Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory.

Idiopathic hypogonadotropic hypogonadism (IHH) is defined by absent or incomplete puberty and characterised biochemically by low levels of sex steroids, with low or inappropriately normal gonadotropin hormones. IHH is frequently accompanied by non-reproductive abnormalities, most commonly anosmia, which is present in 50-60% of cases and defines Kallmann syndrome. The understanding of IHH has undergone rapid evolution, both in respect of genetics and breadth of phenotype. Once considered in monogenic Mendelian terms, it is now more coherently understood as a complex genetic condition. Oligogenic and complex genetic-environmental interactions have now been identified, with physiological and environmental factors interacting in genetically susceptible individuals to alter the clinical course and phenotype. These potentially link IHH to ancient evolutionary pressures on the ancestral human genome.

L'exploitation des traces dans les accidents de la circulation

Les investigations dans le milieu des accidents de la circulation sont très complexes. Elles nécessitent la mise en oeuvre d'un grand nombre de spécialités venant de domaines très différents. Si certains de ces domaines sont déjà bien exploités, d'autres demeurent encore incomplets et il arrive de nos jours d'observer des lacunes dans la pratique, auxquelles il est primordial de remédier.Ce travail de thèse, intitulé « l'exploitation des traces dans les accidents de la circulation », est issu d'une réflexion interdisciplinaire entre de multiples aspects des sciences forensiques. Il s'agit principalement d'une recherche ayant pour objectif de démontrer les avantages découlant d'une synergie entre les microtraces et l'étude de la dynamique d'un accident. Afin de donner une dimension très opérationnelle à ce travail, l'ensemble des démarches entreprises a été axé de manière à optimiser l'activité des premiers intervenants sur les lieux.Après une partie introductive et ayant trait au projet de recherche, traitant des aspects théoriques de la reconstruction d'une scène d'accident, le lecteur est invité à prendre connaissance de cinq chapitres pratiques, abordés selon la doctrine « du général au particulier ». La première étape de cette partie pratique concerne l'étude de la morphologie des traces. Des séquences d'examens sont proposées pour améliorer l'interprétation des contacts entre véhicules et obstacles impliqués dans un accident. Les mécanismes de transfert des traces de peinture sont ensuite étudiés et une série de tests en laboratoire est pratiquée sur des pièces de carrosseries automobiles. Différents paramètres sont ainsi testés afin de comprendre leur impact sur la fragilité d'un système de peinture. Par la suite, une liste de cas traités (crash-tests et cas réels), apportant des informations intéressantes sur le traitement d'une affaire et permettant de confirmer les résultats obtenus est effectuée. Il s'ensuit un recueil de traces, issu de l'expérience pratique acquise et ayant pour but d'aiguiller la recherche et le prélèvement sur les lieux. Finalement, la problématique d'une banque de données « accident », permettant une gestion optimale des traces récoltées est abordée.---The investigations of traffic accidents are very complex. They require the implementation of a large number of specialties coming from very different domains. If some of these domains are already well exploited, others remain still incomplete and it happens nowadays to observe gaps in the practice, which it is essential to remedy. This thesis, entitled "the exploitation of traces in traffic accidents", arises from a multidisciplinary reflection between the different aspects of forensic science. It is primarily a research aimed to demonstrate the benefits of synergy between microtrace evidence and accidents dynamics. To give a very operational dimension to this work, all the undertaken initiatives were centred so as to optimise the activity of the first participants on the crime scene.After an introductory part treating theoretical aspects of the reconstruction of an accident scene the reader is invited to get acquainted with five practical chapters, according to the doctrine "from general to particular". For the first stage of this practical part, the problem of the morphology of traces is approached and sequences of examinations are proposed to improve the interpretation of the contacts between vehicles and obstacles involved in an accident. Afterwards, the mechanisms of transfer of traces of paint are studied and a series of tests in laboratory is practised on pieces of automobile bodies. Various parameters are thus tested to understand their impact on the fragility of a system of paint. It follows that a list of treated cases (crash-tests and real cases) is created, allowing to bring interesting information on the treatment of a case and confirm the obtained results. Then, this work goes on with a collection of traces, stemming from the acquired experience that aims to steer the research and the taking of evidence on scenes. Finally, the practical part of this thesis ends with the problem of a database « accident », allowing an optimal management of the collected traces.

