263 resultados para Importance post


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Résumé : Introduction : l'ostéoporose est une maladie caractérisée par une masse osseuse diminuée et une structure osseuse appauvrie amenant à une fragilité osseuse augmentée et par conséquent à une augmentation du risque fracturaire. Elle est associée à une morbidité et mortalité importantes. Il existe de nombreuses substances à disposition pour son traitement. La modalité d'administration est très variable selon la substance prescrite. Les bisphosphonates, puissants antirésorbeurs osseux, sont la classe médicamenteuse de référence. Malheureusement, prescrits per os, iIs ont fréquemment des effets secondaires digestifs limitant leur usage et sont donc mieux tolérés en iv. C'est le pamidronate qui a été le premier prescrit et reste le plus utilisé. Méthode : le meilleur régime d'administration du pamidronate n'étant pas connu, nous avons testé son effet à différentes doses sur les marqueurs du remodelage osseux et la densitométrie osseuse. Trois modalités d'administration pour une dose annuelle constante (30 mg tous les 3 mois, 40 mg tous les 4 mois et 60 mg tous les 6 mois) ont été comparées chez des femmes postménopausées avec une ostéoporose. 39 patientes ont été recrutées sur 2 ans et réparties en 2 groupes appelés EFAP 1 et 2 pour Evaluation de la Fréquence d'Administration du Pamidronate selon la fréquence des contrôles de sang. Résultats : au cours des 6 premiers mois de traitement, on observe une chute rapide des télopeptides sanguins dès le premier mois qui suit l'injection de 30, 40 ou 60 mg de pamidronate avec toutefois, une inhibition de la résorption osseuse plus efficace à long terme pour les traitements fractionnés (30 et 40 mg). Des résultats similaires sont obtenus pour l'ostéocalcine. Il n'existe en revanche pas de modifications significatives des autres paramètres (calcémie, PTH, vitamine D et phosphatase alcaline) dans les 3 groupes. Ces résultats se confirment après 24 mois de traitement avec une efficacité plus marquée pour les traitements 30 et 40 mg. Sur le plan des valeurs de densitométrie osseuse, après 2 ans de traitement, les valeurs sont augmentées de façon significative sur la colonne lombaire avec les trais dosages, de façon non significatives sur le col fémoral et de façon significative pour le trochanter avec le dosage de 40 mg seulement. Conclusions : bien que cette étude démontre des gains de densité osseuse quasi identiques entre les 3 modes d'administration pour une dose annuelle cumulée de 120 mg, l'inhibition du remodelage osseux est beaucoup plus importante avec les doses de 30 ou 40 mg tous les 3 ou 4 mois qu'avec 60 mg tous les 6 mois. Ces deux modes d'administration permettent de mieux expliquer le lien entre l'effet sur les marqueurs et sur la densitométrie osseuse.

