Type I hyperprolinemia: genotype/phenotype correlations.

Type I hyperprolinemia (HPI) is an autosomal recessive disorder associated with cognitive and psychiatric troubles, caused by alterations of the Proline Dehydrogenase gene (PRODH) at 22q11. HPI results from PRODH deletion and/or missense mutations reducing proline oxidase (POX) activity. The goals of this study were first to measure in controls the frequency of PRODH variations described in HPI patients, second to assess the functional effect of PRODH mutations on POX activity, and finally to establish genotype/enzymatic activity correlations in a new series of HPI patients. Eight of 14 variants occurred at polymorphic frequency in 114 controls. POX activity was determined for six novel mutations and two haplotypes. The c.1331G>A, p.G444D allele has a drastic effect, whereas the c.23C>T, p.P8L allele and the c.[56C>A; 172G>A], p.[Q19P; A58T] haplotype result in a moderate decrease in activity. Among the 19 HPI patients, 10 had a predicted residual activity <50%. Eight out of nine subjects with a predicted residual activity > or = 50% bore at least one c.824C>A, p.T275N allele, which has no detrimental effect on activity but whose frequency in controls is only 3%. Our results suggest that PRODH mutations lead to a decreased POX activity or affect other biological parameters causing hyperprolinemia.

Bacterial biosensors for measuring availability of environmental pollutants

Abstract: Traditionally, pollution risk assessment is based on the measurement of a pollutant's total concentration in a sample. The toxicity of a given pollutant in the environment, however, is tightly linked to its bioavailability, which may differ significantly from the total amount. Physico-chemical and biological parameters strongly influence pollutant fate in terms of leaching, sequestration and biodegradation. Bacterial sensorreporters, which consist of living micro-organisms genetically engineered to produce specific output in response to target chemicals, offer an interesting alternative to monitoring approaches. Bacterial sensor-reporters detect bioavailable and/or bioaccessible compound fractions in samples. Currently, a variety of environmental pollutants can be targeted by specific biosensor-reporters. Although most of such strains are still confined to the lab, several recent reports have demonstrated utility of bacterial sensing-reporting in the field, with method detection limits in the nanomolar range. This review illustrates the general design principles for bacterial sensor-reporters, presents an overview of the existing biosensor-reporter strains with emphasis on organic compound detection. A specific focus throughout is on the concepts of bioavailability and bioaccessibility, and how bacteria-based sensing-reporting systems can help to improve our basic understanding of the different processes at work.

Biochemical markers of fatal hypothermia.

The aim of this study was to investigate the usefulness of postmortem biochemical investigations in the diagnosis of fatal hypothermia. 10 cases of fatal hypothermia and 30 control cases were selected. A series of biochemical parameters, such as glucose, acetone, 3-beta-hydroxybutyrate, isopropyl alcohol, free fatty acids, adrenaline, growth hormone, adrenocorticotropic hormone, thyroid-stimulating hormone, cortisol, calcium, magnesium, C-reactive protein, procalcitonin as well as markers of renal and cardiac functions were measured in blood, postmortem serum from femoral blood, urine, vitreous and pericardial fluid. The results suggested that deaths due to hypothermia, especially in free-ethanol cases, are characterized by increased ketone levels in blood and other biological fluids, increased adrenaline concentrations in urine, increased cortisol levels in postmortem serum from femoral blood and increased free cortisol values in urine. Increased or decreased levels of other biological parameters are either the result of terminal metabolic changes or the expression of preexisting diseases and may provide information to elucidate the death process on a case-by-case basis.

Predictive factors of adrenal insufficiency in patients admitted to acute medical wards: a case control study.

