High glycemic variability: An underestimated determinant of stroke functional outcome following large vessel occlusion.

BACKGROUND AND PURPOSE: Early glycemic variability (GV) in diabetic patients is a poor prognosis factor following cardiovascular events. However, its influence on the course of acute ischemic stroke (AIS) with large vessel occlusion remains unclear. We investigated the relationship between high GV during acute stroke and three-month functional outcome among patients treated with combined intravenous thrombolysis and endovascular therapy for large vessel occlusion. METHODS: A single-center retrospective analysis of AIS patients with proximal intracranial occlusion who underwent thrombolysis and mechanical thrombectomy between January 2015 and May 2017. Early GV was assessed using standard deviation (SD) of blood glucose levels for the first 24hours. The main outcome was functional status at three months as defined by the modified Rankin scale (mRS). Secondary outcomes were change in NIHSS score from baseline to 24hours and occurrence of severe hemorrhagic transformation. Multivariate logistic regression analyses including GV, admission glycemia and mean glycemia were performed. RESULTS: Among the 93 patients evaluated, 26 had early high GV (≥20.9mg/dl). High GV was associated with poor functional outcome (OR=8.00; 95%CI [1.34-47.89]; P=0.02) unlike admission glycemia and mean glycemia (OR=2.92; 95%CI [0.51-16.60]; P=0.23 and OR=0.36; 95%CI [0.05-2.6]; p=0.31, respectively). High GV was not associated with NIHSS at 24hours or hemorrhagic transformation. CONCLUSION: Acute high GV contributes to poorer functional outcome following AIS related to large vessel occlusion and should be considered as a new target in acute stroke management.

Echocardiographic evaluation and N-terminal pro-brain natriuretic peptide measurement of patients hospitalized for heart failure during weaning from mechanical ventilation.

BACKGROUND: Weaning patients with heart failure who have required mechanical ventilation remains challenging. We evaluated echocardiographic indexes and N-terminal pro-brain natriuretic peptide (NT-proBNP) as markers of acute cardiac dysfunction before and after spontaneous breathing trials (SBT) in such patients to assess their ability to predict subsequent successful extubation. METHODS: Forty-four patients who underwent their first SBT were prospectively included. Plasma levels of NT-proBNP and transthoracic echocardiography indices including cardiac index, E/A ratio and E/Ea ratio were recorded immediately before commencing and just before the end of SBT. RESULTS: Ten patients (22.7%) failed their SBT. No significant difference was observed concerning baseline echocardiographic data and NT-proBNP level between the patients who succeeded the SBT or those that failed. Cardiac index increased significantly at end-SBT in patients who passed (3.3 [3.06-3.77] vs. 3 [2.68-3.3] L/min/m(2), P<0.001), whereas it remained unchanged in those that failed. E/Ea ratio (16.8 [8.5-27.3] vs. 10.7 [6.7-20.5], P=0.006) and NT-proBNP level (8199 [3106-10949] vs. 4200 [1855-7125] pg/mL, P=0.004) increased significantly in those who failed the SBT, in contrast to the weaning success group where they remained unchanged. CONCLUSION: Neither NT-proBNP level nor the studied echocardiographic indices before SBT were able to predict SBT outcome in patients presenting with severe heart failure. Failure to increase the cardiac index and increases in both E/Ea ratio and NT-proBNP levels were seen at end-SBT in patients who failed the SBT, and may reflect failure of myocardial reserve to cope with the stress of SBT.

Estimation of renal function in patients with diabetes.

Diabetes is the leading cause of chronic kidney disease (CKD), which makes estimation of renal function crucial. Serum creatinine is not an ideal marker of glomerular filtration rate (GFR), which also depends on digestive absorption, and the production of creatinine in muscle and its tubular secretion. Formulas have been devised to estimate GFR from serum creatinine but, given the wide range of GFR, proteinuria, body mass index and specific influence of glycaemia on GFR, the uncertainty of these estimations is a particular concern for patients with diabetes. The most popular recommended formulas are the simple Cockcroft-Gault equation, which is inaccurate and biased, as it calculates clearance of creatinine in proportion to body weight, and the MDRD equation, which is more accurate, but systematically underestimates normal and high GFR, being established by a statistical analysis of results from renal-insufficient patients. This underestimation explains why the MDRD equation is repeatedly found to give a poor estimation of GFR in patients with recently diagnosed diabetes and is a poor tool for reflecting GFR decline when started from normal, as well as the source of unexpected results when applied to epidemiological studies with a 60mL/min/1.73m(2) threshold as the definition of CKD. The more recent creatinine-based formula, the Mayo Clinic Quadratic (MCQ) equation, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) improve such underestimation, as both were derived from populations that included subjects with normal renal function. Determination of cystatin C is also promising, but needs standardisation.

