La chaîne des secours: le modèle vaudois [An efficient example of a Swiss pre-hospital chain of survival: the state of Vaud model].

The state of Vaud model of the pre-hospital chain of survival is an example of an efficient way to deal with pre-hospital emergencies. It revolves around a centrally located dispatch center managing emergencies according to specific key words, allowing dispatchers to send out resources among which we find general practitioners, ambulances, physician staffed fast response cars or physician staffed helicopters and specific equipment. The Vaud pre-hospital chain of survival has been tailored according to geographical, demographical and political necessities. It undergoes constant reassessment and needs continuous adaptations to the ever changing demographics and epidemiology of pre-hospital medicine.

Influence of CYP2D6 activity on pre-emptive analgesia by the N-methyl-D-aspartate antagonist dextromethorphan in a randomized controlled trial of acute pain.

BACKGROUND: There is some evidence that dextromethorphan (DM) is effective as a pre-emptive analgesic agent.  DM is mainly metabolized to dextrorphan (DOR) by CYP2D6 whose activity can be inhibited by pharmacologic intervention. OBJECTIVES: To investigate the efficacy of DM as a pre-emptive analgesic agent and describe the population pharmacokinetics in the presence of normal and poor CYP2D6 metabolism in acute post-operative pain. STUDY DESIGN: Double blind, randomized, placebo-controlled trial SETTING: Post-surgical analgesic consumption after knee ligament surgery, a setting of acute pain. METHODS: Forty patients were randomized to a single oral dose of 50 mg quinidine or placebo, administered 12 hours before 50 mg DM. Patients were genotyped for the major CYP2D6 and ABCB1 variants and phenotyped for CYP2D6 using urine DM/DOR metabolic ratios and blood samples for population pharmacokinetic modeling. RESULTS: Quinidine was effective in inhibiting CYP2D6 activity, with 2-fold reduction of DM to DOR biotransformation clearance, prolonged DM half-life, and increased DM systemic availability. Patients in the quinidine group required significantly less often NSAIDs than patients in the placebo group (35.3% vs. 75.0%, P = 0.022). The odds ratio for NSAID consumption in the placebo vs. quinidine group was 5.5 (95% confidence interval (CI) 1.3 - 22.7) at 48 hours after surgery. LIMITATIONS: While this study shows an impact of DM on pre-emptive analgesia and is mechanistically interesting, the findings need to be confirmed in larger trials. CONCLUSION: CYP2D6 inhibition by quinidine influenced the pre-emptive analgesic effectiveness of DM confirming that CYP2D6 phenotypic switch increases the neuromodulatory effect of oral dextromethorphan.

Will endoscopists soon replace pathologists in the diagnosis of (pre-)neoplastic and inflammatory mucosal lesions?

This short review addresses the question whether pathologists will continue to play a central role in the diagnosis of mucosal lesions of the gastrointestinal tract or whether their role will soon be assumed by clinical colleagues equipped with modern high-resolution endoscopes. In order to support the raison d'etre of the pathologist - at least for the time being and the near future - the author lists three arguments, related to (i) the differences in the orientation of the plane of view (histology: perpendicular to the mucosal surface vs. endoscopy: parallel to the mucosal surface), (ii) the advantages of staining and immunostaining tissue sections, and (iii) the possibility to perform deeper sections and to consul with colleagues in the case of difficult diagnoses.

Parametric imaging for characterizing focal liver lesions in contrast-enhanced ultrasound.

The differentiation between benign and malignant focal liver lesions plays an important role in diagnosis of liver disease and therapeutic planning of local or general disease. This differentiation, based on characterization, relies on the observation of the dynamic vascular patterns (DVP) of lesions with respect to adjacent parenchyma, and may be assessed during contrast-enhanced ultrasound imaging after a bolus injection. For instance, hemangiomas (i.e., benign lesions) exhibit hyper-enhanced signatures over time, whereas metastases (i.e., malignant lesions) frequently present hyperenhanced foci during the arterial phase and always become hypo-enhanced afterwards. The objective of this work was to develop a new parametric imaging technique, aimed at mapping the DVP signatures into a single image called a DVP parametric image, conceived as a diagnostic aid tool for characterizing lesion types. The methodology consisted in processing a time sequence of images (DICOM video data) using four consecutive steps: (1) pre-processing combining image motion correction and linearization to derive an echo-power signal, in each pixel, proportional to local contrast agent concentration over time; (2) signal modeling, by means of a curve-fitting optimization, to compute a difference signal in each pixel, as the subtraction of adjacent parenchyma kinetic from the echopower signal; (3) classification of difference signals; and (4) parametric image rendering to represent classified pixels as a support for diagnosis. DVP parametric imaging was the object of a clinical assessment on a total of 146 lesions, imaged using different medical ultrasound systems. The resulting sensitivity and specificity were 97% and 91%, respectively, which compare favorably with scores of 81 to 95% and 80 to 95% reported in medical literature for sensitivity and specificity, respectively.

