Preoperative immunonutrition in patients at nutritional risk: results of a double-blinded randomized clinical trial.

Background/Objectives:To evaluate the impact of preoperative immunonutrition (IN) on postoperative morbidity in patients at risk of malnutrition undergoing major gastrointestinal (GI) surgery.Subjects/Methods:The combination of malnutrition and major GI surgery entails high morbidity. The Nutritional Risk Score (NRS) reliably identifies patients who need preoperative nutrition; the optimal nutritional formula for these patients still needs to be defined. In all, 152 patients with a NRS3 and undergoing elective major GI surgery were randomized between IN or isocaloric-isonitrogenous nutrition (ICN) given for 5 days preoperatively. Patients and caregivers were blinded for the allocated intervention. Thirty days complication rate was the primary endpoint. Infections, length of hospital stay and compliance were considered as secondary outcomes.Results:Overall, 145 patients were available for analysis; the 73 patients in the IN group matched well with the 72 ICN patients with regards to patient's and surgical characteristics. In all, 39 IN and 33 ICN patients experienced a total of 48 and 50 postoperative complications, respectively (P=0.723). Both groups did not differ significantly concerning infectious (13 vs 9) complications. Independent risk factors for overall complications were malignant disease (odds ratio (OR)=4.304; confidence interval (CI) 1.317-14.002) and operative time (OR=1.004; CI 1.000-1.008).Conclusion:In patients at nutritional risk, complications, infections and hospital stay after major GI surgery were comparable regardless of preoperative supplementation with IN or ICN.

A prospective randomised double-blind controlled trial evaluating the effect of trans-sacral magnetic stimulation in women with overactive bladder.

Overactive bladder (OAB) is a prevalent condition with 16% of adults having one or more symptoms that significantly affect quality of life. Transcutaneous electrical nerve stimulation and neuromodulators have had success in treating OAB but are expensive, invasive, and sometimes cumbersome. We developed an alternative neuromodulatory technique that involves electromagnetic stimulation of the sacral nerve roots with a portable electromagnetic device to produce trans-sacral stimulation of the S3 and S4 sacral nerve roots. The aim of this study was to evaluate the impact of this device on OAB symptoms in women with a prospectively randomised double-blind controlled study. Following a power analysis, women with symptoms of OAB were prospectively recruited with ethical approval for randomisation to an active treatment (n = 33) or placebo group (n = 30) in a double-blind trial. The patient, at home, used the belt device daily for 20 min over 12 weeks. Outcome measures included a 3-day voiding diary, 1 h pad test, visual analogue score (VAS) for symptom impact (0-100%), Kings Health Questionnaire (KHQ) and Australian Quality of Life questionnaire (AQOL) at baseline, 6 and 12 weeks. Overall, no difference was found between groups for any of the research questions. Specifically, we were unable to demonstrate any difference between the active and sham device groups in frequency, nocturia, urinary leakage, or quality of life, nor was there any evidence of a placebo effect. The quality of the data was high with the number of missing observations (especially for disease specific KHQ and general AQOL) being few. This attempt to promote trans-sacral electromagnetic neuromodulation with a specially created device was ineffective on the symptoms of OAB.

Allergy to betalactam antibiotics in children: a prospective follow-up study in retreated children after negative responses in skin and challenge tests.