Impact of HLA A2 and cytomegalovirus serostatus on outcomes in patients with leukemia following matched-sibling myeloablative allogeneic hematopoietic cell transplantation.

BACKGROUND AND OBJECTIVES: Donor cytomegalovirus seropositivity was reported to improve leukemia outcomes in HLA-A2 identical hematopoietic cell transplant (HCT) recipients, due to a possible cross-reactivity of donor HLA-A2-restricted CMV-specific T cells with minor histocompatibility (H) antigen of recipient cells. This study analyzed the role of donor CMV serostatus and HLA-A2 status on leukemia outcomes in a large population of HLA-identical HCT recipients. DESIGN AND METHODS: Leukemia patients transplanted between 1992 and 2003 at the Fred Hutchinson Cancer Research Center were categorized as standard risk [leukemia first remission, chronic myeloid leukemia in chronic phase (CML-CP)] and high risk (advanced disease) patients. Time-to-event analysis was used to evaluate the risk of relapse and death associated with HLA-A2 status and donor CMV serostatus. RESULTS: In standard risk patients, acute leukemia (p<0.001) and sex mismatch (female to male, p=0.004)) independently increased the risk of death, while acute leukemia increased the risk of relapse (p<0.001). In high risk patients acute leukemia (p=0.01), recipient age > or = 40 (p=0.005) and herpes simplex virus (HSV) seropositivity (p<0.001) significantly increased the risk death; HSV seropositivity (p=0.006) increased the risk of relapse. Donor CMV serostatus had no significant effect on mortality or relapse in any HLA group. INTERPRETATION AND CONCLUSION: This epidemiological study did not confirm the previously reported effect of donor CMV serostatus on the outcomes of leukemia in HLA-A2-identical HCT recipients. Addressing the question of cross-reactivity of HLA-A2-restricted CMV-specific T cells with minor H antigens in a clinical study would require knowledge of the patient's minor H antigen genotype. However, because of the unbalanced distribution of HLA-A2-restricted minor H antigens in the population and their incomplete identification, this question might be more appropriately evaluated in in vitro experiments than in a clinical study.

Wind Monitoring of the Saylorville and Red Rock Reservoir Bridges with Remote, Cellular-Based Notifications, May 2012

Following high winds on January 24, 2006, at least five people claimed to have seen or felt the superstructure of the Saylorville Reservoir Bridge in central Iowa moving both vertically and laterally. Since that time, the Iowa Department of Transportation (DOT) contracted with the Bridge Engineering Center at Iowa State University to design and install a monitoring system capable of providing notification of the occurrence of subsequent high winds. Although measures were put into place following the 2006 event at the Saylorville Reservoir Bridge, knowledge of the performance of this bridge during high wind events was incomplete. Therefore, the Saylorville Reservoir Bridge was outfitted with an information management system to investigate the structural performance of the structure and the potential for safety risks. In subsequent years, given the similarities between the Saylorville and Red Rock Reservoir bridges, a similar system was added to the Red Rock Reservoir Bridge southeast of Des Moines. The monitoring system developed and installed on these two bridges was designed to monitor the wind speed and direction at the bridge and, via a cellular modem, send a text message to Iowa DOT staff when wind speeds meet a predetermined threshold. The original intent was that, once the text message is received, the bridge entrances would be closed until wind speeds diminish to safe levels.

Detection of coronary thrombosis after multi-phase postmortem CT-angiography.

The aim of this study was to compare postmortem angiography-based, autopsy-based and histology-based diagnoses of acute coronary thrombosis in a series of medicolegal cases that underwent postmortem angiographies according to multiphase CT-angiography protocol. Our study included 150 medicolegal cases. All cases underwent native CT-scan, postmortem angiography, complete conventional autopsy and histological examination of the main organs and coronary arteries. In 10 out of the 150 investigated cases, postmortem angiographies revealed coronary arterial luminal filling defects and the absence of collateral vessels, suggesting acute coronary thromboses. Radiological findings were confirmed by autopsy and histological examinations in all cases. In 40 out of 150 cases, angiograms revealed complete or incomplete coronary arterial luminal filling defects and the presence of collateral vessels. Histological examinations did not reveal free-floating or non-adherent thrombi in the coronary arteries in any of these cases. Though postmortem angiography examination has not been well-established for the diagnosis of acute coronary thrombosis, luminal filling defects in coronary arteries suggesting acute thromboses can be observed through angiography and subsequently confirmed by autopsy and histological examinations.

