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International audience; BACKGROUND:Copeptin - the C-terminal section of vasopressin precursor - is a novel biomarker, that has been shown to be a useful prognostic factor in heart failure, ischemic stroke and in acute myocardial infarction (MI) but with restricted population and follow-up in ST-segment elevation MI (STEMI) setting. We evaluated in this study the hypothesis that copeptin measured on admission is an independent predictor of one-year all-cause mortality after a STEMI.METHODS:Copeptin was measured immediately on arrival in the catheterization laboratory in a cohort of unselected STEMI patients and was compared to the peak of cardiac troponin I as a prognosis marker. One-year follow-up was performed.RESULTS:We included 401 STEMI patients (77% of men, mean age 64 ± 14 years) treated by primary percutaneous coronary intervention. Copeptin on admission was significantly higher in patients who died during the one-year follow-up than in survivors (154.8 pmol/L; IQR [63.9-304.8] vs 30.3 pmol/L; IQR [10.8-93.5]); p

ObjectivesN-terminal probrain natriuretic peptide (NT-proBNP) predicts mortality and the development of heart failure in hypertrophic cardiomyopathy (HCM). Mid-regional proatrial natriuretic peptide (MR-proANP) is a stable by-product of production of atrial natriuretic peptide. We sought to compare the prognostic value of MR-proANP and NT-proBNP in HCM.MethodsWe prospectively enrolled a cohort of patients with HCM from different European centres and followed them. All patients had clinical, ECG and echocardiographic evaluation and measurement of MR-proANP and NT-proBNP at inclusion.ResultsOf 357 patients enrolled, the median age was 52 (IQR: 36–65) years. MR-proANP and NT-proBNP were both independently associated with age, weight, New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), wall thickness and left atrial dimension. During a median follow-up of 23 months, 32 patients had a primary end point defined as death (n=6), heart transplantation (n=8), left ventricular assist device implantation (n=1) or heart failure hospitalisation (n=17). Both NT-proBNP and MR-proANP (p–4) were strongly associated with the primary endpoint, and the areas under the receiver operating characteristic (ROC) curves for both peptides were not significantly different. However, in a multiple stepwise regression analysis, the best model for predicting outcome was NYHA 1–2 vs 3–4 (HR=0.35, 95% CI 0.16 to 0.77, pConclusionsMR-proANP emerges as a valuable biomarker for the prediction of death and heart failure related events in patients with HCM.

Early diagnostic orientation for differentiating pneumonia from pneumonitis at the early stage after aspiration would be valuable to avoid unnecessary antibiotic therapy. We assessed the accuracy of procalcitonin (PCT) in diagnosing aspiration pneumonia (AP) in intensive care unit (ICU) patients requiring mechanical ventilation after out-of-hospital coma. Prospective observational 2-year cohort study in a medical-surgical ICU. PCT, C-reactive protein (CRP) and white blood cell count (WBC) were measured at admission (H0) and 6 h (H), H12, H24, H48, H96, and H120 after inclusion. Lower respiratory tract microbiological investigations performed routinely in patients with aspiration syndrome were the reference standard for diagnosing AP. Performance of PCT, CRP, and WBC up to H48 in diagnosing AP was compared based on the areas under the ROC curves (AUC) and likelihood ratios (LR+ and LR−) computed for the best cutoff values. Of 103 patients with coma, 45 (44%) had AP. Repeated PCT assays demonstrated a significant increase in patients with AP versus without AP from H0 to H120. Among the three biomarkers, PCT showed the earliest change. ROC-AUC values were poor for all three biomarkers. Best ROC-AUC values for diagnosing AP were for CRP at H24 [0.73 (95%CI 0.61–0.84)] and PCT at H48 [0.73 (95%CI 0.61–0.84)]. LR+ was best for PCT at H24 (3.5) and LR− for CRP and WBC at H24 (0.4 and 0.4, respectively). Early and repeated assays of PCT, CRP, and WBC demonstrated significant increases in all three biomarkers in patients with versus without AP. All three biomarkers had poor diagnostic performance for ruling out AP. Whereas PCT had the fastest kinetics, PCT assays within 48 h after ICU admission do not help to diagnose AP in ICU patients with coma.

BACKGROUND: Procalcitonin (PCT) is increasingly being used for the diagnostic and prognostic work up of patients with suspected infections in the emergency department (ED). Recently, B.R.A.H.M.S PCT direct, the first high sensitive point-of-care test (POCT), has been developed for fast PCT measurement on capillary or venous blood samples. METHODS: This is a prospective, international comparison study conducted in three European EDs. Consecutive patients with suspicion of bacterial infection were included. Duplicate determination of PCT was performed in capillary (fingertip) and venous whole blood (EDTA), and compared to the reference method. The diagnostic accuracy was evaluated by correlation and concordance analyses. RESULTS: Three hundred and three patients were included over a 6-month period (60.4% male, median age 65.2 years). The correlation between capillary or venous whole blood and the reference method was excellent: r2=0.96 and 0.97, sensitivity 88.1% and 93.0%, specificity 96.5% and 96.8%, concordance 93% and 95%, respectively at a 0.25 mug/L threshold. No significant bias was observed (-0.04 and -0.02 for capillary and venous whole blood) although there were 6.8% and 5.1% outliers, respectively. B.R.A.H.M.S PCT direct had a shorter time to result as compared to the reference method (25 vs. 144 min, difference 119 min, 95% CI 110-134 min, p>0.0001). CONCLUSIONS: This study found a high diagnostic accuracy and a faster time to result of B.R.A.H.M.S PCT direct in the ED setting, allowing shortening time to therapy and a more wide-spread use of PCT.

Early diagnostic orientation for differentiating pneumonia from pneumonitis at the early stage after aspiration would be valuable to avoid unnecessary antibiotic therapy. We assessed the accuracy of procalcitonin (PCT) in diagnosing aspiration pneumonia (AP) in intensive care unit (ICU) patients requiring mechanical ventilation after out-of-hospital coma.Prospective observational 2-year cohort study in a medical-surgical ICU. PCT, C-reactive protein (CRP) and white blood cell count (WBC) were measured at admission (H0) and 6 h (H), H12, H24, H48, H96, and H120 after inclusion. Lower respiratory tract microbiological investigations performed routinely in patients with aspiration syndrome were the reference standard for diagnosing AP. Performance of PCT, CRP, and WBC up to H48 in diagnosing AP was compared based on the areas under the ROC curves (AUC) and likelihood ratios (LR+ and LR-) computed for the best cutoff values.Of 103 patients with coma, 45 (44%) had AP. Repeated PCT assays demonstrated a significant increase in patients with AP versus without AP from H0 to H120. Among the three biomarkers, PCT showed the earliest change. ROC-AUC values were poor for all three biomarkers. Best ROC-AUC values for diagnosing AP were for CRP at H24 [0.73 (95%CI 0.61-0.84)] and PCT at H48 [0.73 (95%CI 0.61-0.84)]. LR+ was best for PCT at H24 (3.5) and LR- for CRP and WBC at H24 (0.4 and 0.4, respectively).Early and repeated assays of PCT, CRP, and WBC demonstrated significant increases in all three biomarkers in patients with versus without AP. All three biomarkers had poor diagnostic performance for ruling out AP. Whereas PCT had the fastest kinetics, PCT assays within 48 h after ICU admission do not help to diagnose AP in ICU patients with coma.