BACKGROUND: Up to 10% of the patients in whom suspected betalactam hypersensitivity (HS) has been excluded by skin and challenge tests report suspected allergic reactions during subsequent treatments with the same or very similar betalactams. It has been suggested that the reactions may result from a resensitization induced by the challenge performed at the time of the allergological work-up. However, most patients did not undergo a second allergological work-up, to determine if the reactions resulted from betalactam HS or not. OBJECTIVES: We aimed to determine if children diagnosed nonallergic to betalactams have tolerated subsequent treatments with the initially suspected and/or other betalactams, and, in case of a reaction, if the reaction resulted from betalactam HS. Methods: We sent a questionnaire concerning the clinical history of their children to the parents of 256 children previously diagnosed nonallergic to betalactams. A second allergological work-up was performed in the children reporting suspected allergic reactions during subsequent treatments with the same and/or other betalactams. Skin tests were performed with the soluble form of the suspected (or very similar) betalactams and other betalactams from the same and other classes. Skin test responses were assessed at 15-20 min (immediate), 6-8 h (semi-late) and 48-72 h (late). Oral challenge (OC) was performed in children with negative skin tests, either at the hospital (immediate and accelerated reactions), or at home (delayed reactions). RESULTS: A response was obtained from 141 children (55.3%). Forty-eight (34%) of those children had not been treated with the betalactams for whom a diagnosis of allergy had been ruled out previously. Seven (7.5%) of the 93 children who had been treated again reported suspected allergic reactions. Skin tests and OC were performed in six of those children, and gave negative results in five children. In one child previously diagnosed nonallergic to amoxicillin associated with clavulanic acid, we diagnosed a delayed HS to clavulanic acid and a serum sickness-like disease to cefaclor. Thus, the frequency of reactions resulting from betalactam HS in children with negative skin and challenge tests is very low, and does not exceed 2.1% (2/93) if we consider that the child which refused a second allergological work-up is really allergic to betalactams. CONCLUSION: Our results in a very large number of children show that reactions presumed to result from betalactam HS are rare in children in whom the diagnosis of betalactam allergy has been ruled out previously. Moreover, they suggest that, as shown for the initial reactions, most of the reactions during subsequent treatments are rather a consequence of the infectious diseases for whom betalactams have been prescribed than a result of betalactam HS. Finally, they suggest that the risk of resensitization by OC is very low, and do not support the notion that skin testing should be repeated in children diagnosed nonallergic to betalactams.

Analgesic efficacy of intravenous perfusion of lidocaine, ketamine or a combination after laparotomy in a placebo-controlled, randomized, double-blind prospective study

In acute postoperative pain management intravenous lidocaine and/or ketamine have been advocated because of their morphine-sparing effect. The goal of this prospective, randomised, double-blind study was to assess morphine consumption with different regimens of intravenous infusion of lidocaine, ketamine or both during 48 hours following laparotomy. Patients were randomised into four groups. Group L, K, and KL received intravenous lidocaine, ketamine or a combination, respectively, before incision and during 48 hours postoperatively. The control group (C) received a similar volume of saline bolus and infusion. Postoperative analgesia included morphine delivered by a patient-controlled analgesia device. Primary outcome was the cumulative morphine consumption and pain, sedation scores, pressure algometry and side effects were our secondary outcomes. Cognition and psychomotor performance were also tested. Out of 57 eligible patients, 44 completed the study. Lidocaine reduced the cumulative morphine consumption compared with the control group (mean 0.456 mg.kg-1 +/- 0.244 (SD) versus 0.705 +/- 0.442, respectively, Ρ < 0.001). Pain scores during movement were statistically lower in all three treatment groups. Psychometric tests showed that the lidocaine group expressed more depressed feelings and sadness compared to the control group. Lidocaine administration had a morphine-sparing effect with a 36% reduction of morphine consumption while ketamine alone or combined with lidocaine did not. As a whole, our results suggest that intravenous lidocaine may offer advantages for postoperative analgesia. We propose lidocaine as a new alternative for pain control that needs to be studied further in future multicentric studies.

Asymmetric effects of monetary policy in the US: Positive vs. negative or big vs. small?

This paper reconsiders the empirical evidence on the asymmetricoutput effects of monetary policy. Asymmetric effects is a common feature ofmany theoretical models, and there are many different versions of suchasymmetries. We concentrate on the distinctions between positive andnegative money-supply changes, big and small changes in money-supply, andpossible combinations of the two asymmetries. Earlier research has foundempirical evidence in favor of the former of these in US data. Using M1 asthe monetary variable we find evidence in favor of neutrality of big shocksand non-neutrality of small shocks. The results may, however, be affected bystructual instability of M1 demand. Thus, we substitute M1 with the federalfunds rate. In these data we find that only small negative shocks affectreal aggregate activity. The results are interpreted in terms of menu-costmodels.

Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4.

Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex, plays a fundamental role in the sensing of LPS from gram-negative bacteria. Activation of TLR4 signaling pathways by LPS is a critical upstream event in the pathogenesis of gram-negative sepsis, making TLR4 an attractive target for novel antisepsis therapy. To validate the concept of TLR4-targeted treatment strategies in gram-negative sepsis, we first showed that TLR4(-/-) and myeloid differentiation primary response gene 88 (MyD88)(-/-) mice were fully resistant to Escherichia coli-induced septic shock, whereas TLR2(-/-) and wild-type mice rapidly died of fulminant sepsis. Neutralizing anti-TLR4 antibodies were then generated using a soluble chimeric fusion protein composed of the N-terminal domain of mouse TLR4 (amino acids 1-334) and the Fc portion of human IgG1. Anti-TLR4 antibodies inhibited intracellular signaling, markedly reduced cytokine production, and protected mice from lethal endotoxic shock and E. coli sepsis when administered in a prophylactic and therapeutic manner up to 13 h after the onset of bacterial sepsis. These experimental data provide strong support for the concept of TLR4-targeted therapy for gram-negative sepsis.

Tracking the invisible hand: Convergence of double auctions to competitive equilibrium

Economics is the science of want and scarcity. We show that want andscarcity, operating within a simple exchange institution (double auction),are sufficient for an economy consisting of multiple inter--related marketsto attain competitive equilibrium (CE). We generalize Gode and Sunder's(1993a, 1993b) single--market finding to multi--market economies, andexplore the role of the scarcity constraint in convergence of economies to CE.When the scarcity constraint is relaxed by allowing arbitrageurs in multiple markets to enter speculative trades, prices still converge to CE,but allocative efficiency of the economy drops. \\Optimization by individual agents, often used to derive competitive equilibria,are unnecessary for an actual economy to approximately attain such equilibria.From the failure of humans to optimize in complex tasks, one need not concludethat the equilibria derived from the competitive model are descriptivelyirrelevant. We show that even in complex economic systems, such equilibriacan be attained under a range of surprisingly weak assumptions about agentbehavior.

Mathey [Dean] joueur de tennis [américain, jouant en double avec Watson Washburn, qualificatifs pour les Jeux interalliés à la Croix-Catelan, le 1er juin 1919] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 54160

Prevention of preterm delivery with vaginal progesterone in women with preterm labour (4P): randomised double-blind placebo-controlled trial.

OBJECTIVE: To evaluate the effectiveness of 200 mg of daily vaginal natural progesterone to prevent preterm birth in women with preterm labour. DESIGN: Multicentre, randomised, double-blind, placebo-controlled trial. SETTING: Twenty-nine centres in Switzerland and Argentina. POPULATION: A total of 385 women with preterm labour (24(0/7) to 33(6/7)  weeks of gestation) treated with acute tocolysis. METHODS: Participants were randomly allocated to either 200 mg daily of self-administered vaginal progesterone or placebo within 48 hours of starting acute tocolysis. MAIN OUTCOME MEASURES: Primary outcome was delivery before 37 weeks of gestation. Secondary outcomes were delivery before 32 and 34 weeks, adverse effects, duration of tocolysis, re-admissions for preterm labour, length of hospital stay, and neonatal morbidity and mortality. The study was ended prematurely based on results of the intermediate analysis. RESULTS: Preterm birth occurred in 42.5% of women in the progesterone group versus 35.5% in the placebo group (relative risk [RR] 1.2; 95% confidence interval [95% CI] 0.93-1.5). Delivery at <32 and <34 weeks did not differ between the two groups (12.9 versus 9.7%; [RR 1.3; 95% CI 0.7-2.5] and 19.7 versus 12.9% [RR 1.5; 95% CI 0.9-2.4], respectively). The duration of tocolysis, hospitalisation, and recurrence of preterm labour were comparable between groups. Neonatal morbidity occurred in 44 (22.8%) cases on progesterone versus 35 (18.8%) cases on placebo (RR: 1.2; 95% CI 0.82-1.8), whereas there were 4 (2%) neonatal deaths in each study group. CONCLUSION: There is no evidence that the daily administration of 200 mg vaginal progesterone decreases preterm birth or improves neonatal outcome in women with preterm labour.

