Incorporation and washout of n-3 PUFA after high dose intravenous and oral supplementation in healthy volunteers.

BACKGROUND & AIMS: Although the physiological effects of n-3 polyunsaturated fatty acids (n-3PUFA) are generally thought to require several weeks of exposure to allow their incorporation into plasma membranes, intravenous (IV) n-3PUFA attenuate the cardiovascular and neuroendocrine response to stress within 3 h. Whether oral n-3 PUFA exert similar early effects remains unknown. OBJECTIVE: To assess whether acute IV or short term oral n-3PUFA administration reproduces the metabolic effects of long term oral supplements during exercise, and how it relates to their incorporation into platelets and red blood cells (RBC) membranes. DESIGN: Prospective single center open label study in 8 healthy subjects receiving a 3-h infusion of 0.6 g/kg body weight n-3PUFA emulsion, followed one week later by an oral administration of 0.6 g/kg over 3 consecutive days. Maximal power output (cycling exercise), maximal heart rate (HR), blood lactate at exhaustion, and platelet function were measured at baseline and after IV or 3-day oral supplementation; platelet and RBC membrane composition were assessed until 15 days after n-3PUFA administration. RESULTS: Both IV and oral n-3PUFA significantly decreased maximal HR (-6% and -5%), maximal power output (-10%) and peak blood lactate (-47% and -52%) Platelet function tests were unchanged. The EPA and DHA membrane contents of RBC and platelets increased significantly, but only to 1.7-1.9% of fatty acid content. CONCLUSION: The cardiovascular and metabolic effects of n-3 PUFA during exercise occur already within 1-3 days of exposure, and may be unrelated to changes in membranes composition. Effects occur within hours of administration and are unrelated to lipid membrane composition. Trial registered at clinicaltrials.gov as NCT00516178.

Spatial behavior in groups: an agent-based approach

We present an agent-based model with the aim of studying how macro-level dynamics of spatial distances among interacting individuals in a closed space emerge from micro-level dyadic and local interactions. Our agents moved on a lattice (referred to as a room) using a model implemented in a computer program called P-Space in order to minimize their dissatisfaction, defined as a function of the discrepancy between the real distance and the ideal, or desired, distance between agents. Ideal distances evolved in accordance with the agent's personal and social space, which changed throughout the dynamics of the interactions among the agents. In the first set of simulations we studied the effects of the parameters of the function that generated ideal distances, and in a second set we explored how group macrolevel behavior depended on model parameters and other variables. We learned that certain parameter values yielded consistent patterns in the agents' personal and social spaces, which in turn led to avoidance and approaching behaviors in the agents. We also found that the spatial behavior of the group of agents as a whole was influenced by the values of the model parameters, as well as by other variables such as the number of agents. Our work demonstrates that the bottom-up approach is a useful way of explaining macro-level spatial behavior. The proposed model is also shown to be a powerful tool for simulating the spatial behavior of groups of interacting individuals.

A single dose of intravenous esomeprazole decreases gastric secretion in healthy volunteers.

BACKGROUND: Data suggest that esomeprazole decreases gastric secretion. AIMS: To assess the effect of a single i.v. esomeprazole dose on gastric secretion volume 3 h after drug administration, as a primary endpoint, and to evaluate, as secondary endpoints, the reduction 1 and 5 h after dosing; time when the gastric pH was <2.5 and esomeprazole's safety. METHODS: In all, 23 healthy Helicobacter pylori-negative volunteers (10 men, 13 women, mean age 28.2 +/- 6) participated in this single-centre, randomized, double-blind, placebo-controlled, 2-way, single-dose cross-over study. In different sessions, volunteers received i.v. either esomeprazole 40 mg or placebo. An inserted double-lumen nasogastric tube perfused and aspirated gastric liquid. Mechanical fractioned aspiration measured secretion volume; aliquot spectrophotometry assessed gastric secretion volume lost to the duodenum. RESULTS: Three hours post-i.v. esomeprazole, average gastric secretion decreased by 77.6% (vs. baseline) compared to placebo. Values 1 and 5 h after dosing were 73.5% and 74.5%. Five hours after esomeprazole, the gastric pH was <2.5 3.9% of the time and 73.3% after placebo (P < 0.002). Esomeprazole was well-tolerated. No serious adverse events occurred. CONCLUSIONS: Intravenous esomeprazole decreases gastric secretions. The potential clinical impact in averting bronchoaspiration during anaesthesia induction and in intensive care patients should be investigated in further studies.

