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International audience; Vitamin A (retinol) and its active derivatives (retinoic acids) are essential for growth and development of the mammalian fetus. Maternally derived retinol must pass the placenta to reach the developing fetus. Despite its apparent importance, little is known concerning placental transfer and metabolism of retinol, and particularly of placental production and storage of retinyl esters. To elucidate this metabolic pathway, we incubated, in the presence of retinol, 1) human full-term placental explants and 2) primary cultures of major cells types contributing to placental function: trophoblasts and villous mesenchymal fibroblasts. We used HPLC to determine the types and concentrations of retinyl esters produced by these explants and cells. About 14% of total cellular retinol in placental explants was esterified. The most abundant esters were myristate and palmitate. Primary cell cultures showed that fibroblasts efficiently produced retinyl esters, but trophoblasts did not. In both types of experiments, no retinyl esters were detected in the culture medium, suggesting that retinyl esters were produced for storage purpose. These results suggest that villous mesenchymal fibroblasts are primary sites of retinol esterification and storage in the placenta. (Pediatr Res 48: 565-572, 2000)

Several retinoid binding proteins and nuclear receptors are specifically expressed in murine placenta. However, little is known about molecular events and target genes regulated by retinoids during placentation. Here, we report that several retinoic acid-inducible (Stra) genes, originally isolated by a differential screening procedure, exhibit specific expression patterns in mouse placental tissues. Three Stra genes, including the ephrinB1 receptor tyrosine kinase ligand, are prominently expressed in the regions of exchanges between maternal and embryonic circulations, i.e. the yolk sac and/or the labyrinthine zone of the mature placenta. The Meis2 homeobox gene appears to be specifically expressed in maternally-derived cell populations. Three other Stra genes, including the AP-2-related gene AP-2gamma, are differentially expressed in the trophoblastic cell lineage. Thus, retinoids may regulate various signaling pathways in specific placental cell-types.

International audience; Background: Environmental tobacco smoke (ETS) is a recognised air pollutant. Its harmful effects have been found to be implicated in health disorders, including unfavourable pregnancy outcomes. The discrepancy between self-reported emvironmental tobacco smoke exposure and cotinine levels in pregnant non-smokers in France was examined.Method: Plasma cotinine was determined by a CPG-SM method on women who had answered a self-questionnaire describing their habits and environment during pregnancy.Results: Of 698 pregnant women reported as non-smokers, 305 (43.7%) claimed not to be exposed to ETS, yet 196 of these (64.3%) had plasma cotinine levels above the limit of detection.Conclusion: Self-reported data on ETS exposure in pregnant women therefore underestimate actual exposure. However, cotinine assay cab rectify this misclassification. An accurate identification of this risk factore will help to change attitudes towards ETS and avert its adverse effects on mother and fetus.

We describe the molecular cloning of murine (m) Transcriptional Enhancer Factor (TEF)-5 belonging to the TEF family of transcription factors. We show that mTEF-5 is specifically expressed in trophoblast giant cells and other extra-embryonic structures at early stages of development. At later stages, mTEF-5 is specifically expressed in the labyrinthine region of the placenta and in several embryonic tissues. We further show that the other mTEFs are differentially expressed in extraembryonic structures and in the mature placenta. Interestingly, human (h)TEF-5 is specifically expressed in the differentiated syncytiotrophoblast of the human term placenta and its expression is upregulated during the differentiation of cytotrophoblasts to syncytiotrophoblast in vitro, whereas that of hTEF-1 is down-regulated. Together with previous results describing hTEF-binding sites in the human placental lactogen-B gene enhancer, these novel observations support a role for hTEF-5 in the regulation of this gene. We further propose that the hTEF factors may play a more general role in placental gene regulation and development.

The expression patterns of the three mouse retinoic acid (RA) receptor gene isotypes (RARalpha, RARbeta, and RARgamma) and retinoid X receptor gene isotypes (RXRalpha, RXRbeta, and RXRgamma) have been investigated by in situ hybridization analysis of their RNA transcripts in the inner ear of mouse fetuses at 18.5 days of gestation. Two RARs (RARalpha and RARgamma) and two RXRs (RXRalpha and RXRbeta) presented an almost ubiquitous transcript distribution with overlapping expression in several regions of the cochlea, such as Kölliker's organ, the organ of Corti, the spiral limbus, and nervous structures. The organ of Corti showed an enhanced in situ labeling with RARalpha and RXRbeta. By contrast, RARbeta and RXRgamma displayed more restricted expression patterns. RXRgamma in particular was strongly expressed in Kölliker's organ and in the spiral ganglion. This expression pattern suggests that RA may be involved in the differentiation of several cochlear cell types. Moreover, the colocalization of several RAR and RXR gene transcripts suggests possible heterodimerization between these receptors in several regions of the cochlea.