Glucose flux in controlled hyperglycaemia before and after oral glucose ingestion in men with mild type 2 diabetes.

AIMS: This study aimed to determine how insufficiently suppressed endogenous glucose production vs. reduced peripheral glucose uptake contribute to postprandial hyperglycaemia in type 2 diabetes (T2D). METHODS: Eight men with T2D (age: 52+/-7 years; BMI: 26.6+/-2.3 kg/m(2); fasting glycaemia: 7.1+/-1.5 mmol/L) were compared with eight non-diabetic controls (age: 51+/-5 years; BMI: 24.6+/-2.9 kg/m(2); fasting glycaemia: 4.9+/-0.4 mmol/L). Their glucose turnover rates and hepatic glucose cycles were measured by monitoring [2H7]glucose infusion, with m+7 and m+6 enrichment, 3 h before and 4 h after the ingestion of [6,6-2H2]-labelled glucose, while maintaining glycaemia at 10 mmol/L using the pancreatic clamp technique. RESULTS: Of the 700 mg/kg oral glucose load, 71% appeared in the systemic circulation of the T2D patients vs. 63% in the controls (NS). Endogenous glucose production and hepatic glucose cycles did not differ from normal either before or after oral glucose ingestion, while peripheral glucose uptake was reduced by 40% in the T2D group both before (P<0.01) and after (P<0.05) ingestion of oral glucose. CONCLUSION: When T2D patients were compared with non-diabetic subjects with similarly controlled levels of hyperglycaemia after oral glucose ingestion, they essentially differed only in peripheral glucose uptake, whereas endogenous glucose production was apparently unaltered.

Influence of protein- versus carbohydrate-enriched feedings on physiological responses during an ultraendurance climbing race.

This study investigated effects of a high protein (PROT) versus a high carbohydrate (CHO) diet on performance and physiological responses during an ultraendurance climbing race at moderate altitude. On two different periods, in a randomised crossover design, ten climbers (30.0+/-0.9 years) participated in the race (duration 29 h approximately, energy expenditure 43.6+/-1.2 MJ.day (-1)) and were fed either with the PROT (30% protein content) or the CHO diet (68% carbohydrate) each providing 16.74 MJ. Mental performance was assessed by the Stroop test and we estimated maximal voluntary strength of quadriceps muscle. We quantified metabolic and hormonal circulating concentrations. Mental performance was unaffected after the two races, while muscular performance and body weight were decreased (both p<0.01) with no diet effects. Decreases were measured for IGF-I concentration and its binding protein IGFBP-3 (p<0.001), and increases for cortisol and norepinephrine (p<0.01) with no diet effects. Glucose concentration decreased (p<0.05) without diet effects, while amino acids (leucine, isoleucine, valine, and tyrosine) decreased in CHO group (p<0.001). Leptin concentration decreased (p<0.001) without diet effects, whereas total ghrelin increased in CHO group (p<0.01). Our results showed that a high PROT or high CHO intake during physical exertion at moderate altitude maintained mental performance, but did not limit muscle force reduction and body weight loss. There was decreased glucose availability, and hormonal responses indicated both catabolism and extreme energy deficiency induced by exercise with opposite responses of ghrelin and leptin. The ghrelin response was additionally indicative of macronutrient intake during the race.

Early decrease in resting energy expenditure with bedtime insulin therapy.

