Evaluation des tests biologiques pour le diagnostic d'évènements coronariens aigus en médecine d'urgence

L'objectif de cette thèse était d'évaluer les performances de marqueurs cardiaques pour le diagnostic de syndrome coronaire aigu non ST+ en médecine d'urgence puis de faire une analyse critique des méthodes utilisées pour l'évaluation de ces marqueurs dans la littérature. Nous avons réalisé une étude multidisciplinaire, monocentrique d'évaluation de tests diagnostiques. Nous avons inclus tout patient pris en charge en urgence pour une douleur thoracique non traumatique d'allure angineuse. Nous avons évalué les performances de trois marqueurs de SCA : l'h-Fatty Acid Binding Protein (h-FABP), l'Ischemia Modifie Albumin (IMA) et l'hyperglycémie. Nous avons montré que : 1/ Les performances de l'IMA sont insuffisantes pour le diagnostic de SCA. 2/ L'h-FABP, dosée par une méthode qualitative, est un marqueur diagnostique de SCA non ST+ dont les performances sont insuffisantes pour améliorer la prise en charge des patients. 3/ L'h-FABP, dosée par une méthode quantitative, n'apporte pas non plus d'information supplémentaire au modèle prédictif de SCA. La concordance entre les 2 tests (qualitatif et quantitatif) était médiocre (kappa=0,4). 4/ L'hyperglycémie est un facteur indépendant associé au diagnostic de SCA, mais ne modifie pas la classification des patients mesurée par la statistique c. Dans la deuxième partie de ce travail, nous avons voulu savoir pourquoi nos résultats étaient discordants par rapport aux données de la littérature. Nous avons élaboré une grille d'expertise méthodologique adaptée à l'analyse des performances diagnostiques des tests dans le SCA que nous avons appliquée aux articles sélectionnés dans Medline. L'analyse de la littérature a montré que les études étaient le plus souvent méthodologiquement médiocres, réalisées sur des populations sélectionnées et avec des critères de jugement non pertinents. Ceci nous conduit à une réflexion sur les conditions et les modalités qui peuvent conduire un test de la mise au point technique à la pratique en routine.We studied the performance of cardiac biomarkers for diagnosis of non ST elevation acute coronary syndrome (ACS) in emergency medicine and performed a critical analysis of methods used to evaluate these markers in the literature. We conducted a multidisciplinary study, single center evaluation of diagnostic tests. Consecutive patients admitted in the emergency department for a chest pain suspected of ACS were included. The performances of three markers were studied: h-Fatty Acid Binding Protein (h-FABP), Ischemia Modified Albumin (IMA) and hyperglycemia. We found that: 1 / The performances of the IMA were insufficient for the diagnosis of SCA. 2 / h-FABP measured with a qualitative test, was a diagnostic marker of non ST ACS but did not add information to a predictive model that included the usual diagnostic tools. 3 / h-FABP measured with a quantitative test also did not add incremental information in the predictive model of ACS. Concordance between the qualitative and quantitative test was poor (kappa = 0.4). 4 / Hyperglycemia was an independent factor associated with the diagnosis of ACS, but did not change the patient classification measured by the c-statistic. In the second part of this work we wanted to know why our results were discordant compared to literature data. We have developed a checklist of methodological expertise for performance analysis of ACS diagnostic tests, which we applied to the articles selected in Medline. The analysis of the literature showed that studies were often methodologically weak, conducted on selected population and with endpoints improving test performance. Then, we considered steps and conditions that lead a diagnostic test from its technical development to its use in practice routine

Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations Associated with First-Line Stavudine-Containing Antiretroviral Therapy: Programmatic Implications for Countries Phasing Out Stavudine

Background The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. Methods We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. Results Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. Conclusions Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therap

Antiretroviral-naive and -treated HIV-1 patients can harbour more resistant viruses in CSF than in plasma

Objectives The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study. Methods Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were >50 copies/mL in both compartments and bulk genotypic tests were realized. Results On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P = 0.0455) and T215Y (P = 0.0455). Conclusions In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performe

Evaluation de la pertinence d'un algorithme de prise en charge du Syndrome Coronarien Aigu sans sus-décalage du segment ST aux urgences de Rangueil