We report the distribution of transcripts from genes encoding the retinol bind- ing protein (RBP), the cellular retinol binding proteins (CRBP I, II) and retinoic acid binding proteins(CRABPI,II),theretinaldehydedehydro- genase type 2 (RALDH-2), the retinoic acid recep- tors (RARs), and the retinoid X receptors (RXRs) in mouse placental tissues from 6.5 to 19.5 days postcoitum (dpc). During early placentation, RBP and RALDH-2 gene expression are restricted to the endoderm of the visceral yolk sac and the outer uterine epithelium, respectively, whereas CRBP I transcripts are detected in the visceral yolk sac and in the presumptive chorioallantoic placenta. By 15.5 dpc, CRBP I expression is down- regulated in the yolk sac where CRBP II becomes strongly expressed. Expression of CRBP II is also detected in the trophoblastic giant cells. Through- out placentation, the expression patterns of the CRABP I and II genes partly overlap in the decidual tissue and the vacuolar zones of the decidua, suggesting a role for these binding pro- teins in sequestering free retinoic acid from ma- ternal blood, thus regulating its availability to the embryo. RARa is ubiquitously expressed in all placental tissues, except in trophoblastic giant cells, at all stages studied. During early placenta- tion, RARb and RARg are co-expressed in the de- cidua but differentially expressed in the chorionic region (RARb, 10.5 to 12.5 dpc) and the presumptive labyrinth (RARg, 7.5 to 12.5 dpc). During the same stages, RXRa is strongly expressed in the presump- tive placenta. RARg remains weakly expressed in the labyrinth until 15.5 dpc, whereas RXRaexhib- its a strong expression in this zone until birth, suggesting a role for these receptors in the devel- opment and function of the definitive placenta. Dev. Dyn. 208:199-210, 1997. r 1997 Wiley-Liss, Inc.

Journal de Gynecologie Obstetrique et Biologie de la Reproduction - Vol. 33 - N° 4 - p. 367-368

Background The recommended dietary allowance (RDA) for protein intake has been set at 1.0-1.3 g/kg/day for senior. To date, no consensus exists on the lower threshold intake (LTI = RDA/1.3) for the protein intake (PI) needed in senior patients ongoing both combined caloric restriction and physical activity treatment for metabolic syndrome. Considering that age, caloric restriction and exercise are three increasing factors of protein need, this study was dedicated to determine the minimal PI in this situation, through the determination of albuminemia that is the blood marker of protein homeostasis. Methods Twenty eight subjects (19 M, 9 F, 61.8 ± 6.5 years, BMI 33.4 ± 4.1 kg/m2) with metabolic syndrome completed a three-week residential programme (Day 0 to Day 21) controlled for nutrition (energy balance of −500 kcal/day) and physical activity (3.5 hours/day). Patients were randomly assigned in two groups: Normal-PI (NPI: 1.0 g/kg/day) and High-PI (HPI: 1.2 g/kg/day). Then, patients returned home and were followed for six months. Albuminemia was measured at D0, D21, D90 and D180. Results At baseline, PI was spontaneously 1.0 g/kg/day for both groups. Albuminemia was 40.6 g/l for NPI and 40.8 g/l for HPI. A marginal protein under-nutrition appeared in NPI with a decreased albuminemia at D90 below 35 g/l (34.3 versus 41.5 g/l for HPI, p Conclusion During the treatment based on restricted diet and exercise in senior people with metabolic syndrome, the lower threshold intake for protein must be set at 1.2 g/kg/day to maintain blood protein homeostasis.

