Denis Monneret

Altitude illness is related to low hypoxic chemoresponse and low oxygenation during sleep

Altitude illness remains a major cause of mortality. Reduced chemosensitivity, irregular breathing leading to central apnoeas/hypopnoeas, and exaggerated pulmonary vasoconstriction may compromise oxygenation. All factors could enhance susceptibility to acute mountain sickness (AMS). We compared 12 AMS-susceptible individuals with recurrent and severe symptoms (AMS+) with 12 “AMS-nonsusceptible” subjects (AMS-), assessing sleep-breathing disorders in simulated altitude as well as chemoresponsive and pulmonary vasoconstrictive responses to hypoxia. During exposure to simulated altitude, mean blood oxygen saturation during sleep was lower in AMS+ subjects (81.6±2.6 versus 86.0±2.4%, p<0.01), associated with a lower central apnoea/hypopnoea index (18.2±18.1 versus 33.4±24.8 events·h−1 in AMS+ and AMS- subjects, respectively; p=0.038). A lower hypoxic (isocapnic) chemoresponsiveness was observed in AMS+ subjects (0.40±0.49 versus 0.97±0.46 L·min−1·%; p<0.001). This represented the only significant and independent predictive factor for altitude intolerance, despite a higher increase in pulmonary artery systolic pressure in response to hypoxia, a lower lung diffusing capacity and a higher endothelin-1 level at baseline in AMS+ subjects (p<0.05). AMS+ subjects were more hypoxaemic whilst exhibiting fewer respiratory events during sleep owing to lower hypoxic (isocapnic) chemoresponsiveness. In conclusion, the reduction in peripheral hypoxic chemosensitivity appears to be a major causative factor for altitude intolerance.

Independent Association of Urinary F2-Isoprostanes With Survival in Pulmonary Arterial Hypertension

OBJECTIVESnWithin the past decade, biochemical markers have emerged as attractive tools to assess pulmonary arterial hypertension (PAH) prognosis, being noninvasive and easily repeatable.The objective of this study was to determine whether biomarkers measured at initial diagnostic right-sided heart catheterization predict 3-year all-cause mortality for incident cases of PAH independently of clinical and hemodynamic parameters.nnnMETHODSnPatients with incident PAH were enrolled between December 2003 and April 2006 in six centers from the French Network on Pulmonary Hypertension and followed for 3 years.Venous blood samples were taken during right-sided heart catheterization, and analyses were centralized.nnnRESULTSnAmong 110 enrolled patients, 11 underwent lung or heart/lung transplantation, and 27 died during follow-up. The Kaplan-Meier estimates of survival were 91%, 78%, and 75% at 1, 2, and 3 years, respectively. Plasma big endothelin-1 (hazard ratio [HR] per 1-SD increase, 1.48; 95% CI,1.14-1.92), serum troponin T . 0.01 mg/L (HR, 2.35; 95% CI, 1.05-5.29), and urinary F 2 -isoprostanes(15-F2t -isoprostane) (HR per 1-SD increase, 1.76; 95% CI, 1.31-2.36) were associated with increased unadjusted hazard of death. In multivariate analysis adjusting for patient characteristics, the level of urinary F 2 -isoprostanes was the only biomarker that remained independently associated with increased hazard of death (HR per 1-SD increase, 1.82; 95% CI, 1.28-2.60).nnnCONCLUSIONSnThis study shows that levels of urinary F 2 -isoprostane, a biomarker of lipid peroxidation,quantified at initial diagnostic right-sided heart catheterization are independently associated with mortality in a cohort of patients with incident PAH.

The Severity of Nocturnal Hypoxia but Not Abdominal Adiposity Is Associated with Insulin Resistance in Non-Obese Men with Sleep Apnea

