Increased Plasma Lactate Levels Research Articles

Biological significance and clinical utility of lactate in sepsis.

Sepsis is a global health problem; progression to septic shock is associated with a marked increase in morbidity and mortality. In this setting, increased plasma lactate levels demonstrated to be an indicator of severity and a predictor of mortality, and are usually interpreted almost exclusively as a marker of low tissue perfusion. However, a recent paradigm shift has occurred in the exegesis of lactate metabolism and its biological properties. Indeed, metabolic adaptation to stress, even with an adequate oxygen supply, may account for high circulating lactate levels. Likewise, other pathophysiological consequences of sepsis, such as mitochondrial dysfunction, are associated with the development of hyperlactatemia, which is not necessarily accompanied by low tissue perfusion. Interpreting the origin and function of lactate may be of great clinical utility in sepsis, especially when circulating lactate levels are the basis for resuscitative measures.

EFFECTS OF PETROL CONTAMINATED DIET AND WATER ONGLUCOSE, LIVER GLYCOGEN, PLASMA LACTATE AND LIPID PROFILE IN MALE WISTAR RATS

Exposure to petrol have been shown to cause detrimental health effects. Literature is sparse on whether exposure to petrol causes metabolic disorders. This study investigated the effects of petrol contaminated diet andwater on blood glucose, liver glycogen, plasma lactate, triglycerides and lipid profile in male Wistar rats. The study was divided into two phases. Phase one study consisted of 15 male Wistar rats divided into three groups (n = 5/group). Groups 1-3 were given distilled water, petrol-contaminated diet (20 mL petrol/200 g rodent chow PCD), and petrol-contaminated water (0.5 mL/kg PCW) orally and respectively for .two weeks. In the phase two study, 15 male Wistar rats were divided into three groups (n = 5/group), animals in groups 1-3 received distilled water, petrol contaminated diet, and petrol-contaminated water orally and respectively for four weeks.At the end of the experiment, fasting blood glucose, liver glycogen, plasma lactate, triglycerides and lipid profie were measured.The results of this study showed that the administration of petrol contaminated diet and water caused significant increase in plasma lactate levels, triglycerides (TG),total cholesterol (TC), low density lipoprotein (LDL), very low density lipoprotein (VLDL)and a significant reduction in liver glycogen and high density lipoprotein( HDL) in male Wistar rats. In conclusion, the study revealed that, exposure of rats to petrol contaminated diet and water caused changes in lipid profile, altered glucose and lipid metabolism in male Wistar rats. Exposure to petrol should therefore be restricted or avoided.

Early decreased respiratory chain capacity in resuscitated experimental sepsis is a major contributor to lactate production.

Increased plasma lactate levels in patients with sepsis may be due to insufficient oxygen delivery, but mitochondrial dysfunction or accelerated glycolysis may also contribute. We studied the effect of the latter on muscle metabolism by using microdialysis in a sepsis model with sustained oxygen delivery and decreased energy consumption or mitochondrial blockade. Pigs were subjected to continuous E. coli infusion (sepsis group, n = 12) or saline infusion (sham group, n = 4) for 3 hours (h). Protocolized interventions were applied to normalize the oxygen delivery and blood pressure. Microdialysis catheters were used to monitor muscle metabolism (naïve). The same catheters were used to block the electron transport chain with cyanide or the Na+/K+-ATPase inhibitor, ouabain locally. All pigs in the sepsis group had positive blood cultures and a Sequential Organ Failure Assessment (SOFA) score increase by at least 2, fulfilling the sepsis criteria. Plasma lactate was higher in the sepsis group than in the sham group (p < 0.001), whereas muscle glucose was lower in the sepsis group (p < 0.01). There were no changes in muscle lactate levels over time but lactate to pyruvate ratio (LPR) was elevated in the Sepsis vs. the Sham group (p < 0.05). Muscle lactate, LPR, and glutamate levels were higher in the sepsis group than in the sham group in the cyanide catheters (p < 0.001, all comparisons) and did not normalize in the former group. In this experimental study on resuscitated sepsis, we observed increased aerobic metabolism and preserved mitochondrial function. Sepsis and electron transport chain inhibition led to increased LPR, suggesting a decreased mitochondrial reserve capacity in early sepsis.

