Detection, analysis and monitoring of slope movements by high-resolution digital elevation models

Summary Detection, analysis and monitoring of slope movements by high-resolution digital elevation modelsSlope movements, such as rockfalls, rockslides, shallow landslides or debris flows, are frequent in many mountainous areas. These natural hazards endanger the inhabitants and infrastructures making it necessary to assess the hazard and risk caused by these phenomena. This PhD thesis explores various approaches using digital elevation models (DEMs) - and particularly high-resolution DEMs created by aerial or terrestrial laser scanning (TLS) - that contribute to the assessment of slope movement hazard at regional and local scales.The regional detection of areas prone to rockfalls and large rockslides uses different morphologic criteria or geometric instability factors derived from DEMs, i.e. the steepness of the slope, the presence of discontinuities, which enable a sliding mechanism, and the denudation potential. The combination of these factors leads to a map of susceptibility to rockfall initiation that is in good agreement with field studies as shown with the example of the Little Mill Campground area (Utah, USA). Another case study in the Illgraben catchment in the Swiss Alps highlighted the link between areas with a high denudation potential and actual rockfall areas.Techniques for a detailed analysis and characterization of slope movements based on high-resolution DEMs have been developed for specific, localized sites, i.e. ancient slide scars, present active instabilities or potential slope instabilities. The analysis of the site's characteristics mainly focuses on rock slopes and includes structural analyses (orientation of discontinuities); estimation of spacing, persistence and roughness of discontinuities; failure mechanisms based on the structural setting; and volume calculations. For the volume estimation a new 3D approach was tested to reconstruct the topography before a landslide or to construct the basal failure surface of an active or potential instability. The rockslides at Åknes, Tafjord and Rundefjellet in western Norway were principally used as study sites to develop and test the different techniques.The monitoring of slope instabilities investigated in this PhD thesis is essentially based on multitemporal (or sequential) high-resolution DEMs, in particular sequential point clouds acquired by TLS. The changes in the topography due to slope movements can be detected and quantified by sequential TLS datasets, notably by shortest distance comparisons revealing the 3D slope movements over the entire region of interest. A detailed analysis of rock slope movements is based on the affine transformation between an initial and a final state of the rock mass and its decomposition into translational and rotational movements. Monitoring using TLS was very successful on the fast-moving Eiger rockslide in the Swiss Alps, but also on the active rockslides of Åknes and Nordnesfjellet (northern Norway). One of the main achievements on the Eiger and Aknes rockslides is to combine the site's morphology and structural setting with the measured slope movements to produce coherent instability models. Both case studies also highlighted a strong control of the structures in the rock mass on the sliding directions. TLS was also used to monitor slope movements in soils, such as landslides in sensitive clays in Québec (Canada), shallow landslides on river banks (Sorge River, Switzerland) and a debris flow channel (Illgraben).The PhD thesis underlines the broad uses of high-resolution DEMs and especially of TLS in the detection, analysis and monitoring of slope movements. Future studies should explore in more depth the different techniques and approaches developed and used in this PhD, improve them and better integrate the findings in current hazard assessment practices and in slope stability models.Résumé Détection, analyse et surveillance de mouvements de versant à l'aide de modèles numériques de terrain