BACKGROUND: Adrenal insufficiency is a rare and potentially lethal disease if untreated. Several clinical signs and biological markers are associated with glucocorticoid failure but the importance of these factors for diagnosing adrenal insufficiency is not known. In this study, we aimed to assess the prevalence of and the factors associated with adrenal insufficiency among patients admitted to an acute internal medicine ward. METHODS: Retrospective, case-control study including all patients with high-dose (250 μg) ACTH-stimulation tests for suspected adrenal insufficiency performed between 2008 and 2010 in an acute internal medicine ward (n = 281). Cortisol values <550 nmol/l upon ACTH-stimulation test were considered diagnostic for adrenal insufficiency. Area under the ROC curve (AROC), sensitivity, specificity, negative and positive predictive values for adrenal insufficiency were assessed for thirteen symptoms, signs and biological variables. RESULTS: 32 patients (11.4%) presented adrenal insufficiency; the others served as controls. Among all clinical and biological parameters studied, history of glucocorticoid withdrawal was the only independent factor significantly associated with patients with adrenal insufficiency (Odds Ratio: 6.71, 95% CI: 3.08 -14.62). Using a logistic regression, a model with four significant and independent variable was obtained, regrouping history of glucocorticoid withdrawal (OR 7.38, 95% CI [3.18 ; 17.11], p-value <0.001), nausea (OR 3.37, 95% CI [1.03 ; 11.00], p-value 0.044), eosinophilia (OR 17.6, 95% CI [1.02; 302.3], p-value 0.048) and hyperkalemia (OR 2.41, 95% CI [0.87; 6.69], p-value 0.092). The AROC (95% CI) was 0.75 (0.70; 0.80) for this model, with 6.3 (0.8 - 20.8) for sensitivity and 99.2 (97.1 - 99.9) for specificity. CONCLUSIONS: 11.4% of patients with suspected adrenal insufficient admitted to acute medical ward actually do present with adrenal insufficiency, defined by an abnormal response to high-dose (250 μg) ACTH-stimulation test. A history of glucocorticoid withdrawal was the strongest factor predicting the potential adrenal failure. The combination of a history of glucocorticoid withdrawal, nausea, eosinophilia and hyperkaliemia might be of interest to suspect adrenal insufficiency.

Revue des arthroplasties totales de la hanche et du genou infectées--à propos de 28 cas [Review of infected total arthroplasties of the hip and knee--apropos of 28 cases]

This study is a long-term analysis of a group of patients with infected arthroplasties of the hip or the knee. We identified 28 patients with an infected arthroplasty (22 hips, 6 knees) documented by bacterial culture or on direct examination. At the time of diagnosis and on follow-up (a mean of 46 months after treatment) we evaluated the clinical picture, the radiological appearances of the articulation and the biological parameters. 19/28 patients showed a typical clinical picture, whereas in 9 others the picture was more doubtful. The treatments were 14 two-stage replacements of the arthroplasties, 7 simple resections, 5 conservative treatments and 2 one-stage replacements. On follow-up, 25 patients were considered as cured of their infection and 3 as failures. From a functional viewpoint, 9 patients showed no limitation, whereas 19 were limited in the daily activity. Half of the patients had no pain. Radiology showed that 20/26 evaluated patients had no signs of recurrence. Paraclinical examinations are important in the diagnosis of persistent low grade infections, particularly the demonstration of bacteria by pre-surgical sampling (fine needle aspiration, culture from draining sinuses). In spite of the cure of infection, the functional and painful sequellae are often considerable. As a result of our experience, we recommend a two-stage surgical procedure. Only when the general condition of the patient is poor, or when the infection is not under control, would we envisage an alternative procedure (arthrodesis, girdelstone, conservative).

Reticulocyte dynamic and hemoglobin variability in hemodialysis patients treated with Darbepoetin alfa and C.E.R.A.: a randomized controlled trial.