THE ROLE OF ADRENERGIC RECEPTORS IN THE ACTION OF ADRENALINE ON PLASMA LACTATE, GLUCOSE, LIVER, AND SKELETAL MUSCLE GLYCOGEN IN THE COMMON AFRICAN TOAD BUFO REGULARIS

In mammals, the roles of liver and skeletal muscle glycogen in adrenaline-induced hyperglycaemia are well known. However, in amphibians, there is limited information on the relative contribution of liver and skeletal muscle glycogen in adrenaline-induced hyperglycaemia. This study investigated the effects of adrenaline on blood glucose, plasma lactate, liverand skeletal muscle glycogen and the role of adrenergic receptors in the common African toad, bufo regularis. One hundred and twenty-five adult common African toads (70-100g) of both sexes were randomly collected and used in the study.Blood samples were collected from truncus arteriosus to estimate glucose and lactate levels. Blood glucose was determined immediately by modified glucose oxidase method. Plasma lactate was determined by modification of the Barker-Summerson method. Liver and gastrocnemius muscle glycogen were determined using anthrone reagents method. Adrenaline caused significant increase in blood glucose, lactate levels and significant reduction in liver and muscle glycogen. When toads were pre-treated with propranolol or prazosin, adrenalines reduction in liver and muscle glycogen was significantly reduced while the increase in blood glucose and lactate levels was prevented. Combination of both blockers abolished the increase in blood glucose, lactate levels and blocked reduction in liver and muscle glycogen produced by adrenaline. The results of this study showed that adrenalinecaused liver and skeletal muscle glycogen breakdown, increase in plasma lactate levels which resulted in hyperglycaemia in the common African toad bufo regularis. The study also showed that both alpha- and beta-adrenergic receptors are involved in mediating the effects of adrenaline on blood glucose, plasma lactate, liver, and muscle glycogenolysis and gluconeogenesis.

Use of adrenaline continuous infusion to treat hypotension during general anaesthesia in a cow and a calf

BackgroundHypotension is one of the most common complications observed during inhalation anaesthesia in veterinary patients. Treatment of hypotension in cattle is more challenging than in other species, owing to the limited number of drugs licensed in food producing animals. The use of adrenaline as an infusion to support blood pressure has not been described previously in bovines.Case presentationA cow and a calf presented to University College Dublin Veterinary Hospital for bilateral mandibular fracture repair and bladder rupture repair respectively, developed severe anaesthetic related hypotension unresponsive to conventional treatments. In both cases an adrenaline infusion was started and slowly increased to effect, with infusion rates ranging from 0.01 to 0.25 μg/kg/min. Blood pressure increased as the adrenaline infusion rate increased, but clinically significant improvements in blood pressure were only observed with infusion rates exceeding 0.05 μg/kg/min. The side effect observed with adrenaline infusion was an increase in plasma lactate levels in both cases. Both animals were euthanised due to non-anaesthetic related complications.ConclusionsMaintenance of normotension is important during bovine anaesthesia to prevent the development of post-anaesthetic complications. In the cases described here, adrenaline was effective as an additional treatment of anaesthetic related hypotension. Further research is required to establish the recommended infusion rates, cardiovascular effects and possible side effects of adrenaline infusion administration as a treatment for hypotension in bovines.

Citrus fruit-derived flavonoid naringenin and the expression of hepatic organic cation transporter 1 protein in diabetic rats treated with metformin.