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SUMMARY Both proteasomes and additional proteases play an essential role in the generation of most antigenic peptides presented by MHC class I molecules. Therefore, it is of major importance to characterize the mechanisms leading to the production of correct antigenic peptides to improve the design of vaccines. As a model determinant we used the melanoma-associated protein Melan-A, which contains the immunodominant CTL-epitope Melan-A26/27-35/HLA-A*0201 and against which a high frequency of T lymphocytes has been detected in many melanoma patients. In a first part, we have studied the effects of antigen processing on the induction of a specific T cell response in vivo. Our results have shown that the immunoproteasome, expressed in most cells after exposure to Interferon-γ (IFN-γ) and constitutively in some specialized cells such as dendritic cells, does not efficiently process the HLA¬A2-restricted peptide Melan-A26-35. We have produced recombinant lentiviral vectors (rec. 1v) and vaccinia virus (rec. vv) encoding either preprocessed Melan-A26-35(A27L) peptide or full-length Melan-A(A27L). The immunization of HLA-A2/Kb mice with thoses viruses indicates that immunoproteasomes negatively affect the induction of anti-Melan-A T cell responses in animals immunized with vectors coding for the full- length protein. This negative effect was abrogated in HLA-A2/Kb LMP2-/- mice, lacking the immunoproteasomes. Therefore, we can conclude that the expression of immunoproteasomes limits the induction of the anti-Melan-A T cell response. In a second part, we show that the in vitro degradation of a Melan-A26/27-35 precursor by the proteasomes produces both the final antigenic peptide and N-terminally extended intermediates. When human melanoma cells expressing the corresponding fragments were exposed to specific CTL, those expressing the minimal antigenic sequence were recognized more efficiently than those expressing the N-terminally extended intermediates. We demonstrated that the N-terminally extended intermediates were inefficiently trimmed by cytosolic proteases. These results imply that both proteasomes and post-proteasomal peptidases influence the availability of antigenic peptides and that the efficiency of presentation may be affected by conditions that alter the ratio between fully and partially processed proteasomal products. RESUME Le protéasome ainsi que d'autres protéases jouent un rôle essentiel dans l'apprêtement de la plupart des peptides antigéniques présentés par les molécules de MHC classe I. Il est donc particulièrement important de connaître les mécanismes menant à la production du peptide antigénique correct afin de pouvoir mieux définir de futurs vaccins. Nous avons utilisé la protéine associée au mélanome, Melan-A, contenant un épitope immunodominant Melan-A26/27-35/HLA-A*0201 contre lequel une fréquence élevée de lymphocytes T a été detectée dans plusieurs patients atteints de mélanome. Dans une première partie, nous avons étudié les effets de l'apprêtement du peptide antigéniques Melan-A26-35 sur l'induction de cellules T spécifiques dans la souris. Nos résultats ont démontré que l'immunoprotéasome, exprimé dans la plupart des cellules après exposition à de l'IFN-γ et exprimé constitutivement dans certaines cellules spécialisées, telles les cellules dendritiques, n'apprête pas efficacement le peptide antigénique Melan-A26-35 restreint par HLA-A2 in vitro. Nous avons produit des vecteurs lentiviraux recombinants ainsi que des virus vaccinia codant pour le peptide antigénique Melan-A26-35(A27L) et pour la protéine entière Melan-A(A27L). L'immunisation de souris HLA-A2/Kb avec ces virus démontre que l'immunoprotéasome affecte négativement l'induction d'une réponse T contre Melan¬-A dans les souris immunisées avec des virus contenant la séquence de la protéine entière. Cet effet négatif est complètement aboli dans les souris HLA-A2/Kb LMP2-/- qui n'expriment pas l'immunoprotéasome. Deuxièmement, nous avons demontré que la dégradation d'un peptide précurseur contenant Melan-A26/27-35 par le protéasome produit à la fois le peptide antigénique ainsi que des peptides rallongés à leurs extrémités N-terminales. Lorsque ces fragments sont exprimés dans des cellules humaines et exposés à des cellules T cytotoxiques (CTL), celles qui expriment le peptide antigénique final sont reconnus plus efficacement que celles exprimant les peptides rallongés en N-terminus. Nous avons démontré que les peptides rallongés en N-terminus ne sont pas apprêtés efficacement par les peptidases du cytosol. L'inefficacité de l'apprêtement des peptides rallongés dans le cytosol offre un certain avantage pour les peptides directement produits par le protéasome. Ces résultats impliquent donc que le protéasome ainsi que les peptidases post-proteasomales influencent l'accessibilité des peptides antigéniques.

