Brief resolved unexplained event: Severity-associated factors at admission in the pediatric emergency ward.

OBJECTIVE: A brief resolved unexplained event (BRUE) is a recent clinical entity that has now replaced the term "infant discomfort". Despite the availability of recent recommendations, identification of patients requiring further examination remains difficult. METHOD: We aimed to identify factors associated with severe pathology and/or recurrence by studying the medical files of 767 patients admitted to the pediatric emergency department of a French university hospital for a BRUE. RESULTS: Overall, 255 files were studied; 45 patients had a recurrence and 23 patients had a severe diagnosis. The most frequently found etiology was gastroesophageal reflux in the benign diagnosis group and apnea or central hypoventilation in the severe diagnosis group. Prematurity (p = 0.032) and time since last meal >1 h (p = 0.019) were the main factors associated with severe disease. Most of the routine examination results remained non-contributive to the etiology. CONCLUSION: As prematurity is a factor associated with severe diagnosis, special attention should be given to this population, without subjecting them to multiple tests, since the main complication was found to be apnea or central hypoventilation. Prospective research is needed to establish the usefulness and prioritization of diagnostic tests for infants who are at "high risk" of experiencing a BRUE.

The Secretome Deregulations in a Rat Model of Endotoxemic Shock.

INTRODUCTION: Septic shock is a systemic inflammatory response syndrome associated with organ failures. Earlier clinical diagnosis would be of benefit to a decrease in the mortality rate. However, there is currently a lack of predictive biomarkers. The secretome is the set of proteins secreted by a cell, tissue, or organism at a given time and under certain conditions. The plasma secretome is easily accessible from biological fluids and represents a good opportunity to discover new biomarkers that can be studied with nontargeted "omic" strategies. AIMS: To identify relevant deregulated proteins (DEP) in the secretome of a rat endotoxemic shock model. METHODS: Endotoxemic shock was induced in rats by intravenous injection of lipopolysaccharides (LPS, S. enterica typhi, 0.5 mg/kg) and compared to controls (Ringer Lactate, iv). Under isoflurane anesthesia, carotid cannulation allowed mean arterial blood pressure (MAP) and heart rate (HR) monitoring and blood sampling at different time points (T0 and T50 or T0 and T90, with EDTA and protease inhibitor). Samples were prepared for large-scale tandem mass spectrometry (MS-MS) based on a label-free quantification to allow identification of the proteins deregulated upon endotoxemic conditions. A Gene Ontology (GO) analysis defined several clusters of biological processes (BP) in which the DEP are involved. RESULTS: Ninety minutes after shock induction, the LPS group presents a reduction in MAP (-45%, p < 0.05) and increased lactate levels (+27.5%, p < 0.05) compared to the control group. Proteomic analyses revealed 10 and 33 DEP in the LPS group, respectively, at 50 and 90 minutes after LPS injection. At these time points, GO-BP showed alterations in pathways involved in oxidative stress response and coagulation. CONCLUSION: This study proposes an approach to identify relevant DEP in septic shock and brings new insights into the understanding of the secretome adaptations upon sepsis.

From hypotonic maintenance fluid to severe hyponatremia: a case report.

BACKGROUND: The principles for maintenance intravenous fluid prescription in children were developed in the 1950s. These guidelines based on the use of hypotonic solutions have been challenged regularly for they seem to be associated with an increased risk of hospital-acquired hyponatremia. CASE PRESENTATION: We report the case of a 4-week-old Caucasian child admitted for acute bronchiolitis who received hypotonic maintenance fluids and developed severe hyponatremia (94 mmol/L) with hyponatremic encephalopathy. CONCLUSION: This clinical situation can serve as a reminder of the latest recommendations from the American Academy of Pediatrics regarding the use of intravenous fluids that promote the use of isotonic fluids in children.

Increased ß2-adrenergic vasorelaxation at the early phase of endotoxemic shock in rats.