Background An aging population and better management of various heart diseases explain the exponential growth in incidence and prevalence of chronic heart failure, with poor prognosis and heavy health costs. Medical management is codified in international guidelines. The management of heart failure in over-80 year-old patients follows these guidelines, but no clinical trials have been able to confirm benefit. Moreover, registries show down-prescription of heart failure treatments in the elderly and over-80s. Methods/Design We present the design of the HF-80 ("Is there benefit in optimising heart failure treatment in over-80 year-old patients?") study, which is a prospective randomised open-label clinical trial with blinded end-points, designed to evaluate the effect of optimising management by adhering to guidelines in over-80 year-old heart failure patients. Patients over 80 years of age admitted with acute heart failure will be included. The primary endpoint is to assess quality of life at 6 months on the Minnesota questionnaire. The secondary endpoints are to assess the effect of optimised management on quality of life, mortality, readmission for acute heart failure, cardiac fibrosis and economic data at 12 months. 80 patients will be included, divided into 2 groups: group A, with usual heart failure management by general practitioners; and group B, with optimised management based on international guidelines. Discussion It is necessary to assess the benefit of guidelines in over-80 year-old heart failure patients because of the fragility of this population and the elevated risk of iatrogenic complications. Trial Registration Clinical trials.gov number: NCT01437371.

Serum creatinine is a late marker of acute kidney injury (AKI). Plasma neutrophil gelatinase (pNGAL) is an early biomarker of AKI after cardiac surgery. The purpose of this study was to assess the ability of pNGAL to predict AKI in ICU patients.

OnLine Journal Article Number : R116 The electronic version of this article is the complete one and can be found online at: http://ccforum.com/content/12/5/R116; International audience; INTRODUCTION: Controlled mechanical ventilation (CMV) induces profound modifications of diaphragm protein metabolism, including muscle atrophy and severe ventilator-induced diaphragmatic dysfunction. Diaphragmatic modifications could be decreased by spontaneous breathing. We hypothesized that mechanical ventilation in pressure support ventilation (PSV), which preserves diaphragm muscle activity, would limit diaphragmatic protein catabolism. METHODS: Forty-two adult Sprague-Dawley rats were included in this prospective randomized animal study. After intraperitoneal anesthesia, animals were randomly assigned to the control group or to receive 6 or 18 hours of CMV or PSV. After sacrifice and incubation with 14C-phenylalanine, in vitro proteolysis and protein synthesis were measured on the costal region of the diaphragm. We also measured myofibrillar protein carbonyl levels and the activity of 20S proteasome and tripeptidylpeptidase II. RESULTS: Compared with control animals, diaphragmatic protein catabolism was significantly increased after 18 hours of CMV (33%, P = 0.0001) but not after 6 hours. CMV also decreased protein synthesis by 50% (P = 0.0012) after 6 hours and by 65% (P < 0.0001) after 18 hours of mechanical ventilation. Both 20S proteasome activity levels were increased by CMV. Compared with CMV, 6 and 18 hours of PSV showed no significant increase in proteolysis. PSV did not significantly increase protein synthesis versus controls. Both CMV and PSV increased protein carbonyl levels after 18 hours of mechanical ventilation from +63% (P < 0.001) and +82% (P < 0.0005), respectively. CONCLUSIONS: PSV is efficient at reducing mechanical ventilation-induced proteolysis and inhibition of protein synthesis without modifications in the level of oxidative injury compared with continuous mechanical ventilation. PSV could be an interesting alternative to limit ventilator-induced diaphragmatic dysfunction.

Specimens of living S. mansoni worms and Biomphalaria alexandrina snails were grounded separately into sterile mortar after adding 5ml. of sterile saline. After centrifugation sterile supernatant were tested for 1. HCV Antigen by ElISA 2. Detection of HCV-RNA by RT-PCR 3. HCV-RNA quantitation Results: 1. HCV-Antigen: Worms, Miracidia, Snails and Cercariae of S. mansoni were Positive for HCV-Ag. The Snails gave strong positive result. Eggs gave negative result. 2. HCV-RNA by RT-PCR: Worms, Miracidia, Snails and Cercariae of S. mansoni tested for HCV-RNA By Qualitative RT-PCR were Positive. The eggs gave negative result. 3. HCV-RNA Quantitation: Miracidia were positive (800 Copies/ml) and Snails were positive (1100 Copies/ml) while other specimens gave negative results. Conclusions: 1. Existence of virus and its replication in parasite 2. S. mansoni parasite carries HCV and considered as a non-human vector for transmission of HCV infection 3. Parasitic and viral co-infection will change already known pathology of hepatic schistosomiasis from periportal fibrosis to cirrhosis with its expected outcome of hepatic decompansation as well as the development of HCC.