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RESUME :Introduction. Les maladies cardiovasculaires représentent la première cause de mortalité dans les pays développés et l'insuffisance cardiaque (IC) est la plus fréquente. Suite à un infarctus, le coeur des patients subit un remodelage ventriculaire pouvant évoluer vers un état d'IC. L'IC se définit comme un état dans lequel le coeur n'est plus capable d'approvisionner suffisamment les organes et cet état s'accompagne souvent de troubles du rythme cardiaque. Le remodelage ventriculaire touche de nombreux gènes codant à la fois pour les voies métaboliques et pour des canaux ioniques favorisant ainsi l'apparition des arythmies responsables de la mort subite des patients atteints d'IC. Comprendre ce passage entre remodelage et IC est crucial afin de pouvoir un jour prévenir l'IC et les complications médicales qui l'accompagnent. Nous nous sommes intéressés aux canaux potassiques dépendants de l'ATP (KATP) car ces canaux ont la capacité de coupler le métabolisme de la cellule à son activité électrique. En effet, les canaux KATP s'ouvrent quand la charge énergétique (rapport ATP/ ADP) de la cellule chute. Dans les cardiomyocytes, l'ouverture des KATP induit une hyperpolarisation de la membrane cellulaire ce qui diminue indirectement la surcharge calcique et de ce fait préserve la cellule. Les canaux KATp sont formés de 4 sous-unités Kir6.x (Kir6.1 ou Kir6.2) formant le pore du canal associées à 4 sous-unités régulatrices SUR. Les propriétés électrophysiologiques ainsi que la sensibilité pharmacologique des canaux KATP dépendent de leur composition et seuls les canaux KATP formés par la sous-unité Kirô.l sont activés par le diazoxyde.Méthodes et résultats. Nous avons d'abord montré dans un modèle in vivo d'IC chez le rat adulte que les sous-unités Kir6.1 et SUR sont surexprimées dans ces conditions pathologiques. Par ailleurs, les cardiomyocytes issus des coeurs infarcis deviennent sensibles au diazoxyde reflétant la surexpression de Kir6.1. Les potentiels d'action qui sont prolongés dans l'IC et qui sont à l'origine d'arythmies majeures sont normalisés par l'ouverture des canaux KATp induite par le diazoxyde. Ainsi, l'ouverture pharmacologique des canaux KATp contribuerait à la cardio-protection. Dans une seconde partie, nous avons déterminé quels étaient les facteurs de transcription responsables de ce changement d'expression des sous-unités formant les KATP. Dans notre modèle, nous avons pu montrer que la surexpression de Kirô.l est due aux facteurs de transcription Fox03 et FoxF2 qui est aussi responsable de la surexpression des sous-unités SUR. Dans la dernière partie de ce travail, nous avons mis au point un modèle d'IC in vitro en cultivant les cardiomyocytes de rats adultes en présence d'angiotensine II (Angll) ou de TNFa. Ce modèle expérimental nous a non seulement permis de mettre en relation l'importance de L'AnglI et du TNFa sur le remodelage des canaux KATP mais aussi de développer un modèle in vitro présentant les mêmes caractéristiques que le modèle in vivo concernant le remodelage des KATP lors de l'IC. Ce dernier modèle expérimental ouvre des perspectives afin de mieux caractériser les voies de signalisation impliquées dans le remodelage des canaux KATp lors de l'IC.Conclusion. Les canaux KATp subissent un remodelage lors de l'IC et les résultats obtenus montrent le potentiel cardio-protecteur de ces canaux.ABSTRACT :Background and aim. Cardiovascular disease is the leading cause of death in developed countries and heart failure (HF) is the most common. Following myocardial infarction, the heart of the patient undergoes ventricular remodeling which may evolve toward a state of HF. HF is defined as a state in which heart is unable to supply enough blood to organs and this state is often accompanied by cardiac arrhythmias. Ventricular remodeling involves many genes coding for both metabolic enzymes and ion channels. Changes in ion channel expression can promote arrhythmias responsible for sudden death in patients with HF. A better understanding of the transition between remodeling and HF is crucial in order to prevent the complications associated to HF We were interested in ATP-dependent potassium channels (KATp) because they couple cell metabolism to electrical activity of the cell. Indeed, KATP channels open when the energy charge (ratio of ATP / ADP) of the cell collapses. In cardiomyocytes, the opening of KATP channels induces hyper- polanzation of the cell membrane which reduces calcium overload and thereby protects the cell. KATp channels are composed by 4 Kir6.x subumts (Kir6.1 or Kir6.2) forming the pore channel associated with 4 regulatory subunits SUR. The electrophysiological properties as well as pharmacological sensitivity of KATp channels depend on their composition and only KATP channels formed by Kir6.1 subunit are activated by diazoxide.Methods and results. Firstly, using an in vivo model of HF in adult rats, we showed that Kir6.1 and SUR subunits are overexpressed in HF. In addition, cardiomyocytes from post-infarction hearts became sensitive to diazoxide reflecting the overexpression of the Kir6.1 subunit. The opening of KATP by diazoxide tended to reduce the action potential duration (APD) which is extended in HF. This increase in APD is known to be a major source of arrhythmias during HF. Therefore, the opening of KATP channels by diazoxide would be cardio-protective. Secondly, we wanted to determine which transcription factors were responsible for this KATP remodeling. In our model of HF, we showed that overexpression of Kir6.1 is due to the transcription factors Fox03 and FOXF2 which is also responsible for SUR subunits overexpression. Thirdly, we developed an in vitro model of HF by cultivation of adult rat cardiomyocytes in the presence of angiotensin II (Angll) or TNFa. This model is very interesting not only because it underlines the importance of Angll and TNFa in KATp remodeling but also because this in vitro model presents the same KATP remodeling as the in vivo model of HF. These findings show that our in vitro model of HF opens up many possibilities to investigate more precisely the signaling pathways involved in remodeling of the KATP channels in HF.Conclusion. KATP channels undergo remodeling during HF and our results show the cardio¬protective potential of KATP channels in this disease.