Postmortem angiography after vascular perfusion with diesel oil and a lipophilic contrast agent.

OBJECTIVE: The objective of our study was to establish optimal perfusion conditions for high-resolution postmortem angiography that would permit dynamic visualization of the arterial and venous systems. MATERIALS AND METHODS: Cadavers of two dogs and one cat were perfused with diesel oil through a peristaltic pump. The lipophilic contrast agent Lipiodol Ultra Fluide was then injected, and angiography was performed. The efficiency of perfusion was evaluated in the chick chorioallantoic membrane. RESULTS: Vessels could be seen up to the level of the smaller supplying and draining vessels. Hence, both the arterial and the venous sides of the vascular system could be distinguished. The chorioallantoic membrane assay revealed that diesel oil enters microvessels up to 50 microm in diameter and that it does not penetrate the capillary network. CONCLUSION: After establishing a postmortem circulation by diesel oil perfusion, angiography can be performed by injection of Lipiodol Ultra Fluide. The resolution of the images obtained up to 3 days after death is comparable to that achieved in clinical angiography.

A pilot study on ocular safety and efficacy of infliximab as an antifibrotic agent after experimental filtration surgery

Purpose To evaluate the safety and efficacy of infliximab as an antifibrotic agent after experimental glaucoma filtration surgery in rabbits. Methods In a randomized, prospective, masked-observer study, 30 New Zealand Albino rabbits underwent glaucoma filtration surgery. The animals were allocated to receive either intraoperative application of infliximab (group A) or mitomycin C (MMC) at a concentration of 0.2mg/ml (group B) or balanced salt solution (BSS, control)(group C). Different infliximab doses, namely 1.0mg, 2.0mg, 3.0mg, 4.0mg, 5.0mg in 0.1ml were applied. Bleb survival and characteristics were evaluated over a 30day period. The animals were killed on postoperative day 15 and 30. Histology of the operated eyes was performed to evaluate and grade the amount of scarring in each group.Cellular density was evaluated in each case. Results Infliximab did not appear to improve the outcome of filtration surgery in this model of glaucoma filtration surgery.There was a significant decrease in cellular density in the MMC group compared to the control group (p=0.0352). There was neither a significant decrease in cellular density between the infliximab group and the control group nor between the infliximab group and the MMC group. Overall there was no difference in terms of fibrosis between the three different groups. There was slightly less inflammation in the infliximab group, but not significant. Conclusions In this study intraoperative application of infliximab does not appear to be superior to the application of MMC or a control with regard to bleb survival and fibrosis. This study however demonstrates that intraoperative application of MMC significantly reduces the cellular density of the filtration bleb.

Pegfilgrastim to accelerate neutrophil engraftment following peripheral blood stem cell transplant and reduce the duration of neutropenia, hospitalization, and use of intravenous antibiotics: a phase II study in multiple myeloma and lymphoma and comparison with filgrastim-treated matched controls.

This trial was aimed to explore the efficacy of pegfilgrastim to accelerate neutrophil engraftment after stem cell autotransplant. Twenty patients with multiple myeloma and 20 with lymphoma received pegfilgrastim 6 mg on day +1. Forty cases treated with daily filgrastim starting at median day +7 (5-7), matched by age, sex, diagnosis, high-dose chemotherapy schedule, CD34 +  cell-dose, and prior therapy lines, were used for comparison. Median time to neutrophil engraftment was 9.5 vs. 11 days for pegfilgrastim and filgrastim, respectively (p < 0.0001). Likewise, duration of neutropenia, intravenous antibiotic use, and hospitalization favored pegfilgrastim, while platelet engraftment, transfusion requirement, and fever duration were equivalent in both groups. No grade  ≥ 3 toxicities were observed. Patients with lymphoma performed similarly to the entire cohort, while patients with myeloma showed faster neutrophil engraftment and shorter neutropenia but not shorter hospitalization and antibiotic use. The possibility of different outcomes for lymphoma and myeloma suggests that stratification by diagnosis may be useful in future phase III studies.

Occurrence of sectoral choroidal occlusive vasculopathy and retinal arteriolar embolization after superselective ophthalmic artery chemotherapy for advanced intraocular retinoblastoma.