BACKGROUND AND PURPOSE: The early management of the cardiovascular dysfunction of septic shock is critical as it is associated with a poor outcome. Although the use of catecholamines is a common therapy in this syndrome, no data are available on the involvement of ß-adrenoceptor (ß-AR) subtypes and only few studies report an alteration of ß-adrenergic-induced vasodilation in septic shock. The purpose of the study was to evaluate vascular ß1, ß2 and ß3-AR expression and function in an endotoxemic rat model. EXPERIMENTAL APPROACH: Endotoxemia was induced in rats by intravenous injection of lipopolysaccharide (LPS). ß1, ß2 and ß3-AR mRNA expression was evaluated by RT-PCR in aorta and vascular ß1, ß2 and ß3-AR responses were determined on conducting (aorta) and/or resistance (mesenteric and renal) arteries by constructing relaxation curves in response to different ß-AR agonists. RESULTS: The maximal effect of isoproterenol decreased by 31 to 61% in the three vascular beds of LPS-treated rats compared to controls. In aortas from LPS-treated rats, ß1 and ß3-AR mRNA expression was decreased and associated to a reduced ß1 and ß3-induced vasodilation. Conversely, albeit ß2-AR mRNA was unchanged, the maximal ß2-AR-induced vasodilation increased by 49% in aortas from LPS-treated rats compared to controls. This increase was not affected by endothelium removal but was abolished in the presence of a ß2-AR antagonist or an adenylate cyclase inhibitor. CONCLUSIONS: In endotoxemia, ß2-AR vasodilation was increased by a potential recruitment of ß2-AR located on smooth muscle cells. This study suggests that vascular ß2-AR should be a putative new therapeutic target in septic shock.

Time course of asymmetric dimethylarginine (ADMA) and oxidative stress in fructose-hypertensive rats: a model related to metabolic syndrome.

OBJECTIVE: Asymmetric dimethylarginine (ADMA) is an endogenous modulator of endothelial function and oxidative stress, and increased levels of this molecule have been reported in some metabolic disorders and cardiovascular diseases. The aim of this work was to analyze the time course of dimethylarginine compounds and oxidative stress levels and the relationship between these and cardiovascular function in fructose-hypertensive rats. METHODS AND RESULTS: 90 male Sprague-Dawley rats were randomized into 2 groups, fed for 3 months with standard (C) chow supplemented or not with fructose (F, 60%). After sacrifice at different weeks (W), the aorta and plasma were harvested to assess the vascular and biochemical parameters. Our work showed that the plasma levels of ADMA in the fructose-fed rats increased after 2 weeks of the diet (1.6 ± 0.3 µM vs. 1.2 ± 0.3 µM, p < 0.05) with no changes in plasma levels of either SDMA or L-arginine and after an increase in glycemia. Levels of vascular oxidative stress, estimated in aortic segments using an oxidative fluorescence technique, were higher in the F group (W2: 1.14 ± 0.2% vs. 0.33 ± 0.02%, p < 0.01). An increase in expression levels of nitrotyrosine (3-fold) and iNOS (2-fold) were noted in the fructose-fed rats. After 1 month, this was associated with a significant increase in NAD(P)H oxidase activity. Concerning vascular function, a 15% decrease in maximal endothelium-dependent relaxation was found in the aorta of the F group. Our work showed that the presence of exogenous L-MMA, an inhibitor of NO synthase, was associated with a significant reduction in endothelium-dependent relaxation in isolated aorta rings of the C group; this effect was not observed in the vessels of fructose-fed rats. CONCLUSION: Our findings suggest that the elevated levels of ADMA observed could in part be secondary to the early development of oxidative stress associated with the development of hypertension.

Antioxidant properties of alpha-lipoic acid: effects on red blood membrane permeability and adaptation of isolated rat heart to reversible ischemia.

The aim of our work was to study (1) the antioxidant properties of lipoic acid (LA) and its reduced metabolite dihydrolipoic acid (DHLA) formed by reduction of LA and (2) the effects of treatment with LA and DHLA on (a) K(+) efflux from human red blood cells and (b) post-ischemic recovery and oxidative stress in isolated perfused rat hearts challenged with an ischemia-reperfusion (IR) sequence. In vitro, we used xanthine and xanthine oxidase to generate superoxide anion, which is not directly measurable by electron paramagnetic resonance (EPR), but specifically oxidizes the spin probe CPH into an EPR-detectable long lasting CP(*) nitroxide radical. While 5 mM of LA was ineffective in reducing the kinetics of CP(*) nitroxide formation, DHLA was shown to lessen this rate in a dose-dependent manner and at 30 mM was even more efficient than 300 UI/ml SOD. These results are in agreement with the fact that DHLA is able to directly scavenge superoxide anion. Red cells are a good model to investigate oxidative damage in biological membranes; hence, we used a suspension of erythrocytes incubated with 2,2(')-azobis(2-amidinopropane) hydrochloride (AAPH) which generates in vitro free radicals. DHLA provided more effective protection of red cells membranes than LA; DHLA was comparable to Trolox for its antioxidant potency. In vivo, treatment of rats (50 mg/kg/day i.p. for 7 days) with LA induced a slight increase in coronary flow (CF) in isolated perfused hearts, after 30 min of global total ischemia. This effect was not associated with an improvement in contractile function and reduction of myocardial oxidative stress. In conclusion, because of their ability to scavenge free radicals, LA and to an even greater degree DHLA were able to protect the membranes of red blood cells. This finding suggests that LA and DHLA might be useful in the treatment of diseases associated with oxidative stress such as diabetes.