de haute résolutionDes mouvements de versant, tels que des chutes de blocs, glissements de terrain ou laves torrentielles, sont fréquents dans des régions montagneuses et mettent en danger les habitants et les infrastructures ce qui rend nécessaire d'évaluer le danger et le risque causé par ces phénomènes naturels. Ce travail de thèse explore diverses approches qui utilisent des modèles numériques de terrain (MNT) et surtout des MNT de haute résolution créés par scanner laser terrestre (SLT) ou aérien - et qui contribuent à l'évaluation du danger de mouvements de versant à l'échelle régionale et locale.La détection régionale de zones propices aux chutes de blocs ou aux éboulements utilise plusieurs critères morphologiques dérivés d'un MNT, tels que la pente, la présence de discontinuités qui permettent un mécanisme de glissement ou le potentiel de dénudation. La combinaison de ces facteurs d'instabilité mène vers une carte de susceptibilité aux chutes de blocs qui est en accord avec des travaux de terrain comme démontré avec l'exemple du Little Mill Campground (Utah, États-Unis). Un autre cas d'étude - l'Illgraben dans les Alpes valaisannes - a mis en évidence le lien entre les zones à fort potentiel de dénudation et les sources effectives de chutes de blocs et d'éboulements.Des techniques pour l'analyse et la caractérisation détaillée de mouvements de versant basées sur des MNT de haute résolution ont été développées pour des sites spécifiques et localisés, comme par exemple des cicatrices d'anciens éboulements et des instabilités actives ou potentielles. Cette analyse se focalise principalement sur des pentes rocheuses et comprend l'analyse structurale (orientation des discontinuités); l'estimation de l'espacement, la persistance et la rugosité des discontinuités; l'établissement des mécanismes de rupture; et le calcul de volumes. Pour cela une nouvelle approche a été testée en rétablissant la topographie antérieure au glissement ou en construisant la surface de rupture d'instabilités actuelles ou potentielles. Les glissements rocheux d'Åknes, Tafjord et Rundefjellet en Norvège ont été surtout utilisés comme cas d'étude pour développer et tester les diverses approches. La surveillance d'instabilités de versant effectuée dans cette thèse de doctorat est essentiellement basée sur des MNT de haute résolution multi-temporels (ou séquentiels), en particulier des nuages de points séquentiels acquis par SLT. Les changements topographiques dus aux mouvements de versant peuvent être détectés et quantifiés sur l'ensemble d'un glissement, notamment par comparaisons des distances les plus courtes entre deux nuages de points. L'analyse détaillée des mouvements est basée sur la transformation affine entre la position initiale et finale d'un bloc et sa décomposition en mouvements translationnels et rotationnels. La surveillance par SLT a démontré son potentiel avec l'effondrement d'un pan de l'Eiger dans les Alpes suisses, mais aussi aux glissements rocheux d'Aknes et Nordnesfjellet en Norvège. Une des principales avancées à l'Eiger et à Aknes est la création de modèles d'instabilité cohérents en combinant la morphologie et l'agencement structural des sites avec les mesures de déplacements. Ces deux cas d'étude ont aussi démontré le fort contrôle des structures existantes dans le massif rocheux sur les directions de glissement. Le SLT a également été utilisé pour surveiller des glissements dans des terrains meubles comme dans les argiles sensibles au Québec (Canada), sur les berges de la rivière Sorge en Suisse et dans le chenal à laves torrentielles de l'Illgraben.Cette thèse de doctorat souligne le vaste champ d'applications des MNT de haute résolution et particulièrement du SLT dans la détection, l'analyse et la surveillance des mouvements de versant. Des études futures devraient explorer plus en profondeur les différentes techniques et approches développées, les améliorer et mieux les intégrer dans des pratiques actuelles d'analyse de danger et surtout dans la modélisation de stabilité des versants.

Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial.

PURPOSE: Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer, to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting. PATIENTS AND METHODS: Formalin-fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively collected and DNA was extracted from tissue sections from 1,404 cases. Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction. Survival analyses were based on univariate and multivariate proportional hazard regression models. RESULTS: KRAS and BRAF tumor mutation rates were 37.0% and 7.9%, respectively, and were not significantly different according to tumor stage. In a multivariate analysis containing stage, tumor site, nodal status, sex, age, grade, and microsatellite instability (MSI) status, KRAS mutation was associated with grade (P = .0016), while BRAF mutation was significantly associated with female sex (P = .017), and highly significantly associated with right-sided tumors, older age, high grade, and MSI-high tumors (all P < 10(-4)). In univariate and multivariate analysis, KRAS mutations did not have a major prognostic value regarding relapse-free survival (RFS) or overall survival (OS). BRAF mutation was not prognostic for RFS, but was for OS, particularly in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003). CONCLUSION: In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.

Copeptin as a diagnostic biomarker for sepsis-related deaths.

Copeptin has been shown to increase in patients with sepsis, severe sepsis and septic shock. In the study herein described, copeptin was measured in a series of sepsis-related fatalities and control cases that underwent medico-legal investigations. No age-dependent differences in copeptin levels in either sepsis or control cases were observed. No correlation between copeptin concentrations and postmortem interval was identified in either group. Copeptin levels were significantly higher in sepsis cases. Moreover, copeptin concentrations in septic cases correlated with procalcitonin, C-reactive protein and interleukin 6 values. These preliminary findings seem to indicate that copeptin can be reliably measured in biological samples collected during postmortem investigations. These results also suggest that hemodynamic instability associated with sepsis and septic shock can be characterized by copeptin measurement also in the forensic casework.

The role of the Fanconi anemia network in the response to DNA replication stress.

Fanconi anemia is a genetically heterogeneous disorder associated with chromosome instability and a highly elevated risk for developing cancer. The mutated genes encode proteins involved in the cellular response to DNA replication stress. Fanconi anemia proteins are extensively connected with DNA caretaker proteins, and appear to function as a hub for the coordination of DNA repair with DNA replication and cell cycle progression. At a molecular level, however, the raison d'être of Fanconi anemia proteins still remains largely elusive. The thirteen Fanconi anemia proteins identified to date have not been embraced into a single and defined biological process. To help put the Fanconi anemia puzzle into perspective, we begin this review with a summary of the strategies employed by prokaryotes and eukaryotes to tolerate obstacles to the progression of replication forks. We then summarize what we know about Fanconi anemia with an emphasis on biochemical aspects, and discuss how the Fanconi anemia network, a late acquisition in evolution, may function to permit the faithful and complete duplication of our very large vertebrate chromosomes.

Whole anterior segment proton beam radiotherapy for diffuse iris melanoma.

AIM: To report the results of whole anterior segment proton beam radiotherapy (PBR) for diffuse iris melanoma. METHODS: Between 2000 and 2011, 12 patients with iris melanoma received PBR to the entire iris and ciliary body. RESULTS: Patients had a mean age of 57 years and a median follow-up of 3.5 years (range 1-11.6 years). Tumour iris involvement was 1-4 h in five patients, 5-8 h in four and 9-12 h in three. Angle involvement was 6-8 h in five patients and 9-12 h in seven. The visual acuity (VA) before treatment was 6/5-6/6 in six patients, 6/8-6/9 in three and 6/18-6/38 in three. No tumour recurrence occurred during the follow-up period. Glaucoma treatment was required in 11 of 12 patients. The visual acuity at the last follow-up was 6/5-6/9 in five patients, 6/18-6/24 in three, 6/60-1/60 in two and no light perception in two. Four patients developed varying non-severe degrees of limbal stem cell deficiency, which was treatable with conservative measures. CONCLUSIONS: Whole anterior segment PBR is a useful alternative to enucleation for diffuse iris melanoma. Most patients will need treatment for glaucoma and some may require treatment for tear-film instability and/or stem cell failure.

79-OR: Measurement of β-tryptase in postmortem serum in cardiac death

Mast cells are well known for their role in hypersensitivity reactions. However, there is increasing evidence that they might also participate in both developing and weakening atherosclerotic plaques, potentially causing plaque instability. Some clinical studies have therefore postulated the existence of relationships between blood β-tryptase levels and acute coronary syndromes. In this study, we investigated postmortem serum β-tryptase levels in a series of 90 autopsy cases with various degrees of coronary atherosclerosisthat had undergone medico-legal investigations. β-tryptase concentrations in these cases were compared to levels observed in 6 fatal anaphylaxis cases following contrast material administration. Postmortem serum β-tryptase concentrations in the anaphylactic deaths ranged from 146 to 979 ng/ml. In 9 out of 90 cases of cardiac deaths, β-tryptase levels were higher than clinical reference values of 11.4 ng/ml and ranged from 21 to 65 ng/ml. These results indicate that increased postmortem serum β-tryptase levels can be observed, though not systematically, in cardiac deaths with varying degrees of coronary atherosclerosis disease, thereby suggesting that mast cell activation in this disease cannot be ascertained by postmortem serum β-tryptase measurements.