BACKGROUND Hyponatremia is a common feature of acute illness and associated with increased mortality. This may be explained by a stress-mediated activation of the vasopressin system with an increase in free-water reabsorption. OBJECTIVES To investigate whether the association between hyponatremia and mortality could be explained by activation of the vasopressin system. METHODS We prospectively enrolled adult, medical patients seeking emergency care in three centres in Switzerland, France and the United States. We investigated associations between admission plasma sodium and copeptin, a stable portion of the vasopressin-precursor peptide, with 30-day mortality. We performed uni- and multivariate regression analysis. RESULTS Of 6962 included patients, 18% had hyponatremia (sodium ≤135 mmol L-1 ), which doubled their risk for mortality compared to patients with normonatremia (8.3% vs. 3.8%). This association was confirmed in a multivariate-adjusted logistic regression analysis [adjusted odds ratio (OR) 1.47, 95% CI 1.12-1.93, P = 0.005]. Vasopressin levels, mirrored by copeptin, were also increased in nonsurvivors and strongly associated with mortality (adjusted OR 3.42, 95% CI 2.76-4.25, P < 0.001). The association between hyponatremia and mortality remained unchanged when adding copeptin levels to the regression model (fully adjusted OR 1.53, 95% CI 1.16-2.00, P = 0.002). CONCLUSION This prospective study including medical patients upon emergency room admission found hyponatremia as well as an activation of the vasopressin system to be independently associated with mortality. This suggests that stress- and vasopressin-independent mechanisms are responsible for the association of low sodium levels with mortality.

Martin Dres,1,2 Pierre Hausfater,3,4 Frantz Foissac,5,6 Maguy Bernard,7 Luc-Marie Joly,8 Mustapha Sebbane,9 Anne-Laure Philippon,3,4 Cédric Gil-Jardiné,10 Jeannot Schmidt,11 Maxime Maignan,12 Jean-Marc Treluyer,13 Nicolas Roche14,15 On behalf of the UTAPE Study Investigators and Scientific Committee 1Pulmonary and Critical Care Department, Pitié-Salpêtrière Hospital, AP-HP, 2UMRS1158: Clinical and Experimental Respiratory Neurophysiology, Paris 6 University, 3Emergency Department, Hôpital Pitié-Salpêtrière, AP-HP, 4Sorbonne Universités UPMC Univ-Paris06, GRC-14 BIOSFAST, 5Clinical Research Department, Necker Cochin Hospital, AP-HP, 6EA 7323, Sorbonne Paris-Cité, 7Biochemistry Department, Pitié-Salpêtrière Hospital, AP-HP, Paris, 8Emergency Department, Charles Nicolle Hospital, Rouen, 9Department of Emergency Medicine, Lapeyronie Hospital, Montpellier, 10Emergency Department, Pellegrin Hospital, Bordeaux, 11Emergency Department, Gabriel Montpied Hospital, Clermont-Ferrand, 12Emergency Department, Grenoble University Hospital, Grenoble, 13Clinical Research Department, Paris Descartes University, Hôpital Cochin, AP-HP, 14Pulmonary Department, Cochin Hospital, AP-HP, 15Paris Descartes University, Paris, France Background: Exacerbations of COPD (ECOPD) are a frequent cause of emergency room (ER) visits. Predictors of early outcome could help clinicians in orientation decisions. In the current study, we investigated whether mid-regional pro-adrenomedullin (MR-proADM) and copeptin, in addition to clinical evaluation, could predict short-term outcomes.Patients and methods: This prospective blinded observational study was conducted in 20 French centers. Patients admitted to the ER for an ECOPD were considered for inclusion. A clinical risk score was calculated, and MR-proADM and copeptin levels were determined from a venous blood sample. The composite primary end point comprised 30-day death or transfer to the intensive care unit or a new ER visit.Results: A total of 379 patients were enrolled in the study, of whom 277 were eventually investigated for the primary end point that occurred in 66 (24%) patients. In those patients, the median (interquartile range [IQR]) MR-proADM level was 1.02 nmol/L (0.77–1.48) versus 0.83 nmol/L (0.63–1.07) in patients who did not meet the primary end point (P=0.0009). In contrast, copeptin levels were similar in patients who met or did not meet the primary end point (P=0.23). MR-proADM levels increased with increasing clinical risk score category: 0.74 nmol/L (0.57–0.89), 0.83 nmol/L (0.62–1.12) and 0.95 nmol/L (0.75–1.29) for the low-, intermediate- and high-risk categories, respectively (P

The aim of this study was to evaluate the accuracy of procalcitonin (PCT) in predicting bacterial infection and survival without transplantation upon admission in the ICU for acute liver failure (ALF).From January 2009 until October 2015, all cases of ALF patients admitted in our ICU were retrospectively reviewed and included in the study if the PCT level upon admission was available. Patients with pre-existing liver pathology or ALF in a context of already advanced multiorgan failure were excluded. The main clinical and biological characteristics of patients were recorded, as well as the etiology of ALF, diagnosis of bacterial infection (bacteriologically documented or suspected), and outcome.35 patients were included: 46% men, mean age 42 years, initial prothrombin ratio 31%, PCT 9.8 mg/l (0.7-49), and PCT more than 2 mg/l in 54% of cases. Etiology was acetaminophen intoxication in 18/35 (51%) cases. Sepsis was diagnosed in 9/35 (26%) cases, most frequently pneumonia with 4/9 cases. Survival without liver transplantation (LT) was observed in 28 (80%) cases. The median PCT was not different in patients with or without bacterial infection [6.3 mg/l (0.6-16) vs. 1.2 mg/l (0.8-9.7), P=0.8]. The median PCT was not different in patients who survived without LT [7.1 mg/l (0.9-16.1) vs. 0.75 mg/l (7.7-11.5), P=0.06]. In patients with ALF unrelated to acetaminophen intoxication, the median PCT was higher in patients with bacterial infection [1.1 mg/l (0.9-4) vs. 0.5 mg/l (0.3-0.8), P=0.01], but was similar in patients who did not survive without LT [0.7 mg/l (0.4-1.1) vs. 0.8 mg/l (0.4-2.2), P=0.6]. In the overall cohort, the median C-reactive protein (CRP) and leukocyte count were higher in patients who developed bacterial infection [40 mg/l (19-60) vs. 16 mg/l (6-34), P=0.04; 11.9 G/l (8.3-19) vs. 7.9 G/l (6-12.6), P=0.05]. The median CRP and leukocyte count were not significantly different in survivors versus nonsurvivors without LT.PCT was an accurate predictor for the diagnosis of bacterial infection only in patients with ALF unrelated to acetaminophen intoxication. CRP was higher in patients who developed infection and could also be an interesting tool in ALF patients.

BACKGROUND Tumor marker measurements are becoming essential for prognosis and follow-up of patients in oncology. In this context, we aimed to compare a new analyzer, Lumipulse(®) G1200 (Fujirebio group, distributed in Europe by the Innogenetics group) with Kryptor(®) (Thermo Fisher Scientific B.R.A.H.M.S, Asnieres, France) and Modular(®) Elecsys E170 (Roche Diagnostics, Meylan, France) for the measurement of seven tumor markers: PSA, AFP, CEA, CA 15-3, CA 125, CA 19-9, and Cyfra 21-1. METHODS A total of 471 serum samples from patients with elevated tumor markers and 100 serum from healthy patients were analyzed with Lumipulse(®) G1200 and either Kryptor(®) (for AFP) or Modular(®) (for the six other markers). RESULTS The good precision of Lumipulse(®) G1200 assays was confirmed with CVs 95% and tumor marker kinetics were all similar. CONCLUSION We confirmed the analytical performances of Lumipulse(®) tumor marker assays except for the CYFRA 21-1 assay for which performances were poor in this study. We noticed a few discrepancies for the CEA assay. Besides, values obtained for CA 19-9 were higher with Lumipulse leading to a bias (slope = 1.5). But for the four other tumor markers assays (PSA, AFP, CA 125, CA 15-3), the results were directly transferable between Lumipulse and Kryptor or Modular, thus facilitating an eventual substitution of one system by another.