Naringenin possesses many pharmacological effects and may modulate metformin disposition. The purpose of this study was to evaluate the role of naringenin on hepatic expression of organic cation transporter 1 (OCT1) protein and its associated effects on metformin-associated hyperlactataemia in diabetes. Forty-nine male Sprague Dawley rats randomly assigned to seven groups (n=7) were orally treated daily with 3.0mL/kg body-weight (BW) of distilled water (group 1) or 60mg/kg BW of naringenin (groups 2 and 5) or 250mg/kg BW of metformin (groups 3 and 6), respectively, dissolved in distilled water. Similarly, group 7 was given metformin and naringenin. Groups 4, 5, 6 and 7 were administered intraperitoneally with streptozotocin at a single dose of 60mg/kg BW to induce diabetes. Glucose tolerance tests were performed. The animals were killed after 8weeks of treatment, blood was collected, and livers excised for further biochemical analysis. Lowered body-weight, increased polydipsia and reduced hepatic glycogen concentrations were observed in diabetic rats compared to controls. Naringenin only significantly decreased plasma lactate levels, while metformin only or with naringenin significantly increased plasma lactate levels in diabetic compared to non-treated diabetic animals. Metformin only but not naringenin significantly increased plasma lactate levels in non-diabetic compared to control rats. Furthermore, naringenin with or without metformin but not metformin only significantly increased hepatic organic cation transporter 1 (OCT1) expression in diabetic compared to non-treated diabetic rats. Contrastingly, metformin only but not naringenin significantly increased hepatic OCT1 expression in non-diabetic rats compared to controls. Diabetic rats treated with metformin exhibited significantly increased plasma metformin concentrations compared to non-diabetic but naringenin significantly dropped this parameter. Conversely, hepatic metformin concentrations were significantly lower in diabetic rats treated with metformin compared to non-diabetic rats but significantly increased when naringenin was added. These results suggest that naringenin ameliorated hyperglycaemia-induced reduction in hepatic OCT1 expression leading to metformin accumulation and increased lactic acid production.

Acute Inflammation Induces Lactate Release By Bone Marrow Neutrophils That Promotes Their Mobilization Via Endothelial GPR81 Signaling

Innate immune neutrophils provide the first line of host defense against bacterial infections. Neutrophils under steady state rely almost entirely on glycolysis and exhibit very low levels of oxidative phosphorylation. The metabolite lactate has long been considered a "waste byproduct" of cell metabolism which accumulates during inflammation and sepsis. Increased plasma lactate levels in human patients is used as a marker for sepsis diagnosis. However, the direct effector actions of lactate, particularly in regulating neutrophil mobilization and function during inflammation has remained obscure. To better understand the metabolic consequences of BM neutrophil activation during the onset of inflammation, we tested how bacterial lipopolysaccharides (mimicking gram negative bacterial inflammation) introduced intraperitoneally (i.p.) affect neutrophil metabolism and mobilization. RNAseq of sorted BM neutrophils revealed that LPS-activated neutrophils upregulate enzymes catalyzing the first part of glycolysis (hexokinase and PFKL) and downregulate the expression of TCA cycle enzymatic genes. In addition, LPS enhanced neutrophil lactate production and release as indicated by higher levels of BM lactate and higher expression of LDHA and MCT4. In addition, LPS increased NADPH oxidase (NOX)-mediated reactive oxygen species and HIF-1α levels in BM neutrophils, which are up-stream of glycolytic enzymes and lactate production and release. Recently, we reported that i.p. lactate administration rapidly activated and mobilized neutrophils from BM to the circulation (ASH, 2017). To test if lactate acts preferentially on neutrophils, we also examined other types of hematopoietic cells. Interestingly, we found that lactate specifically and rapidly (i.e., within 4 hrs) mobilized neutrophils to the circulation whereas the levels of peripheral blood (PB) monocytes, lymphocytes, granulocyte monocyte progenitors (GMPs) and hematopoietic progenitor stem cells (LSK) were reduced following lactate administration. LPS treatment failed to mobilize activated ROShigh neutrophils to the PB in NOX-/- mice, while lactate administration partially rescued this defect following LPS treatment. Our data also reveal that the NOX/ROS axis operates upstream of lactate production in BM neutrophils since abnormal metabolic rates were found in NOX-/- neutrophils during the onset of the acute inflammatory responses. Moreover, we found that BM endothelial cells (BMEC) abundantly express the highly selective lactate receptor GPR81, and that neutrophil-released lactate increased BM vascular permeability via BMEC GPR81 signaling (ASH, 2017). Consistent with a role of the lactate/GPR81 axis in enhanced vascular permeability, we find that i.p. injected LPS reduced VE-Cadherin expression on highly permeable sBMECs in GPR81 dependent manner. Notably, neutralizing VE-Cadherin in GPR81-/- mice can rescue and elevate PB neutrophil levels, similarly to wild-type (WT) mice, suggesting that VE-Cadherin is downstream of GPR81 signaling and plays a role in neutrophil mobilization. Finally, to examine the potential clinical relevance of our findings, we infected WT, NOX-/- and GPR81-/- mice with Salmonella Typhimurium and found out that this pathogen drove high generation of ROS, elevated HIF-1αlevels, and triggered lactate production and release in WT BM neutrophils. In contrast, BM neutrophils of infected NOX-/- mice exhibited significantly lower HIF-1αand impaired lactate production and release. Consequently, WT mice infected with Salmonella had a higher levels of neutrophils in the blood, as compared to their NOX-/- or GPR81-/- mice counterparts. Altogether, our data reveal that the same regulatory mechanisms by which neutrophils respond to LPS challenges are used during bacterial infection with Salmonella. Our study highlights lactate released by BM neutrophils as a key pro-inflammatory stimulus of a novel immune-metabolic crosstalk which is triggered by infection and locally opens the BM vascular barrier to facilitate neutrophil mobilization and recruitment to sites of inflammation. Targeting this immune-metabolic crosstalk between lactate-producing neutrophils and the BM endothelium could be useful for the control of pathological neutrophil activation and mobilization during bacterial infections and help treatments of neutrophil related immune disorders. Disclosures No relevant conflicts of interest to declare.