BACKGROUND:: Superselective ophthalmic artery chemotherapy (SOAC) has recently been proposed as an alternative to intravenous chemoreduction for advanced intraocular retinoblastoma. Preliminary results appear promising in terms of tumor control and eye conservation, but little is known regarding ocular toxicity and visual prognosis. In this study, we report on the vascular adverse effects observed in our initial cohort of 13 patients. METHODS:: The charts of 13 consecutive patients with retinoblastoma who received a total of 30 injections (up to 3 injections of a single agent per patient at 3-week interval) of melphalan (0.35 mg/kg) in the ophthalmic artery between November 2008 and June 2010 were retrospectively reviewed. RetCam fundus photography and fluorescein angiography were performed at presentation and before each injection. Vision was assessed at the latest visit. RESULTS:: Enucleation and external beam radiotherapy could be avoided in all cases but one, with a mean follow-up of 7 months. Sectoral choroidal occlusive vasculopathy leading to chorioretinal atrophy was observed temporally in 2 eyes (15%) 3 weeks to 6 weeks after the beginning of SOAC and retinal arteriolar emboli in 1 eye 2 weeks after injection. There was no stroke or other clinically significant systemic side effects except a peroperative transient spasm of the internal carotid artery in one patient. Vision ranged between 20/1600 and 20/32 depending on the status of the macula. CONCLUSION:: Superselective ophthalmic artery chemotherapy was effective in all patients with no stroke or other systemic vascular complications. Unlike intravenous chemoreduction, SOAC is associated with potentially sight-threatening adverse effects, such as severe chorioretinal atrophy secondary to subacute choroidal occlusive vasculopathy or central retinal artery embolism, not to mention the risk of ophthalmic artery obstruction, which was not observed in this series. Further analysis of the risks and benefits of SOAC will define its role within the therapeutic arsenal. Meanwhile, we suggest that SOAC should be given in one eye only and restricted to advanced cases of retinoblastoma, as an alternative to enucleation and/or external beam radiotherapy.

Intravenous fish oil blunts the physiological response to endotoxin in healthy subjects

Résumé L'administration par voie orale d'acides gras polyinsaturés de type ω-3 contenus dans l'huile de poisson exerce des effets bénéfiques sur la réponse métabolique et inflammatoire chez des sujets sains soumis à une injection d'endotoxine. Ce modèle expérimental a été validé pour l'investigation clinique. Il simule un sepsis et induit une réponse comparable à un état grippal, accompagné de modifications métaboliques et inflammatoires. L'objectif de cette étude est de déterminer les effets de l'huile de poisson administré par voie intraveineuse sur la réponse à l'endotoxine chez le sujet sain. L'hypothèse est qu'il sera possible de réduire le temps de latence en comparaison avec la voie orale. Pour ce faire, nous avons inclut dans une étude prospective randomisée 16 volontaires sains âgés de 16 à 35 ans et les avons répartis en 2 groupes : l'un recevant une émulsion lipidique contenant les acides gras polyinsaturés EPA et DHA et l'autre, sans traitement, constituant le groupe contrôle. Huit sujets reçoivent une perfusion continue de 0.5g/kg d'huile de poisson durant 6h, 48h et 24h avant la journée test. Lors de cette journée test, tous les volontaires ont reçu une dose d'endotoxine (2mg/kg) au temps t0. Les paramètres vitaux sont monitorés et enregistrés : fréquence cardiaque, respiratoire, pression artérielle, saturation artérielle en oxygène, ainsi que température. Des prises de sang sont effectuées à intervalles réguliers pour déterminer 1) l'incorporation membranaire des thrombocytes en EPA et DHA ; 2) le taux plasmatique d'hormones (insulin, glucagon, cortisol, ACTH et catécholamines), de marqueurs inflammatoires (TNF-α, IL-6, hsCRP), ainsi que de substrats énergétiques (glucose, lactate, acides gras libres et triglycérides). La dépense énergétique est déterminée par calorimétrie indirecte. L'analyse statistique est effectuée par analyse de variance (ANOVA). Les résultats montrent une incorporation significative de EPA et DHA au niveau membranaire des thrombocytes. L'huile de poisson induit une atténuation significative de la réponse neuro-endocrinienne et inflammatoire en réponse à l'injection d'endotoxine avec diminution de la fièvre (-0.7°C), ainsi que du taux plasmatique ,d'ACTH (-68%), TNF-α (-63%) et de noradrénaline (-%) dans le groupe huile de poisson. En conclusion, cette étude montre que la supplémentation de 2 doses d'huile de poisson par voie intraveineuse modifie la composition phospholipidique des membranes des thrombocytes et diminue la réaction inflammatoire et neuroendocrinienne en réponse à l'endotoxine. Ces résultats positifs ouvrent la perspective d'une supplémentation parentérale préopératoire en acides gras polyinsaturés ω-3 pour diminuer le stress lié à la chirurgie majeure.

