Detection of hemorrhage source: the diagnostic value of post-mortem CT-angiography.

The aim of this study was to compare the diagnostic value of post-mortem computed tomography angiography (PMCTA) to conventional, ante-mortem computed tomography (CT)-scan, CT-angiography (CTA) and digital subtraction angiography (DSA) in the detection and localization of the source of bleeding in cases of acute hemorrhage with fatal outcomes. The medical records and imaging scans of nine individuals who underwent a conventional, ante-mortem CT-scan, CTA or DSA and later died in the hospital as a result of an acute hemorrhage were reviewed. Post-mortem computed tomography angiography, using multi-phase post-mortem CTA, as well as medico-legal autopsies were performed. Localization accuracy of the bleeding was assessed by comparing the diagnostic findings of the different techniques. The results revealed that data from ante-mortem and post-mortem radiological examinations were similar, though the PMCTA showed a higher sensitivity for detecting the hemorrhage source than did ante-mortem radiological investigations. By comparing the results of PMCTA and conventional autopsy, much higher sensitivity was noted in PMCTA in identifying the source of the bleeding. In fact, the vessels involved were identified in eight out of nine cases using PMCTA and only in three cases through conventional autopsy. Our study showed that PMCTA, similar to clinical radiological investigations, is able to precisely identify lesions of arterial and/or venous vessels and thus determine the source of bleeding in cases of acute hemorrhages with fatal outcomes.

Prevalence and significance of anti-HILA antibodies after liver transplantation : P236

Background: The pathogenic role of anti-HLA antibodies (AHA) after kidney transplantation is well established. However, its significance after liver transplantation remains unclear. The aim of our study was to determine the prevalence and significance of AHA after liver transplantation. Methods: Between January 2007 and November 2007, all liver transplant recipients who were greater than 6 months posttransplantation and followed regularly at our transplant outpatient clinic (n = 95) were screened for AHA. All clinical and electronic records were reviewed. Serum samples were tested using multiplex technology (Luminex). A liver biopsy had been performed in 55 out of the 95 patients based on clinical grounds but no routine protocol biopsies were performed. Immunosuppression was calcineurin inhibitor-based in 90 patients, sirolimus-based in 4 patients and one patient had no anti-rejection therapy (operationally tolerant recipient). Results: The mean time from transplantation to study was 85 months (range 6-248 months). Overall, AHA were found in 23/95 (24.2%) of patients (5 had anti-class I alone, 13 anti-class II alone, and 4 had both anti-class I and II). However, only 4/95 patients (4.2%) had donor-specific antibodies (DSA) (one anti-class I and 3 anti-class II). Twenty-one out of 95 patients (22.1%) had a history of past or current biopsy-proven or radiological biliary complications (chronic rejection, ischemic cholangitis, ischemic type biliary lesions or biliary anastomosis stricture). Among patients with AHA, 4/23 (17,4%) had biliary complications, while it was 17/72 (23.6%) in patients without AHA (NS). Among patients with DSA, 3/4 (75%) had biliary complications (two with biopsy-proven chronic rejection in association with biliary strictures and one with ischemic cholangitis following hepatic artery thrombosis), versus 1/19 (5.3%) patients with AHA but no DSA (p = 0.009), versus 16/72 (22.2%) patients without AHA (p = 0.046). In patients with DSA, immunosuppression was not different than in patients without DSA. Conclusions: We found a 24% AHA prevalence. The presence of DSA, but not of AHA, was significantly associated with an increased incidence of biliary complications including chronic liver allograft rejection. The exact mechanisms and possible causal relationship linking DSA to biliary complications remain to be studied. Larger prospective trials are thus needed to further define the role of AHA and in particular of DSA after liver transplantation.

Structural macro factors and the affine term structure of interest rates

This work consists of three essays investigating the ability of structural macroeconomic models to price zero coupon U.S. government bonds. 1. A small scale 3 factor DSGE model implying constant term premium is able to provide reasonable a fit for the term structure only at the expense of the persistence parameters of the structural shocks. The test of the structural model against one that has constant but unrestricted prices of risk parameters shows that the exogenous prices of risk-model is only weakly preferred. We provide an MLE based variance-covariance matrix of the Metropolis Proposal Density that improves convergence speeds in MCMC chains. 2. Affine in observable macro-variables, prices of risk specification is excessively flexible and provides term-structure fit without significantly altering the structural parameters. The exogenous component of the SDF is separating the macro part of the model from the term structure and the good term structure fit has as a driving force an extremely volatile SDF and an implied average short rate that is inexplicable. We conclude that the no arbitrage restrictions do not suffice to temper the SDF, thus there is need for more restrictions. We introduce a penalty-function methodology that proves useful in showing that affine prices of risk specifications are able to reconcile stable macro-dynamics with good term structure fit and a plausible SDF. 3. The level factor is reproduced most importantly by the preference shock to which it is strongly and positively related but technology and monetary shocks, with negative loadings, are also contributing to its replication. The slope factor is only related to the monetary policy shocks and it is poorly explained. We find that there are gains in in- and out-of-sample forecast of consumption and inflation if term structure information is used in a time varying hybrid prices of risk setting. In-sample yield forecast are better in models with non-stationary shocks for the period 1982-1988. After this period, time varying market price of risk models provide better in-sample forecasts. For the period 2005-2008, out of sample forecast of consumption and inflation are better if term structure information is incorporated in the DSGE model but yields are better forecasted by a pure macro DSGE model.

