez 353 patients consécutifs admis avec un STEMI et traités par ICPP, l'heure à la survenue des symptômes, le pic de créatine kinase (reflet de la taille d'un infarctus) et le suivi à 30 jours ont été collectés. Les patients ont été répartis en 4 groupes en fonction de l'heure de survenue de leurs symptômes (00 :00 - 05h59, 06:00 - 11 59 12 00-17h59 et 18h00-23h59). Résultats Aucune différence statistiquement significative n'a été retrouvée entre les différents groupes en ce qui concerne les caractéristiques des patients ou de leur prise en charge. Après analyse multivariée, nous avons mis en évidence une différence statistiquement significative entre les pics de créatine kinase chez les patients avec survenue des symptômes entre 00 :00 et 05:59, qui étaient plus élevés que les pics de créatine kinase chez les patients avec survenue des symptômes à tout autre moment de la journée (augmentation moyenne de 38,4%, ρ <0.05). A 30 jours, la mortalité des patients avec survenue des symptômes entre 00 :00 et 05:59 était également significativement plus élevé que celle des patients avec survenue à tout autre moment de la journée (p <0.05). Conclusion Notre étude démontre une corrélation indépendante entre la taille d'un infarctus STEMI traité par ICPP et le moment de la journée où les symptômes apparaissent. Ces résultats suggèrent que ce moment devrait être un paramètre important à prendre en compte pour évaluer le pronostic des patients.

Hypobaric versus normobaric hypoxia: same effects on postural stability?

AIMS: To test the hypothesis that postural stability would be more affected during acute exposure in hypobaric (HH) than in normobaric (NH) hypoxia.¦METHODS: In separate trials, 12 subjects stood on a posturographic platform for two successive 25.6 sec tests in three conditions: eyes open (EO), eyes closed (EC), and verbal dual task (DT). Ambient pressure in O(2) was matched between HH and NH at 1700 and 3000 m, respectively.¦RESULTS: Compared to NH, the length of Centre of Pression trajectory in Y-axis was increased (p<0.05) in HH for EO at 1700 m, EC at 1700 and 3000 m, and for DT at 1700 m, whereas the variance of speed of CoP was decreased (p<0.05) in EO, EC, and DT at 1700 m. Compared to normobaric normoxia (NN; 400 m), the surface of CoP trajectory was increased (p<0.05) in HH in EO and EC at 3000 m.¦CONCLUSIONS: HH deteriorated postural stability in the antero-posterior plane, for the variance of speed and the surface of CoP in 3 conditions, whereas no difference was observed between NH and NN. These results suggest that hypobaria instead of hypoxia per se plays an important role to the altered balance classically reported in altitude.

Influence of socioeconomic factors on delays, management and outcome amongst patients with acute myocardial infarction undergoing primary percutaneous coronary intervention.

The outcome after primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI) is strongly affected by time delays. In this study, we sought to identify the impact of specific socioeconomic factors on time delays, subsequent STEMI management and outcomes in STEMI patients undergoing pPCI, who came from a well-defined region of the French part of Switzerland. A total of 402 consecutive patients undergoing pPCI for STEMI in a large tertiary hospital were retrospectively studied. Symptom-to-first-medical-contact time was analysed for the following socioeconomic factors: level of education, origin and marital status. Main exclusion criteria were: time delay beyond 12 hours, previous treatment with fibrinolytic agents or patients immediately referred for coronary artery bypass graft surgery. Therefore, 222 patients were finally included. At 1 year, there was no difference in mortality between the different socioeconomic groups. Furthermore, there was no difference in management characteristics between them. Symptom-to-first-medical-contact time was significantly longer for patients with a low level of education, Swiss citizens and unmarried patients, with median differences of 23 minutes, 18 minutes and 13 minutes, respectively (p <0.05). Nevertheless, no difference was found regarding in-hospital management and clinical outcome. This study demonstrates that symptom-to-first-medical-contact time is longer amongst people with a lower educational level, Swiss citizens and unmarried people. Because of the low mortality rate in general, these differences in delays did not affect clinical outcomes. Still, tertiary prevention measures should particularly focus on these vulnerable populations.

Muscarinic receptor M1 and phosphodiesterase 1 are key determinants in pulmonary vascular dysfunction following perinatal hypoxia in mice.

Perinatal adverse events such as limitation of nutrients or oxygen supply are associated with the occurrence of diseases in adulthood, like cardiovascular diseases and diabetes. We investigated the long-term effects of perinatal hypoxia on the lung circulation, with particular attention to the nitric oxide (NO)/cGMP pathway. Mice were placed under hypoxia in utero 5 days before delivery and for 5 days after birth. Pups were then bred in normoxia until adulthood. Adults born in hypoxia displayed an altered regulation of pulmonary vascular tone with higher right ventricular pressure in normoxia and increased sensitivity to acute hypoxia compared with controls. Perinatal hypoxia dramatically decreased endothelium-dependent relaxation induced by ACh in adult pulmonary arteries (PAs) but did not influence NO-mediated endothelium-independent relaxation. The M(3) muscarinic receptor was implicated in the relaxing action of ACh and M(1) muscarinic receptor (M(1)AChR) in its vasoconstrictive effects. Pirenzepine or telenzepine, two preferential inhibitors of M(1)AChR, abolished the adverse effects of perinatal hypoxia on ACh-induced relaxation. M(1)AChR mRNA expression was increased in lungs and PAs of mice born in hypoxia. The phosphodiesterase 1 (PDE1) inhibitor vinpocetine also reversed the decrease in ACh-induced relaxation following perinatal hypoxia, suggesting that M(1)AChR-mediated alteration of ACh-induced relaxation is due to the activation of calcium-dependent PDE1. Therefore, perinatal hypoxia leads to an altered pulmonary circulation in adulthood with vascular dysfunction characterized by impaired endothelium-dependent relaxation and M(1)AChR plays a predominant role. This raises the possibility that muscarinic receptors could be key determinants in pulmonary vascular diseases in relation to "perinatal imprinting."