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BACKGROUND: Radiation optic neuropathy (RON) is a rare, unpredictable, late complication of radiotherapy secondary to obliterative endarteritis. Tumor recurrence has to be ruled out by a clinical and neuroradiological examination. METHODS: Five patients with RON were investigated by magnetic resonance imaging (MRI) during 1992. RESULTS: Radiation-induced lesions of the intracranial visual pathways were easily visible on MRI. Without Gadolinium, a sectorial swelling was detectable, which markedly enhanced with Gadolinium. Intracranial optic nerve was affected in 5/5 cases, optic chiasm in 3/5 cases, and optic tract in 2/5 cases. CONCLUSIONS: MRI is the examination of choice when RON is suspected: it will easily delineate the extent of the lesion, and compression/infiltration by a recurrent tumor will be formally ruled out. A segmental swelling of visual pathway with marked Gadolinium enhancement on MRI is highly suggestive of radionecrosis.

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AIM: This study aims to investigate the clinical and demographic factors influencing gentamicin pharmacokinetics in a large cohort of unselected premature and term newborns and to evaluate optimal regimens in this population. METHODS: All gentamicin concentration data, along with clinical and demographic characteristics, were retrieved from medical charts in a Neonatal Intensive Care Unit over 5 years within the frame of a routine therapeutic drug monitoring programme. Data were described using non-linear mixed-effects regression analysis ( nonmem®). RESULTS: A total of 3039 gentamicin concentrations collected in 994 preterm and 455 term newborns were included in the analysis. A two compartment model best characterized gentamicin disposition. The average parameter estimates, for a median body weight of 2170 g, were clearance (CL) 0.089 l h(-1) (CV 28%), central volume of distribution (Vc ) 0.908 l (CV 18%), intercompartmental clearance (Q) 0.157 l h(-1) and peripheral volume of distribution (Vp ) 0.560 l. Body weight, gestational age and post-natal age positively influenced CL. Dopamine co-administration had a significant negative effect on CL, whereas the influence of indomethacin and furosemide was not significant. Both body weight and gestational age significantly influenced Vc . Model-based simulations confirmed that, compared with term neonates, preterm infants need higher doses, superior to 4 mg kg(-1) , at extended intervals to achieve adequate concentrations. CONCLUSIONS: This observational study conducted in a large cohort of newborns confirms the importance of body weight and gestational age for dosage adjustment. The model will serve to set up dosing recommendations and elaborate a Bayesian tool for dosage individualization based on concentration monitoring.