Pathogenesis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. The major aetiologies and risk factors for the development of HCC are well defined and some of the multiple steps involved in hepatocarcinogenesis have been elucidated in recent years. However, no clear picture of how and in what sequence these factors interact at the molecular level has emerged yet. Malignant transformation of hepatocytes may occur as a consequence of various aetiologies, such as chronic viral hepatitis, alcohol, and metabolic disorders, in the context of increased cellular turnover induced by chronic liver injury, regeneration and cirrhosis. Activation of cellular oncogenes, inactivation of tumour suppressor genes, genomic instability, including DNA mismatch repair defects and impaired chromosomal segregation, overexpression of growth and angiogenic factors, and telomerase activation may contribute to the development of HCC. Overall, HCCs are genetically very heterogeneous tumours. New technologies, including gene expression profiling and proteomic analyses, should allow us to further elucidate the molecular events underlying HCC development and identify novel diagnostic markers as well as therapeutic targets.

A new technique to improve tissue grip and contact force in arthroscopic capsulolabral repair: the MIBA stitch.

The success of anatomic repair of Bankart lesion diminishes in the presence of a capsule stretching and/or attenuation is reported in a variable percentage of patients with a chronic gleno-humeral instability. We introduce a new arthroscopic stitch, the MIBA stitch, designed with a twofold aim: to improve tissue grip to reduce the risk of soft tissue tear, particularly cutting through capsular-labral tissue, to and address capsule-labral detachment and capsular attenuation using a double loaded suture anchor. This stitch is a combination of horizontal mattress stitch passing through the capsular-labral complex in a "south-to-north" direction and an overlapping single vertical suture passing through the capsule and labrum in a "east-to-west" direction. The mattress stitch is tied before the vertical stitch in order to reinforce the simple vertical stitch, improving grip and contact force between capsular-labral tissue and glenoid bone.

Reticulocyte dynamic and hemoglobin variability in hemodialysis patients treated with Darbepoetin alfa and C.E.R.A.: a randomized controlled trial.

BACKGROUND: In a simulation based on a pharmacokinetic model we demonstrated that increasing the erythropoiesis stimulating agents (ESAs) half-life or shortening their administration interval decreases hemoglobin variability. The benefit of reducing the administration interval was however lessened by the variability induced by more frequent dosage adjustments. The purpose of this study was to analyze the reticulocyte and hemoglobin kinetics and variability under different ESAs and administration intervals in a collective of chronic hemodialysis patients. METHODS: The study was designed as an open-label, randomized, four-period cross-over investigation, including 30 patients under chronic hemodialysis at the regional hospital of Locarno (Switzerland) in February 2010 and lasting 2 years. Four subcutaneous treatment strategies (C.E.R.A. every 4 weeks Q4W and every 2 weeks Q2W, Darbepoetin alfa Q4W and Q2W) were compared with each other. The mean square successive difference of hemoglobin, reticulocyte count and ESAs dose was used to quantify variability. We distinguished a short- and a long-term variability based respectively on the weekly and monthly successive difference. RESULTS: No difference was found in the mean values of biological parameters (hemoglobin, reticulocytes, and ferritin) between the 4 strategies. ESAs type did not affect hemoglobin and reticulocyte variability, but C.E.R.A induced a more sustained reticulocytes response over time and increased the risk of hemoglobin overshooting (OR 2.7, p = 0.01). Shortening the administration interval lessened the amplitude of reticulocyte count fluctuations but resulted in more frequent ESAs dose adjustments and in amplified reticulocyte and hemoglobin variability. Q2W administration interval was however more favorable in terms of ESAs dose, allowing a 38% C.E.R.A. dose reduction, and no increase of Darbepoetin alfa. CONCLUSIONS: The reticulocyte dynamic was a more sensitive marker of time instability of the hemoglobin response under ESAs therapy. The ESAs administration interval had a greater impact on hemoglobin variability than the ESAs type. The more protracted reticulocyte response induced by C.E.R.A. could explain both, the observed higher risk of overshoot and the significant increase in efficacy when shortening its administration interval.Trial registrationClinicalTrials.gov NCT01666301.