Background Beyond obesity, sleep apnea syndrome is frequently associated with excess abdominal adiposity that could contribute to the deteriorated cardiometabolic risk profile of apneic patients. Methods The present study addressed the respective contribution of the severity of sleep apnea syndrome and excess abdominal adiposity to the cardiometabolic risk profile of 38 non obese men with polysomnography-diagnosed sleep apnea syndrome (apnea-hypopnea index >15 events/hour). These otherwise healthy men performed a 75g-oral glucose tolerance test (OGTT) with plasma lipid/inflammatory and redox profiles. Twenty-one apneic men with high-waist circumference (>94 cm) were compared to 17 apneic men with low-waist circumference. Results Apneic men with high-waist circumference had higher AUC glucose and AUC insulin than apneic men with low-waist circumference. Accordingly, apneic men with high-waist circumference had higher hepatic insulin resistance as reflected by higher HOMA-resistance index, and lower global insulin sensitivity as reflected by lower insulin sensitivity index of Matsuda (derived from OGTT). The sleep structure and the apnea-hypopnea index were not different between the two groups. However, apneic men with high-waist circumference presented with lower mean nocturnal oxyhemoglobin (SpO2). In the 38 men, waist circumference and mean nocturnal SpO2 were inversely correlated (ru200a=u200a−0.43, pu200a=u200a0.011) and were both associated with plasma glucose/insulin homeostasis indices: the higher the waist circumference, the lower the mean nocturnal SpO2, the lower the insulin-sensitivity. Finally, in multivariable regression model, mean nocturnal SpO2 and not waist circumference was associated with insulin-resistance. Conclusion Thus, excess abdominal adiposity in non obese apneic men was associated with a deteriorated insulin-sensitivity that could be driven by a more severe nocturnal hypoxemia.

Plasma 15-F2t isoprostane concentrations are increased during acute fructose loading in type 2 diabetes

OBJECTIVEnFructose consumption is increasing worldwide and is likely to play a role in metabolic disorders. Dietary fructose is often recommended for diabetic patients, as this form of carbohydrate leads to a lower postprandial rise in plasma glucose and insulin. However, fructose contributes to the generation of free radicals. The aim of this work was to investigate the acute effects of a fructose load in patients with type 2 diabetes mellitus (T2DM), compared with healthy controls, on several metabolic oxidative biomarkers, particularly plasma 15-F2t isoprostanes (15-F2t isoPs).nnnRESEARCH DESIGN AND METHODSnSix T2DM patients and six healthy subjects were recruited. All patients underwent a single fructose tolerance test (75 g of anhydrous fructose). Plasma 15-F2t isoPs concentrations, plasma total antioxidant capacity (TAS) and thiobarbituric acid reactive substances (TBARS) were measured at baseline, and at 60, 120, 180 and 240 min after fructose absorption.nnnRESULTSnBaseline plasma 15-F2t isoPs concentrations were significantly increased in T2DM patients compared with controls (310+/-47 versus 237+/-20 pg/mL, respectively; P<0.01) and rose significantly (P<0.01) to 414+/-45 pg/mL in diabetic patients. No change in TAS or TBARS was observed in either group.nnnCONCLUSIONnPlasma 15-F2t isoPs are increased during acute fructose loading in T2DM. Knowing the potentially deleterious effect of plasma 15-F2t isoPs-in particular, vascular lesions-and in light of our results, it is necessary to reconsider fructose consumption in T2DM patients, as we can now show, for the first time, a possible association between acute fructose loading and deleterious effects in such patients.

Variability in definitions of transaminase upper limit of the normal impacts the APRI performance as a biomarker of fibrosis in patients with chronic hepatitis C: “APRI c’est fini ?”

BACKGROUNDnThe aspartate aminotransferase platelet ratio index (APRI) is a validated, non-patented blood test for diagnosing fibrosis or cirrhosis in patients with chronic hepatitis C. We assess the impact of two limitations, the variability of the upper limit of normal for aspartate aminotransferase (AST-ULN) and the risk of overestimating fibrosis stage due to necroinflammatory activity.nnnMETHODSnThe variability of AST-ULN was assessed by an overview of the literature and an assessment of AST-ULN in 2 control populations 7521 healthy volunteers and 393 blood donors. We assessed the impact of AST-ULN variability on APRI performance for estimating fibrosis prevalence and on the Obuchowski measure using individual data of 1651 patients with APRI, FibroTest and biopsy.nnnRESULTSnThe overview, and the analysis of the control populations found that ULN-AST ranged from 26 to 49 IU/L according to gender, body mass index and serum cholesterol. When this AST-ULN variability was applied to the chronic hepatitis group, the prevalence of advanced fibrosis and cirrhosis as presumed by APRI varied (P<0.001) from 34.7% to 68.5%, and from 11.4% to 32.3%, respectively. This spectrum effect induced variability in APRI performance, which could be similar 0.862 (if AST-ULN=26 IU/L) or lower 0.820 (AST-ULN≥30IU/L) than the stable FibroTest performance (0.867; P=0.35 and P<0.0001 respectively). When applied to 18 acute hepatitis C patients, the rate of false positives of APRI varied from 0% to 61% due to AST-ULN.nnnCONCLUSIONnThe AST-ULN variability is high highly associated with the variability of metabolic risk factors between the different control groups. This variability induces a spectrum effect, which could cause misleading interpretations of APRI performance for the staging of fibrosis, comparisons of APRI with other non-invasive tests, and estimates of false positive rate.