To examine the expression of transcription factor Kruppel-like factor-6 (KLF6) in the cornea and lens of mouse eyes throughout developmental stages.C57BL/6 mice were set up for timed mating. Embryos on embryonic day (E)10.5, E12.5, E15.5, and E18.5 and eyes from mice on postnatal day (P)0, P7, P11, P15, P30, and P60 were collected for immunofluorescence staining. Transcript of KLF6 was detected by in situ hybridization with digoxigenin-labeled RNA probes. Relative quantitative reverse transcription (RT)-PCR was performed to measure the KLF6 transcript level in eyes enucleated at embryonic stages, and the corneas and lenses isolated at postnatal stages.Staining for the KLF6 protein was observed at E10.5 in the lens pit and at E12.5 in the ectoderm, the mesenchyme, and the lens epithelium. Nuclear staining for KLF6 protein was evident at E15.5 in the corneal epithelium and the stroma. The staining was abundant between E18.5 and P60. In the lens epithelium, nuclear staining was detected at P0, P7, and P11. The staining intensity declined subsequently. The KLF6 transcript was found in the lens pit at E10.5 and in the ectoderm and mesenchyme at E12.5. The KLF6 mRNA level in corneal layers remained relatively constant until P60. In the lens epithelium, it was high during embryonic stages but decreased with development.KLF6 is expressed in both the cornea and the lens in mouse eyes. Its expression in the lens is temporally regulated, suggesting that it has a central role in lens development.

L’evaluation du pronostic des victimes de traumatismes crâniens graves (TCG) est difficile dans la prise en charge de ces patients. Devant la faible sensibilite du score de Glasgow, la proteine S100B semble etre un bon marqueur pronostique. Cependant peu d’etudes sont basees sur des prelevements centraux en jugulaire. L’objectif de notre etude est de comparer l’interet de cinetiques arterielles et jugulaires des concentrations seriques de S100B chez le patient victime d’un TCG. Pour cela, nous avons mene une etude prospective au sein du CHU de Clermont-Ferrand, sur 17 patients orientes en service de reanimation suite a un TCG, dans le but d’evaluer l’interet d’une cinetique de dosages seriques de la proteine S100B en arteriel et en jugulaire au decours de leur prise en charge. Le dosage de la proteine S100B a demontre une concentration mediane de 0,16 μg/L en arteriel et de 0,25 μg/L en jugulaire. Pour l’ensemble des prelevements des 17 patients, la mediane de concentration arterielle en S100B est significativement differente de la mediane de concentration jugulaire. Cette difference significative arterio-jugulaire n’est pas retrouvee dans le sous-groupe des TCG de mauvaise evolution ni dans le sous-groupe des prelevements realises avant les 24 premieres heures post traumatisme. Dans le sous-groupe des TCG de mauvais pronostic, il n’existe pas, contrairement a ce que l’on observe en arteriel, de diminution significative du taux jugulaire de S100B apres les 24 premieres heures post traumatisme. En regard de ces resultats, les dosages en jugulaire semblent donc presenter un meilleur interet pronostique qu’en arteriel.

Vitamin A (retinol) and its active derivatives (the retinoids) are essential for growth and development of the mammalian fetus. Maternally-derived retinol has to pass through the placenta to reach the developing fetus. Despite its apparent importance, little is known about placental metabolism of retinol, and particularly placental production and/or secretion of active retinoids. It has been previously considered that retinoids are recruited from the uterine environment to influence placental development and function during gestation. We have studied retinoid metabolism in the human choriocarcinoma cell line JEG-3 and demonstrate, for the first time, that active retinoids are produced endogenously by the JEG-3 cell line from retinol. These retinoids induce gene expression from a retinoic acid-responsive enhancer element reporter plasmid and modulate placental transglutaminase activity. Furthermore, retinoids are secreted from JEG-3, as shown by the activation of retinoic acid-responsive beta lacZ reporter cells grown in conditioned media. These results suggest that there could be an active role for trophoblast-derived retinoids during human development.