Pre-analytical and methodological challenges in red blood cell microparticle proteomics.

Microparticles are phospholipid vesicles shed mostly in biological fluids, such as blood or urine, by various types of cells, such as red blood cells (RBCs), platelets, lymphocytes, endothelial cells. These microparticles contain a subset of the proteome of their parent cell, and their ready availability in biological fluid has raised strong interest in their study, as they might be markers of cell damage. However, their small size as well as their particular physico-chemical properties makes them hard to detect, size, count and study by proteome analysis. In this review, we report the pre-analytical and methodological caveats that we have faced in our own research about red blood cell microparticles in the context of transfusion science, as well as examples from the literature on the proteomics of various kinds of microparticles.

Pre-Mesozoic Alpine basements - Their place in the European Paleozoic framework

Prior to their Alpine overprinting, most of the pre-Mesozoic basement areas in Alpine orogenic structures shared a complex evolution, starting with Neoproterozoic sediments that are thought to have received detrital input from both West and East Gondwanan cratonic sources. A subsequent Neoproterozoic-Cambrian active margin setting at the Gondwana margin was followed by a Cambrian-Ordovician rifting period, including an Ordovician cordillera-like active margin setting. During the Late Ordovician and Silurian periods, the future Alpine domains recorded crustal extension along the Gondwana margin, announcing the future opening of the Paleotethys oceanic domain. Most areas then underwent Variscan orogenic events, including continental subduction and collisions with Avalonian-type basement areas along Laurussia and the juxtaposition and the duplication of terrane assemblages during strike slip, accompanied by contemporaneous crustal shortening and the subduction of Paleotethys under Laurussia. Thereafter, the final Pangea assemblage underwent Triassic and Jurassic extension, followed by Tertiary shortening, and leading to the buildup of the Alpine mountain chain. Recent plate-tectonic reconstructions place the Alpine domains in their supposed initial Cambrian-Ordovician positions in the eastern part of the Gondwana margin, where a stronger interference with the Chinese blocks is proposed, at least from the Ordovician onward. For the Visean time of the Variscan continental collision, the distinction of the former tectonic lower-plate situation is traceable but becomes blurred through the subsequent oblique subduction of Paleotethys under Laurussia accompanied by large-scale strike slip. Since the Pennsylvanian, this global collisional scenario has been replaced by subsequent and ongoing shortening and strike slip under rising geothermal conditions, and all of this occurred before all these puzzle elements underwent the complex Alpine reorganization.

Non-invasive quantification of brain glycogen absolute concentration.

The only currently available method to measure brain glycogen in vivo is 13C NMR spectroscopy. Incorporation of 13C-labeled glucose (Glc) is necessary to allow glycogen measurement, but might be affected by turnover changes. Our aim was to measure glycogen absolute concentration in the rat brain by eliminating label turnover as variable. The approach is based on establishing an increased, constant 13C isotopic enrichment (IE). 13C-Glc infusion is then performed at the IE of brain glycogen. As glycogen IE cannot be assessed in vivo, we validated that it can be inferred from that of N-acetyl-aspartate IE in vivo: After [1-13C]-Glc ingestion, glycogen IE was 2.2 +/- 0.1 fold that of N-acetyl-aspartate (n = 11, R(2) = 0.77). After subsequent Glc infusion, glycogen IE equaled brain Glc IE (n = 6, paired t-test, p = 0.37), implying isotopic steady-state achievement and complete turnover of the glycogen molecule. Glycogen concentration measured in vivo by 13C NMR (mean +/- SD: 5.8 +/- 0.7 micromol/g) was in excellent agreement with that in vitro (6.4 +/- 0.6 micromol/g, n = 5). When insulin was administered, the stability of glycogen concentration was analogous to previous biochemical measurements implying that glycogen turnover is activated by insulin. We conclude that the entire glycogen molecule is turned over and that insulin activates glycogen turnover.