Influence of rosuvastatin on the NAD(P)H oxidase activity in the retina and electroretinographic response of spontaneously hypertensive rats.

BACKGROUND AND PURPOSE: Retinal complications may be encountered during the development of hypertension as a response to oxidative stress. Statins may reduce the risk of developing hypertension and ocular diseases. We evaluate the effects of rosuvastatin (ROSU) on retinal functionality and oxidative stress levels in normotensive and spontaneously hypertensive rats (SHR). EXPERIMENTAL APPROACH: Wistar Kyoto (WKY) and SHR were treated for 3 weeks with rosuvastatin (10 mg kg(-1) day(-1)). Electroretinograms (ERG) were recorded before and after rosuvastatin treatment. Reactive oxygen species (ROS) were determined in the retina with dihydroethidium staining and NAD(P)H oxidase activity was evaluated. KEY RESULTS: Retinal ganglion cell ROS and retinal NAD(P)H oxidase activity were higher in SHR than in WKY rats, respectively (17.1+/-1.1 vs 10.2+/-1.2 AU, P<0.01; 38095+/-8900 vs 14081+/-5820 RLU mg(-1); P<0.05). The ERG b-wave amplitude in SHR was significantly lower than that in WKY rats. Rosuvastatin reduced SBP in SHR but did not change plasma lipid levels. Rosuvastatin treatment in SHR significantly decreased ROS levels (11.2+/-1.3, P<0.01), NAD(P)H activity in retinal ganglion cells (9889+/-4290; P<0.05), and increased retinal plasmalogen content in SHR, but did not modify the ERG response. CONCLUSIONS AND IMPLICATIONS: Rosuvastatin, beyond lowering cholesterol levels, was able to lower ROS in the retina induced by hypertension, but without improving retinal function in SHR. These findings point to a complex relationship between ROS in the pathogenesis of retinal disease and hypertension.

[A treatment with rosuvastatin induced a reduction of arterial pressure and a decrease of oxidative stress in spontaneously hypertensive rats]. / Un traitement par la rosuvastatine induit une réduction de la pression artérielle et une diminution du niveau du stress oxydatif chez le rat spontanément hypertendu.

The aim of this study was to appreciate consequences of rosuvastatin administration on hemodynamic function, vascular oxidative stress and ischemia/reperfusion disorders in normotensive and hypertensive rats. At 10 weeks of age, spontaneously hypertensive rats (SHR, n=20) and normotensive Wistar Kyoto male rats (WKY, n=20) were divided into four groups and given, either vehicle or 10 mg/kg/day of rosuvastatin by gavage for 3 weeks. Systolic blood pressure was assessed every week. At the end of these treatments, vascular NADPH oxidase activity was evaluated by chemiluminescence (lucigenin 0.5 microM). Hearts were isolated and perfused according to the Langendorff method and were subjected to 30 min of global ischemia. Reactive oxygen species (ROS) produced during reperfusion were quantified by electron spin resonance (ESR) spectroscopy using a spin probe (CP-H, 1 mM). After one week of treatment, rosuvastatin reduced the arterial pressure in SHR rats (180.3 +/- 2.1, SHR vs 169.7 +/- 2.3 mmHg, SHR+rosuvastatin; p < 0.01), without lowering plasma cholesterol levels; these effects were not observed in WKY. NADPH activity was 25% higher in control SHR rat aortas compared to control WKY, and was reduced by rosuvastatin in SHR rats. In isolated rat hearts subjected to ischemia/reperfusion sequences, there was a deterioration in functional parameters in control SHR compared to control WKY hearts. Rosuvastatin decreased post-ischemic contracture in WKY hearts by 50% (41.5 +/- 7.5, WKY control vs 18.4 +/- 4.6 mmHg, WKY+rosuvastatin; p < 0.01) and increased left ventricular developed pressure. This beneficial effect was accompanied by a decrease in ROS detected by ESR during reperfusion (312.5 +/- 45.3, WKY control; vs 219.3 +/- 22.9 AUC/mL, WKY+rosuvastatin; p < 0.05). In conclusion, these results are in accordance with the hypothesis that oxidative stress plays a crucial role in the pathogenesis of cardiovascular diseases including hypertension, and demonstrate the beneficial effects of rosuvastatin.