Auditory verbal hallucinations of epileptic origin.

Complex auditory hallucinations are often characterized by hearing voices and are then called auditory verbal hallucinations (AVHs). While AVHs have been extensively investigated in psychiatric patients suffering from schizophrenia, reports from neurological patients are rare and, in most cases, incomplete. Here, we characterize AVHs in 9 patients suffering from pharmacoresistant epilepsy by analyzing the phenomenology of AVHs and patients' neuropsychological and lesion profiles. From a cohort of 352 consecutively examined patients with epilepsy, 9 patients suffering AVHs were identified and studied by means of a semistructured interview, neuropsychological tests, and multimodal imaging, relying on a combination of functional and structural neuroimaging data and surface and intracranial EEG. We found that AVHs in patients with epilepsy were associated with prevalent language deficits and damage to posterior language areas and basal language areas in the left temporal cortex. Auditory verbal hallucinations, most of the times, consisted in hearing a single voice of the same gender and language as the patient and had specific spatial features, being, most of the times, perceived in the external space, contralateral to the lesion. We argue that the consistent location of AVHs in the contralesional external space, the prominence of associated language deficits, and the prevalence of lesions to the posterior temporal language areas characterize AVHs of neurological origin, distinguishing them from those of psychiatric origin.

Cardiologie [Cardiology].

The present review provides a selected choice of clinical research in the field of interventional cardiology, electrophysiology and cardiac imaging. We also focused on the new guidelines published by the European society of cardiology in 2010 (revascularization, atrial fibrillation and device therapy in heart failure).

An Essential Role for Insulin and IGF1 Receptors in Regulating Sertoli Cell Proliferation, Testis Size, and FSH Action in Mice.

Testis size and sperm production are directly correlated to the total number of adult Sertoli cells (SCs). Although the establishment of an adequate number of SCs is crucial for future male fertility, the identification and characterization of the factors regulating SC survival, proliferation, and maturation remain incomplete. To investigate whether the IGF system is required for germ cell (GC) and SC development and function, we inactivated the insulin receptor (Insr), the IGF1 receptor (Igf1r), or both receptors specifically in the GC lineage or in SCs. Whereas ablation of insulin/IGF signaling appears dispensable for GCs and spermatogenesis, adult testes of mice lacking both Insr and Igf1r in SCs (SC-Insr;Igf1r) displayed a 75% reduction in testis size and daily sperm production as a result of a reduced proliferation rate of immature SCs during the late fetal and early neonatal testicular period. In addition, in vivo analyses revealed that FSH requires the insulin/IGF signaling pathway to mediate its proliferative effects on immature SCs. Collectively, these results emphasize the essential role played by growth factors of the insulin family in regulating the final number of SCs, testis size, and daily sperm output. They also indicate that the insulin/IGF signaling pathway is required for FSH-mediated SC proliferation.

Origin of siderite mineralisation in Petrova and Trgovska Gora Mts., NW Dinarides