Óleo essencial de Aloysia triphylla é efetivo no transporte de tilápia do Nilo

Este estudo avaliou o uso do óleo essencial de Aloysia triphylla (OEAT) como redutor de estresse no transporte de tilápia do Nilo, Oreochromis niloticus. Juvenis foram transportados em carro por 8 h em sacos plásticos contendo água com 0 (controle), 20 ou 30 μL L-1 OEAT (em triplicata). Nós avaliamos qualidade da água, fluxos iônicos (Clâˆ"™, Na+ e K+), parí­¢metros plasmáticos (cortisol, glicose, lactato e paraoxonase) e taxa de ventilação (TV) de tilápia do Nilo. Nenhuma mortalidade ocorreu durante o transporte. Juvenis de tilápia do Nilo transportados com 20 ou 30 μL L-1 OEAT apresentaram menor pH da água do que o grupo controle e com 30 μL L-1 OEAT apresentaram menor condutividade, alcalinidade e fluxos de Clâˆ"™, Na+ e K+ da água comparado aos demais tratamentos. O OEAT não alterou ní­­veis de cortisol e paraoxonase do plasma, mas reduziu TV, e 30 μL L-1 OEAT reduziu os ní­­veis de glicose plasmática comparada ao grupo controle depois do transporte. O uso de 20 μL L-1 OEAT aumentou os ní­­veis plasmáticos de lactato comparado aos demais tratamentos. O uso de 30 μL L-1 OEAT para sedação em transporte de 8 h de tilápia do Nilo é recomendado por melhorar qualidade de água e reduzir perdas iônicas, ní­­veis plasmáticos de glicose e TV.

Stress-related physiological changes and post-release survival of elephant fish (Callorhinchus milii) after longlining, gillnetting, angling and handling in a controlled setting

Stress-related physiological changes and post-release survival of elephant fish (Callorhinchus milii) in response to fishing capture and handling were assessed by experimental simulation using several different fishing gears for various periods under controlled laboratory conditions and by repeated blood sampling during a subsequent 72-h period to monitor the animals’ condition. Capture and handling caused physiological changes in elephant fish indicated by elevated plasma lactate, potassium and osmolality and immediately depressed plasma glucose. Maximum values of plasma potassium and osmolality occurred mainly immediately after capture (0 h), and maximum levels of plasma lactate at 0 and 3 h. Elevated plasma lactate concentrations returned to baseline values after 12 h of capture. Minimum levels of plasma glucose were recorded 3 h after capture. Hypoglycaemia followed by hyperglycaemia after stress was recorded. Handling alone significantly increased plasma lactate levels. Gillnet capture caused the greatest physiological stress, followed by longline, and then angling. Immediate mortality was 0% for all capture treatments, but delayed mortality varied widely among the capture treatments. Post-release survival rates were 70% (i.e. 30% delayed mortality) for longline and gillnet depending on fishing duration and 100% (i.e. 0% delayed mortality) for hook and line (angling) provided the animals were returned to the water immediately following capture. The best indicators of poor condition in this species were low plasma glucose concentration, red eyes (blood-shot), pale skin and impaired swimming.