Citrate- vs. acetate-based dialysate in bicarbonate haemodialysis: consequences on haemodynamics, coagulation, acid-base status, and electrolytes.

BACKGROUND: A concentrate for bicarbonate haemodialysis acidified with citrate instead of acetate has been marketed in recent years. The small amount of citrate used (one-fifth of the concentration adopted in regional anticoagulation) protects against intradialyser clotting while minimally affecting the calcium concentration. The aim of this study was to compare the impact of citrate- and acetate-based dialysates on systemic haemodynamics, coagulation, acid-base status, calcium balance and dialysis efficiency. METHODS: In 25 patients who underwent a total of 375 dialysis sessions, an acetate dialysate (A) was compared with a citrate dialysate with (C+) or without (C) calcium supplementation (0.25 mmol/L) in a randomised single-blind cross-over study. Systemic haemodynamics were evaluated using pulse-wave analysis. Coagulation, acid-base status, calcium balance and dialysis efficiency were assessed using standard biochemical markers. RESULTS: Patients receiving the citrate dialysate had significantly lower systolic blood pressure (BP) (-4.3 mmHg, p < 0.01) and peripheral resistances (PR) (-51 dyne.sec.cm-5, p < 0.001) while stroke volume was not increased. In hypertensive patients there was a substantial reduction in BP (-7.8 mmHg, p < 0.01). With the C+ dialysate the BP gap was less pronounced but the reduction in PR was even greater (-226 dyne.sec.cm-5, p < 0.001). Analyses of the fluctuations in PR and of subjective tolerance suggested improved haemodynamic stability with the citrate dialysate. Furthermore, an increase in pre-dialysis bicarbonate and a decrease in pre-dialysis BUN, post-dialysis phosphate and ionised calcium were noted. Systemic coagulation activation was not influenced by citrate. CONCLUSION: The positive impact on dialysis efficiency, acid-base status and haemodynamics, as well as the subjective tolerance, together indicate that citrate dialysate can significantly contribute to improving haemodialysis in selected patients.

Hemoglobin concentration and cerebral metabolism in patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The optimal hemoglobin (Hgb) target after aneurysmal subarachnoid hemorrhage is not precisely known. We sought to examine the threshold of Hgb concentration associated with an increased risk of cerebral metabolic dysfunction in patients with poor-grade subarachnoid hemorrhage. METHODS: Twenty consecutive patients with poor-grade subarachnoid hemorrhage who underwent multimodality neuromonitoring (intracranial pressure, brain tissue oxygen tension, cerebral microdialysis) were studied prospectively. Brain tissue oxygen tension and extracellular lactate/pyruvate ratio were used as markers of cerebral metabolic dysfunction and the relationship between Hgb concentrations and the incidence of brain hypoxia (defined by a brain tissue oxygen tension <20 mm Hg) and cell energy dysfunction (defined by a lactate/pyruvate ratio >40) was analyzed. RESULTS: Compared with higher Hgb concentrations, a Hgb concentration <9 g/dL was associated with lower brain tissue oxygen tension (27.2 [interquartile range, 21.2 to 33.1] versus 19.9 [interquartile range, 7.1 to 33.1] mm Hg, P=0.02), higher lactate/pyruvate ratio (29 [interquartile range, 25 to 38] versus 36 [interquartile range, 26 to 59], P=0.16), and an increased incidence of brain hypoxia (21% versus 52%, P<0.01) and cell energy dysfunction (23% versus 43%, P=0.03). On multivariable analysis, a Hgb concentration <9 g/dL was associated with a higher risk of brain hypoxia (OR, 7.92; 95% CI, 2.32 to 27.09; P<0.01) and cell energy dysfunction (OR, 4.24; 95% CI, 1.33 to 13.55; P=0.02) after adjusting for cerebral perfusion pressure, central venous pressure, PaO(2)/FIO(2) ratio, and symptomatic vasospasm. CONCLUSIONS: A Hgb concentration <9 g/dL is associated with an increased incidence of brain hypoxia and cell energy dysfunction in patients with poor-grade subarachnoid hemorrhage.

