Effects of endotoxin on lactate metabolism in humans.

ABSTRACT: INTRODUCTION: Hyperlactatemia represents one prominent component of the metabolic response to sepsis. In critically ill patients, hyperlactatemia is related to the severity of the underlying condition. Both an increased production and a decreased utilization and clearance might be involved in this process, but their relative contribution remains unknown. The present study aimed at assessing systemic and muscle lactate production and systemic lactate clearance in healthy human volunteers, using intravenous endotoxin (LPS) challenge. METHODS: Fourteen healthy male volunteers were enrolled in 2 consecutive studies (n = 6 in trial 1 and n = 8 in trial 2). Each subject took part in one of two investigation days (LPS-day with endotoxin injection and placebo-day with saline injection) separated by one week at least and in a random order. In trial 1, their muscle lactate metabolism was monitored using microdialysis. In trial 2, their systemic lactate metabolism was monitored by means of a constant infusion of exogenous lactate. Energy metabolism was monitored by indirect calorimetry and glucose kinetics was measured with 6,6-H2 glucose. RESULTS: In both trials, LPS increased energy expenditure (p = 0.011), lipid oxidation (p<0.0001), and plasma lactate concentration (p = 0.016). In trial 1, lactate concentration in the muscle microdialysate was higher than in blood, indicating lactate production by muscles. This was, however, similar with and without LPS. In trial 2, calculated systemic lactate production increased after LPS (p = 0.031), while lactate clearance remained unchanged. CONCLUSIONS: LPS administration increases lactatemia by increasing lactate production rather than by decreasing lactate clearance. Muscle is, however, unlikely to be a major contributor to this increase in lactate production. TRIAL REGISTRATION: ClinicalTrials.gov NCT01647997

‘1-8 interferon inducible gene family': putative colon carcinoma-associated antigens

Db−/−xβ2 microglobulin (β2m) null mice transgenic for a chimeric HLA-A2.1/Db-β2m single chain (HHD mice) are an effective biological tool to evaluate the antitumour cytotoxic T-lymphocyte response of known major histocompatibility-restricted peptide tumour-associated antigens, and to screen for putative unknown novel peptides. We utilised HHD lymphocytes to identify immunodominant epitopes of colon carcinoma overexpressed genes. We screened with HHD-derived lymphocytes over 500 HLA-A2.1-restricted peptides derived from colon carcinoma overexpressed genes. This procedure culminated in the identification of seven immunogenic peptides, three of these were derived from the ‘human 1-8D gene from interferon inducible gene' (1-8D). The 1-8D gene was shown to be overexpressed in fresh tumour samples. The three 1-8D peptides were both antigenic and immunogenic in the HHD mice. The peptides induce cytotoxic T lymphocytes that were able to kill a colon carcinoma cell line HCT/HHD, in vitro and retard its growth in vivo. One of the peptides shared by all the 1-8 gene family primed efficiently normal human cytotoxic T lymphocyte precursors. These results highlight the 1-8D gene and its homologues as putative immunodominant tumour-associated antigens of colon carcinoma

When Flexibility Is Stable: Implicit Long-Term Shaping of Olfactory Preferences

Preferences are traditionally assumed to be stable. However, empirical evidence such as preference modulation following choices calls this assumption into question. The evolution of such postchoice preference over long time spans, even when choices have been explicitly forgotten, has so far not been studied. In two experiments, we investigated this question by using a variant of the free choice paradigm: In a first session, participants evaluated the pleasantness of a number of odors. We then formed pairs of similarly rated odors, and asked participants to choose their favorite, for each pair. Participants were then presented with all odors again, and asked for another pleasantness rating. In a second session 1 week later, a third pleasantness rating was obtained, and participants were again asked to choose between the same options. Results suggested postchoice preference modulation immediately and 1 week after choice for both chosen and rejected options, even when choices were not explicitly remembered. A third experiment, using another paradigm, confirmed that choice can have a modulatory impact on preferences, and that this modulation can be long-lasting. Taken together, these findings suggest that although preferences appear to be flexible because they are modulated by choices, this modulation also appears to be stable over time and even without explicit recollection of the choice. These results bring a new argument to the idea that postchoice preference modulation could rely on implicit mechanisms, and are consistent with the recent proposal that cognitive dissonance reduction could to some extent be implicit