Abstract 14341: A Depressed Cardiac Output in Patients With Advanced Heart Failure is Not Accompanied by Increased Plasma Lactate Levels in the Majority of Patients: Is it Time for a New Definition of Heart Failure?

Introduction: Heart failure (HF) has been defined as a condition in which the heart is unable to deliver sufficient oxygen to match the needs of the metabolizing tissues. This definition, which was based on observations in patients with terminal HF, has never been validated. Moreover, the application of this definition led to the use of inotropes , and discouraged the use of beta-blockers, delaying the development of appropriate HF therapies. Methods: To determine whether the heart was unable to meet the metabolic demands of the body, we retrospectively analyzed Arterio-Venous oxygen difference (AV O2) and plasma lactate levels in NYHA class IV heart failure patients that subsequently received a Left Ventricular Assist Device (LVAD). Results: We identified 359 patients with a right heart catheterization (RHC) performed prior to LVAD implantation. Plasma lactate was available for 96 patients. RHC showed that 93% of the patients had an AV O2 difference above normal (&gt; 5 ml/100 ml). Among patients with measured lactate levels the prevalence of elevated lactate (&gt; 2.1 mmol/L) was only 25% (95% CI 16.7-34.9). AV O2 was widened in all patients with elevated lactate, but plasma lactate did not correlate with AV O2 (R=0.02) and only 27% of patients with increased AV O2 had elevated plasma lactate ( Figure ). Patients with widened AV O2 and elevated lactate were sicker than patients with widened AV O2 and normal lactate, as shown by a higher prevalence of low INTERMACS class, elevated INR and reduced serum albumin. However, there was no obvious hemodynamic difference between the two groups. Conclusions: Approximately 75% of the patients in this NYHA class IV HF sample with a depressed cardiac output had normal lactate levels, suggesting that cardiac output was sufficient to meet the metabolic demands of the body. Given that approximately 4% of HF patients are NYHA class IV, these findings suggest that the classic definition of heart failure may be valid in only 1% of the total heart failure population.

Roux-en-Y gastric bypass surgery reduces bone mineral density and induces metabolic acidosis in rats

Roux-en-Y gastric bypass (RYGB) surgery leads to bone loss in humans, which may be caused by vitamin D and calcium malabsorption and subsequent secondary hyperparathyroidism. However, because these conditions occur frequently in obese people, it is unclear whether they are the primary causes of bone loss after RYGB. To determine the contribution of calcium and vitamin D malabsorption to bone loss in a rat RYGB model, adult male Wistar rats were randomized for RYGB surgery, sham-operation-ad libitum fed, or sham-operation-body weight-matched. Bone mineral density, calcium and phosphorus balance, acid-base status, and markers of bone turnover were assessed at different time points for 14 wk after surgery. Bone mineral density decreased for several weeks after RYGB. Intestinal calcium absorption was reduced early after surgery, but plasma calcium and parathyroid hormone levels were normal. 25-hydroxyvitamin D levels decreased, while levels of active 1,25-dihydroxyvitamin D increased after surgery. RYGB rats displayed metabolic acidosis due to increased plasma lactate levels and increased urinary calcium loss throughout the study. These results suggest that initial calcium malabsorption may play a key role in bone loss early after RYGB in rats, but other factors, including chronic metabolic acidosis, contribute to insufficient bone restoration after normalization of intestinal calcium absorption. Secondary hyperparathyroidism is not involved in postoperative bone loss. Upregulated vitamin D activation may compensate for any vitamin D malabsorption.