The Petrova and Trgovska Gora Mts. (Gora=Mountain) are Variscan basement units incorporated into the northwestern Dinarides during the Alpine orogeny. They host numerous siderite-quartz-polysulphide, siderite-chalcopyrite, siderite-galena and barite veins, as well as stratabound hydrothermal-replacement ankerite bodies within carbonates in non-metamorphosed, flysch-like Permo-Carboniferous sequences. The deposits have been mined for Cu, Pb, Ag and Fe ores since Medieval times. Fluid inclusion studies of quartz from siderite-polysulphide-quartz and barite veins of both regions have shown the presence of primary aqueous NaCl-CaCl(2)+/- MgCl(2)-H(2)O +/- CO(2) inclusions. The quartz-sulphide stage of both regions show variable salinities; 2.7-26.2 wt% NaCl eq. for the Trgovska Gora region and 3.4-23.4 wt% NaCl eq. for the Petrova gora region, and similar homogenisation temperatures (100-230A degrees C). Finally, barite is precipitated from low salinity-low temperature solutions (3.7-15.8 wt % NaCl equ. and 115-145A degrees C). P-t conditions estimated via isochore construction yield formation temperatures between 180-250A degrees C for the quartz-sulphide stage and 160-180A degrees C for the barite stage, using a maximum lithostatic pressure of 1 kbar (cc. 3 km of overburden). The sulphur isotope composition of barite from both deposits indicates the involvement of Permian seawater in ore fluids. This is supported by the elevated bromium content of the fluid inclusion leachates (120-660 ppm in quartz, 420-960 ppm in barite) with respect to the seawater, indicating evaporated seawater as the major portion of the ore-forming fluids. Variable sulphur isotope compositions of galena, pyrite and chalcopyrite, between -3.2 and +2.7aEuro degrees, are interpreted as a product of incomplete thermal reduction of the Permian marine sulphate mixed with organically- and pyrite-bound sulphur from the host sedimentary rocks. Ore-forming fluids are interpreted as deep-circulating fluids derived primarily from evaporated Permian seawater and later modified by interaction with the Variscan basement rocks. (40)Ar/(39)Ar data of the detrital mica from the host rocks yielded the Variscan age overprinted by an Early Permian tectonothermal event dated at 266-274 Ma. These ages are interpreted as those reflecting hydrothermal activity correlated with an incipient intracontinental rifting in the Tethyan domain. Nevertheless, 75 Ma recorded at a fine-grained sericite sample from the alteration zone is interpreted as a result of later resetting of white mica during Campanian opening/closure of the Sava back arc in the neighbouring Sava suture zone (Ustaszewski et al. 2008).

Integrated methodologies to study human transcriptional regulation from functional genomics data

Abstract : The human body is composed of a huge number of cells acting together in a concerted manner. The current understanding is that proteins perform most of the necessary activities in keeping a cell alive. The DNA, on the other hand, stores the information on how to produce the different proteins in the genome. Regulating gene transcription is the first important step that can thus affect the life of a cell, modify its functions and its responses to the environment. Regulation is a complex operation that involves specialized proteins, the transcription factors. Transcription factors (TFs) can bind to DNA and activate the processes leading to the expression of genes into new proteins. Errors in this process may lead to diseases. In particular, some transcription factors have been associated with a lethal pathological state, commonly known as cancer, associated with uncontrolled cellular proliferation, invasiveness of healthy tissues and abnormal responses to stimuli. Understanding cancer-related regulatory programs is a difficult task, often involving several TFs interacting together and influencing each other's activity. This Thesis presents new computational methodologies to study gene regulation. In addition we present applications of our methods to the understanding of cancer-related regulatory programs. The understanding of transcriptional regulation is a major challenge. We address this difficult question combining computational approaches with large collections of heterogeneous experimental data. In detail, we design signal processing tools to recover transcription factors binding sites on the DNA from genome-wide surveys like chromatin immunoprecipitation assays on tiling arrays (ChIP-chip). We then use the localization about the binding of TFs to explain expression levels of regulated genes. In this way we identify a regulatory synergy between two TFs, the oncogene C-MYC and SP1. C-MYC and SP1 bind preferentially at promoters and when SP1 binds next to C-NIYC on the DNA, the nearby gene is strongly expressed. The association between the two TFs at promoters is reflected by the binding sites conservation across mammals, by the permissive underlying chromatin states 'it represents an important control mechanism involved in cellular proliferation, thereby involved in cancer. Secondly, we identify the characteristics of TF estrogen receptor alpha (hERa) target genes and we study the influence of hERa in regulating transcription. hERa, upon hormone estrogen signaling, binds to DNA to regulate transcription of its targets in concert with its co-factors. To overcome the scarce experimental data about the binding sites of other TFs that may interact with hERa, we conduct in silico analysis of the sequences underlying the ChIP sites using the collection of position weight matrices (PWMs) of hERa partners, TFs FOXA1 and SP1. We combine ChIP-chip and ChIP-paired-end-diTags (ChIP-pet) data about hERa binding on DNA with the sequence information to explain gene expression levels in a large collection of cancer tissue samples and also on studies about the response of cells to estrogen. We confirm that hERa binding sites are distributed anywhere on the genome. However, we distinguish between binding sites near promoters and binding sites along the transcripts. The first group shows weak binding of hERa and high occurrence of SP1 motifs, in particular near estrogen responsive genes. The second group shows strong binding of hERa and significant correlation between the number of binding sites along a gene and the strength of gene induction in presence of estrogen. Some binding sites of the second group also show presence of FOXA1, but the role of this TF still needs to be investigated. Different mechanisms have been proposed to explain hERa-mediated induction of gene expression. Our work supports the model of hERa activating gene expression from distal binding sites by interacting with promoter bound TFs, like SP1. hERa has been associated with survival rates of breast cancer patients, though explanatory models are still incomplete: this result is important to better understand how hERa can control gene expression. Thirdly, we address the difficult question of regulatory network inference. We tackle this problem analyzing time-series of biological measurements such as quantification of mRNA levels or protein concentrations. Our approach uses the well-established penalized linear regression models where we impose sparseness on the connectivity of the regulatory network. We extend this method enforcing the coherence of the regulatory dependencies: a TF must coherently behave as an activator, or a repressor on all its targets. This requirement is implemented as constraints on the signs of the regressed coefficients in the penalized linear regression model. Our approach is better at reconstructing meaningful biological networks than previous methods based on penalized regression. The method is tested on the DREAM2 challenge of reconstructing a five-genes/TFs regulatory network obtaining the best performance in the "undirected signed excitatory" category. Thus, these bioinformatics methods, which are reliable, interpretable and fast enough to cover large biological dataset, have enabled us to better understand gene regulation in humans.