Le développement des interactions triadiques mère-père-enfant = The development of mother-father-child triadic interactions

Cet article présente un état des lieux des recherches menées selon le paradigme de « l'alliance familiale » sur le développement des interactions triadiques mère-père-enfant lors de la transition à la parentalité. Ces recherches ont montré tout d'abord que la qualité des interactions triadiques tend à être stable au cours des deux premières années de vie de l'enfant, et qu'elle peut être anticipée durant la grossesse par l'observation d'interactions dans une simulation de jeu triadique. Ensuite, elles ont montré qu'une altération de ces interactions a une influence sur le développement de l'enfant qui se manifeste tout au long des cinq premières années, tant au niveau affectif que cognitif (par exemple : la capacité d'attention triangulaire lors des premiers mois, ou le développement de la théorie de l'esprit et les difficultés de comportements à cinq ans). Cette influence s'exerce en plus de celle d'autres variables comme la relation d'attachement mère-enfant, ou la personnalité de l'enfant lui-même évaluée selon son tempérament. La triade constitue donc un contexte de développement en soi qui doit être pris en compte dans la prise en charge et l'intervention auprès de jeunes enfants.This paper presents the main results of researches on the development of mother-father-child triadic interactions during the transition to parenthood, according to the « family alliance » model. First, these researches have shown that the quality of triadic interactions tends to be stable through the first two years, and that it can be predicted during pregnancy by observation of a simulated triadic play. Then, they have shown that disturbances in triadic interactions have an impact on several affective and cognitive developmental outcomes for the child throughout the first five years (for example, the triangular attention capacity during the first months, or the development of theory of mind and externalized behaviors at age five). This impact is specific, and triadic interactions exert an influence on the development of the child over and above other variables like the mother-child attachment relationship, or the personality of the child assessed in terms of temperament. The triad constitutes then a context of development per se which has to be taken into account when working clinically with young children.

Therapeutic Drug Monitoring (TDM) of Imatinib: Effectiveness of Bayesian dose adjustment for CML patients enrolled in the Imatinib Concentration Monitoring (I-COME) study

Introduction: As imatinib pharmacokinetics are highly variable, plasma levels differ largely between patients under the same dosage. Retrospective studies in chronic myeloid leukemia (CML) patients showed significant correlations between low levels and suboptimal response, as well as between high levels and poor tolerability. Monitoring of trough plasma levels, targeting 1000 μg/L and above, is thus increasingly advised. Our study was launched to assess prospectively the clinical usefulness of systematic imatinib TDM in CML patients. This preliminary analysis addresses the appropriateness of the dosage adjustment approach applied in this study, which targets the recommended trough level and allows an interval of 4-24 h after last drug intake for blood sampling. Methods: Blood samples from the first 15 patients undergoing 1st TDM were obtained 1.5-25 h after last dose. Imatinib plasma levels were measured by LC-MS/MS and the concentrations were extrapolated to trough based on a Bayesian approach using a population pharmacokinetic model. Trough levels were predicted to differ significantly from the target in 12 patients (10 <750 μg/L; 2 >1500 μg/L along with poor tolerance) and individual dose adjustments were proposed. 8 patients underwent a 2nd TDM cycle. Trough levels of 1st and 2nd TDM were compared, the sample drawn 1.5 h after last dose (during distribution phase) was excluded from the analysis. Results: Individual dose adjustments were applied in 6 patients. Observed concentrations extrapolated to trough ranged from 360 to 1832 μg/L (median 725; mean 810, CV 52%) on 1st TDM and from 720 to 1187 μg/L (median 950; mean 940, CV 18%) on 2nd TDM cycle. Conclusions: These preliminary results suggest that TDM of imatinib using a Bayesian interpretation is able to target the recommended trough level of 1000 μg/L and to reduce the considerable differences in trough level exposure between patients (with CV decreasing from 52% to 18%). While this may simplify blood collection in daily practice, as samples do not have to be drawn exactly at trough, the largest possible interval to last drug intake yet remains preferable to avoid sampling during distribution phase leading to biased extrapolation. This encourages the evaluation of the clinical benefit of a routine TDM intervention in CML patients, which the randomized Swiss I-COME trial aims to.

Orosomucoid (alpha1-acid glycoprotein) plasma concentration and genetic variants: effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation.

BACKGROUND AND OBJECTIVE: Protease inhibitors are highly bound to orosomucoid (ORM) (alpha1-acid glycoprotein), an acute-phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CL(app)) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug. METHODS: Plasma and cells samples were collected from 434 human immunodeficiency virus-infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined. RESULTS: Indinavir CL(app) was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CL(app) was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CL(app) was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics. CONCLUSION: ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.