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The pancreatic beta cell presents functional abnormalities in the early stages of development of non-insulin dependent diabetes mellitus (NIDDM). The disappearance of the first phase of insulin secretion induced by a glucose load is a early marker of NIDDM. This abnormality could be secondary to the low expression of the pancreatic glucose transporter GLUT2. Together with the glucokinase enzyme, GLUT2 is responsible for proper beta cell sensing of the extracellular glucose levels. In NIDDM, the GLUT2 mRNA levels are low, a fact which suggests a transcriptional defect of the GLUT2 gene. The first phase of glucose-induced insulin secretion by the beta pancreatic cell can be partly restored by the administration of a peptide discovered by a molecular approach, the glucagon-like peptide 1 (GLP-1). The gene encoding for the glucagon is expressed in a cell-specific manner in the A cells of the pancreatic islet and the L cells of the intestinal tract. The maturation process of the propeptide encoded by the glucagon gene is different in the two cells: the glucagon is the main hormone produced by the A cells whereas the glucagon-like peptide 1 (GLP-1) is the major peptide synthesized by the L cells of the intestine. GLP-1 is an incretin hormone and is at present the most potent insulinotropic peptide. The first results of the administration of GLP-1 to normal volunteers and diabetic patients are promising and may be a new therapeutic approach to treating diabetic patients.

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It has been demonstrated in earlier studies that patients with a cochlear implant have increased abilities for audio-visual integration because the crude information transmitted by the cochlear implant requires the persistent use of the complementary speech information from the visual channel. The brain network for these abilities needs to be clarified. We used an independent components analysis (ICA) of the activation (H2 (15) O) positron emission tomography data to explore occipito-temporal brain activity in post-lingually deaf patients with unilaterally implanted cochlear implants at several months post-implantation (T1), shortly after implantation (T0) and in normal hearing controls. In between-group analysis, patients at T1 had greater blood flow in the left middle temporal cortex as compared with T0 and normal hearing controls. In within-group analysis, patients at T0 had a task-related ICA component in the visual cortex, and patients at T1 had one task-related ICA component in the left middle temporal cortex and the other in the visual cortex. The time courses of temporal and visual activities during the positron emission tomography examination at T1 were highly correlated, meaning that synchronized integrative activity occurred. The greater involvement of the visual cortex and its close coupling with the temporal cortex at T1 confirm the importance of audio-visual integration in more experienced cochlear implant subjects at the cortical level.

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Cervicofacial actinomycosis is an uncommon, progressive infection caused by bacilli of the Actinomyces genus. Actinomyces are common commensal saprophytes in the oral cavity which may have medical importance as facultative pathogens. Subsequent to local injuries to the oral mucosa, they may penetrate the deep tissues and be responsible for suppurative or granulomatous infections. We herein report a case of a 65-year-old man who underwent surgery followed by chemotherapy and radiotherapy for a tonsillar carcinoma. An ulcerous lesion in the base of the tongue developed and spread to the carotid artery wall. The man died of a massive hemorrhage due to left carotid artery rupture. Postmortem computed tomography angiography performed prior to autopsy allowed the precise localization of the source of bleeding to be detected. Postmortem biochemical investigations confirmed the presence of inflammation associated with local bacterial infection. Histological investigations revealed the rupture of the left carotid artery surrounded by numerous colonies of Actinomyces. Acute and chronic inflammation with tissue necrosis as well as post-actinic, fibrotic changes were also found in the tissues surrounding the ruptured artery wall.

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In 2006, two municipalities located in the canton of Fribourg (Switzerland), La Tour-de-Trême and Bulle, amalgamated. In this study, we report on the evolution of citizen perceptions as well as try to better understand the reasons behind the respondents various positions concerning this new political and territorial entity. Five-hundred individuals were surveyed almost four years after the amalgamation came into effect. Our results show that if the amalgamation was voted again, it would be necessary to be particularly attentive to citizen access to municipal offices and to local service provisions, to citizen identification to their municipality as well as to the life of the local associations. Indeed, these are clearly important issues for small localities. Furthermore, citizens of the newly amalgamated municipality are mostly sensitive to access to municipal offices and to contact with local representatives. Improving the population's perceptions of these particular issues could lead to a 12 percentage point increase in support for the amalgamation.