Impact of etanercept-methotrexate therapy on patient-reported outcomes in rheumatoid arthritis patients with up to 12 months of symptoms.

Background/Purpose: Patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) are critical in evaluating RA treatment effects on function and health-related quality of life (HR-QoL). Significant improvement in PROs has been reported in RA studies of biologic agents, including etanercept (ETN), but most studies have been conducted in patients with established disease. In addition to assessing treatment effects in early RA, there is interest in therapeutic strategies that allow dose reduction or withdrawal of biologic therapy (biologic-free) after induction of response. The PRIZE trial is an ongoing, 3-period study to evaluate the efficacy of combined ETN and methotrexate (MTX) therapy in patients with early, moderate-to-severe RA and to assess whether efficacy (remission) can be maintained with ETN dose reduction or biologic-free (Period 2) or drug-free (Period 3). Herein we report PROs associated with ETN 50 mg QW plus MTX (ETN50/MTX) therapy administered for 52 wks in Period 1 (induction) of the PRIZE trial. Methods: In Period 1, MTX- and biologic-naı‥ve patients with early, active RA (symptom onset 12 mo from enrollment; DAS28 _3.2) received open-label ETN50/MTX for 52 wks. The starting dose of MTX was 10 mg QW; at the discretion of the investigator, titration was permitted up to a maximum of 25 mg QW to achieve remission. Corticosteroid boosts were administered to patients not achieving low disease state at wks 13 and 26, unless contraindicated or not tolerated. PROs were assessed using the Health Assessment Questionnaire (HAQ) total score; Patient Acceptable Symptom State (PASS); EuroQol-5 Dimensions (EQ-5D) total index; Short Form Health Survey (SF-36); Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue; Work Instability Scale for Rheumatoid Arthritis (RAWIS); and Work Productivity and Activity Impairment Questionnaire: Rheumatoid Arthritis (WPAI:RA). Results: A total of 306 patients received treatment in Period 1 (mITT population); 222 (73%) patients completed the period. The majority of patients were female (70%), with a mean age of 50 y, mean DAS28 of 6.0 (median, 6.0), and duration of disease symptoms from onset of 6.5 months (median, 6.3 mo). Significant and clinically meaningful improvements in PROs, including in HAQ, EQ-5D, SF-36, and FACIT-Fatigue, were demonstrated with ETN50/MTX therapy from baseline to the final on therapy visit (Table; P_0.0001). Similar improvements were observed in all dimensions of RA-WIS and WPAI:RA (Table; P_0.0001). Conclusion: Combination therapy with ETN50/MTX for 52 wks in patients with _12 mo of symptomatic, active RA resulted in significant, clinically important improvements in measures of physical function, including normal HAQ (66.6% of patients), HR-QoL, fatigue, and work productivity. These outcomes are consistent with those reported in prior studies in patients with more established disease.

Anterior subluxation after reduction of a posterior traumatic sterno-clavicular dislocation: a case report and a review of the literature.

Sternoclavicular dislocations represent a rare injury. Based on our clinical experience with a patient showing an anterior subluxation after reduction of a posterior traumatic dislocation, we review the literature. The emergent reduction of the dislocation is mandatory, always keeping in mind the potentially devastating neurovascular complications. If the treatment of a residual anterior instability remains controversial, a residual posterior instability should be treated by a surgical procedure. The optimal treatment depends mainly on each surgeon's choice and practice.

