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Biomedical subjects

Lucas Liaudet

Publications and source records attributed to Lucas Liaudet.

At least 37 records · Page 2Linked to original sources
PubMed2004

Poly(ADP-ribose) polymerase activation in the reperfused myocardium.

The activation of poly(ADP-ribose) polymerase (PARP) is now considered a final common effector in various types of tissue injury including systemic inflammation, circulatory shock and ischemia/reperfusion. Free radical and oxidant production and related cytotoxicity during ischemia/reperfusion leads to DNA strand breakage which activates the nuclear enzyme PARP and initiates an energy-consuming, inefficient cellular metabolic cycle with transfer of the ADP-ribosyl moiety of NAD+ to protein acceptors. During the last 5 years, a growing number of experimental studies demonstrated the beneficial effects of PARP inhibition in cell cultures through rodent models and more recently in pre-clinical large animal models of regional and global ischemia/reperfusion injury. The objective of the current review is to provide an overview of the experimental evidence implicating PARP as a pathophysiological modulator of myocardial injury in vitro and in vivo.

Animals↗
PubMed2004

Acetylcholine-induced vasodilation and reactive hyperemia are not affected by acute cyclo-oxygenase inhibition in human skin.

OBJECTIVE: To examine whether prostaglandins are involved in endothelium-dependent vasodilatory responses of the skin microcirculation. METHODS: Twenty-three young male volunteers were studied on 2 different days 1-3 weeks apart. On each experimental day the forearm skin blood flow response to iontophoretically applied acetylcholine (Ach, an endothelium-dependent vasodilator) was determined with laser Doppler imaging following the intravenous administration of either the cyclo-oxygenase inhibitor lysine acetylsalicylate (L-AS), 900 mg, or the oral intake of indomethacin, 75 mg. Acetylcholine was iontophoresed both in presence and in absence of surface anesthesia. In some subjects, the effects of L-AS on skin reactive hyperemia were also assessed. RESULTS: Acute cyclo-oxygenase inhibition with either drug influenced neither the skin blood flow response to 4 different doses of Ach (0.28, 1.4, 7, and 14 mC/cm2) nor reactive hyperemia. The peak vasodilatory response to Ach was significantly increased by skin anesthesia, regardless of whether the subjects received the cyclo-oxygenase inhibitor or not. For example, the mean response (+/-SD) to the largest dose of Ach (tested in 6 subjects, expressed in perfusion units) were as follows: in absence of anesthesia: L-AS 339 +/- 105, placebo 344 +/- 68; with anesthesia: L-AS 453 +/- 76, placebo 452 +/- 65 (p <.01 for effect of anesthesia). CONCLUSIONS: These data give no support for a contribution of prostaglandins to acetylcholine-induced vasodilation or to reactive hyperemia in the skin microcirculation. In this vascular bed, local anesthesia seems to amplify acetylcholine-induced vasodilation via a prostaglandin-independent mechanism.

Acetylcholine↗
PubMed2004

Dose-dependent vasodilatory effects of acetylcholine and local warming on skin microcirculation.

The assessment of the skin microvasculature response to iontophoretically applied acetylcholine (ACh) and local warming makes it possible to explore noninvasively in humans the functional integrity of endothelium. The present study aimed to examine whether these two stimuli of nitric oxide (NO) release have a dose-dependent vasorelaxant activity. For this purpose we assessed in healthy subjects using a laser-Doppler imaging system the increase in forearm blood flow following transdermal application of increasing amounts of ACh [with an iontophoretic current of either 0.28 mC/cm2 (n = 18), 0.56 mC/cm2 (n = 14), 1.4 mC/cm2 (n = 26), 7 mC/cm2 (n = 14), 28 mC/cm2 (n = 14), or 48 mC/cm2 (n = 6)] or graded warming of the skin [to either 37 degrees C (n = 8), 39 degrees C (n = 4) or 41 degrees C (n = 12)]. The maximal vasodilation was significantly smaller with the lowest dose than with the higher doses of ACh, and a plateau was reached with the 1.4 mC/cm2 dose. The skin blood flow responses to ACh were not dependent on the pulsed or continuous pattern of iontophoretic administration. The hyperemia induced by the local heating to 41 degrees C was significantly greater than that observed with the other temperatures. When measured in the same subjects, the magnitude of the maximal ACh-mediated skin blood flow increase was significantly smaller than the vasodilation associated with the warming to 41 degrees C. In summary, transdermally applied ACh and local heating of the skin induce a dose-dependent vasorelaxation. These techniques represent a unique means to investigate noninvasively the functional vasodilatory capacity of the skin microvasculature.