Purification and characterization of the human Rad51 protein, an analogue of E. coli RecA.

In bacteria, genetic recombination is catalysed by RecA protein, the product of the recA gene. A human gene that shares homology with Escherichia coli recA (and its yeast homologue RAD51) has been cloned from a testis cDNA library, and its 37 kDa product (hRad51) purified to homogeneity. The human Rad51 protein binds to single- and double-stranded DNA and exhibits DNA-dependent ATPase activity. Using a topological assay, we demonstrate that hRad51 underwinds duplex DNA, in a reaction dependent upon the presence of ATP or its non-hydrolysable analogue ATP gamma S. Complexes formed with single- and double-stranded DNA have been observed by electron microscopy following negative staining. With nicked duplex DNA, hRad51 forms helical nucleoprotein filaments which exhibit the striated appearance characteristic of RecA or yeast Rad51 filaments. Contour length measurements indicate that the DNA is underwound and extended within the nucleoprotein complex. In contrast to yeast Rad51 protein, human Rad51 forms filaments with single-stranded DNA in the presence of ATP/ATP gamma S. These resemble the inactive form of the RecA filament which is observed in the absence of a nucleotide cofactor.

Laparoscopic inguinal hernia repair with extraperitoneal double-mesh technique.

Totally extraperitoneal laparoscopic hernia repair is an efficient but technically demanding procedure. As mechanisms of hernia recurrence may be related to these technical difficulties, we have modified a previously described double-mesh technique in an effort to simplify the procedure. Extraperitoneal laparoscopic hernia repairs were performed in 82 male and 17 female patients having inguinal, femoral, and recurrent bilateral hernias. A standard propylene mesh measuring 15 x 15 cm was cut into two pieces of 4 x 15 cm and 11 x 15 cm. The smaller mesh was placed over both inguinal rings without splitting. The larger mesh was then inserted over the first mesh and stapled to low-risk zones, reinforcing the large-vessel area and the nerve transition zone. The mean procedure duration was 60 minutes for unilateral and 100 minutes for bilateral hernia repair. Patients were discharged from the hospital within 48 hours. The mean postoperative follow-up was 22 months, with no recurrences, neuralgia, or bleeding complications. Over a 2-year period, this technique was found to be satisfactory without recurrences or significant complications. In our hands, this technique was easier to perform: it allows for a less than perfect positioning of the meshes and avoids most of the stapling to crucial zones.

Autoreactive T cells that bypass negative selection are not tolerant and respond to self-antigen stimulation during infection