In VivoEvidence for Lactate as a Neuronal Energy Source

Cerebral energy metabolism is a highly compartmentalized and complex process in which transcellular trafficking of metabolites plays a pivotal role. Over the past decade, a role for lactate in fueling the energetic requirements of neurons has emerged. Furthermore, a neuroprotective effect of lactate during hypoglycemia or cerebral ischemia has been reported. The majority of the current evidence concerning lactate metabolism at the cellular level is based on in vitro data; only a few recent in vivo results have demonstrated that the brain preferentially utilizes lactate over glucose. Using voltage-sensitive dye (VSD) imaging, beta-probe measurements of radiotracer kinetics, and brain activation by sensory stimulation in the anesthetized rat, we investigated several aspects of cerebral lactate metabolism. The present study is the first in vivo demonstration of the maintenance of neuronal activity in the presence of lactate as the primary energy source. The loss of the voltage-sensitive dye signal found during severe insulin-induced hypoglycemia is completely prevented by lactate infusion. Thus, lactate has a direct neuroprotective effect. Furthermore, we demonstrate that the brain readily oxidizes lactate in an activity-dependent manner. The washout of 1-[(11)C]L-lactate, reflecting cerebral lactate oxidation, was observed to increase during brain activation from 0.077 ± 0.009 to 0.105 ± 0.007 min(-1). Finally, our data confirm that the brain prefers lactate over glucose as an energy substrate when both substrates are available. Using [(18)F]fluorodeoxyglucose (FDG) to measure the local cerebral metabolic rate of glucose, we demonstrated a lactate concentration-dependent reduction of cerebral glucose utilization during experimentally increased plasma lactate levels.

Prospective follow-up study of children with univentricular heart: Neurodevelopmental outcome at age 12 months

Despite recent advances in the treatment of children with univentricular heart, their neurodevelopmental outcome remains a major concern. This prospective follow-up study evaluated the neurodevelopmental outcome of 23 patients with hypoplastic left heart syndrome, 14 with other forms of univentricular heart, and 46 healthy control subjects at a median age of 12.2 months. The Griffiths Developmental Scale and Alberta Infant Motor Scale served for developmental evaluation. The mean Griffiths developmental quotient of children with hypoplastic left heart syndrome was significantly less (91.6) than that of control children (106.8, P < .001). Patients with univentricular heart scored significantly lower than control subjects only in the gross motor domain (P = .001) but not in overall development (100.6). Alberta Infant Motor Scale scores were significantly lower in children with hypoplastic left heart syndrome (37.5, P < .001) and univentricular heart (43.5, P = .011) than in control subjects (53.3). In linear regression a diagnosis of hypoplastic left heart syndrome (P = .016), a clinical history of seizure (P = .002), and the highest plasma lactate level after the bidirectional Glenn operation (P = .045) were significantly associated with the developmental quotient. At age 1 year, the level of development of children with univentricular heart was significantly lower than for control subjects only in motor skills, whereas children with hypoplastic left heart syndrome had a more widespread developmental delay. The diagnosis, a clinical seizure history, and increased plasma lactate levels after the bidirectional Glenn operation emerged as risk factors.

Responses to hypoxia and recovery: repayment of oxygen debt is not associated with compensatory protein synthesis in the Amazonian cichlid,Astronotus ocellatus

Oxygen consumption, as an indicator of routine metabolic rate (RoMR), and tissue-specific changes in protein synthesis, as measured by (3)H-labelled phenylalanine incorporation rates, were determined in Astronotus ocellatus to investigate the cellular mechanisms behind hypoxia-induced metabolic depression and recovery. RoMR was significantly depressed, by approximately 50%, when dissolved oxygen levels reached 10% saturation (0.67+/-0.01 mg l(-1) at 28+/-1 degrees C). This depression in RoMR was accompanied by a 50-60% decrease in liver, heart and gill protein synthesis, but only a 30% decrease in brain protein synthesis. During recovery from hypoxia, an overshoot in RoMR to 270% of the normoxic rate was observed, indicating the accumulation of an oxygen debt during hypoxia. This conclusion was consistent with significant increase in plasma lactate levels during the hypoxic exposure, and the fact that lactate levels rapidly returned to pre-hypoxic levels. In contrast, a hyperactivation of protein synthesis did not occur, suggesting the overshoot in oxygen consumption during recovery is attributed to an increase in cellular processes other than protein synthesis.

High residual chloroquine blood levels in African children with severe malaria seeking healthcare