Anisoylated plasminogen streptokinase activator complex versus streptokinase in acute myocardial infarction. Preliminary results of a randomised study.

25 patients with acute myocardial infarction pain lasting more than 20 minutes which was not relieved by nitrates, whose ECGs showed ST segment elevations of 1 mm or more in 2 or more ECG leads, and who presented less than 3 hours after onset of their symptoms were randomly assigned to one of 2 thrombolytic treatment groups: a single intravenous bolus of anisoylated plasminogen streptokinase activator complex (APSAC) 30U in 5 minutes or an intravenous infusion of streptokinase 1,500,000U over 60 minutes. 3 to 4 hours after the administration of the thrombolytic agent, all patients received intravenous heparin at full dosage for 24 hours. The patency of the infarct-related coronary vessels was assessed by angiography 1 to 4 hours after administration of the thrombolytic agent. Clinical signs, ECGs, pulse, blood pressure and temperature were monitored regularly for 24 hours after treatment or as clinically appropriate. APSAC seemed to be at least as effective as streptokinase in terms of patency of the infarct-related vessel (92% vs 63%, respectively). The adverse events were similar and none was life-threatening. APSAC and streptokinase caused similar falls in blood fibrinogen levels. APSAC, given as a bolus injection over 5 minutes, was easier to administer than streptokinase, which was given as an infusion during 60 minutes.

Intravenous pamidronate as treatment for osteoporosis after heart transplantation: a prospective study.

Fractures due to osteoporosis are one of the major complications after heart transplantation, occurring mostly during the first 6 months after the graft, with an incidence ranging from 18% to 50% for vertebral fractures. Bone mineral density (BMD) decreases dramatically following the graft, at trabecular sites as well as cortical sites. This is explained by the relatively high doses of glucocorticoids used during the months following the graft, and by a long-term increase of bone turnover which is probably due to cyclosporine. There is some evidence for a beneficial effect on BMD of antiresorptive treatments after heart transplantation. The aim of this study was to assess prospectively the effect on BMD of a 3-year treatment of quarterly infusions of 60 mg of pamidronate, combined with 1 g calcium and 1000 U vitamin D per day, in osteoporotic heart transplant recipients, and that of a treatment with calcium and vitamin D in heart transplant recipients with no osteoporosis. BMD of the lumbar spine and the femoral neck was measured by dual-energy X-ray absorptiometry in all patients every 6 months for 2 years and after 3 years. Seventeen patients, (1 woman, 16 men) aged 46+/-4 years (mean +/- SEM) received only calcium and vitamin D. A significant decrease in BMD was observed after 6 months following the graft, at the lumbar spine (- 6.6%) as well as at the femoral neck (-7.8%). After 2 years, BMD tended to recover at the lumbar spine, whereas the loss persisted after 3 years at the femoral neck. Eleven patients (1 woman and 10 men) aged 46+/-4 years (mean +/- SEM) started treatment with pamidronate on average 6 months after the graft, because they had osteoporosis of the lumbar spine and/or femoral neck (BMD T-score below -2.5 SD). Over the whole treatment period, a continuous increase in BMD at the lumbar spine was noticed, reaching 18.3% after 3 years (14.3% compared with the BMD at the time of the graft). BMD at the femoral neck was lowered in the first year by -3.4%, but recovered totally after 3 years of treatment. In conclusion, a 3-year study of treatment with pamidronate given every 3 months to patients with existing osteoporosis led to a significant increase in lumbar spine BMD and prevented loss at the femoral neck. However, since some of these patients were treated up to 14 months after the transplant, they may already have passed through the phase of most rapid bone loss. In patients who were not osteoporotic at baseline, treatment with calcium and vitamin D alone was not able to prevent the rapid bone loss that occurs immediately after transplantation.