Le répertoire cellulaire Τ a pour but d'être tolérant aux antigènes du soi afin d'éviter l'induction de maladies autoimmunes. C'est pourquoi les lymphocytes Τ autoréactifs sont éliminés dans le thymus lors de leur développement par le processus de sélection négative. La plupart des recherches étudient les lymphocytes Τ de haute avidité. Ces lymphocytes Τ de haute avidité sont très sensibles et réagissent fortement à un antigène du soi. En conséquence, ces cellules induisent le développement de maladies autoimmunes lorsqu'elles ciblent des organes exprimant l'antigène du soi. Plusieurs études ont montré que les lymphocytes Τ qui réagissent faiblement aux antigènes spécifiques à un tissu, nommé lymphocytes Τ de faible avidité, peuvent contourner les mécanismes de tolérance centrale et périphérique. J'ai utilisé des souris Rip-mOva qui expriment l'Ovalbumine comme antigène du soi spécifique à un tissu. Dans ces souris transgéniques Rip-mOva, les lymphocytes Τ de faible avidité survivent à la sélection négative. Une fois stimulés à la périphérie, ces lymphocytes Τ CD8+ de faible avidité ont la capacité d'infiltrer les organes qui expriment l'antigène du soi chez les souris Rip-mOva et peuvent induire une destruction tissulaire. L'objectif principal de mon projet de thèse était de comprendre les caractéristiques phénotypiques et fonctionnelles de ces lymphocytes Τ dans un état d'équilibre et dans un contexte infectieux. Pour étudier ces cellules dans un modèle murin bien défini, nous avons généré des souris exprimant un récepteur de cellule Τ transgénique appelé OT-3. Ces souris transgéniques OT-3 ont des lymphocytes Τ CD8+ de faible avidité spécifiques à l'épitope SIINFEKL de l'antigène Ovalbumine. Nous avons démontré qu'un grand nombre de lymphocytes Τ CD8+ OT-3 ne sont pas éliminés lors de la sélection négative dans le thymus après avoir rencontré l'antigène du soi. Par conséquent, les lymphocytes Τ OT-3 de faible avidité sont présents dans une fenêtre de sélection comprise entre la sélection positive et négative. Cette limite se définie comme le seuil d'affinité et est impliquée dans l'échappement de certains lymphocytes Τ OT- 3 autoréactifs. A la périphérie, ces cellules sont capables d'induire une autoimmunité après stimulation au cours d'une infection, ce qui nous permet de les définir comme étant non tolérante et non dans un état anergique à la périphérie. Nous avons également étudié le seuil d'activation des lymphocytes Τ OT-3 à faible avidité à la périphérie et avons constaté que des ligands peptidiques plus faibles que l'épitope natif SIINFEKL sont capables de les activer au cours d'une infection ainsi que de les différencier en lymphocytes Τ effecteurs et mémoires. Les données illustrent une déficience lors de la sélection négative dans le thymus de lymphocytes Τ CD8+ autoréactifs de faible avidité contre un antigène du soi spécifique à tissu et montrent que ces cellules sont entièrement compétentes lors d'une infection. - The diverse Τ cell repertoire needs to be tolerant to self-antigen to avoid the induction of autoimmunity. This is why autoreactive developing Τ cells are deleted in the thymus. The deletion of self-reactive Τ cells occurs through the process of negative selection. Most studies investigated high avidity Τ cells. These high avidity Τ cells are very sensitive and strongly react to a self-antigen. As a consequence, these cells induce the development of autoimmunity when they target organs which express the self-antigen. High avidity autoreactive CD8+ Τ cells are deleted in the thymus. However, several studies have shown Τ cells that weakly respond to tissue-restricted antigen, referred to as low avidity Τ cells, can bypass central and peripheral tolerance mechanisms. I used Rip-mOva mice that expressed Ovalbumin as a neo self-antigen in a tissue-restricted fashion. In these transgenic Rip-mOva mice low avidity CD8+ Τ cells survive negative selection. Upon stimulation in the periphery, these low avidity CD8+ Τ cells have the ability to infiltrate organs that express the self-antigen in the Rip-mOva mice and can also induce the destruction of the tissue. The major aim of my PhD project was to understand the phenotypic and functionality characteristics of these Τ cells in a steady-state condition and in a context of an infection. To study these cells in a well-defined mouse model, we generated OT-3 Τ cell receptor transgenic mice that express low avidity CD8+ Τ cells that are specific for the SIINFEKL epitope of the Ovalbumin antigen. We have been able to demonstrate that a large number of OT-3 CD8+ Τ cells survive negative selection in the thymus after encountering the self-antigen. Thus, low avidity OT-3 Τ cells are present in a window of selection comprised between positive and negative selection. This boundary defined as the affinity threshold is involved in the escape of some autoreactive low avidity OT-3 Τ cells. Once they circulate in the periphery, they are able to induce autoimmunity after stimulation during an infection, allowing us to allocate these cells as being non-tolerant and not in an anergic state in the periphery. We have also looked at the threshold of activation of low avidity OT-3 CD8+ Τ cells in the periphery and found that peptide ligands that are weaker than the native SIINFEKL epitope are able to activate OT-3 Τ cells during an infection and to differentiate them into effector and memory Τ cells. The data illustrate the impairment of negatively selecting low avidity autoreactive CD8+ Τ cells against a tissue-restricted antigen in the thymus and shows that these cells are fully competent upon an infection.