La néphropathie ischémique par athérosclérose aortorénale : acquisitions thérapeutiques [Atherosclerotic renal artery disease management update]

In the case of atherosclerotic renal artery disease, the best conclusive results lie principally not in the degree of the stenosis but rather in the degree the renal parenchymal disease beyond the stenosis itself. These determining factors involve the controlling of the patients blood pressure, the improvement in the renal function and the beneficial results to the cardiovascular system. Besides the indispensable medical treatment, a revascularisation by angioplasty may be indicated. This procedure with or without vascular stent often allows satisfactory angiographic results. A treatment by surgical revascularisation is only recommended in the case of extensive atherosclerotic lesions of the aorta, complex lesions of the latter or an abdominal aortic aneurism. Although the frequency of restenosis of angioplasty with stent remains extremely low, the risk of cholesterol emboli due to the diffuse atherosclerotic lesions of the abdominal aorta, must be considered at the time of each aortic catheterization. The therapeutic approach of atherosclerotic renal artery disease must be dictated by the whole cardiovascular risk factors and by the threat of target organs. The control of the blood pressure and the maintenance of the renal function must be integrated in the decisional algorithm as well as the possible risks in carrying out an eventual revascularisation procedure. Finally, the renal angioplasty should in numerous situations be integrated in the overall assumption of responsibility of the atherosclerotic vascular diseases, and should be part of the medical treatment. Several questions still do exist; at what moment an atherosclerotic renal artery stenosis should and e considered critical, and which procedure should be considered for which patient? The purpose of this review is to propose a decisional tool for individualized treatments in the light of results from randomized and controlled studies.

Intracellular thiol-mediated modulation of epithelial sodium channel activity.

The epithelial sodium channel ENaC is physiologically important in the kidney for the regulation of the extracellular fluid volume, and in the lungs for the maintenance of the appropriate airway surface liquid volume that lines the pulmonary epithelium. Besides the regulation of ENaC by hormones, intracellular factors such as Na(+) ions, pH, or Ca(2+) are responsible for fast adaptive responses of ENaC activity to changes in the intracellular milieu. In this study, we show that ENaC is rapidly and reversibly inhibited by internal sulfhydryl-reactive molecules such as methanethiosulfonate derivatives of different sizes, the metal cations Cd(2+) and Zn(2+), or copper(II) phenanthroline, a mild oxidizing agent that promotes the formation of disulfide bonds. At the single channel level, these agents applied intracellularly induce the appearance of long channel closures, suggesting an effect on ENaC gating. The intracellular reducing agent dithiothreitol fully reverses the rundown of ENaC activity in inside-out patches. Our observations suggest that changes in intracellular redox potential modulate ENaC activity and may regulate ENaC-mediated Na(+) transport in epithelia. Finally, substitution experiments reveal that multiple cysteine residues in the amino and carboxyl termini of ENaC subunits are responsible for this thiol-mediated inhibition of ENaC.

The 16p11.2 rearrangments genetic paradigms for obesity and neurodevelopmental disorders.