AIMS: In type 2 diabetes (T2D), insulin-induced weight gain may stem from a reduction in resting energy expenditure (REE). We sought to determine the early effects of insulin introduction on REE in 20 poorly controlled T2D patients. METHODS: After improving the glycaemia, REE was measured on Day 0 and Day 4 during two treatment regimens: bedtime insulin (n=10, group 1); and one off (3-day) intravenous insulin infusion (n=10, group 2). RESULTS: Both groups were similar in age, gender, BMI, C-peptide, HbA(1c) and initial REE. By Day 4, fasting glycaemia had similarly improved in both groups: group 1: -5.3+/-2.7mmol/L vs group 2: -5.8+/-4.2 mmol/L. In group 2, the second REE was measured 12h after stopping the intravenous insulin infusion, whereas subcutaneous insulin was maintained in group 1. REE did not change in group 2 (-1.3+/-6.5%), whereas it decreased significantly in group 1 (-8.0+/-7.0%; P<0.05). CONCLUSION: Bedtime insulin led to an early and specific reduction in REE.

Cystatin C improves the diagnosis and stratification of chronic kidney disease, and the estimation of glomerular filtration rate in diabetes.

AIMS: Estimation of glomerular filtration rate (GFR) is recommended to diagnose and stratify chronic kidney disease (CKD). Can cystatin-C (cysC) assay improve the results in diabetic patients? METHODS: In 124 diabetic patients with a wide range of GFR, as determined by 51Cr-EDTA clearance (i-GFR), we estimated 'e-GFR' by: the recommended Cockcroft-Gault (CG) formula and Modification of Diet in Renal Disease (MDRD) study equation; the new Mayo Clinic quadratic (MCQ) equation; the recently proposed composite estimation including both serum creatinine and cysC; and a simplified approach dividing the MDRD by cysC if less than 1.10mg/L. RESULTS: The highest diagnostic accuracy (receiver operating characteristic [ROC] curves) and the highest proportions of well-stratified patients were obtained by cysC and the MDRD which, however, underestimated i-GFR for patients without CKD (-17%, P<0.001). The CG overestimated GFR in KDOQI stages 1 and 2, ignored stage 5 and was the least accurate. The MCQ equation overrepresented stage 2, overestimating GFR at this stage (+23%, P<0.005). The composite estimation (54.7+/-27.0mL per minute 1.73m(2)) correlated best with i-GFR (56.1+/-35.3; r=0.90, P<0.001), and did not significantly differ from it across the entire population and within each Kidney Disease Outcome Quality Initiative (KDOQI) stage but was also biased (Bland-Altman procedure). Simply dividing the MDRD by cysC ifless than1.10mg/L produced a comparable performance and eliminated the bias. CONCLUSION: The recommended creatinine-based estimations of GFR need to be improved. CysC assay helps in the diagnosis and stratification of CKD and leads to better estimates of GFR in diabetic patients without any substantial increase in complexity.

The 24 h urinary cortisol/cortisone ratio and epinephrine/norepinephrine ratio for monitoring training in young female tennis players.

The effect of training variations on the 24 h urinary cortisol/cortisone (C/Cn) ratio and the epinephrine/norepinephrine (E/NE) ratio in relation with mood (evaluated using the Brunel Mood Scale: BRUMS) and performance was investigated in seven trained young female tennis players (12.8 +/- 1.7 years). Like the proposed model in adults, the monitoring of hormonal and mood parameters could be a useful index in training follow-up in young sportswomen. Assessment of nutritional intake, nitrogen excretion rate and nitrogen balance were also determined to measure the dietary practice of these athletes. Nitrogen balance was calculated from the mean daily protein intake and the urinary nitrogen excretion. Data were collected after a 1-month rest (September, T1), 3 months after T1 (after technical and endurance training: December, T2) and 7 months after T1 (after 4 months of increasing-volume/high-intensity training: March, T3). A significant increase in C/Cn ratio (+ 30 %, p < 0.05) were noted from T1 to T3. In the same time, urinary NE concentrations decreased significantly. The E/NE ratio increased from T1 to T2 and decreased at T3 (T1 vs. T3: - 30 %, p < 0.05). The BRUMS inventory at T3 reflected changes in specific mood states with a significant increase in fatigue and anger scores, while vigor scores decreased significantly compared to T1. This period also corresponded with the lowest percentage of matches won and with the highest training load. Energy intake was about 16 % lower than the French recommendations for girls of the same age. However, a positive nitrogen balance was observed from a mean intake of 1.0 g x kg (-1) x day (-1). Our results reveal that an increase of overnight urinary C/Cn ratio and a decrease of E/NE ratio are concomitant with alterations in mood state and performance, all these parameters being associated with physical and psychological stress.

Antioxidant defences and oxidative stress markers in erythrocytes and plasma from normally nourished elderly Alzheimer patients.