Blunting the response to endotoxin in healthy sujects : effects of various dose of intravenous fish oil

Enjeux et contexte La recherche de cette dernière décennie sur les acides gras n-3 PUFA contenus dans l'huile de poisson a montré que ceux-ci, et particulièrement l'ΕΡΑ et le DHA, avaient des propriétés anti¬inflammatoires et anti arythmiques puissantes, potentiellement utiles chez les septiques et « cardiaques ». Les mécanismes sous-jacents sont nombreux, incluant l'incorporation des acides gras dans les membranes de phopholipides, la réduction de la production de médiateurs pro-inflammatoires (prostaglandines, leukotrienes, thromboxane), l'augmentation de la production de résolvines et protectines dérivées du DHA, et la régulation de voies de signalisation cellulaire. Cependant, les doses de n-3 PUFA utilisées dans les études cliniques et chez le sujet sain avant le travail de Yann-Karim Pittet étaient nettement supérieures aux doses nutritionnelles de l'ordre de 5-8 g/j par voie orale ou 1 g/kg par voie intraveineuse. De plus, la voie entérale avait la réputation de nécessiter plusieurs jours à semaines de traitement avant d'aboutir à une incorporation d'acides gras membranaire suffisante pour avoir un impact clinique; quant au temps minimal requis pour obtenir cet effet par voie IV, il était inconnu. Depuis, le développement d'émulsions lipidiques intraveineuses destinées à la nutrition parentérale a permis d'imaginer l'administration de prétraitements IV rapides. Pour les étudier, notre laboratoire a développé un modèle d'endotoxine (LPS d'E.Coli) qui mime les réponses physiologique, endocrinienne et biologique du sepsis chez le sujet sain, utilisant des doses de 2 ng/kg IV. Les réponses sont totalement réversibles en 8 heures. Dans le but de réduire à la fois la dose de lipides et le temps de perfusion, ce travail a étudié l'influence de 3 doses dégressives de n-3 PUFA sur les réponses à l'endotoxine, et sur l'incorporation membranaire de ces acides gras. Méthodes Etude prospective chez 3 groupes consécutifs de sujets sains soumis à un challenge d'endotoxine. Intervention : perfusions d'huile de poisson (0.5 et 0.2 g/kg de n-3 PUFA, Omegaven® 10%) ou placebo, administrées en 3 heures ou en 1 heure, soit le jour avant ou le jour-même du test d'endotoxine. Mesures : variables physiologiques (T°, fc, tension artérielle, calorimétrie indirecte) Laboratoire - prises de sang à T0, 60, 120 et 360 min après l'injection de LPS: TNF-α, hs-CRP, hormones de stress, composition en acides gras des membranes plaquettaires. Statistiques Les résultats ont été rapportés en moyennes et écarts types. Des aires sous la courbe (AUC) ont été calculées avec la méthode des parallélépipèdes pour toutes les variables déterminées de manière répétée. L'effet du temps a été exploré par des two-way ANOVA pour mesures répétées. Les comparaisons post-hoc ont été réalisées avec des tests de Dunnett's ou de Scheffe. Les modifications de composition membranaires ainsi que les AUC ont été analysées par des tests non-paramétriques (Kruskal-Wallis). Résultats Après LPS, la température, les concentrations d'ACTH et TNF-α ont augmenté dans les 3 groupes. Ces réponse ont été significativement atténuées (p<0.0001) par l'huile de poisson comparé à ce que nous avions observé dans le groupe contrôle de Pluess et al (ICM 2007). Les concentrations les plus faibles d'ACTH, de TNF-α, et les AUC les plus basses des températures, ont été observées après une dose unique de 0.2 g/kg de n-3 PUFA administrée 1 heure avant le LPS. Par contre, l'incorporation membranaire d'EPA est dose-dépendante. Conclusions Sachant que la réponse à l'endotoxine est reproductible, cette étude montre que 3 doses différentes d'huile de poisson atténuent de manière différente cette réponse. La perfusion de 0.2 g/kg administrée juste avant l'endotoxine s'est avérée la plus efficace à atténuer la réponse fébrile, les cytokines et les hormones de stress, suggérant une capture de l'endotoxine par l'émulsion lipidique qui se surajoute aux effets systémiques et membranaires.