BACKGROUND: In a simulation based on a pharmacokinetic model we demonstrated that increasing the erythropoiesis stimulating agents (ESAs) half-life or shortening their administration interval decreases hemoglobin variability. The benefit of reducing the administration interval was however lessened by the variability induced by more frequent dosage adjustments. The purpose of this study was to analyze the reticulocyte and hemoglobin kinetics and variability under different ESAs and administration intervals in a collective of chronic hemodialysis patients. METHODS: The study was designed as an open-label, randomized, four-period cross-over investigation, including 30 patients under chronic hemodialysis at the regional hospital of Locarno (Switzerland) in February 2010 and lasting 2 years. Four subcutaneous treatment strategies (C.E.R.A. every 4 weeks Q4W and every 2 weeks Q2W, Darbepoetin alfa Q4W and Q2W) were compared with each other. The mean square successive difference of hemoglobin, reticulocyte count and ESAs dose was used to quantify variability. We distinguished a short- and a long-term variability based respectively on the weekly and monthly successive difference. RESULTS: No difference was found in the mean values of biological parameters (hemoglobin, reticulocytes, and ferritin) between the 4 strategies. ESAs type did not affect hemoglobin and reticulocyte variability, but C.E.R.A induced a more sustained reticulocytes response over time and increased the risk of hemoglobin overshooting (OR 2.7, p = 0.01). Shortening the administration interval lessened the amplitude of reticulocyte count fluctuations but resulted in more frequent ESAs dose adjustments and in amplified reticulocyte and hemoglobin variability. Q2W administration interval was however more favorable in terms of ESAs dose, allowing a 38% C.E.R.A. dose reduction, and no increase of Darbepoetin alfa. CONCLUSIONS: The reticulocyte dynamic was a more sensitive marker of time instability of the hemoglobin response under ESAs therapy. The ESAs administration interval had a greater impact on hemoglobin variability than the ESAs type. The more protracted reticulocyte response induced by C.E.R.A. could explain both, the observed higher risk of overshoot and the significant increase in efficacy when shortening its administration interval.Trial registrationClinicalTrials.gov NCT01666301.

The shrew of the Eastern Canary Islands: a new species (Mammalia: Soricidae)

The karyotype, morphology and biology of Crocidura from Fuerteventura (Canary Islands) are described. The species has a diploid chromosome number of 2n = 36, thus differing from all other species of the genus. A detailed morphological comparison of the shrews from Fuerteventura, Lanzarote and other islets with C. russula from Morocco revealed specific characters for both taxa. Differences were also observed in biological parameters. It is concluded that the Canary Island populations of Crocidura form a biological species which is consequently named Crocidura canariensis sp. nov.

Eumelanin-based coloration and fitness parameters in birds: a meta-analysis

Although melanin is the most common pigment in animal integuments, the adaptive function of variation in melanin-based coloration remains poorly understood. The individual fitness returns associated with melanin pigments can be variable across species as these pigments can have physical and biological protective properties and genes involved in melanogenesis may vary in the intensity of pleiotropic effects. Moreover, dark and pale coloration can also enhance camouflage in alternative habitats and melanin-based coloration can be involved in social interactions. We investigated whether darker or paler individuals achieve a higher fitness in birds, a taxon wherein associations between melanin-based coloration and fitness parameters have been studied in a large number of species. A meta-analysis showed that the degree of melanin-based coloration was not significantly associated with laying date, clutch size, brood size, and survival across 26 species. Similar results were found when restricting the analyses to non-sexually dimorphic birds, colour polymorphic and monomorphic species, in passerines and non-passerines and in species for which inter-individual variation in melanism is due to colour intensity. However, eumelanic coloration was positively associated with clutch and brood size in sexually dimorphic species and those that vary in the size of black patches, respectively. Given that greater extent of melanin-based coloration was positively associated with reproductive parameters and survival in some species but negatively in other species, we conclude that in birds the sign and magnitude of selection exerted on melanin-based coloration is species- or trait-specific.