OBJECTIVES: to investigate blood markers of oxidative stress, and enzymatic and non-enzymatic antioxidants in normally nourished elderly people with Alzheimer's disease. DESIGN: case-control study. SUBJECTS: twenty patients with Alzheimer's disease and 23 elderly control subjects, living at home, free from disease and not undergoing any treatment known to have a strong influence on blood oxidative stress markers or antioxidant defence systems. METHODS: we performed a nutritional evaluation, including anthropometric and biological measures and a 3-day dietary record. We determined concentrations of antioxidant vitamins (alpha-tocopherol, retinol) and malondialdehyde in plasma and erythrocytes. We also measured erythrocyte enzymatic activities of glutathione peroxidase and copper-zinc superoxide dismutase. RESULTS: the two groups were similar in age, body mass index, dietary record and serum albumin concentration. After adjustment for age, sex and cardiovascular co-morbidity, mean plasma concentration of alpha-tocopherol was lower in those with Alzheimer disease than in control subjects (15+/-3.5 mg/l compared with 18.2+/-3.5; P=0.002), as was the mean plasma concentration of retinol (0.54+/-0.2 mg/l vs 0.7+/-0.2; P=0.014). The mean concentration of free plasma malondialdehyde was higher in those with Alzheimer's disease (0.70+/-0.2 mmol/l vs 0.5+/-0.1; P=0.036). In Alzheimer disease patients, free plasma malondialdehyde concentrations were inversely correlated with levels of alpha-tocopherol (P=0.002) and retinol (P=0.025). Erythrocyte levels of vitamins and enzymatic activities were similar in the two groups. CONCLUSION: lower plasma concentrations of alpha-tocopherol and retinol in normally nourished elderly patients with Alzheimer's disease than in controls could suggest that these antioxidant vitamins had been consumed as a result of excessive production of free radicals.

Butyrate impairs energy metabolism in isolated perfused liver of fed rats.

This study was designed to test the effects of short-chain fatty acids (SCFA) with an even number of carbon atoms on hepatic energy metabolism. The effect of the SCFA was evaluated by measuring liver ATP content and oxygen consumption. The ATP content was evaluated using (31)P nuclear magnetic resonance in isolated liver from fed rats. In addition, respiratory activity (VO(2)) was assessed using Clark electrodes. The livers were perfused with acetate, butyrate or a medium chain length fatty acid, octanoate, at a concentration of 0.05--5.0 mmol/L. The addition of each substrate enhanced the rate of the net ATP consumption (V(i)), establishing a new ATP steady state that required a perfusion time of > or = 20 min, dependent on the chain length and concentration of the fatty acid (FA). The initial V(i) was unchanged for acetate and the ATP level stabilized at 58% of the initial level. Both butyrate and octanoate induced a dose-dependent increase in V(i). This may reflect an ATP-consuming process for the intracellular pH regulation observed during the acidosis associated with the beta-oxidation pathway. At the new steady state, the ATP concentration was approximately 45% of the initial level for both FA. VO(2) was both rapidly and reversibly increased, and the change was a function of butyrate or octanoate concentration and of the chain length. K(m) values were similar for butyrate and octanoate. Because all of the effects were similar for butyrate and octanoate, in contrast to acetate, we suggest that the impairment of the energy metabolism by butyrate resulted from an increase in the FADH(2)/NADH ratio due to beta-oxidation. In conclusion, the difference in the hepatic oxidation pathways of two products of intestinal fermentation (acetate and butyrate) explains their different actions on energy metabolism.

Use of diethyl(2-methylpyrrolidin-2-yl)phosphonate as a highly sensitive extra- and intracellular 31P NMR pH indicator in isolated organs. Direct NMR evidence of acidic compartments in the ischemic and reperfused rat liver.