Is intracerebral hemorrhage a time-dependent phenomenon after successful combined intravenous and intra-arterial therapy?

BACKGROUND AND PURPOSE: Onset-to-reperfusion time (ORT) has recently emerged as an essential prognostic factor in acute ischemic stroke therapy. Although favorable outcome is associated with reduced ORT, it remains unclear whether intracranial bleeding depends on ORT. We therefore sought to determine whether ORT influenced the risk and volume of intracerebral hemorrhage (ICH) after combined intravenous and intra-arterial therapy. METHODS: Based on our prospective registry, we included 157 consecutive acute ischemic stroke patients successfully recanalized with combined intravenous and intra-arterial therapy between April 2007 and October 2011. Primary outcome was any ICH within 24 hours posttreatment. Secondary outcomes included occurrence of symptomatic ICH (sICH) and ICH volume measured with the ABC/2. RESULTS: Any ICH occurred in 26% of the study sample (n=33). sICH occurred in 5.5% (n=7). Median ICH volume was 0.8 mL. ORT was increased in patients with ICH (median=260 minutes; interquartile range=230-306) compared with patients without ICH (median=226 minutes; interquartile range=200-281; P=0.008). In the setting of sICH, ORT reached a median of 300 minutes (interquartile range=276-401; P=0.004). The difference remained significant after adjustment for potential confounding factors (adjusted P=0.045 for ICH; adjusted P=0.002 for sICH). There was no correlation between ICH volume and ORT (r=0.16; P=0.33). CONCLUSIONS: ORT influences the rate but not the volume of ICH and appears to be a critical predictor of symptomatic hemorrhage after successful combined intravenous and intra-arterial therapy. To minimize the risk of bleeding, revascularization should be achieved within 4.5 hours of stroke onset.

Mycobactéries non tuberculeuses maladie pulmonaire: quoi de neuf [Non tuberculous mycobacteria pulmonary disease: what's new?].

The incidence of NTM (non tuberculous mycobacteria) pulmonary disease is increasing. The diagnosis must be established in the presence of clinical, radiological and microbiological findings. Groups at risk to contract pulmonary disease due to NTM are patients with underlying structural lung disease. Treatment of NTM is long and requires multiple drugs combinations. Relapses and re-infection are not rare. Our understanding in many matters of NTM pulmonary disease is incomplete. Further research is necessary in order to understand the host's defense mechanisms against NTM, and the factors that influence the evolution to lung disease.