Recent discoveries of recurrent and reciprocal Copy Number Variants (CNVs) using genome- wide studies have led to a new understanding of the etiology of neuropsychiatric disorders. CNVs represent loss (deletion) or gain (duplication) of genomic material. This thesis work is focused on CNVs at the 16p11.2 BP4-BP5 locus, which are among the most frequent etiologies of neurodevelopmental disorders and have been associated with Autism Spectrum Disorders (ASD), schizophrenia, cognitive impairment, alterations of brain size as well as obesity and underweight. Because deletion and duplication of the 16p11.2 locus occur frequently and recurrently (with the same breakpoints), CNVs at this locus represent a powerful paradigm to understand how a genomic region may modulate cognitive and behavioral traits as well as the relationship and shared mechanisms between distinct psychiatric diagnoses such as ASD and schizophrenia. The present dissertation includes three studies: 1) The first project aims at identifying structural brain-imaging endophenotypes in 16p11.2 CNVs carriers at risk for ASD and schizophrenia. The results show that gene dosage at the 16p11.2 locus modulates global brain volumes and neural circuitry, including the reward system, language and social cognition circuits. 2) The second investigates the neuropsychological profile in 16p11.2 deletion and duplication carriers. While deletion carriers show specific deficits in language and inhibition, the profile of duplication carriers is devoid of specific weaknesses and presents enhanced performance in a verbal memory task. 3) The third study on food-related behaviors in 16p11.2 deletion and duplication carriers shows that alterations of the reponse to satiety are present in CNV carriers before the onset of obesity, pointing toward a potential mechanism driving the Body Mass Index increase in deletion carriers. Dysfunctions in the reward system and dopaminergic circuitries could represent a common mechanism playing a role in the phenotype and could be investigated in future studies. Our data strongly suggest that complex cognitive traits correlate to gene dosage in humans. Larger studies including expression data would allow elucidating the contribution of specific genes to these different gene dosage effects. In conclusion, a systematic and careful investigation of cognitive, behavioral and intermediate phenotypes using a gene dosage paradigm has allowed us to advance our understanding of the 16p11.2 BP4-BP5 locus and its effects on neurodevelopment. -- La récente découverte de variations du nombre de copies (CNVs pour 'copy number variants') dans le génome humain a amélioré nos connaissances sur l'étiologie des troubles neuropsychiatriques. Un CNV représente une perte (délétion) ou un gain (duplication) de matériel génétique sur un segment chromosomique. Ce travail de thèse est focalisé sur les CNVs réciproques (délétion et duplication) dans la région 16p11.2 BP4-BP5. Ces CNVs sont une cause fréquente de troubles neurodéveloppementaux et ont été associés à des phénotypes « en miroir » tels que obésité/sous-poids ou macro/microcéphalie mais aussi aux troubles du spectre autistique (TSA), à la schizophrénie et au retard de développement/déficience intellectuelle. La fréquence et la récurrence de la délétion et de la duplication aux mêmes points de cassure font de ces CNVs un paradigme unique pour étudier la relation entre dosage génique et les traits cognitifs et comportementaux, ainsi que les mécanismes partagés par des troubles psychiatriques apparemment distincts tels que les TSA et la schizophrénie. Ce travail de thèse comporte trois études distinctes : 1) l'étude en neuroimagerie structurelle identifie les endophénotypes chez les porteurs de la délétion ou de la duplication. Les résultats montrent une influence du dosage génique sur le volume cérébral total et certaines structures dans les systèmes de récompense, du langage et de la cognition sociale. 2) L'étude des profils neuropsychologiques chez les porteurs de la délétion ou de la duplication montre que la délétion est associée à des troubles spécifiques du langage et de l'inhibition alors que les porteurs de la duplication ne montrent pas de faiblesse spécifique mais des performances mnésiques verbales supérieures à leur niveau cognitif global. 3) L'étude sur les comportements alimentaires met en évidence une altération de la réponse à la satiété qui est présente avant l'apparition de l'obésité. Un dysfonctionnement dans le système de récompense et les circuits dopaminergiques pourrait représenter un mécanisme commun aux différents phénotypes observés chez ces individus porteurs de CNVs au locus 16p11.2. En conclusion, l'utilisation du dosage génique comme outil d'investigation des phénotypes cliniques et endophénotypes nous a permis de mieux comprendre le rôle de la région 16p11.2 BP4-BP5 dans le neurodéveloppement.

Breast implant-associated anaplastic large cell lymphoma: two distinct clinicopathological variants with different outcomes.

BACKGROUND: ALK-negative anaplastic large cell lymphoma associated with breast implant (i-ALCL) has been recently recognized as a distinct entity. Among 43 830 lymphomas registered in the French Lymphopath network since 2010, 300 breast lymphomas comprising 25 peripheral T-cell lymphomas (PTCL) were reviewed. Among PTCL, ALK-negative ALCL was the most frequent and all of them were associated with breast implants. PATIENTS AND METHODS: Since 2010, all i-ALCL cases were collected from different institutions through Lymphopath. Immuno-morphologic features, molecular data and clinical outcome of 19 i-ALCLs have been retrospectively analyzed. RESULTS: The median age of the patients was 61 years and the median length between breast implant and i-ALCL was 9 years. Most implants were silicone-filled and textured. Implant removal was performed in 17 out of 19 patients with additional treatment based on mostly CHOP or CHOP-like chemotherapy regimens (n = 10/19) or irradiation (n = 1/19). CHOP alone or ABVD following radiation without implant removal have been given in two patients. The two clinical presentations, i.e. effusion and less frequently tumor mass correlated with distinct histopathologic features: in situ i-ALCL (anaplastic cell proliferation confined to the fibrous capsule) and infiltrative i-ALCL (pleomorphic cells massively infiltrating adjacent tissue with eosinophils and sometimes Reed-Sternberg-like cells mimicking Hodgkin lymphoma). Malignant cells were CD30-positive, showed a variable staining for EMA and were ALK negative. Most cases had a cytotoxic T-cell immunophenotype with variable T-cell antigen loss and pSTAT3 nuclear expression. T-cell receptor genes were clonally rearranged in 13 out of 13 tested cases. After 18 months of median follow-up, the 2-year overall survival for in situ and infiltrative i-ALCL was 100% and 52.5%, respectively. CONCLUSIONS: In situ i-ALCLs have an indolent clinical course and generally remain free of disease after implant removal. However, infiltrative i-ALCLs could have a more aggressive clinical course that might require additional therapy to implant removal.