The novel phosphorylated pyrrolidine diethyl(2-methylpyrrolidin-2-yl)phosphonate (DEPMPH) was evaluated as a (31)P NMR probe of the pH changes associated with ischemia/reperfusion of rat isolated hearts and livers. In vitro titration curves indicated that DEPMPH exhibited a 4-fold larger amplitude of chemical shift variation than inorganic phosphate yielding an enhanced NMR sensitivity in the pH range of 5.0-7.5 that allowed us to assess pH variations of less than 0.1 pH units. At the non-toxic concentration of 5 mm, DEPMPH distributed into external and cytosolic compartments in both normoxic organs, as assessed by the appearance of two resonance peaks. An additional peak was observed in normoxic and ischemic livers, assigned to DEPMPH in acidic vesicles (pH 5.3-5.6). During severe myocardial ischemia, a third peak corresponding to DEPMPH located in ventricular and atrial cavities appeared (pH 6.9). Mass spectrometry and NMR analyses of perchloric extracts showed that no significant metabolism of DEPMPH occurred in the ischemic liver. Reperfusion with plain buffer resulted in a rapid washout of DEPMPH from both organs. It was concluded that the highly pH-sensitive DEPMPH could be of great interest in noninvasive ex vivo studies of pH gradients that may be involved in many pathological processes.

Liposomes as fatty acids carriers in isolated rat liver: effect on energy metabolism and on isolated mitochondria activity.

The effects of fatty acids (FA)-carrier, egg-lecithin liposomes (LIPO) as alternative to BSA, on ATP, glycogen and glucose contents in isolated perfused liver of fed rats were non-invasively studied using 31P/13C nuclear magnetic resonance (NMR). Oxidative phosphorylation was studied in isolated mitochondria from the same liver consecutively to the NMR experiments. ATP content decreased slowly and ATP turnover was similar during the perfusion with saline solution (KHB) or LIPO. However, LIPO induced an enhancement of respiratory control ratio in isolated mitochondria. Tissue glycogen and glucose content decreased when FA (linoleate or linolenate) were perfused with defatted BSA (3%) or LIPO (600 mg/l) whereas glucose excretion level was unchanged and lactate excretion tended to increase, reflecting changes in the cytosolic redox state and/or an enhancement of glycolysis. Addition of FA (0.5 or 1.5 mM) to LIPO caused a dramatic fall in liver ATP, a mitochondrial uncoupling and an impairment of the phosphorylation activity. Perfusion with FA (1.5 mM) carried by BSA significantly increased the ATP degradation without change of mitochondrial function. Owing to the higher affinity of BSA than LIPO for FA, these latter could be more easily released from complex LIPO-FA, increasing their uncoupling effect. Hence, the FA concentrations have to be largely decreased from the above currently used concentrations to avoid this effect. It will then be possible to minimize the effector action of FA and to study their more specific metabolic function as fuel. It was concluded that LIPO were appropriate carriers to study the different metabolic effects of FA.

New perspectives on the cardioprotective phosphonate effect of the spin trap 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide: an hemodynamic and 31P NMR study in rat hearts.

The spin trap 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide (DEPMPO) is an improved ESR probe to assess superoxide (O2*-) formation in the postischemic heart. We recently found that DEPMPO pretreatment improves recovery of cardiac function with the concomitant inhibition of postischemic O2*- production. By perfusing diethyl methylphosphonate MeP(O)(OEt)2 to ischemic-reperfused isolated rat hearts, we provide hemodynamic evidence that this preservation, which exerts during ischemia, is in fact specific to the phosphonate group. Using 31P NMR on intact rat hearts, it was also found that the "phosphonate effect" of DEPMPO is related to the preservation of ATP levels during ischemia, when compared to 5,5-dimethyl-1-pyrroline N-oxide. This mechanism may be a means of reducing the potency of cardiac tissue to produce O2*- during reperfusion.

13C nuclear magnetic resonance study of glycogen resynthesis in muscle after glycogen-depleting exercise in healthy men receiving an infusion of lipid emulsion.