Controls on ostracod valve geochemistry: Part 2. Carbon and oxygen isotope compositions

The stable carbon and oxygen isotope compositions of fossil ostracods are powerful tools to estimate past environmental and climatic conditions. The basis for such interpretations is that the calcite of the valves reflects the isotopic composition of water and its temperature of formation. However, calcite of ostracods is known not to form in isotopic equilibrium with water and different species may have different offsets from inorganic precipitates of calcite formed under the same conditions. To estimate the fractionation during ostracod valve calcification, the oxygen and carbon isotope compositions of 15 species living in Lake Geneva were related to their autoecology and the environmental parameters measured during their growth. The results indicate that: (1) Oxygen isotope fractionation is similar for all species of Candoninae with an enrichment in 18O of more than 30/00 relative to equilibrium values for inorganic calcite. Oxygen isotope fractionation for Cytheroidea is less discriminative relative to the heavy oxygen, with enrichments in 18O for these species of 1.7 to 2.30/00. Oxygen isotope fractionations for Cyprididae are in-between those of Candoninae and Cytheroidea. The difference in oxygen isotope fractionation between ostracods and inorganic calcite has been interpreted as resulting from a vital effect. (2) Comparison with previous work suggests that oxygen isotope fractionation may depend on the total and relative ion content of water. (3) Carbon isotope compositions of ostracod valves are generally in equilibrium with DIC. The specimens' δ13C values are mainly controlled by seasonal variations in δ13CDIC of bottom water or variation thereof in sediment pore water. (4) Incomplete valve calcification has an effect on carbon and oxygen isotope compositions of ostracod valves. Preferential incorporation of at the beginning of valve calcification may explain this effect. (5) Results presented here as well as results from synthetic carbonate growth indicate that different growth rates or low pH within the calcification site cannot be the cause of oxygen isotope 'vital effects' in ostracods. Two mechanisms that might enrich the 18O of ostracod valves are deprotonation of that may also contribute to valve calcification, and effects comparable to salt effects with high concentrations of Ca and/or Mg within the calcification site that may also cause a higher temperature dependency of oxygen isotope fractionation.

Cancer du sein et obésité, une liaison dangereuse [Breast cancer and obesity, a dangerous relation].

Obesity is associated with different cancers including breast cancer, whose incidence is increased in postmenopausal women. It has an adverse impact on the prognosis of the patients, regardless of their menopausal status. The fact of receiving a systemic adjuvant therapy does not neutralize the prognostic role of obesity. Moderate weight loss after cancer diagnosis could improve the outcome of the patients, while a weight gain during treatment seems without significant effect. Currently available data are still too incomplete to justify systematic programs to lose weight with an oncologic therapeutic aim. However, it is worth to encourage and support our patients to have an optimal diet, physical activity, and to lose weight as promotion of general health.

Laparoscopic surgery for coeliac artery compression syndrome: current management and technical aspects.

Objectives: The study aims to assess the feasibility and midterm outcome of trans-peritoneal laparoscopy for coeliac artery compression syndrome (CACS).Design: Retrospective chart review involving four European vascular surgery departments and two surgical teams.Materials and methods: charts for patients who underwent laparoscopy for symptomatic CACS between December 2003 and November 2009 were reviewed. Preoperative computed tomography (CT) angiography and postoperative duplex scan and/or CT angiography were performed.Results: Eleven consecutive patients (nine women) with a median age of 52 years (interquartile range: 42.5-59 years) underwent trans-peritoneal laparoscopy for CACS. All patients had a history of postprandial abdominal pain; weight loss exceeded 10% of the body mass in eight cases. Preoperative CT angiography revealed coeliac trunk stenosis >70% in all cases. One patient had additional aortitis and inferior mesenteric artery occlusion, while another patient presented with an occluded superior mesenteric artery. Two conversions occurred (one difficult dissection and one aorto-hepatic bypass needed for incomplete release of CACS). The median blood loss was 195 ml (range: 50-900 ml) and median operative time was 80 min (interquartile range: 65-162.5 years). Symptoms improved immediately in 10/11 patients (no residual stenosis) while one remained unchanged despite a residual stenosis treated by a percutaneous angioplasty. Symptoms reappeared in one patient due to coeliac axis occlusion. The mean follow-up period was 35 +/- 23 months (range: 12-78 months).Conclusion: Our study demonstrates that trans-peritoneal laparoscopy for treating median arcuate ligament syndrome is safe and feasible. Additional patients and a longer follow-up are needed for long-term assessment of this laparoscopic technique. (C) 2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.