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Performance du premier dosage de la troponine I ultra-sensible dans le diagnostic des infarctus du myocarde non ST+

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Hyperglycémie dans les douleurs thoraciques en urgence (facteur prédictif de syndrome coronarien aigu)

Le diabète mais aussi les autres anomalies du métabolisme glucidique sont associés à un risque accru de pathologies cardiovasculaires. Nous avons étudié la prévalence et la valeur prédictive diagnostique et pronostique de l'hyperglycémie chez les patients se présentant en urgence pour douleur thoracique évocatrice d'un syndrome coronarien aigu (SCA). Sur les 663 patients analysés,178 ont eu un diagnostic de SCA authentifié. On a retrouvé 12,4% de patients diabétiques et 17,4% de patients dysglycémiques. Les patients ayant une hyperglycémie à l'admission ont un risque augmenté d'avoir un diagnostic de SCA de 2,3 à 3,3 suivant le seuil de glycémie. Le rôle pronostique de l'hyperglycémie n'a pu être analysé, cependant, l'hyperglycémie a été un facteur prédictif fort et indépendant de diagnostic de SCA chez les patients pris en charge en urgence pour douleur thoracique.TOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Dépistage systématique des intoxications au monoxyde de carbone dans un Service d'accueil des urgences du 15/01/01 au 28/02/02

TOULOUSE3-BU Santé-Centrale (315552105) / SudocTOULOUSE3-BU Santé-Allées (315552109) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

L’Ile du Rohrschollen : Réserve naturelle ou socio-éco-techno-système ?

International audienc

Dermenkephalin and deltorphin I reveal similarities within ligand-binding domains of μ- and δ-opioid receptors and an additional address subsite on the δ-receptor

International audienceDermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), dermenkephalin (Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2) and deltorphin I (Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) are the first naturally occurring peptides highly potent for and almost specific to the mu- and delta-opioid receptors, respectively. The amino-terminal domains Tyr-D-X-Phe (where X is either Ala or Met) of these peptides behave as selective and potent mu-receptor ligands. Routing of Tyr-D-X-Phe to the delta- or the mu- receptor is associated with the presence or the absence at the C-terminus of an additional hydrophobic and negatively charged tetrapeptide by-passing the mu-addressing ability of the amino-terminal moiety. A study of 20 Tyr-D-X-Phe-Y-NH2 analogs with substitution of X and Y by neutral, hydrophobic, aromatic amino acids as well as by charged amino acid residues shows that tetrapeptides maintain high binding affinity and selectivity for the mu-opioid receptor. Although residue in position 4 serves a delta-address function, the tripeptide motif at the C-terminus of dermenkephalin and deltorphin I are critical components for high selectivity at delta-opioid receptor. Results demonstrate that mu- and delta-opioid receptors share topologically equivalent ligand-binding domains, or ligand-binding sequences similarities, that recognized Tyr-D-X-Phe as a consensus message-binding sequence. The delta-receptor additionally contains a unique address subsite at or near the conserved binding domain that accommodates the C-terminal tetrapeptide motif of dermenkephalin and deltorphin I

The aspartic acid in deltorphin I and dermenkephalin promotes targeting to δ-opioid receptor independently of receptor binding

International audienceRecent studies on the highly potent and selective δ-opioid agonists demenkephalin (Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2) and deltorphin I (Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) suggested that key structural features necessary for specific targetting to the δ-opioid receptor are located within the C-terminal halves of these naturally occurring heptapeptides. To investigate the contribution of aspartic acid 4 residue in deltorphin I and aspartic acid 7 residue in dermenkephalin to the δ-addressing ability of the C-terminal ends, fourteen analogs were synthesized and assessed for their ability to bind to μ and δ-opioid receptors in rat brain membrane homogenates. Results showed that i/ although the tetrapeptide C-terminus of dermenkephalin and deltorphin I differ in amino acid composition, they play a similar role in specifying correct addressing of these peptides to the δ-receptor, ii/ the negatively charged side chain of aspartic acid 4 residue in deltorphin I and aspartic acid 7 residue in dermenkephalin is not involved in binding contact at the δ-receptor site, nor in maintaining a δ-bioactive folding of the peptides, iii/ these side chains are, in contrast, functionnally or structurally required to confer high δ-selectivity by preventing μ-site recognition and / or binding