Amniotic fluid embolism (AFE) is a rare complication of pregnancy, which, in France, is the second leading cause of maternal mortality. It results from the passage of amniotic fluid into the maternal circulation, but mechanisms leading to clinical signs are not yet clearly identified. After a literature review, we report on the case of a 34 years old patient occurred during labor. Laboratory tests were performed during acute phase to diagnose coagulopathy and to monitor vital parameters. Further laboratory tests were conducted to support the diagnosis: cytology, study of insulin-like growth factor-binding protein 1, tryptase and alpha-foetoprotein. Performances and place of these laboratory tests must be precised as no specific test can attest the diagnosis.

International audience; In colorectal cancer (CRC), KRAS mutations are a strong negative predictor for treatment with the EGFR-targeted antibodies cetuximab and panitumumab. Since it can be difficult to obtain appropriate tumor tissues for KRAS genotyping, alternative methods are required. Circulating tumor cells (CTCs) are believed to be representative of the tumor in real time. In this study we explored the capacity of a size-based device for capturing CTCs coupled with a multiplex KRAS screening assay using droplet digital PCR (ddPCR). We showed that it is possible to detect a mutant ratio of 0.05% and less than one KRAS mutant cell per mL total blood with ddPCR compared to about 0.5% and 50–75 cells for TaqMeltPCR and HRM. Next, CTCs were isolated from the blood of 35 patients with CRC at various stage of the disease. KRAS genotyping was successful for 86% (30/35) of samples with a KRAS codon 12/13 mutant ratio of 57% (17/30). In contrast, only one patient was identified as KRAS mutant when size-based isolation was combined with HRM or TaqMeltPCR. KRAS status was then determined for the 26 available formalin-fixed paraffin-embedded tumors using standard procedures. The concordance between the CTCs and the corresponding tumor tissues was 77% with a sensitivity of 83%. Taken together, the data presented here suggest that is feasible to detect KRAS mutations in CTCs from blood samples of CRC patients which are predictive for those found in the tumor. The minimal invasive nature of this procedure in combination with the high sensitivity of ddPCR might provide in the future an opportunity to monitor patients throughout the course of disease on multiple levels including early detection, prognosis, treatment and relapse as well as to obtain mechanistic insight with respect to tumor invasion and metastasis.

Summary “A Desintegrin And Metalloprotease 12” (ADAM12) metalloprotease involved into growth and cell-cell interactions, is synthesised by placenta during pregnancy and is implicated in fetal growth. Recently, its overexpression has been described in various human cancers. This multidomain transmembrane enzyme possesses proteolytic function on many substrates (IGFBP and HB-EGF…) suggesting its role in cell growth and hypertrophy. In addition, ADAM12 with its disintegrin-like domain, plays a role in apoptic process, differenciation and organogenesis. Because of the development of automatized techniques, maternal serum ADAM12 has been proposed as supplementary marker in Down'syndrome screening or as potential marker of aneuploidy and pre-eclampsia. The various results due to analytical variability suggest studies on larger series of samples. ADAM12 seems to play an important role in various pathological situations (cancer, musculosketal disorders, cardiac hypertrophy, neurological disorders). At last, inhibition of ADAM12 has been proposed as therapeutic target in cardiology or to treat cancer.

Summary Pregnancy-associated plasma protein A (PAPP-A), metalloglycoprotein isolated from pregnancy serum, has been also found in different cell systems (vascular cells of smooth muscle, osteoblasts…). Two forms exist: a high-molecular-weight heterotetrameric complex particularly during pregnancy, and an active free form. PAPP-A has been found to proteolytically cleave insulin-like growth factor (IGFBP-4). Automated techniques have been developed particularly for use in prenatal Down's syndrome (DS) screening. Serum PAPP-A concentrations increase during pregnancy, and decreased PAPP-A values have been found to be associated with fetal DS. It is used, in association with free βhCG and measurement of nuchal translucency, in first trimester DS screening. PAPP-A has also been used as a marker of aneuploidies or preeclampsia and predictor of adverse outcome. Moreover, PAPP-A has been described as a marker of instability of atherosclerotic plaque activity and might predict complications in cardiology. But this application requires more sensitive tests in comparison with prenatal diagnosis.

Summary Background Reduced duration of antibiotic treatment might contain the emergence of multidrug-resistant bacteria in intensive care units. We aimed to establish the effectiveness of an algorithm based on the biomarker procalcitonin to reduce antibiotic exposure in this setting. Methods In this multicentre, prospective, parallel-group, open-label trial, we used an independent, computer-generated randomisation sequence to randomly assign patients in a 1:1 ratio to procalcitonin (n=311 patients) or control (n=319) groups; investigators were masked to assignment before, but not after, randomisation. For the procalcitonin group, antibiotics were started or stopped based on predefined cut-off ranges of procalcitonin concentrations; the control group received antibiotics according to present guidelines. Drug selection and the final decision to start or stop antibiotics were at the discretion of the physician. Patients were expected to stay in the intensive care unit for more than 3 days, had suspected bacterial infections, and were aged 18 years or older. Primary endpoints were mortality at days 28 and 60 (non-inferiority analysis), and number of days without antibiotics by day 28 (superiority analysis). Analyses were by intention to treat. The margin of non-inferiority was 10%. This trial is registered with ClinicalTrials.gov, number NCT00472667. Findings Nine patients were excluded from the study; 307 patients in the procalcitonin group and 314 in the control group were included in analyses. Mortality of patients in the procalcitonin group seemed to be non-inferior to those in the control group at day 28 (21·2% [65/307] vs 20·4% [64/314]; absolute difference 0·8%, 90% CI −4·6 to 6·2) and day 60 (30·0% [92/307] vs 26·1% [82/314]; 3·8%, −2·1 to 9·7). Patients in the procalcitonin group had significantly more days without antibiotics than did those in the control group (14·3 days [SD 9·1] vs 11·6 days [SD 8·2]; absolute difference 2·7 days, 95% CI 1·4 to 4·1, p Interpretation A procalcitonin-guided strategy to treat suspected bacterial infections in non-surgical patients in intensive care units could reduce antibiotic exposure and selective pressure with no apparent adverse outcomes. Funding Assistance Publique-Hopitaux de Paris, France, and Brahms, Germany.