Nonunion after fracture of the anterior tibial spine: case report and review of the literature.

Nonunion of anterior tibial spine of tibia in children is quite rare, but it could be associated with significant instability of the knee as it involves the fixation of anterior cruciate ligament. We report one case in which open reduction and internal fixation was carried out with good functional results. A literature review was performed to identify the cases reported of tibial eminence nonunion in children.

Interhospital aeromedical transfers: need for a specific training

Introduction: The interhospital aeromedical transfers concern mainly unstable patients presenting with multiple organ failure and among whom the intensity, as well as the difficulty of care are often underestimated. Material and method: Retrospective analysis of 2094 interhospital transfers made by the Rega helicopter of Lausanne between 2003 and 2008, with description of the pathologies, the demographic characteristics, as well as the medical and technical difficulties. Results: Male patient are overrepresented (65 vs 35%), their age being 40-80 years old. On the other hand, we note an important number (10%) of patients less than 10 years. The average time of flight is 13 minutes, with a high rate of night transfers (34%). In 73% of the cases, the transfers concern medical, especially cardiovascular and neurological situations. Trauma and surgical situations account for less than 20%. The transferred patients often require mechanical ventilation (27%), as well as invasive measure of blood pressure (11%), particularly in cases of neurological, pulmonary or cardiac diseases. In 6% of the cases, we note a haemodynamic instability, requiring the use of catecholamines. In 1% a cardiopulmonary resuscitation was initiated during the flight. The overall mortality at 48 hours is about 5%. Conclusions: In spite of relatively brief flights, the complexity and the variety of the pathologies require a specific training for the medical teams involved in the transfers, concerning the aspects of resuscitation, mechanical ventilation, and the knowledge of advanced life support in paediatrics, traumatology and cardiopulmonary intensive care.

Lésions traumatiques rachidiennes et indications au traitement chirurgical [Surgical indications in spinal trauma]

Surgical indications in spinal trauma remain a controversial topic. In general, unstable cervical injuries such as displaced odontoid fractures, burst fractures or tear drop fractures require surgical intervention. Thoracolumbar compression injuries without posterior wall involvement or significant kyphosis can be treated conservatively. Surgery is indicated in fractures-dislocations and burst fractures with significant canal narrowing and/or major kyphosis. The role of emergency decompression as well as that of steroids remain uncertain since no study to date has convincingly proven their efficacy.