Environmental and biological controls on the geochemistry (δ18O, δ13C, Mg/Ca, and Sr/Ca) of living ostracods from Lake Geneva

ABSTRACT : Ostracods are benthic microcrustaceans enclosed in low-Mg calcite bivalves. Stable isotope compositions, Mg/Ca, and Sr/Ca ratios of ostracod fossil valves have proven useful to reconstruct past environmental conditions. Yet, several discrepancies persist and the influence of many factors remains unclear. It is the aim of this study to improve the use of ostracod valve geochemistry as palaeoenvironmental proxies by examining the extent of isotope fractionation and trace element partitioning during valve calcification. To achieve this, the environmental parameters (pH, temperature) and chemical composition of water (C-and O-isotope composition and calcium, magnesium, and strontium content) were measured at sites where living ostracods were sampled. The sampling was on a monthly basis over the course of one year at five different water depths (2, 5, 13, 33, and 70 m) in Lake Geneva, Switzerland. The one-year sampling enabled collection of environmental data for bottom and interstitial pore water. In littoral to sublittoral zones, C-isotope composition of DIC and the Mg/Ca and Sr/Ca ratios of water are found to vary concomitantly with water temperature. This is due to the precipitation of calcite, which is induced by higher photosynthetic activity as temperature and/or solar radiation intensify in summer. In deeper zones, environmental parameters remain largely constant throughout the year. Variations of pH, DIC concentrations and C-isotope compositions in interstitial water result from aerobic as well as anaerobic respiration, calcite dissolution and methanogenesis. Bathymetric distribution, life cycles, and habitats were derived for 15 ostracod species and are predominantly related to water temperature and sediment texture. O-isotope compositions of ostracod valves in Lake Geneva reflect that of water and temperature. However, offsets of up to 3 permil are observed in comparison with proposed inorganic calcite precipitation equilibrium composition. Deprotonation of HCO3- and/or salt effect at crystallisation sites may explain the disequilibrium observed for O-isotopic compositions. C-isotope compositions of ostracod valves are not as well constrained and appear to be controlled by a complex interaction between habitat preferences and seasonal as well as spatial variations of the DIC isotope composition. For infaunal forms, C-isotope compositions reflect mainly the variation of DIC isotope composition in interstitial pore waters. For epifaunal forms, C-isotope compositions reflect the seasonal variation of DIC isotope compositions. C-isotope compositions of ostracod valves is at equilibrium with DIC except for a small number of species (L. inopinata, L. sanctipatricii and possibly C. ophtalmica, and I. beauchampi). Trace element uptake differs considerably from species to species. For most epifaunal forms, trace element content follows the seasonal cycle, recording temperature increases and/or variations of Mg/Ca and Sr/Ca ratios of water. In contrast, infaunal forms are predominantly related to sediment pore water chemistry. RÉSUMÉ EN FRANÇAIS : Les ostracodes sont de petits crustacés benthiques qui possèdent une coquille faite de calcite à faible teneur en magnésium. La composition isotopique et les rapports Mg/Ca et Sr/Ca d'ostracodes fossiles ont été utilisés maintes fois avec succès pour effectuer des reconstructions paléoenvironnementales. Néanmoins, certains désaccords persistent sur l'interprétation de ces données. De plus, l'influence de certains facteurs pouvant biaiser le signal reste encore inconnue. Ainsi, le but de cette étude est de rendre plus performant l'emploi de la composition géochimique des ostracodes comme indicateur paléoenvironnemental. Pour réaliser cela, cinq sites situés dans le Léman à 2, 5, 13, 33 et 70 m de profondeur ont été choisis pour effectuer les