Background: Vitamin A (retinol), which is required for normal fetal development and successful gestation, circulates in the blood bound to a specific protein, the retinol binding protein (RBP). Little is known about the transport and metabolism of this complex protein or about retinol status during normal human pregnancy. Objective: The aim of this study was to assess retinol status and transport modalities of retinol in well-nourished women with normal pregnancies, a population poorly investigated compared with pathologic and malnourished pregnant women. Design: The maternal blood and cord blood concentrations of retinol, vitamin E, β-carotene, RBP, and transthyretin of pregnant French women at term (n = 27) were measured and compared with values from a nonpregnant control group in = 27). In addition, holo-RBP (retinol bound), apo-RBP (retinol free), and total protein were assessed in both groups to enable the hemodilution occurring during pregnancy to be taken into consideration and to evaluate the extent of saturation of RBP with retinol. Results: Healthy pregnant women at term had normal serum circulatory amounts of retinol, vitamin E, binding proteins, and β-carotene. However, they had less binding of retinol to RBP (holo-RBP: 49.9% in pregnant women, 54.0% in cord blood, and 77.5% in the control group). Conclusion: The results of this study suggest that retinol homeostasis and transport are modified during normal human pregnancy.

Le traumatisme crânien est une pathologie extrêmement fréquente notamment dans le milieu du sport et d’autant plus dans les sports de contact tels que le rugby, où le terme « commotion cérébrale » désigne généralement le traumatisme crânien léger.Les moyens de dépistage et de suivi actuel reposent principalement sur une évaluation clinique ne permettant pas toujours de dépister correctement les commotions et exposant les joueurs à une reprise prématurée du jeu avec un risque pour leur santé désormais bien décrit.Les biomarqueurs de souffrance cérébrale, tels que la protéine S100B, utilisée en routine aux service d’accueil des Urgence de Clermont-Ferrand pour discriminer un traumatisme crânien léger nécessitant ou non un scanner cérébral, ou encore le tandem GFAP/UCH-L1, validé par la FDA pour la même indication, pourraient à l’avenir permettre un meilleur dépistage et suivi des commotions cérébrales.Pour cela il est préalablement nécessaire d’établir les taux de base de chaque joueur afin d’en étudier ensuite la cinétique au cours de la saison dans cette population particulièrement exposée.Dans ce travail, nous avons donc comparé les taux sériques et plasmatiques de bases des protéines S100B, GFAP et UCH-L1 chez 43 joueurs de rugby professionnels de l’équipe ASM-CA, prélevés au début de la saison, à distance de tout effort et de tout contact (minimum 48h).Un lien de corrélation déjà connu dans la littérature a été retrouvé entre le phototype et les taux basaux de S100B (p=0.012). L’ensemble des dosages de GFAP/UCH-L1 ont donné des résultats inférieurs au seuil de mesure, semblant indiquer que ces biomarqueurs ne sont impactés ni par l’âge, le sexe, la taille, le poids, le poste de jeu ou le phototype.