Objective Women with antiphospholipid (aPL) biology present obstetric complications. The α-fetoprotein (AFP) serum levels of these patients are higher than in general population. Because AFP is involved in the calculation of the risk of trisomy 21 (T21), we studied the effect of AFP variations in the presence of aPL during T21 screening. Methods The study group (aPL group) was comprised of 64 pregnancies in women with aPL antibodies. The control group was comprised of 21 655 pregnancies included in the national program for routine Down syndrome (DS) screening by maternal serum markers [human chorionic gonadotrophin (hCG) and AFP] between 14 + 0 and 18 + 6 weeks of gestation. Results AFP values, converted in logarithm of multiples of the median (MoM), were significantly higher in the aPL group (0.03 vs 0.10; p = 0.018). After a matricial transformation of AFP MoM and hCG MoM in the aPL group, new T21 risks presented a median of one in 1665 versus one in 2574 (p < 0.0001 with a rank-sign test). Conclusion Our results highlight the fact that in the presence of aPL antibodies, the calculated risk of T21 is underestimated. Therefore, clinicians should interpret the screening borderline results in aPL patients with caution. Copyright © 2009 John Wiley & Sons, Ltd.

The glycosidase activities (beta-D-mannosidase, alpha-L-fucosidase and N-acetyl-beta-D-glucosaminidase) have been compared in whole and split ejaculate samples from men whose couple suffers from infertility. The site of secretion of enzymatic activities is either prostatic or epididymal. The three enzymatic activities have possibly different origin and should constitute new biochemical markers of male genital tract.

Resume Le diagnostic de l’infarctus du myocarde postoperatoire est souvent difficile, les criteres habituels de diagnostic s’averant peu sensibles (examen clinique, ECG pour les infarctus non-transmuraux), peu specifiques (marqueurs enzymatiques, anomalies echographiques), ou difficiles de realisation et d’interpretation (anomalies scintigraphiques). La mise a la disposition des cliniciens de marqueurs biochimiques cardiospecifiques, ont permis des 1995, de revoir la place de la biologie dans le diagnostic de l’infarctus du myocarde postoperatoire. Le but de cette revue de la litterature est de dresser un etat des lieux apres 13 ans d’utilisation du dosage des troponines.

Resume Le dosage des marqueurs seriques maternels (MSM) propose a toutes les femmes enceintes entre 14 et 18 semaines d’amenorrhee permet de definir un risque individuel de trisomie 21 fœtale. Le calcul est realise par un logiciel (Maciel Prenatal Interpretive Software) associe a un systeme d’analyse (AxSYM ® Abbott Diagnostics). Il prend en compte differentes donnees maternelles ainsi que les concentrations seriques d’hormone gonadochorionique (hCG) et d’α-fœtoproteine (AFP) exprimees en multiples de la mediane. Ces medianes doivent etre etablies pour chaque âge gestationnel et pour chaque marqueur biologique. Le changement du standard international d’hCG est a l’origine d’une diminution de 20 % des concentrations. Les medianes utilisees ne sont donc plus adaptees. Leur ajustement est realise par cette etude, sur les serums de 377 patientes analyses au laboratoire dans le cadre des MSM. L’hCG est respectivement dosee avec les deux standards. L’equation de correlation obtenue appliquee aux medianes de reference permet de determiner les medianes utilisables avec la nouvelle calibration. Leur exactitude et leur repercussion clinique, verifiees grâce a la reanalyse des 377 dossiers, ne montrent pas de retentissement sur la prise en charge des patientes. Ces nouvelles medianes ont ete appliquees avec les reactifs correspondant au nouveau standard le 1 er janvier 2007.

Chronic kidney disease and metabolic syndrome are recognized as major cardiovascular risk factors. It has been shown that cystatin C has a stronger association with mortality risk than creatinine-based estimations of glomerular filtration rate. We measured cystatin values in dyslipidemic patients and looked for correlations between renal function, cystatin, and metabolic syndrome.There were 925 dyslipidemic patients prospectively included in this cross-sectional study and evaluated over 10 months. Each visit included clinical and biological assessment.Most patients exhibited cardiovascular risk factors other than dyslipidemia: hypertension in 34%, diabetes in 11%, and smoking in 18%. Mean triglycerides were 149 +/- 136 mg/dL, mean high-density lipoprotein cholesterol 54 +/- 14 mg/dL, and low-density lipoprotein 167 +/- 48 mg/dL. Metabolic syndrome was present in 238 (26%) patients. Plasma creatinine did not differ between control group and metabolic syndrome patients (80 +/- 26 vs 82 +/- 20 micromol/L, respectively, P = .2), but creatinine clearance evaluated by abbreviated Modification of Diet in Renal Disease Study formula was lower in the metabolic syndrome group than in the non-metabolic-syndrome group (83.3 +/- 18.8 mL/min/1.73 m(2) vs 86.8+/-16.9 mL/min/1.73 m(2), respectively, P.007). Cystatin value was significantly higher in metabolic syndrome patients than in others (0.86 +/- 0.23 vs 0.79 +/- 0.20 mg/L, respectively, P.0001), independently of serum creatinine level and creatinine clearance. Furthermore, there was a progressive increase in cystatin, as a function of the number of metabolic syndrome components.Our study shows that cystatin is associated with metabolic syndrome in dyslipidemic patients. Cystatin may be an interesting marker of metabolic syndrome and of increased cardiovascular and renal risk.

To assess the predictive capacity for the diagnosis of ventilator-associated pneumonia (VAP) of serum procalcitonin levels before and on the day it is suspected. Single-center observational study in the intensive care unit of a teaching hospital. Consecutive patients whose serum procalcitonin levels were available on the day that VAP was clinically suspected (day 1) and at some time within the preceding 5 days (“before”). Serum procalcitonin levels were determined on day 1 and “before”. Among the 73 suspected episodes VAP was confirmed by quantitative bronchoalveolar lavage cultures in 32 and refuted in 41. Respective median “before” procalcitonin levels were 1.89 ng/ml (interquartile range 0.18–6.01) and 2.14 (0.76–5.75) in patients with and without VAP, but their respective median day-1 procalcitonin levels did not differ: 1.07 ng/ml (0.39–6.57) vs. 1.40 (0.67–3.39). On day 1 a 0.5 ng/ml procalcitonin threshold had 72% sensitivity but only 24% specificity for diagnosing VAP. Between “before” and day 1, procalcitonin increased in 41% and 15% of patients with and without VAP, respectively. Thus a procalcitonin rise on day 1, compared to its “before” level, had 41% sensitivity and 85% specificity for diagnosing VAP, with respective positive and negative predictive values of 68% and 65%. Crude values and procalcitonin rise had poor diagnostic value for VAP in this particular setting and thus should not be used to initiate antibiotics when VAP is clinically suspected.

To study the effect of non-exertional heatstroke on serum procalcitonin (PCT) levels.Cohort study.The emergency and intensive care departments of two academic tertiary-care hospitals, Paris, FranceA total of 53 patients with defined heatstroke attending the emergency department and/or the intensive care unit during the August 2003 heat wave in France.None.Serum PCT measurement using a sensitive assay and vital and routine biological variables on arrival of patients presenting with classic heatstroke. Thirty-day mortality was recorded.Among the 53 patients included, 14 (26%) were admitted to an intensive care unit (ICU). At 30 days, 24 patients (45%) had died. Median PCT value was 0.58 microg/l (95% confidence interval 0.16-1.61) and 31 (58%) patients had PCT above 0.2 microg/l (PCT+). Temperature above or equal to 40 degrees C was the only variable significantly associated with fatal outcome. Median PCT values were 1.4 microg/l (0.16-4.71) and 0.18 microg/l (0.12-1.61) in the group of deceased and surviving patients respectively (p = 0.22). All patients admitted in ICU had elevated PCT values. Patients PCT+ initially presented with a more pronounced systemic inflammatory response. Microbiologically or clinically documented infection was not more frequent in PCT+ group.High serum PCT levels can be observed in heatstroke without any concomitant documented bacterial infection. The PCT is not a valid mortality predictor in heatstroke but could be an indicator of the severity of illness. Heatstroke could represent a model of a "non-septic" pathway of PCT synthesis.