échantillonnages. Chaque site a été visité une fois par mois durant une année. Les différents paramètres environnementaux (pH, température) ainsi que la composition géochimique de l'eau (composition isotopique de l'oxygène et du carbone ainsi que teneur en calcium, magnésium et strontium) ont été déterminés pour chaque campagne. Des ostracodes vivants ont été récoltés au cinq sites en même temps que les échantillons d'eau. Ce travail de terrain a permis de caractériser la géochimie de l'eau se trouvant juste au-dessus des sédiments ainsi que celle de l'eau se trouvant dans les interstices du sédiment. Dans les zones littorales à sublittorales, la composition isotopique du carbone inorganique dissout (CID) ainsi que les rapports Mg/Ca et Sr/Ca de l'eau varient linéairement avec la température. Ceci peut être expliqué par la précipitation de calcite qui est contrôlée par l'activité photosynthétique, variant elle même linéairement avec la température. Dans les zones plus profondes, les paramètres environnementaux restent relativement constants tout au long de l'année. Les variations du pH, de la concentration et de la composition isotopique du CID dans les sédiments résultent de la libération de carbone engendrée par la dégradation de la matière organique avec présence d'oxygène ou via réduction de nitrates et de sulfates, par la dissolution de carbonates, ainsi que par la méthanogenèse. La distribution bathymétrique, le cycle de vie ainsi que l'habitat de 15 espèces ont été déterminés. Ceux-ci sont principalement reliés à la température de l'eau et à la texture des sédiments. La composition isotopique de l'oxygène des valves d'ostracodes reflète celle de l'eau et la température qui régnait lors de la calcification. Néanmoins, des écarts pouvant aller jusqu'à 3 0/00 par rapport à l'équilibre théorique ont été obtenus. La déprotonation de HCO3 ou un 'effet de sel' pourrait être à l'origine du déséquilibre observé. La composition isotopique du carbone des valves d'ostracodes n'est pas aussi bien cernée. Celle-ci semble être principalement contrôlée par une interaction complexe entre l'habitat des ostracodes et les variations saisonnières et spatiales de la composition isotopique du CID. Pour les espèces endofaunes, la composition isotopique du carbone reflète principalement la variation de la composition isotopique du CID à l'intérieur des sédiments. Pour les formes épifaunes, c'est la variation saisonnière de la composition du CID qui contrôle celle de la coquille des ostracodes. En général, la composition isotopique du carbone des valves d'ostracodes est en équilibre avec celle de CID, hormis pour quelques rares espèces (L. inopinata, L. sanctipatricii et peut-être C. ophtalmica et I. beauchampi). L'incorporation des éléments traces diffère passablement d'une espèce à l'autre. Pour la plupart des espèces épifaunes, la teneur en éléments traces des coquilles reflète les variations saisonnières. Ces espèces semblent enregistrer les variations soit de la température soit des rapports Mg/Ca et Sr/Ca de l'eau. La teneur en élément traces des formes infaunales, au contraire, est principalement reliée à la chimie de l'eau interstitielle. RÉSUMÉ GRAND-PUBLIC : La connaissance de l'évolution du climat dans le futur est primordiale pour notre société, car elle permet de développer différentes stratégies pour faire face aux problèmes engendrés pas le changement climatique : stratégies environnementale, humanitaire, ou encore économique. Cette problématique est actuellement, à juste titre, sujet d'une vive préoccupation. La géologie peut-elle contribuer à l'effort communautaire entrepris? Naturellement, ce sont les climatologues qui sont sur le devant de la scène. Il n'empêche que ces derniers, pour pouvoir prédire l'avenir, doivent s'appuyer sur le passé. La géologie est alors d'un grand intérêt car c'est effectivement la seule science qui permette d'estimer les variations climatiques à grande échelle sur de longues périodes. Ainsi, voulant moi-même