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PURPOSE: We investigated the incidence and distribution of post-mortem gas detected with multidetector computed tomography (MDCT) to identify factors that could distinguish artifactual gas from cardiac air embolism. MATERIAL AND METHODS: MDCT data of 119 cadavers were retrospectively examined. Gas was semiquantitatively assessed in selected blood vessels, organs, and body spaces (82 total sites). RESULTS: Seventy-four of the 119 cadavers displayed gas (62.2%; CI 95% 52.8-70.9), and 56 (75.7%) displayed gas in the heart. Most gas was detected in the hepatic parenchyma (40%), right heart (38% ventricle, 35% atrium), inferior vena cava (30% infrarenally, 26% suprarenally), hepatic veins (26% left, 29% middle, 22% right), and portal spaces (29%). Male cadavers displayed gas more frequently than female cadavers. Gas was detected 5-84 hours after death; therefore, the post-mortem interval could not reliably predict gas distribution (rho = 0.719, p < 0.0001). We found that a large amount of putrefaction-generated gas in the right heart was associated with aggregated gas bubbles in the hepatic parenchyma (sensitivity = 100%, specificity = 89.7%). In contrast, gas in the left heart (sensitivity = 41.7%, specificity = 100%) or in periumbilical subcutaneous tissues (sensitivity = 50%, specificity = 96.3%) could not predict gas due to putrefaction. CONCLUSION: This study is the first to show that the appearance of post-mortem gas follows a specific distribution pattern. An association between intracardiac gas and hepatic parenchymal gas could distinguish between post-mortem-generated gas and vital air embolism. We propose that this finding provides a key for diagnosing death due to cardiac air embolism.

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We present the study of the geochemical processes associated with the first successful remediation of a marine shore tailings deposit in a coastal desert environment (Bahia de Ite, in the Atacama Desert of Peru). The remediation approach implemented a wetland on top of the oxidized tailings. The site is characterized by a high hydrauliz gradient produced by agricultural irrigation on upstream gravel terraces that pushed river water (similar to 500 mg/L SO(4)) toward the sea and through the tailings deposit. The geochemical and isotopic (delta(2)H(water) and delta(18)O(water), delta(34)S(sulfate) , delta(18)O(sulfate)) approach applied here revealed that evaporite horizons (anhydrite and halite) in the gravel terraces are the source of increased concentrations of SO(4), Cl, and Na up to similar to 1500 mg/L in the springs at the base of the gravel terraces. Deeper groundwater interacting with underlying marine sequences increased the concentrations of SO(4), Cl, and Na up to 6000 mg/L and increased the alkalinity up to 923 mg/L CaCO(3) eq. in the coastal aquifer. These waters infiltrated into the tailings deposit at the shelf-tailings interface. Nonremediated tailings had a low-pH oxidation zone (pH 1-4) with significant accumulations of efflorescent salts (10-20 cm thick) at the surface because of upward capillary transport of metal cations in the arid climate. Remediated tailings were characterized by neutral pH and reducing conditions (pH similar to 7, Eh similar to 100 mV). As a result, most bivalent metals such as Cu, Zn, and Ni had very low concentrations (around 0.01 mg/L or below detection limit) because of reduction and sorption processes. In contrast, these reducing conditions increased the mobility of iron from two sources in this system: (1) The originally Fe(III)-rich oxidation zone, where Fe(II) was reduced during the remediation process and formed an Fe(II) plume, and (2) reductive dissolution of Fe(III) oxides present in the original shelf lithology formed an Fe-Mn plume at 10-m depth. These two Fe-rich plumes were pushed toward the shoreline where more oxidizing and higher pH conditions triggered the precipitation of Fe(HI)hydroxide coatings on silicates. These coatings acted as a filter for the arsenic, which naturally infiltrated with the river water (similar to 500 mu g/L As natural background) into the tailings deposit.

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