Acetylcholine↗
PubMed2004

Carboxyhemoglobin formation as an unexpected side effect of inhaled nitric oxide therapy in severe acute respiratory distress syndrome.

OBJECTIVE: To report an unexpected cause of carboxyhemoglobinemia associated with inhaled nitric oxide therapy in severe acute respiratory distress syndrome. DESIGN: Case report. SETTING: Medical critical care unit at Lausanne University Hospital. PATIENT: One female patient with acute respiratory distress syndrome treated with inhaled nitric oxide, who developed a simultaneous increase in blood methemoglobin and carboxyhemoglobin. CONCLUSIONS: Potential pathophysiologic mechanisms linking acute respiratory distress syndrome, inhaled nitric oxide, methemoglobin, and carboxyhemoglobin are discussed. Since carboxyhemoglobin has a negative influence on oxygen-carrying capacity, this effect may potentially offset the beneficial influence (if any) of inhaled nitric oxide on arterial PO2. This observation does not support the use of inhaled nitric oxide in the treatment of acute respiratory distress syndrome.

Administration, Inhalation↗
PubMed2004

Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity.

Matrix metalloproteinase (MMP) activation contributes to the development of various pathophysiological conditions, including dilated cardiomyopathy, congestive heart failure, and reperfusion injury. Increased oxidative and nitrosative stress have been implicated in the activation of MMPs and also in the cardiotoxicity of doxorubicin (DOX), a commonly used antitumor agent. Thus, we hypothesized that MMP activation occurs in DOX-induced cardiotoxicity. Male Balb/c mice received a single injection of DOX (25 mg/kg i.p.) and were sacrificed 12 h, 1, 2, 3 and 4 days later. Hearts and aortae were harvested for MMP zymography. DOX induced time-dependent activation of MMPs both in the heart and in the aortic tissue with an earlier onset in the latter. These results demonstrate that MMP activation is an early event in DOX-induced cardiotoxicity and raises the possibility that MMP inhibitors may influence the outcome of this severe complication.

Animals↗
PubMed2004

[Heart arrest: which reality and which training for the practitioner?].

Sudden death related to out-of hospital cardiac arrest is an important cause of mortality, which is mainly caused by ventricular fibrillation, a potentially reversible condition. The prognosis of out-of-hospital cardiac arrest remains dismal despite well developed emergency medical services. Witnessed arrest, ventricular fibrillation as the initial arrhythmia, cardiopulmonary resuscitation and early defibrillation are systematically associated with better survival. Key interventions must therefore be enforced to improve survival from out-of-hospital cardiac, introducing the concept of a "chain of survivals". The aim of the present article, which is illustrated by local results, is to review this important public health issue, to emphasize the role of the general practitioner in the chain of survival, and to promote education and training of basic and advanced life support.

Family Practice↗
PubMed2004

[New therapeutic strategies in severe sepsis and septic shock].

Severe sepsis and septic shock are an important cause of mortality. Until recently, in spite of major progresses in our understanding of the pathogenic mechanisms of this syndrome, clinicians had only a limited therapeutic arsenal. Considerable efforts have been made in the past few years to develop novel therapeutic interventions to reduce mortality in sepsis. So far, five specific therapies have proven their efficacy to achieve such goal in large randomised controlled trials: early goal-directed therapy, recombinant activated protein C, moderate doses of steroids, low tidal volume ventilation in acute respiratory distress syndrome and intensive insulin therapy to control hyperglycemia. This review will focus on these recently acquired therapeutic modalities, that are presently available to clinicians for the treatment of severe sepsis and septic shock.

Humans↗
PubMed2004

[Value of non-invasive ventilation in intensive care].