contribuer aux recherches menées dans ce domaine, je me suis tourné à la fin de mes études vers la paléoclimatologie, science qui a pour but de reconstruire le climat des temps anciens. Nous nous sommes rendu compte que l'évolution climatique de la région où nous habitons n'avait pas encore fait le sujet d'études approfondies. Il est pourtant important de connaître la variation locale des changements climatiques pour obtenir des modèles climatiques fiables. En conséquence, un vaste projet a vu le jour : reconstruire, à l'aide des sédiments du lac Léman, les variations paléoclimatiques et paléo-environnementales depuis le retrait du Glacier de Rhône, il y a environ 15'000 ans, jusqu'à nos jours. Pour ce genre de travail, la géochimie, qui est une forme de chimie, utilisée en science de la terre regroupant la chimie classique et la chimie isotopique, est une alliée particulièrement efficace. Elle permet en effet, via différentes mesures faites sur des archives géologiques (par exemple des fossiles ou des sédiments) d'obtenir des informations, souvent quantitatives, sur les conditions (le climat, la flore ou encore la bio productivité, etc...) qui régnaient il y a fort longtemps. Les coquilles d'ostracodes, qui sont de petits animaux vivant au fond des lacs, sont une des archives les plus prometteuses. Ces animaux sont des petits crustacés s'entourant d'une coquille calcaire qu'ils sécrètent eux-mêmes. A la mort de l'animal, la coquille est intégrée dans les sédiments et reste intacte à travers les âges. Des études ont montré qu'en analysant la géochimie de ces coquilles fossiles, il est possible de reconstruire les conditions environnementales qui régnaient à l'époque de vie de ces fossiles. Cette démarche nécessite qu'une condition bien précise soit remplie: la composition géochimique de la coquille doit enregistrer de manière fidèle la chimie de l'eau et/ou la température de l'eau présentes au moment de la sécrétion de la coquille. Le but spécifique de notre recherche a précisément été d'étudier la façon dont la chimie de l'eau ainsi que sa température sont enregistrées dans la coquillé des ostracodes. Une fois les relations entre ces divers paramètres dans l'étant actuel du système établies, il sera alors possible de les utiliser pour interpréter des données issues de coquilles fossiles. Pour ce faire, nous avons mesuré la température de l'eau de manière continue et récolté mensuellement des échantillons d'eau et des ostracodes vivants pendant une année. Cinq sites situés à 2, 5, 13, 33 et 70 mètres de profondeur ont été choisis pour effectuer ces échantillonnages dans le Léman. Le travail de terrain nous a amené à étudier la biologie de 15 espèces. Nous avons pu établir la profondeur à laquelle vivent ces animaux, leur période de développement ainsi que leur habitat respectifs. Ces résultats ont permis de mieux cerner la relation qu'il existe entre la chimie de l'eau, sa température et la composition géochimique des coquilles d'ostracodes. Nous avons ainsi pu confirmer que les coquilles d'ostracodes enregistrent de manière fidèle la composition chimique et isotopique de l'eau. De même, nous avons pu établir de manière plus précise l'effet de la température sur la géochimie des coquilles. Néanmoins, les relations trouvées entre ces trois éléments sont plus complexes pour certaines espèces, cette complexité étant souvent liée à un caractère spécifique de leur écologie. Nous avons mis en lumière certains effets qui biaisent les résultats et défini précisément les conditions dans lesquelles on peut s'attendre à avoir des difficultés dans leur interprétation. Maintenant que nous avons établi les relations entre le climat actuel et la composition géochimique des coquilles d'ostracodes actuels, nous pouvons, sur la base de ce modèle, reconstruire le climat depuis le retrait du Glacier du Rhône jusqu'à nos jours à l'aide d'ostracodes fossiles. Mais cela est une autre histoire et fera, je l'espère, le sujet de nos futures recherches.