The effects of oxidative stress on integrin-mediated cell adhesion to the extracellular matrix (ECM) and related apoptosis were investigated using the EA.hy926 endothelial cells treated (or not) with two oxidants: the hypoxanthine/xanthine oxidase system (HX/XO) or the tert-butyl hydroperoxide (t-BHP) which both increased cell apoptosis. Cell adhesion onto vitronectin (Vn) and fibronectin (Fn) was increased at low concentrations of HX/XO (up to 5 mU/ml) or t-BHP (up to 125 microM) and prevented ROS-induced apoptosis. Flow cytometry analysis of integrin expression showed that the expression of integrin alphav and alpha5 subunits was, respectively, increased and decreased. Cell adhesion inhibition experiments using function-blocking monoclonal antibodies against integrin subunits indicated that alphavbeta1 and alphavbeta3 integrins were involved in adhesion of cells to Vn, and alphavbeta3 integrin played a major role in oxidant-treated cells. For adhesion to Fn, alpha5beta1 and alphavbeta1 integrins were required for oxidant-treated cells. Taken together, the results suggest that reactive oxygen species (ROS) produced either by HX/XO or t-BHP could affect expression and/or activation of specific integrins in the interaction of EA.hy926 cells with ECM.

the BISTRO Investigators; International audience; ObjectiveTo evaluate the performance of S100-B protein and copeptin, in addition to clinical variables, in predicting outcomes of patients attending the emergency department (ED) following a seizure.MethodsWe prospectively included adult patients presented with an acute seizure, in four EDs in France and the United Kingdom. Participants were followed up for 28 days. The primary endpoint was a composite of seizure recurrence, all-cause mortality, hospitalization or rehospitalisation, or return visit in the ED within seven days.ResultsAmong the 389 participants included in the analysis, 156 (40%) experienced the primary endpoint within seven days and 195 (54%) at 28 days. Mean levels of both S100-B (0.11 μg/l [95% CI 0.07–0.20] vs 0.09 μg/l [0.07–0.14]) and copeptin (23 pmol/l [9–104] vs 17 pmol/l [8–43]) were higher in participants meeting the primary endpoint. However, both biomarkers were poorly predictive of the primary outcome with a respective area under the receiving operator characteristic curve of 0.57 [0.51–0.64] and 0.59 [0.54–0.64]. Multivariable logistic regression analysis identified higher age (odds ratio [OR] 1.3 per decade [1.1–1.5]), provoked seizure (OR 4.93 [2.5–9.8]), complex partial seizure (OR 4.09 [1.8–9.1]) and first seizure (OR 1.83 [1.1–3.0]) as independent predictors of the primary outcome. A second regression analysis including the biomarkers showed no additional predictive benefit (S100-B OR 3.89 [0.80–18.9] copeptin OR 1 [1.00–1.00]).ConclusionThe plasma biomarkers S100-B and copeptin did not improve prediction of poor outcome following seizure. Higher age, a first seizure, a provoked seizure and a partial complex seizure are independently associated with adverse outcomes.

Summary Background Mortality related to complications of cirrhosis is increasing in patients with insulin-resistance factors. Hyperlipidaemic patients have multiple risk factors of insulin resistance. It is impossible to perform liver biopsy in such a large number of hyperlipidaemic patients to identify patients with advanced liver fibrosis or with steatohepatitis (non-alcoholic steatohepatitis, NASH). Aims To use the non-invasive biomarkers, FibroTest (FT), SteatoTest and NashTest, and to assess the prevalence of advanced liver disease in a large population of hyperlipidaemic patients. Methods A consecutive cohort of hyperlipidaemic patients was followed prospectively in a lipid centre and the sera were analysed retrospectively. Results A total of 2834 subjects were included: 1909 hyperlipidaemic patients and 925 blood donors (BD). Advanced fibrosis was identified by FT in 53/1909 (2.8%) hyperlipidaemic patients vs. 0/925 BD (0%) (P

The response of three human leukemia cell lines, the proliferative promonocyte THP-1 and the promyeloid HL60 cells and the non-proliferative phorbol ester-treated HL60 cells (HL60/PMA), to oxidative stress induced by tert-butylhydroperoxide (t-BHP) treatment was analyzed by fluorescence microplate assay, anti-oxidant enzyme activity measurements, high performance liquid chromatography, yopro-1/PI incorporation, poly (ADP-ribose) polymerase and caspase 3 cleavages. After t-BHP treatment, the non-proliferative HL60/PMA cells exhibited a weak increase in reactive oxygen species (ROS) production, a better preservation of thiol content, a decrease of glutathione peroxidase activity and a high ability to undergo necrosis rather than apoptosis. Submitted to the same treatment, the proliferative HL60 and THP-1 cells exhibited a high increase of ROS production, a moderate thiol depletion and a high percentage of apoptosis. Under thiol depleting conditions, the oxidative treatment of the HL60/PMA cells resulted in a high ROS production that reached levels similar to those of the two other cell lines and in cell death mainly by necrosis. In conclusion, these results that show proliferative phenotype is essential for cell response towards oxidative stress, are of particular interest in chemotherapy involving an oxidative mechanism.

A new one-step labeling procedure using the membrane permeant fluorescent probe yopro-1 in association with fluorescence microtitration for the rapid determination of apoptosis is reported. Programmed cell death was induced by the pro-apoptotic agents etoposide and staurosporine, and measured in nonadherent HL60 cells and adherent phorbol 12-myristate 13-acetate (PMA)-treated HL60 cells. Cell viability was controlled by trypan blue exclusion and calcein-AM staining. To confirm results of fluorescence microplate assay, apoptosis was measured by flow cytometry analysis using the same fluorescent probe, and results showed corresponding data between both procedures. Development of apoptosis was confirmed by the presence of PARP (poly(ADP-ribose) polymerase cleavage and nuclear DAPI (4,6-diamidino-2-phenylindole) staining, two well-known methods used to investigate apoptosis. The fluorescence microplate assay was also applied to measure apoptosis in cells exposed to an oxidative stress induced by tert-butylhydroperoxide (t-BHP), and results confirmed the potential of the fluorescence microplate assay in measuring events of apoptosis, especially in adherent, cultured, living cells.

Background. Renal transplantation triggers an early bone loss that increases the subsequent risk of osteoporosis and fractures. Little is known about the long-term outcome of bone status and fracture prevalence several years after transplantation. Therefore, we conducted a cross-sectional evaluation of bone status to find out the frequency and predictors of osteoporotic fractures in late kidney graft patients. Methods. Changes in spinal, hip, and total body bone mineral density were assessed using a DEXA Hologic QRD 1000 scanner, and fractures were quantified in all kidney graft patients presenting for routine evaluation with a minimal follow-up of 5 years after transplantation (with a mean follow-up 8.5±3.1 years). We measured biochemical markers of bone metabolism and collected clinical and dietary intake data. Results. Fifty-nine renal graft recipients were enrolled in the study within 9 months. Osteoporosis, according to the World Health Organization definition, was observed in 31 patients (53% of the total population) and fractures occurred in 26 patients (44% of the total population and 51.6% of patients with osteoporosis). Femoral neck bone mineral density was positively correlated with patient's weight and cyclosporin current dosage. Steroid cumulative dosage correlated only to lumbar spine Z score. Dietary calcium, serum 25 hydroxyvitamin D, parathyroid hormone, and urinary N-telopeptides excretion were normal. Conclusions. These data emphasize the substantial prevalence of osteoporosis and fractures among very long-term kidney graft recipients. Therapeutic intervention in these patients is urgently needed.