Treating hepatic encephalopathy in cirrhotic patients admitted to ICU with sodium phenylbutyrate: a preliminary study

Hepatic encephalopathy (HE) influences short‐term and long‐term prognoses. Recently, glycerol phenylbutyrate (PB), that lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion, has shown that it was effective in preventing the occurrence of HE in RCT. The aim was to assess the benefits of sodium PB in cirrhotic patients admitted to ICU for overt HE, in terms of ammonia levels decrease, neurological improvement, and survival. Cirrhotic patients who presented with overt HE, ammonia levels >100 μmol/L, and did not display any contra‐indication were included. Sodium PB was administered at 200 mg/kg/day. Control group included historical controls treated by standard therapy, matched for age, sex, MELD score, and severity of HE. Eighteen patients were included and treated with sodium PB (age: 59 [45–68], male gender: 15 [83%], Child–Pugh B: 8 [44%], Child–Pugh C: 10 [56%], and MELD score: 16 [13–23]). Ammonia levels significantly decreased in the PB as compared to the control group from inclusion to 12 h and from inclusion to 48 h (P = 0.0201 and P = 0.0230, respectively). The proportion of patients displaying neurological improvement was only higher in the PB‐treated group as compared to controls at ICU discharge (15 [83%] vs. 9 [50%], P = 0.0339). ICU discharge survival was significantly higher in patients treated with PB (17 [94%] vs. 9 [50%], P = 0.0017). In cirrhotic patients with overt HE, sodium PB could be effective in reducing ammonia levels and might be effective in improving neurological status and ICU discharge survival. More extensive data, especially a RCT, are mandatory.

Intermittent hypoxia in obese Zucker rats: cardiometabolic and inflammatory effects

What is the central question of this study? This study addresses the relative impact of obesity and intermittent hypoxia in the pathophysiological process of obstructive sleep apnoea by investigating the metabolic, inflammatory and cardiovascular consequences of intermittent hypoxia in lean and obese Zucker rats. What is the main finding and its importance? We found that obesity and intermittent hypoxia have mainly distinct consequences on the investigated inflammatory and cardiometabolic parameters in Zucker rats. This suggests that, for a given severity of sleep apnea, the association of obesity and obstructive sleep apnoea may not necessarily be deleterious.

S100B protein concentration measurement according to two different immunoassays

*Corresponding author: Françoise Imbert-Bismut, AP-HP, Hôpital Pitié-Salpêtrière, Service de Biochimie Métabolique, Paris, 75013, France, E-mail: francoise.bismut@psl.aphp.fr Joffrey Feriel, Fréderic Adamo, Denis Monneret, Séverine Favard and Chantal Tsé: AP-HP, Hôpital Pitié-Salpêtrière, Service de Biochimie Métabolique, Paris, France Virginie Trehel-Tursis and Louis Puybasset: AP-HP, Hôpital PitiéSalpêtrière, Département d’Anesthèsie-Réanimation, Paris, France Dominique Bonnefont-Rousselot: AP-HP, Hôpital Pitié-Salpêtrière, Service de Biochimie Métabolique, Paris, France; UPMC Université Paris 6 UMRS_1166 ICAN, Paris, France; and Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France Letter to the Editor

Isoprostane as a promising prognostic biomarker in pulmonary arterial hypertension: preanalytical and analytical viewpoints

a Department of Metabolic Biochemistry, La Pitié Salpêtrière-Charles Foix University Hospital (AP-HP), Paris, France b HP2 Laboratory INSERM UMR 1042-Univ. Grenoble-Alpes, Grenoble, France c Clinical Pharmacology Unit, INSERM CIC003, Grenoble University Hospital, Grenoble, France d Department of Biochemistry, Faculty of Pharmacy, Paris Descartes University, Paris, France e UPMC University Paris 6, UMR_S1166 Inserm ICAN, Paris, France