A universal fluid cell for the imaging of biological specimens in the atomic force microscope.

Recently, atomic force microscope (AFM) manufacturers have begun producing instruments specifically designed to image biological specimens. In most instances, they are integrated with an inverted optical microscope, which permits concurrent optical and AFM imaging. An important component of the set-up is the imaging chamber, whose design determines the nature of the experiments that can be conducted. Many different imaging chamber designs are available, usually designed to optimize a single parameter, such as the dimensions of the substrate or the volume of fluid that can be used throughout the experiment. In this report, we present a universal fluid cell, which simultaneously optimizes all of the parameters that are important for the imaging of biological specimens in the AFM. This novel imaging chamber has been successfully tested using mammalian, plant, and microbial cells.

Sex-biased dispersal in a migratory bat: a characterization using sex-specific demographic parameters.

We studied the noctule bat (Nyctalus noctula), in which the mitochondrial F(ST) is about 10 times that revealed by nuclear markers, to address two questions. We first verified whether random dispersal of one sex is compatible with highly contrasted mitochondrial and nuclear population structures. Using computer simulations, we then assessed the power of multilocus population differentiation tests when the expected population structure departs only slightly from panmixia. Using an island model with sex-specific demographic parameters, we found that random male dispersal is consistent with the population structure observed in the noctule. However, other parameter combinations are also compatible with the data. We computed the minimum sex bias in dispersal (at least 69% of the dispersing individuals are males), a result that would not be available if we had used more classical population genetic models. The power of multilocus population differentiation tests was unexpectedly high, the tests being significant in almost 100% of the replicates, although the observed population structure infered from nuclear markers was extremely low (F(ST) = 0.6%).

The hematology laboratory in blood doping (bd): 2014 update on the athlete biological passport (APB)

Introduction: Blood doping (BD) is the use of Erythropoietic Stimulating Agents (ESAs) and/or transfusion to increase aerobic performance in athletes. Direct toxicologic techniques are insufficient to unmask sophisticated doping protocols. The Hematological module of the ABP (World Anti-Doping Agency), associates decision support technology and expert assessment to indirectly detect BD hematological effects. Methods: The ABP module is based on blood parameters, under strict pre-analytical and analytical rules for collection, storage and transport at 2-12°C, internal and external QC. Accuracy, reproducibility and interlaboratory harmonization fulfill forensic standard. Blood samples are collected in competition and out-ofcompetition. Primary parameters for longitudinal monitoring are: - hemoglobin (HGB); - reticulocyte percentage (RET); - OFF score, indicator of suppressed erythropoiesis, calculated as [HGB(g/L) * 60-√RET%]. Statistical calculation predicts individual expected limits by probabilistic inference. Secondary parameters are RBC, HCT, MCHC-MCH-MCV-RDW-IFR. ABP profiles flagged as atypical are review by experts in hematology, pharmacology, sports medicine or physiology, and classified as: - normal - suspect (to target) - likely due to BD - likely due to pathology. Results: Thousands of athletes worldwide are currently monitored. Since 2010, at least 35 athletes have been sanctioned and others are prosecuted on the sole basis of abnormal ABP, with a 240% increase of positivity to direct tests for ESA, thanks to improved targeting of suspicious athletes (WADA data). Specific doping scenarios have been identified by the Experts (Table and Figure). Figure. Typical HGB and RET profiles in two highly suspicious athletes. A. Sample 2: simultaneous increases in HGB and RET (likely ESA stimulation) in a male. B. Samples 3, 6 and 7: "OFF" picture, with high HGB and low RET in a female. Sample 10: normal HGB and increased RET (ESA or blood withdrawal). Conclusions: ABP is a powerful tool for indirect doping detection, based on the recognition of specific, unphysiological changes triggered by blood doping. The effect of factors of heterogeneity, such as sex and altitude, must also be considered. Schumacher YO, et al. Drug Test Anal 2012, 4:846-853. Sottas PE, et al. Clin Chem 2011, 57:969-976.

Evaluation of C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as diagnostic parameters in sepsis-related fatalities.