Tumor-Shed PGE2 Impairs IL2Rγc-Signaling to Inhibit CD4+ T Cell Survival: Regulation by Theaflavins

BACKGROUND:Many tumors are associated with decreased cellular immunity and elevated levels of prostaglandin E2 (PGE2), a known inhibitor of CD4+ T cell activation and inducer of type-2 cytokine bias. However, the role of this immunomodulator in the survival of T helper cells remained unclear. Since CD4+ T cells play critical roles in cell-mediated immunity, detail knowledge of the effect tumor-derived PGE2 might have on CD4+ T cell survival and the underlying mechanism may, therefore, help to overcome the overall immune deviation in cancer. METHODOLOGY/PRINCIPAL FINDINGS:By culturing purified human peripheral CD4+ T cells or Jurkat cells with spent media of theaflavin- or celecoxib-pre-treated MCF-7 cells, we show that tumor-shed PGE2 severely impairs interleukin 2 receptor gammac (IL2Rgammac)-mediated survival signaling in CD4+ T cells. Indeed, tumor-shed PGE2 down-regulates IL2Rgammac expression, reduces phosphorylation as well as activation of Janus kinase 3 (Jak-3)/signal transducer and activator of transcription 5 (Stat-5) and decreases Bcl-2/Bax ratio thereby leading to activation of intrinsic apoptotic pathway. Constitutively active Stat-5A (Stat-5A1 6) over-expression efficiently elevates Bcl-2 levels in CD4+ T cells and protects them from tumor-induced death while dominant-negative Stat-5A over-expression fails to do so, indicating the importance of Stat-5A-signaling in CD4+ T cell survival. Further support towards the involvement of PGE2 comes from the results that (a) purified synthetic PGE2 induces CD4+ T cell apoptosis, and (b) when knocked out by small interfering RNA, cyclooxygenase-2 (Cox-2)-defective tumor cells fail to initiate death. Interestingly, the entire phenomena could be reverted back by theaflavins that restore cytokine-dependent IL2Rgammac/Jak-3/Stat-5A signaling in CD4+ T cells thereby protecting them from tumor-shed PGE2-induced apoptosis. CONCLUSIONS/SIGNIFICANCE:These data strongly suggest that tumor-shed PGE2 is an important factor leading to CD4+ T cell apoptosis during cancer and raise the possibility that theaflavins may have the potential as an effective immunorestorer in cancer-bearer

Effects of sodium lactate on ventilation and acid-base balance in healthy humans

Sodium lactate inhibits ventilation when infused in healthy human subjects. This effect has been attributed to lactate-induced metabolic alkalosis. In order to further delineate the mechanisms responsible for this depression of ventilation, healthy humans were infused with sodium lactate with or without acetazolamide. Sodium lactate increased blood pH from 7.37 +/- 0.02 to 7.47 +/- 0.01 and induced a sustained urinary excretion of bicarbonate. PO2 of arterialized blood decreased by 10.3 +/- 2.1 mmHg, indicating an inhibition of ventilation. Acetazolamide decreased lactate-induced alkalinisation of blood (pH after lactate + acetazolamide 7.42 +/- 0.02), but did not prevent the drop in PO2. Acetazolamide alone tended to stimulate ventilation, as indicated by an increase in PO2. These results indicate that sodium lactate inhibits ventilation independently of changes in systemic blood pH. Alkalinization of the cerebrospinal fluid, or other central effects of lactate, is probably responsible for this ventilatory depression

Evolution de la nutrition artificielle aux soins intensifs de chirurgie au cours des dix dernières années : Conséquences pratiques.

La nutrition artificielle fait partie intégrante du traitement du patient agressé. Au cours de la dernière décennie, la nutrition entérale (NE) a pris une place prépondérante aux soins intensifs de chirurgie: elle est utilisée dans près de 30% des journées de traitement, la nutrition parentérale (NPT) étant réservée aux patients avec un tube digestif non fonctionnel (12,4% des journées). La voie jéjunale est utilisée dans 35% des cas de NE. La combinaison de NE et de NPT est pratiquée dans deux tiers des cas. Divers problèmes ont été mis en évidence : la proportion de nutriments réellement administrée est en moyenne de 75% de la quantité prescrite en NE et de 85% en NPT. Pour augmenter l'efficacité de la nutrition, une rubrique spécifique a été créée sur les feuilles de prescription médicales pré-imprimées et sur les dossiers infirmiers