Noninvasive ventilation (NIV) refers to the delivery of mechanical ventilation using a nasal or facial mask. Compared to mechanical ventilation with endotracheal intubation, the occurence of complications, mainly infectious, is reduced by NIV. Reduction of respiratory workload and improvement of gas exchange are achieved with the use of NIV. In patients with exacerbations of chronic obstructive pulmonary disease (COPD), NIV reduces the need for endotracheal intubation, the length of ICU stay and the mortality. It is equally effective in acute cardiogenic pulmonary edema and for ventilatory weaning of patients with COPD. In selected groups of patients with acute hypoxemic respiratory failure, NIV diminishes the rate of endotracheal intubation and improves survival. The purpose of this article is to review the mechanisms, the technical aspects and the indications of NIV for the treatment of acute respiratory failure.

Critical Care↗
PubMed2004

[Infective endocarditis: update].

The pathogenesis of infective endocarditis (IE) is being dissected at the molecular level, which should help redefine new preventive and therapeutic strategies against IE. In spite of improving health care, the incidence of IE has not decreased over the last decades. While classical predisposing conditions such as rheumatic heart disease were being eradicated, new features of IE have emerged. These include IE in intravenous drug users, IE in elderly patients with sclerotic valve disease, prosthetic valve IE and nosocomial IE. The epidemiology, pathogenesis, diagnosis, prevention and treatment of IE are being reviewed in this article.

Endocarditis, Bacterial↗
PubMed2004

[Epidemiology, diagnosis, and treatment of pulmonary embolism].

Pulmonary embolism (PE) is a frequent pathology, the mortality of which remains elevated despite the efficacy of anticoagulation. This is mainly due to diagnostic difficulty, resulting from the low sensibility and specificity of clinical signs and routine exams in PE. The best diagnostic approach relies on decision making algorithms based on the determination of a clinical probability, which in turn dictates the choice of specialized exams (C-scan/scintigraphy, venous duplex, angiography and D-dimers). Risk stratification, which is based on the presence of hemodynamic alterations (right ventricular dysfunction, shock) is essential to guide therapy. In case of shock (massive embolism), treatment relies on systemic thrombolysis. In the presence of right ventricular dysfunction without shock (sub-massive embolism), the advantage of thrombolysis over anticoagulation alone has not been clearly demonstrated. In all other cases, as long as no contraindication exists, therapeutic anticoagulation with heparin must be initiated as soon as PE is suspected, since the mortality of this condition is highest in the two first hours following presentation.

Algorithms↗
PubMed2003

Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction.

BACKGROUND: Increased oxidative stress and dysregulation of nitric oxide have been implicated in the cardiotoxicity of doxorubicin (DOX), a commonly used antitumor agent. Peroxynitrite is a reactive oxidant produced from nitric oxide and superoxide in various forms of cardiac injury. Using a novel metalloporphyrinic peroxynitrite decomposition catalyst, FP15, and nitric oxide synthase inhibitors or knockout mice, we now delineate the pathogenetic role of peroxynitrite in rodent models of DOX-induced cardiac dysfunction. METHODS AND RESULTS: Mice received a single injection of DOX (25 mg/kg IP). Five days after DOX administration, left ventricular performance was significantly depressed, and high mortality was noted. Treatment with FP15 and an inducible nitric oxide synthase inhibitor, aminoguanidine, reduced DOX-induced mortality and improved cardiac function. Genetic deletion of the inducible nitric oxide synthase gene was also accompanied by better preservation of cardiac performance. In contrast, inhibition of the endothelial isoform of nitric oxide synthase with N-nitro-L-arginine methyl ester increased DOX-induced mortality. FP15 reduced the DOX-induced increase in serum LDH and creatine kinase activities. Furthermore, FP15 prevented the DOX-induced increase in lipid peroxidation, nitrotyrosine formation, and metalloproteinase activation in the heart but not NAD(P)H-driven superoxide generation. Peroxynitrite neutralization did not interfere with the antitumor effect of DOX. FP15 also decreased ischemic injury in rats and improved cardiac function and survival of mice in a chronic model of DOX-induced cardiotoxicity. CONCLUSIONS: Thus, peroxynitrite plays a key role in the pathogenesis of DOX-induced cardiac failure. Targeting peroxynitrite formation may represent a new cardioprotective strategy after DOX exposure or in other conditions associated with peroxynitrite formation, including myocardial ischemia/reperfusion injury.

Acute Disease↗
PubMed2003

Endurance training enhances vasodilation induced by nitric oxide in human skin.