Inflammation plays a key role in the physiopathology of atherosclerosis. C-reactive protein (CRP) has been found to predict cardiac events in healthy subjects and in patients with coronary heart disease. However, the relationship between CRP and subclinical atherosclerosis is not well established. We examined the potential relationship between CRP and common carotid artery intima-media thickness and carotid plaques in dyslipidemic subjects. Dyslipidemic patients (n=1051) were recruited for the study. All patients had a complete clinical examination and systematically underwent ultrasonographic evaluation of the extracranial carotid arteries on a duplex system. The serum concentration of CRP was measured by using a sensitive immunoradiometric assay. In a univariate model, a strong positive relationship was found between CRP and the severity of carotid stenosis ( P P =0.0007) in male subjects only. Significant correlations were found between CRP and body mass index ( P

Background: The diagnosis of cardiac complications is particularly challenging in the postoperative course of non-cardiac surgery. Follow-up of patients suggests that silent or symptomatic postoperative myocardial infarction have similar short-term outcomes. Cardiac troponin I (cTnI) has been reported as being a sensitive and specific marker of these complications. Methods: We conducted a prospective study to determine the cut-off values of cTnI which may predict cardiac complications, i: in the postoperative period until discharge, and ii: during a 1-year period after aortic surgery. Three hundred and twenty-nine consecutive patients undergoing infrarenal aortic surgery were included over a 2-year period in a single center. cTnI was measured at recovery and on the 1st, 2nd and 3rd postoperative days. The presence or absence of cardiac complications was classified by reviewers who had no knowledge of cTnI. For evaluation of the ideal discrimination value of cTnI between the complicated and uncomplicated patient groups, we calculated receiver-operator characteristics for the mean values of the peak of cTnI. Results: Thirteen patients (4%) developed 19 postoperative cardiac complications. Thirteen patients (4%) died in the postoperative period. Nine patients (3%) developed 10 cardiac complications during the 1-year follow-up in 316 patients. In 280 patients, cTnI was below 0.5 ng/ml, in 22 patients between 0.5 and 1.5 ng/ml and the 27 remaining patients had a cTnI higher than 1.5 ng/ml. The area under the curve for postoperative cardiac complications was 0.84 (SD=0.21). A limit value of 0.54 ng/ml yielded a sensitivity of 75% and a specificity of 89%. The area under the curve for late cardiac complications was 0.45 (SD=0.13). Conclusion: A cTnI level greater than 0.54 ng/ml appears to be correlated with the occurrence of cardiac complications in the period until discharge, but no value of cTnI is predictive of late cardiac complications occurring in the 1st year after aortic surgery.

Therapeutic response to angiotensin-converting enzyme (ACE) inhibitors was reported to be better related to tissular than to circulating levels of ACE inhibition, especially during chronic therapy. We studied the relations between plasma concentrations of angiotensin I (AI), plasma renin activity (PRA), angiotensin II (AII), and aldosterone (by radioimmunoassay, RIA) and levels of serum and tissue ACE activities during acute and chronic quinapril administration in rats. Forty-eight male Wistar rats received quinapril by gavage for either I day (n = 24) or 15 days (n = 24) at different doses (control, 0.1, 1, and 10 mg/kg/day ; 6 rats at each dose). Plasma hormonal parameters, serum, and tissue (lung, heart, and aorta) ACE activities were measured 3 h after the last gavage. Significant dose-dependent inhibitions of serum and lung ACE during acute and chronic treatments were observed (p < 0.05). Degrees of serum and heart ACE inhibition (at 0.1 mg/kg/day) were significantly lower with chronic than with acute treatment (p < 0.05). Degree of inhibition in lung, which represents the main source of total ACE, was similar during acute and chronic treatments. Among plasma hormonal parameters, plasma AI was correlated to PRA and showed the best correlation with ACE inhibition. After logarithmic transformation, log AI was significantly correlated to ACE activity in lung during chronic treatment (r = -0.85, p < 0.05). This parameter may provide a useful index for ACE inhibitor dosage adjustment during chronic therapy.

Objective: To study the contribution of lactate and procalcitonin (PCT) serum measurements for the diagnosis and the risk-stratification of patients with suspected infection presenting to the ED.Methods: Single-center one year observational study on 462 consecutive patients. Multivariate analysis to assess variables associated with sepsis, severe sepsis, septic shock and severe outcome.Results: Multivariate analysis (Odds ratio [95% CI]), showed that PCT was the best independent variable to identify sepsis (3.98 [2.60–6.10]), while lactate was the best to diagnose severe sepsis (10.88 [6.51–18.19]). Patients with both lactate above 2 mmol·L−1 and PCT above 0.8 ng·mL−1 had an enhanced risk of severe outcome.Conclusions: the dosages of lactate and PCT are complementary for the diagnosis and risk-stratification of patients evaluated in the ED for suspected infection.

In cystic fibrosis (CF) patients, pulmonary inflammation is a major cause of morbidity and mortality. The aim of this study was to further investigate whether oxidative stress could be involved in the early inflammatory process associated with CF pathogenesis. We used a model of CFTR defective epithelial cell line (IB3-1) and its reconstituted CFTR control (S9) cell line cultured in various ionic conditions. This study showed that IB3-1 and S9 cells expressed the NADPH oxidases (NOXs) DUOX1/2 and NOX2 at the same level. Nevertheless, several parameters participating in oxidative stress (increased ROS production and apoptosis, decreased total thiol content) were observed in IB3-1 cells cultured in hypertonic environment as compared to S9 cells and were inhibited by diphenyleneiodonium (DPI), a well-known inhibitor of NOXs; besides, increased production of the proinflammatory cytokines IL-6 and IL-8 by IB3-1 cells was also inhibited by DPI as compared to S9 cells. Furthermore, calcium ionophore (A23187), which upregulates DUOX and NOX2 activities, strongly induced oxidative stress and IL-8 and IL-6 overexpression in IB3-1 cells. All these events were suppressed by DPI, supporting the involvement of NOXs in the oxidative stress, which can upregulate proinflammatory cytokine production by the airway CFTR-deficient cells and trigger early pulmonary inflammation in CF patients.

Les tumeurs de l’ovaire constituent la quatrieme cause de deces par cancer chez la femme en raison d’un diagnostic souvent tardif a un stade avance. Lors de la prise en charge par chimiotherapie, le suivi comprend des dosages reguliers de l’antigene carbohydrate 125 (CA125), glycoproteine membranaire, appartenant a la famille des mucines, secretees par 80 % des tumeurs sereuses ovariennes. Notre objectif est de presenter differentes evolutions de la cinetique du CA125 chez cinq patientes atteintes de carcinomes ovariens de stades avances sous chimiotherapie neoadjuvante. Les dosages sont effectues sur un analyseur Kryptor ® (Thermo-Fisher BRAHMS) et le logiciel « Cinetic System » permet une representation cinetique sur une courbe semi-logarithmique (calcul de la demi-vie, du temps de doublement, detection d’une droite de tendance, indication d’un nadir). Les cinetiques sont suivies pendant un a deux ans. Une tres bonne concordance entre les evolutions cliniques, radiologiques et biologiques est observee. Pour trois patientes, des la prise en charge initiale, l’evolution favorable est associee a une droite de tendance decroissante. Dans un des cas, une courbe bi-exponentielle observee retrospectivement a pu etre reliee a la persistance d’une carcinose peritoneale. Pour deux autres patientes, la normalisation du CA125 n’est jamais obtenue, confirmant l’impossibilite d’operer. Une etude plus importante permettra de confirmer la pertinence clinique de cette approche graphique en association avec les elements cliniques et radiologiques, pour une evaluation plus precoce de la reponse a la chimiotherapie afin de determiner le moment le plus adequat pour realiser une reevaluation chirurgicale.