The aims of this study were to investigate the usefulness of serum C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as postmortem markers of sepsis and to compare C-reactive protein and procalcitonin values in serum, vitreous humor, and cerebrospinal fluid in a series of sepsis cases and control subjects, in order to determine whether these measurements may be employed for the postmortem diagnosis of sepsis. Two study groups were formed, a sepsis group (eight subjects coming from the intensive care unit of two university hospitals, with a clinical diagnosis of sepsis in vivo) and control group (ten autopsy cases admitted to two university medicolegal centers, deceased from natural and unnatural causes, without elements to presume an underlying sepsis as the cause of death). Serum C-reactive protein and procalcitonin concentrations were significantly different between sepsis cases and control cases, whereas serum tumor necrosis factor alpha, interleukin-6, and interleukin-8 values were not significantly different between the two groups, suggesting that measurement of interleukin-6, interleukin-8, and tumor necrosis factor alpha is non-optimal for postmortem discrimination of cases with sepsis. In the sepsis group, vitreous procalcitonin was detectable in seven out of eight cases. In the control group, vitreous procalcitonin was clearly detectable only in one case, which also showed an increase of all markers in serum and for which the cause of death was myocardial infarction associated with multi-organic failure. According to the results of this study, the determination of vitreous procalcitonin may be an alternative to the serum procalcitonin for the postmortem diagnosis of sepsis.

Impact of biological and environmental variabilities on biological monitoring: an approach using toxicokinetic models

Biological monitoring of occupational exposure is characterized by important variability, due both to variability in the environment and to biological differences between workers. A quantitative description and understanding of this variability is important for a dependable application of biological monitoring. This work describes this variability,using a toxicokinetic model, for a large range of chemicals for which reference biological reference values exist. A toxicokinetic compartmental model describing both the parent compound and its metabolites was used. For each chemical, compartments were given physiological meaning. Models were elaborated based on physiological, physicochemical, and biochemical data when available, and on half-lives and central compartment concentrations when not available. Fourteen chemicals were studied (arsenic, cadmium, carbon monoxide, chromium, cobalt, ethylbenzene, ethyleneglycol monomethylether, fluorides, lead, mercury, methyl isobutyl ketone, penthachlorophenol, phenol, and toluene), representing 20 biological indicators. Occupational exposures were simulated using Monte Carlo techniques with realistic distributions of both individual physiological parameters and exposure conditions. Resulting biological indicator levels were then analyzed to identify the contribution of environmental and biological variability to total variability. Comparison of predicted biological indicator levels with biological exposure limits showed a high correlation with the model for 19 out of 20 indicators. Variability associated with changes in exposure levels (GSD of 1.5 and 2.0) is shown to be mainly influenced by the kinetics of the biological indicator. Thus, with regard to variability, we can conclude that, for the 14 chemicals modeled, biological monitoring would be preferable to air monitoring. For short half-lives (less than 7 hr), this is very similar to the environmental variability. However, for longer half-lives, estimated variability decreased. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: tables detailing the CBTK models for all 14 chemicals and the symbol nomenclature that was used.] [Authors]

Are 10 min of seating enough to guarantee stable haemoglobin and haematocrit readings for the athlete's biological passport?

Haemoglobin (Hb) and haematocrit (Hct) are measured as indirect markers of doping in athletes. We studied the effect of posture on these parameters in a typical antidoping setting. Venous blood samples were obtained from nine endurance athletes (six males, three females) and nine control subjects (six males, three females) immediately and after 5, 10, 15, 20 and 30 min after having adopted a seated position from normal daily activity. Hb (CV 0.72%) and Hct (CV 0.87%) were determined using an automated cell counter, plasma volume changes were calculated. Differences between the time points, gender and groups were calculated using a mixed-model procedure. Significant changes were observed in the first 10 min after sitting down but no further changes were noted between 10 and 30 min. Mean directional change for Hb and Hct between 0 min and the average of the period from 10 to 30 min was -2.4% (-0.35 g/dl) for Hb and -2.7% (-1.2%) for Hct. Plasma volume increased accordingly. Neither group nor gender had significant effects. Under typical conditions encountered during blood testing in doping control, a period of 10 min in a seated position is sufficient for the vascular volumes to re-equilibrate and to adapt to the new posture.