Preterm premature rupture of membranes is a pregnancy complication responsible for 30% of all preterm births. This pathology seems more and more to be the consequence of an early process runaway activation usually implicated in the physiologic rupture at term called sterile inflammation. This phenomenon is dependent on some specific molecules called “alarmins” or “Damage-Associated Molecular Patterns” (DAMPs) recognized by Pattern Recognition Receptors (PRRs) leading to a microbial-free inflammatory response. However, it remains unclear how exactly this activation works, and which receptor translates this sterile inflammatory signaling in fetal membranes (FM) to manage a successful physiological rupture not before 37 weeks. In this context, we focused our work on one actor of the sterile inflammation (member of PRR family), the Receptor for Advanced End-Glycation products (RAGE). Following the realization of the RAGE axis members’ ontogenesis into FM, our first objective was to to evaluate the implication of RAGE axis in the arising of fetal membranes inflammation in a physiological context. Here, we revealed differential expression profile of RAGE axis actors in the different zones of the FM, especially an overexpression of RAGE inside the rupture zone. This work demonstrated also that alarmins HMGB1 and AGEs led to an inflammatory response in FM involving RAGE pathway.Then, we focused on the RAGE activation in a pathological context: the maternal tobacco smoking, a well- described risk factor of the pPROM. Our results have demonstrated the RAGE implications in the pro- inflammatory response in amniotic epithelial cells exposed to a Cigarette Smoke Condensate.All this work strongly supports the role of RAGE in FM physiopathological weakening. These data could help to the future development of news strategies of diagnosis and therapeutics to fight against pPROM., La rupture prématurée des membranes fœtales (RPM) représente une complication obstétricale responsable d’un tiers des naissances prématurées. Cette pathologie semble de plus en plus découler de l’emballement précoce d’un processus impliqué dans la rupture physiologique à terme, l’inflammation stérile. Ce phénomène est basé sur la reconnaissance de molécules spécifiques, les alarmines (ou DAMPs), par une famille de récepteurs dénommés PRR pour « Pattern Recognition Receptors ». Cette interaction conduit à une réponse inflammatoire stérile participant à la fragilisation physiopathologique des MF. Cependant, il n’a toujours pas été décrit comment fonctionne exactement cette activation de l’inflammation au sein des MF, quel(s) PRR(s) est(sont) à l’origine de la transduction de ce signal, à moduler de façon à ce que la rupture physiologique n’ait pas lieu avant 37 semaines. Au cours de ma thèse, nous nous sommes focalisés sur un récepteur de la famille des PRR : RAGE (Receptor of Advanced Glycation Endproducts ; récepteur aux produits avancés de glycation).Après avoir étudié l’ontogénèse de l’axe RAGE au sein des MF, notre premier objectif a été d’étudier l’activation de RAGE dans un contexte physiologique en exposant des explants d’amnios et de chorion à deux alarmines phares : HMGB1 et les AGEs. Nous avons alors mis en évidence un profil d’expression différentiel des acteurs de l’axe RAGE au sein des différentes zones des MF, notamment une surexpression de RAGE au sein de la zone de rupture. Par ailleurs, ce travail a révélé une réponse pro- inflammatoire en réponse à HMGB1 ou aux AGEs, au sein des deux feuillets des MF, qui est dépendante de RAGE. Par ailleurs, cette thèse s’est intéressée à l’activation de RAGE dans un contexte plus pathologique : le tabagisme maternel, facteur de risque très connu de la RPM. Nous avons pu démontrer in vitro l’implication de RAGE dans la réponse pro-inflammatoire induite par un condensé de fumée de cigarette au sein des cellules épithéliales de l’amnios.Globalement, l’ensemble de ce travail soutient fortement le rôle de RAGE dans la fragilisation physiopathologique des MF. Ces données pourront potentiellement aider au développement futur de nouveaux outils de diagnostic et de thérapeutique pour lutter contre la RPM.

International audience; Pour citer cet article : Atteintes myocardiques au cours de la maladie à coronavirus 19 (Covid-19) : principaux mécanismes physiopathologiques et utilité clinique des biomarqueurs cardiaques.

International audience; Covid-19 is responsible for myocardial injury in many infected patients, which is associated with severe disease and critical illness. The mechanisms by which SARS-CoV-2 may cause myocardial damage involve direct effect of the virus in cardiac cells and indirect effect due to the clinical consequences of Covid-19. Cardiomyocytes are well known to express Angiotensin-Converting Enzyme-2 receptors (ACE-2) to facilitate the virus cell entry, which could explain the occurrence of myocarditis, functional alterations in the myocardium, and more rarely, myocardial infarction. Myocardial injury may also be secondary to systemic inflammation or coagulopathy due to complicated Covid-19. The existence of a cardio-intestinal axis with alteration of tryptophan metabolism in the small bowel leading first to colitis and then to systemic inflammation has also been evoked to explain the myocardial injury. Morphological and metabolic disturbances of the heart during the Covid-19 are associated with elevated concentrations of cardiac blood biomarkers, mainly troponins and natriuretic peptides. The determination of these biomarkers has proven to be very useful for diagnosis, prognosis, and risk stratification. Indeed, recent data demonstrated that about 20% of infected patients admitted to the hospital have elevated troponin or BNP levels, and Covid-19 patients with elevated troponin concentrations beyond the diagnostic threshold (99th percentile) were associated with a higher risk of in-hospital mortality. In conclusion, after more than a year of a unique global pandemic, it is now clearly established that myocardial injury during Covid-19 is frequent and strongly contributes to the severity of the disease. Cardiac alterations secondary to direct infection of cardiac cells by SARS-CoV-2 or to the clinical consequences of Covid-19 are associated with elevated levels of cardiac biomarkers in blood, whose measurement is crucial in clinical decision making.