Background No prognostic markers of myocardial recovery in patients with refractory cardiogenic shock requiring circulatory support are known, but early identification of patients who will not recover might provide an opportunity to change the treatment strategy to improve outcome. Because N-terminal fragment of the B-type natriuretic peptide, troponin Ic, midregional fragment of the proatrial natriuretic peptide, proadrenomedullin, and copeptin are prognostic markers in patients with cardiac failure, we hypothesized that, among patients with refractory cardiogenic shock of potentially reversible cause supported with extracorporeal membrane oxygenation (ECMO), the kinetics of these markers might help identify patients who would recover. Methods This was a prospective, observational, single-center study in a medical-surgical intensive care unit. Among 41 consecutive patients with refractory cardiogenic shock of potentially reversible cause receiving ECMO support, 18 recovered and were successfully weaned off the machine. Blood N-terminal fragment of the B-type natriuretic peptide, troponin Ic, midregional fragment of the proatrial natriuretic peptide, proadrenomedullin, and copeptin concentrations were determined on days 1, 3, and 7 post-ECMO. Results Neither the absolute values of those biomarkers at days 1, 3, or 7 nor their kinetics during the first week differed between patients weaned or not. Areas under the receiver operating characteristic curves (95% confidence interval) of the day 1-to-day 3 biomarker changes for predicting cardiac recovery were 0.54 (0.36-0.71), 0.61 (0.43-0.78), 0.61 (0.42-0.77), 0.56 (0.38-0.73), and 0.61 (0.43-0.78), respectively. Conclusion In patients with refractory cardiogenic shock of potentially reversible cause receiving ECMO support, early measurements of cardiac biomarkers are not useful for identifying those who would recover.

The aim of this work is to establish a pre-analytical approach suitable for the neuron-specific enolase (NSE) measurement. This enzyme which is synthesized by neurons and neuroendocrine cells, is a marker useful for the diagnosis and the monitoring of patients with neuroendocrine tumors (neuroblastoma, small cell lung cancer) and during stroke to assess neuronal damage. This NSE measurement is very sensitive to hemolysis due to the abundance of the enzyme in red blood cells. Two methods of evaluation of hemolysis have been compared: the determination of free haemoglobin (Hb) by spectrophotometry and the indirect measurement of an hemolytic index with a multiparameter analyzer, the Modular (Roche Diagnostics). The correlation between these 2 methods on 42 samples is very satisfactory: Y (free Hb) = 12.337 X (index) + 31.743 r = 0.997. The NSE assay is based on TRACE (Time Resolved Amplified Cryptate Emission) technology, on a Kryptor (BRAHMS). The influence of hemolysis on the determination of NSE was confirmed by overloading with hemoglobin (hemolysate) 3 pools of serum with NSE concentrations close to the threeshold decision. The determination of NSE shows an increase in concentration parallely to the hemolytic index (about 150% for an hemolytic index of 10). Consequently, in our laboratory the NSE determination is realized only for samples presenting an hemolytic indexor = 10, this allowing a good monitoring of kinetics of this marker.

Resume La chirurgie de l'aorte thoracique, thoraco-abdominale ou de la crosse de l'aorte realisee en hypothermie profonde avec arret circulatoire (HPAC) est grevee d'une lourde morbimortalite, notamment d'origine cardiaque. Le but de cette etude prospective est de determiner les valeurs seuil de la troponine I cardiaque (Tnlc) pour le diagnostic des complications cardiaques chez des patients beneficiant de ce type de chirurgie. L'etude a porte sur 52 patients repartis en deux groupes : chirurgie de la crosse operee par sternotomie (groupe I) et chirurgie de l'aorte thoracique descendante par thoracotomie (groupe II). Seize patients ont presente des complications cardiaques dont neuf furent mortelles. Chez les patients sans complication cardiaque le pic de Tnlc est observe a J1. Les valeurs seuil de Tnlc sont de 12,2 μg L−1 dans le groupe « sternotomie , et plus elevees chez les patients operes par « thoracotomie(20,5 μg L−1). Les resultats suggerent que l'absence de cardioplegie, techniquement difficile a realiser lors d'une thoracotomie, est probablement responsable de l'augmentation considerable de la valeur seuil de la Tnlc dans le groupe II.

Procalcitonin has been advocated as a specific biomarker for bacterial infection. We performed this study to determine whether accuracy of procalcitonin for diagnosis of postoperative bacterial infection is affected by renal function after aortic surgery.Single-center prospective study.University hospital.Two hundred seventy-six patients scheduled for elective major aortic surgery.Blood samples were taken before surgery and each day over the 5-day postoperative period, and measurement of serum procalcitonin was performed. Diagnosis of infection was performed by a blinded expert panel. Renal function was assessed using an estimate of creatinine clearance with the Cockcroft formulas. Renal dysfunction was defined as a creatinine clearance50 mL x min(-1).Infection was diagnosed in 67 patients. Seventy five patients (27%) had postoperative renal dysfunction. Procalcitonin was significantly higher in infected patients, with a peak reached at the fourth postoperative day, but it was significantly higher in patients with impaired renal function in both control and infected patients. The optimal threshold of procalcitonin markedly differed in patients with renal dysfunction compared with patients without renal dysfunction (2.57 vs. 0.80 ng x mL(-1), p.05). The diagnostic accuracy of procalcitonin significantly increased (0.74 vs. 0.70, p.05) when the threshold of procalcitonin was adapted to the renal function. The elevation of procalcitonin occurred 2 days before the medical team was able to diagnose infection.Procalcitonin is a valuable marker of bacterial infections after major aortic surgery, but renal function is a major determinant of procalcitonin levels and thus different thresholds should be applied according to renal function impairment.

Introduction To date, a specific marker to evaluate and predict the clinical course or complication of the liver-transplanted patient is not available in clinical practice. Increased procalcitonin (PCT) levels have been found in infectious inflammation; poor organ perfusion and high PCT levels in the cardiac donor appeared to predict early graft failure. We evaluated PCT as a predictor of early graft dysfunction and postoperative complications. Methods PCT serum concentrations were measured in samples collected before organ retrieval from 67 consecutive brain-dead donors and in corresponding recipients from day 0, before liver transplantation, up to day 7 after liver transplantation. The following parameters were recorded in donors: amount of vasopressive drug doses, cardiac arrest history 24 hours before retrieval, number of days in the intensive care unit, age of donor, and infection in donor, and the following parameters were recorded in recipients: cold and warm ischemia time, veno-venous bypass, transfusion amount during orthotopic liver transplantation (OLT), and occurrence of postoperative complication or hepatic dysfunction. Results In the donor, the preoperative level of PCT was associated with cardiac arrest and high doses of catecholamines before organ retrieval. In the recipient, elevated PCT levels were observed early after OLT, with a peak at day 1 or 2 after OLT, then a decrease until day 7. A postoperative peak of PCT levels was associated neither with preoperative PCT levels in the donor or the recipients nor with hepatic post-OLT dysfunction or other postoperative complications, but with two donor parameters: infection and cardiac arrest. Conclusion PCT level in the donor and early PCT peak in the recipient are not predictive of post-OLT hepatic dysfunction or other complications. Cardiac arrest and infection in the donor, but not PCT level in the donor, are associated with high post-OLT PCT levels in the recipient.