Endurance training modifies the thermoregulatory control of skin blood flow, as manifested by a greater augmentation of skin perfusion for the same increase in core temperature in athletes, in comparison with sedentary subjects. In this study, we tested the hypothesis that a component of this adaptation might reside in a higher ability of cutaneous blood vessels to respond to vasodilatory stimuli. We recruited healthy nonsmoking males, either endurance trained or sedentary, in two different age ranges (18-35 y and >50 y). Skin blood flow was measured in the forearm skin, using a laser Doppler imager, allowing to record the vasodilatory responses to the following stimuli: iontophoresis of acetylcholine (an endothelium-dependent vasodilator), iontophoresis of sodium nitroprusside (a nitric oxide donor), and release of a temporary interruption of arterial inflow (reactive hyperemia). There was no effect of training on reactive hyperemia or the response to acetylcholine. In contrast, the increase in perfusion following the iontophoresis of sodium nitroprusside, expressed in perfusion units, was larger in trained than in sedentary subjects (younger: 398 +/- 54 vs 350 +/- 87, p < 0.05; older 339 +/- 72 vs 307 +/- 66, p < 0.05). In conclusion, endurance training enhances the vasodilatory effects of nitric oxide in the human dermal microcirculation, at least in forearm skin. These observations have considerable physiologic interest in view of recent data indicating that nitric oxide mediates in part the cutaneous vasodilation induced by heat stress in humans. Therefore, the augmentation of nitric oxide bioactivity in the dermal microcirculation might be one mechanism whereby endurance training modifies the thermoregulatory control of skin blood flow.

Adolescent↗
PubMed2003

Respiratory complications of gastroesophageal reflux associated with paraesophageal hiatal hernia.

BACKGROUND: Gastroesophageal reflux disease (GERD) may be associated with episodes of bronchoaspiration, sometimes leading to life-threatening respiratory complications. GERD is frequently observed in the setting of type 1 (sliding type) hiatal hernia, but only infrequently complicates the course of type 2 (paraesophageal) hernia. METHODS OF STUDY: We performed a retrospective analysis of 50 patients operated for type 2 hiatal hernia in our hospital, to determine the prevalence of respiratory complaints related to GERD in this setting. RESULTS: We found 7 cases (14%) of type 2 hiatal hernia complicated by pulmonary manifestations as the only symptoms of GERD. These ranged from dyspnea to severe bronchoconstriction and acute respiratory failure. The series is illustrated by the report of 1 patient who experienced acute bronchospasm and cardiopulmonary arrest as a complication of GERD. In all patients, surgical repair of the hiatal hernia, together with an antireflux procedure, resulted in complete resolution of the respiratory complaints for follow-up periods up to 160 months. CONCLUSIONS: Our data emphasize the particular prevalence of respiratory involvement in the case of GERD complicating type 2 hiatal hernia, and also the excellent symptomatic results obtained by surgical therapy for this condition.

Aged↗
PubMed2003

Flagellin from gram-negative bacteria is a potent mediator of acute pulmonary inflammation in sepsis.

Flagellin is a recently identified bacterial product that elicits immune response via toll-like receptor 5. Here, we demonstrate that flagellin is an extraordinarily potent proinflammatory stimulus in the lung during sepsis. In vitro, flagellin triggers the production of interleukin (IL)-8 by human lung epithelial (A549) cells, with 50% of the maximal response obtained at a concentration of 2 x 10(-14) M. Flagellin also induces the expression of ICAM-1 in vitro. Intravenous administration of flagellin to mice elicited a severe acute lung inflammation that was significantly more pronounced than following lipopolysaccharide (LPS) administration. Flagellin induced a local release of proinflammatory cytokines, the accumulation of inflammatory cells, and the development of pulmonary hyperpermeability. These effects were associated with the nuclear translocation of the transcription NF-kappaB in the lung. Flagellin remained active in inducing pulmonary inflammation at doses as low as 10 ng/mouse. In the plasma of patients with sepsis, flagellin levels amounted to 7.1 +/- 0.1 ng/mL. Plasma flagellin levels showed a significant positive correlation with the lung injury score, with the alveolar-arterial oxygen difference as well as with the duration of the sepsis. Flagellin emerges as a potent trigger of acute respiratory complications in gram-negative bacterial sepsis.

Active Transport, Cell Nucleus↗