Despite widespread resistance, chloroquine remains widely used in West Africa, particularly in home treatment. We examined chloroquine blood levels on admission to a referral hospital with respect to the manifestation of severe malaria in 290 Ghanaian children. Of the patients, 78% exhibited chloroquine concentrations (subtherapeutic, 35%; therapeutic, 37%; supratherapeutic, 6%) and 11% died. Most parasites (78%) carried the pfcrt-T76 chloroquine resistance mutation. High drug concentrations correlated with reduced parasitaemia but also with selection of resistant parasites, lower respiratory and heart rates, increased plasma lactate levels and impaired consciousness. Geometric mean chloroquine concentrations tended to be higher in children who died than in survivors (1.135 vs. 778nmol/l; P=0.09). Supratherapeutic drug levels (>5000nmol/l) were associated with fatal outcome (odds ratio 8.6; 95% CI 1.4-51.7). Residual chloroquine concentrations were found to be abundant in children with severe malaria and to be associated with alterations in the clinical manifestation of the disease and its case fatality. This may result from toxic effects of the drug and/or reflect preceding overtreatment in children with acute life-threatening disease. In areas of intense chloroquine resistance and frequent pre-treatment, additional administration of chloroquine at hospital admission is not only ineffective but may even further endanger patients.

The acute stress response of red porgy, Pagrus pagrus, kept on a red or white background

The skin colour of red porgy, Pagrus pagrus, can be modified by exposure to different background colours. Red and white background colours brighten the dark skin colour that develops under common culture conditions in red porgy. To assess whether skin colour is also modified by aquaculture related handling stress, we subjected red porgy to 5 min of netting stress combined with air exposure. Fish kept on a white background have: (1) a lighter skin colour, which is not influenced by an acute stressor, (2) a less saturated red colour, which significantly decreases 24 h post-handling, and (3) a similar hue as fish kept on a red background. The first plasma parameters to rise after application of the stressor are cortisol, lactate and Na +; then, glucose levels rose. Other plasma ions (Ca 2+, Cl −, K +) were not affected up to 2 h post-stressor, but had decreased at 8 and 24 h after handling. Plasma pH decreased over the first 2 h post-handling, indicative of plasma acidosis upon air exposure. The acidosis then coincided with increases in plasma lactate levels. As αMSH levels were not significantly affected by the stressor while cortisol levels showed a five to tenfold increase, we suggest that following acute stress in red porgy, plasma cortisol release is controlled by ACTH, perhaps in combination with a sympathic stimulation.

Hyperglycemic response to hemorrhage is modulated by baroreceptors unloading but not by peripheral chemoreceptors activation

The aim of this study was to assess the relative participation of carotid baro- and chemoreceptors on plasma glucose and lactate level in response to hemorrhagic hypotension. We also evaluated the effects of selective activation of carotid chemoreceptors. One week before the experiments, male Wistar rats (250–300 g) were submitted to bilateral total carotid denervation (BCD-group), or to bilateral ligature of the carotid body artery (ChD-group). During the same surgical procedure, a chronic jugular catheter for blood sampling and hemorrhage (1.2 mL/100 g/2 min) and polyethylene cannula was inserted into the left femoral artery for cardiovascular monitoring. One group submitted to fictitious surgery was used as a surgical control (Sham-group). Carotid chemoreceptors were selectively activated by sodium cyanide (NaCN, 40 μg/0.1 mL i.v.) in the Sham and ChD group. The results showed that hyperglycemic response to hemorrhage in the BCD-group was reduced whereas in the ChD-group there was no significant change in this parameter compared to the Sham group (8.6 ± 0.5 mM, Sham-hemorrhaged, n = 8; 7.2 ± 0.3 mM, BCD-hemorrhaged, n = 8 and 9.4 ± 0.6 mM, ChD, n = 8, p < 0.05). Increased plasma lactate levels following hemorrhage were observed in all the three experimental groups throughout the experimental period and there were no differences between the groups. Chemoreceptor stimulation by NaCN also produced hyperglycemia, as well as an increase in blood pressure and bradycardia but did not affect plasma lactate concentration. Ligature of the carotid body artery annulled the cardiovascular responses induced by NaCN, but did not change the hyperglycemic response to hypoxia. In conclusion, our data indicate that carotid chemoreceptors do not play any major role in overall metabolic response to hypoxia or hemorrhagic hypotension. Furthermore, the results suggest that carotid baroreceptors unloading play a predominant role as main source of afferent impulses leading to the hyperglycemic response to hemorrhage. In addition our data shows that the metabolic response and cardiovascular adjustment to hypoxia can be dissociated by ligature of the carotid body artery.