Background & Aims: Patients with diabetes are at risk for nonalcoholic fatty liver disease leading to advanced fibrosis, cirrhosis, and liver cancer. We examined the efficacy of a screening strategy with a noninvasive fibrosis biomarker (FibroTest) in patients with diabetes. Methods: We prospectively studied 1131 consecutive patients without a history of liver disease seen for diabetes. The biomarker data were obtained, and patients with presumed advanced fibrosis were reinvestigated by a hepatologist using elastography and, if necessary, ultrasonography, endoscopy, or liver biopsy. Results: The biomarker predicted advanced fibrosis in 63 of 1131 (5.6%) patients. A total of 45 patients was reinvestigated, and advanced fibrosis was confirmed in 32 patients, a 2.8% (32/1131) prevalence of confirmed advanced fibrosis, 5 cases of cirrhosis, and 4 cases of hepatocellular carcinoma. In the population with type 2 diabetes who were 45 years or older, the prevalence of confirmed advanced fibrosis was 4.3% (30/696), and hepatocellular carcinoma was 5.7 of 1000 (4/696). Conclusions: The fibrosis biomarker might be used for the detection of advanced fibrosis in patients with type 2 diabetes.

Background: Cardiopulmonary bypass (CPB) has long been recognised as a main cause of a postoperative complex systemic inflammatory response after coronary artery bypass grafting (CABG). Methods: We determined the kinetics of peripheral blood release of the novel inflammatory biomarkers secretory phospholipase A 2 (sPLA 2 ), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) during the first 6 days following surgery in 16 patients undergoing CABG with (on-pump, n =9) or without (off-pump, n =7) CPB. Kinetic curves for these markers were compared to those of the well-known inflammatory parameters C-reactive protein (CRP) and fibrinogen. Results: sPLA 2 activity exhibited a maximum value on day 2, then decreased until day 6 for both groups and in a similar manner as CRP levels. On the other hand, elevation of plasma levels of both MMP-9 and TIMP-1 occurred as early as on day 1 and remained at this level until day 6. No significant difference in kinetic characteristics (peak value, area under the curve, initial slope) between CABG with and without CPB was observed. Conclusions: These data show that the off- and on-pump groups did not show significantly different kinetics for the releases of all biomarkers studied, including sPLA 2 and biomarkers of the MMP-TIMP network. The off-pump procedure may therefore lead to global surgical trauma as important as CPB in terms of the systemic inflammatory process and matrix proteolysis pathway activation.

We studied the kinetic release of cardiac troponins (cTnI and cTnT) and B-type natriuretic peptides (BNP and NT-proBNP) in patients undergoing off-pump or on-pump coronary artery bypass surgery.Twenty-five consecutive patients were prospectively enrolled. The patients were divided into three groups: beating heart (I), and cardiopulmonary bypass (CPB) with warm (II) or cold cardioplegia (III). Plasma samples were obtained before anesthesia induction until the sixth day after surgery.The data were analyzed first for off-pump versus the CPB procedures and second for warm versus cold cardioplegia. The plasma troponin releases appeared to be significantly higher in the CPB groups in comparison to the beating heart group (P0.001 and P0.002 for cTnI and cTnT peak values, respectively). The peak of the B-type natriuretic peptide release appeared to be more delayed in the groups undergoing CPB than in the beating heart group (day 6 versus days 2 and 4 for NT-proBNP and BNP, respectively). Taken together, our results indicated that the new generation of cTnT assays seemed to be more sensitive than the cTnI assays for the diagnosis of myocardium injury. A lower increase in the cTnT values in the warm cardioplegic group indicated less damage of the myocardium than with cold cardioplegia. Our data also confirm better preservation of the myocardium with off-pump cardiac surgery than with CPB.

We investigated the value of procalcitonin kinetics as a prognostic marker during ventilator-associated pneumonia (VAP). This prospective, observational study was conducted in a medical intensive care unit in a university hospital. All consecutive patients with microbiologically proven VAP who survived 3 days after its diagnosis were included and grouped according to clinical outcome: favorable or unfavorable, defined as death, VAP recurrence, or extrapulmonary infection requiring antibiotics before Day 28. Serum procalcitonin levels were measured on Days 1, 3, and 7 for all patients. Among the 63 patients included, 38 had unfavorable outcomes. On Day 1, they were more critically ill than patients with a favorable outcome. Serum procalcitonin levels decreased during the clinical course of VAP but were significantly higher from Day 1 to Day 7 in patients with unfavorable outcomes. Multivariate analyses retained serum procalcitonin levels on Days 1, 3, and 7 as strong predictors of unfavorable outcome. Based on these data, procalcitonin could be a prognostic marker of outcome during VAP.

Objective— The proteolytic activity of metalloproteinases, proinflammatory enzymes that degrade extracellular matrix, is elevated in lipid-rich atherosclerotic plaques, thereby contributing to plaque fragility and rupture. Pregnancy-associated plasma protein (PAPP-A) is a metalloproteinase, expressed in unstable atherosclerotic plaques, whose circulating levels are elevated in acute coronary syndromes. We evaluated serum PAPP-A levels as a marker of the premature development of atherosclerosis in hyperlipidemic subjects at elevated cardiovascular risk. Methods and Results— Serum PAPP-A levels were determined in asymptomatic hyperlipidemic male subjects (n=64; mean±SD age, 51±7 years) in whom intima-media thickness (IMT) and lesion status in the carotid artery were evaluated by noninvasive ultrasonography and compared with those of a normolipidemic control group (n=25). No difference was observed in circulating PAPP-A levels between hyperlipidemic subjects and controls (8.99±2.93 and 8.03±2.75 mIU/L, respectively; mean±SD) nor between hyperlipidemic subjects who presented with a luminal obstruction of the carotid artery (9.26±2.53 mIU/L) and those who did not (8.85±3.29 mIU/L). By contrast, in patients with atheromatous carotid plaques, a positive association between serum levels of PAPP-A and C-reactive protein was observed ( P P P Conclusions— Elevated serum PAPP-A levels represent a potential marker of the degree of echogenicity of carotid atherosclerotic plaques in asymptomatic hyperlipidemic patients at high cardiovascular risk and equally of an enhanced local inflammatory state involving remodeling of subendothelial extracellular matrix.

Objective: To evaluate serum Monocyte Chemoattractant Protein-1 (MCP-1) as a biologic marker of cardiac allograft vasculopathy (CAV) in heart transplant recipients (HTR). Design and methods: Serum levels of MCP-1 were measured in 49 HTR with and without CAV. Results: HTR exhibited significantly higher serum MCP-1 levels than controls. However, no difference was observed according to the existence of CAV. Conclusion: Serum MCP-1 levels do not constitute a marker of the CAV occurring after heart transplantation.