In healthy individuals, glycogen recovery after a strong depletion is known to be rapid and insulin independent during the initial phase, and subsequently, slow and insulin dependent. Free fatty acids (FFAs) as a putative source of insulin resistance (IR) could thus impair glycogen recovery during the second period. Using in vivo 13C nuclear magnetic resonance (NMR), we studied the effect of long-chain triglyceride emulsion on gastrocnemius glycogen resynthesis during a 3-h recovery period after 90 min of moderate exercise consisting of plantar flexion on overnight-fasted healthy men (n = 8). In separate experiments, each subject was infused with 10% Ivelip (0.015 ml x kg(-1) x min(-1)) or 10% glycerol (0.13 mg x kg(-1) x min(-1)). NMR spectra were acquired before and at the end of the exercise and during the recovery period. Whole-body glucose and lipid oxidation rates (indirect calorimetry), plasma insulin, C-peptide, glucose, lactate, beta-hydroxybutyrate, triglycerides, and FFAs were determined. Glycogen consumption was 47.6 +/- 4.5% (glycerol) and 49.7 +/- 4.8% (Ivelip) of the initial glycogen. An acquired IR in the Ivelip group was significant at the onset of the recovery period by homeostasis model assessment (P = 0.002). Glycogen resynthesis in the glycerol group appeared faster during the 1st h than during the subsequent 2nd h of the postexercise period. The glycogen resynthesis level was significantly lower in the Ivelip group than in the glycerol group during the recovery period (P = 0.04 during the 1st h and P = 0.001 during the next 2 h). During the recovery, plasma lactate and whole-body oxidation rates were similar in the two groups, whereas glycemia was significantly higher in the Ivelip group. A decreased cellular uptake of glucose as a substrate for glycogenosynthesis, rather than a competition between oxidation of carbohydrate and FFA, is discussed.

Role of intracellular buffering power on the mitochondria-cytosol pH gradient in the rat liver perfused at 4 degrees C.

The factors regulating the amplitude and the pH gradient between cytosol and mitochondria (DeltapHmito-cyt) were investigated in the isolated rat liver perfused at 4 degrees C. Liver ATP content, pH, and buffering power of cytosolic and mitochondrial compartments were evaluated in situ using phosphorus-31 nuclear magnetic resonance spectroscopy. No DeltapHmito-cyt was detected in the liver perfused without bicarbonate. Permeant weak acid in the perfusate (H2CO3, 25 mM, or isobutyric acid, 25, 50, or 100 mM) acidified both cytosol and mitochondria and revealed a DeltapHmito-cyt from 0.06 to 0.31 pH unit. Nevertheless, the manipulations of the DeltapHmito-cyt were more effective under bicarbonate-free conditions, due to the absence of buffering by H2CO3/HCO-3. In the absence of bicarbonate, the intracellular buffering power was threefold higher in the mitochondria (110 mmol/pH unit at pHmito 7.16) than in the cytosol (44 mmol/pH unit at pHcyt 7.30) and dependent on the matrix and cytosol pH, respectively. These buffering powers were almost double in the presence of bicarbonate. In the bicarbonate-free perfused liver, the respiratory activity was 0.08 +/- 0.02 micromol O2/min. g liver wet weight and the ATP turnover was only 40 +/- 7 nmol/min. g liver wet weight, indicating the weak activity of liver mitochondria when DeltapHmito-cyt was <0.05 pH unit. The ATP turnover during a 50 mM isobutyric acid load was 35 +/- 4 nmol/min. g liver wet weight whereas DeltapHmito-cyt rose to 0.26 +/- 0.02 pH unit and pHmito remained alkaline. Hence, although DeltapHmito-cyt was increased the ATP turnover remained unchanged. This work is the first evaluation of the mitochondrial buffering power in the isolated liver. The DeltapHmito-cyt observed within various acid loads reflected the differential titration of cytosol and mitochondria containing proteins and H2CO3/HCO-3 buffering systems. Moreover, no direct relationship between DeltapHmito-cyt and ATP turnover could be shown.

Mitochondrial permeability transition during hypothermic to normothermic reperfusion in rat liver demonstrated by the protective effect of cyclosporin A.

The purpose of this study was to test the hypothesis that mitochondrial permeability transition might be implicated in mitochondrial and intact organ dysfunctions associated with damage induced by reperfusion after cold ischaemia. Energetic metabolism was assessed continuously by 31P-NMR on a model system of isolated perfused rat liver; mitochondria were extracted from the livers and studied by using top-down control analysis. During the temperature transition from hypothermic to normothermic perfusion (from 4 to 37 degrees C) the ATP content of the perfused organ fell rapidly, and top-down metabolic control analysis of damaged mitochondria revealed a specific control pattern characterized by a dysfunction of the phosphorylation subsystem leading to a decreased response to cellular ATP demand. Both dysfunctions were fully prevented by cyclosporin A, a specific inhibitor of the mitochondrial transition pore (MTP). These results strongly suggest the involvement of the opening of MTP in vivo during the transition to normothermia on rat liver mitochondrial function and organ energetics.