Effects of dichloroacetate and ubiquinone infusions on glycolysis activity and thermal sensitivity during sepsis

Energy-metabolism disturbances during sepsis are characterized by enhanced glycolytic fluxes and reduced mitochondrial respiration. However, it is not known whether these abnormalities are the result of a specific mitochondrial alteration, decreased pyruvate dehydrogenase (PDH) complex activity, depletion of ubiquinone (CoQ 10; electron donor for the mitochondrial complex III), or all 3. In this study we sought to specify metabolism disturbances in a murine model of sepsis, using either a PDH-activator infusion (dichloroacetate, DCA) or CoQ 10 supplementation. After anesthesia, Sprague-Dawley rats received intravenous saline solution (control; n = 5), DCA ( n = 5; 20 mg/100 g), or CoQ 10 ( n = 5; 1 mg/100 g), before the induction of sepsis. Increased plasma lactate levels and increased muscle glucose content were observed after 4 hours in the control group. In the DCA group, a decrease in the muscle content of lactate ( P < .05) and an increase in muscle glucose content ( P < .05) were observed at 4 hours, but no lactatemia variation was noted. In the CoQ 10 group, only increased plasma lactate levels were observed. Increased muscle glycolysis fluxes were observed after 4 hours in the control group, but to a slighter degree in both the DCA and CoQ 10 groups. Only DCA restored a normal temperature sensitivity in the hyperthermia range, but we noted no differences in survival time. In conclusion, only DCA infusion restores normal glycolysis function.

Flicker light-induced vasodilatation in the human retina: effect of lactate and changes in mean arterial pressure.

Diffuse luminance flicker light increases retinal and optic nerve head blood flow in animals and humans, but the exact mechanisms that mediate increased flow have yet to be identified. In the current study, the effect of increased plasma lactate levels on flicker-induced vasodilatation in the retina was investigated in three independent studies in healthy humans. In the first study, plasma lactate concentrations were increased by bicycle exercise in 12 volunteers, and the change in retinal vessel diameter to 8-Hz square-wave flicker stimulation was measured with the Zeiss Retinal Vessel Analyzer (Carl Zeiss Meditec, Oberkochen, Germany). In a different study, sodium lactate was administered intravenously, and flicker responses were measured in 12 subjects. As a control experiment accounting for pressure increases induced by exercise, the effect of elevated ocular perfusion pressure on the flicker response was investigated during tyramine infusion (n = 12). The increase in plasma lactate concentration during intravenous infusion from 1.3 +/- 0.4 to 6.3 mmol/L and during dynamic exercise from 1.2 +/- 0.3 to 9.4 mmol/L decreased flicker responses in retinal arteries from 5.3% +/- 0.9% to 1.7% +/- 0.6% (P < 0.001) and from 3.6% +/- 0.6% to 2.0% +/- 0.8% (P = 0.03), respectively. In contrast, an increase of mean blood pressure from 81 +/- 3 to 92 +/- 3 mm Hg after tyramine infusion had no significant effect on flicker-induced vasodilatation in retinal arteries and veins. The signaling between neuronal activity and flow response in the human retina is sensitive to changes in blood lactate levels, whereas changes in systemic blood pressure have no major effect. Whether an increased cytosolic redox impairment contributes to flicker-induced vasodilatation has yet to be clarified.

Environment affects stress in exercised turbot

We investigated the interaction of water temperature (10, 18 and 22 °C) and salinity (33.5 and 15‰) on the stress response of juvenile turbot. At each temperature/salinity combination, fish were subjected to 10 min enforced exercise. This induced a moderate stress response, which differed at the various temperature and salinity combinations. High temperatures caused more rapid increases in plasma cortisol and glucose, larger and more rapid increases in plasma lactate levels, which were also influenced by body weight, and a faster recovery in plasma Na + and Cl −. Low salinity ameliorated cortisol responses at low but not at high temperatures. The magnitude of ionic disturbance was reduced at 15‰. Plasma K + did not change at any temperature or salinity. The stress response involved activation of the brain–pituitary–interrenal axis, as indicated by the cortisol elevations. The low magnitude of glucose responses, the mild Na + and Cl − disturbances, and the lacking K +-responses indicated mild activation of the brain–sympathetic-chromaffin cell axis, and hence a low release of catecholamines, which seemed though to occur to a higher extent at higher temperatures. The relatively low catecholaminergic response of turbot may be linked to their inactive sedentary lifestyle. The higher responsiveness at higher water temperatures may reflect a higher overall adaptive capacity.