Fanconi anemia and genome stability : the role of FANCM

RÉSUMÉ: Le génome de toute cellule est susceptible d'être attaqué par des agents endogènes et exogènes. Afin de préserver l'intégrité génomique, les cellules ont développé des multitudes de mécanismes. La réplication de l'ADN, une étape importante durant le cycle cellulaire, constitue un stress et présente un danger important pour l'intégrité du génome. L'anémie de Fanconi est une maladie héréditaire rare dont les protéines impliquées semblent jouer un rôle crucial dans la réponse au stress réplicatif. La maladie est associée à une instabilité chromosomique ainsi qu'à une forte probabilité de développer des cancers. Les cellules des patients souffrant de l'anémie de Fanconi sont sensibles à des agents interférant avec la réplication de l'ADN, et plus particulièrement àdes agents qui fient les deux brins d'ADN d'une manière covalente. L'anémie de Fanconi est une maladie génétiquement hétérogène. Treize protéines ont pu être identifiées. Elles semblent figurer dans une même voie de signalisation qui est aussi connue sous le nom de « FA/BRCA pathway », car un des gènes est identique au gène BRCA2 (breast cancer susceptibility gene 2). Huit protéines forment un complexe nucléaire dont l'intégrité est nécessaire à la monoubiquitination de deux autres protéines, FANCD2 et FANCI, en réponse à un stress réplicatif. A ce jour, la fonction moléculaire des protéines du « FA/BRCA pathway »reste encore mal décrite. Au début de mon travail de thèse, nous avons donc décidé de purifier les protéines du complexe nucléaire et d'étudier leurs propriétés biochimiques. Nous avons tout d'abord étudié les cinq protéines connues à l'époque qui sont FANCA, FANCC, FANCE, FANCF et FANCG. Par la suite, nous avons étendu notre étude à des protéines découvertes plus récemment, FANCL, FANCM et FAAP24, en concentrant finalement notre travail sur la caractérisation de FANCM. FANCM, contrairement aux autres protéines du complexe, est constituée de deux domaines conservés suggérant un rôle important dans le métabolisme de l'ADN. Il s'agit d'un domaine « DEAH box hélicase »situé dans la partie N-terminale et d'un domaine « ERCC4 nuclease »situé dans la partie C-terminale de la protéine. Dans cette étude, nous avons purifié avec succès la protéine FANCM entière à partir d'un système hétérologue. Nous montrons que FANCM s'attache de manière spécifique à des jonctions de Holliday et des fourches de réplication. De plus, nous démontrons que FANCM peut déplacer le point de jonction de ces structures via son domaine hélicase de manière dépendante de l'ATP. FANCM est aussi capable de dissocier de grands intermédiaires de la recombinaison, via la migration de jonctions de Holliday à travers une région d'homologie de 2.6 kb. Tous ces résultats suggèrent que FANCM peut s'attacher spécifiquement à des fourches de réplication et à des jonctions de Holliday in vitro et que son domaine hélicase est associé à une activité migratoire efficace. Nous pensons que FANCM peut avoir un rôle direct sur les intermédiaires de réplication. Ceci est en accord avec l'idée que les protéines de l'anémie de Fanconi coordonnent la réparation de l'ADN au niveau des fourches de réplication arrêtées. Nos résultats donnent une première indication quant au rôle de FANCM dans la cellule et peuvent contribuer à élucider la fonction de cette voie de signalisation peu comprise jusqu'à présent. SUMMARY: The genome of every cell is subject to a constant offence by endogenous and exogenous agents. Not surprisingly; cells have evolved a multitude of mechanisms which aim at preserving genomic integrity. A key step during the life cycle of a cell, DNA replication itself, constitutes a special danger to the integrity of the genome. The proteins defective in the rare hereditary disease Fanconi anemia (FA) are suspected to play a crucial role in the cellular response to DNA replication stress. The disease is associated with chromosomal instability and pronounced cancer susceptibility. Cells from Fanconi anemia patients are sensitive to a variety of agents which interfere with DNA replication, DNA interstrand cross-linking agents being particularly threatening to their survival. Fanconi anemia is a genetically heterogeneous disease with 13 different proteins identified, which seem to work together in a common pathway. Since one of the FA genes is identical to the breast cancer susceptibility gene BRCA2, it is also referred to as the FA/BRCA pathway. Eight proteins form a nuclear complex, whose integriry is required for the monoubiquitination of two other FA proteins, FANCD2 and FANCI, in response to DNA replication stress. Despite intensive research, the function of the FA/BRCA pathway at a molecular level has remained largely elusive so far. At the beginning of my thesis, we therefore decided to purify the proteins of the FA core complex and to investigate their biochemical properties. We started with the five proteins which were known at that time, FANCA, FANCC, FANCE, FANCF, and FACG. Later on, we extended our studies to the newly discovered proteins FANCL, FANCM, and FAAP24, and eventually focused our work on the characterisation of FANCM. In contrast to the other core complex proteins, FANCM contains two conserved domains, which point to a role in DNA metabolism: an N-terminal DEAH box helicase domain and a C-terminal ERCC4 nuclease domain. In this study, we have successfully purified full-length FANCM from a recombinant source. We show that purified FANCM binds to branched DNA molecules, such as Holliday junctions and replication forks, with high specificity and affinity. In addition, we demonstrate that FANCM can translocate the junction point of branched DNA molecules due to its helicase domain in an ATPase-dependent manner. FANCM can even dissociate large recombination intermediates, via branch migration of Holliday junctions through a 2.6 kb region of homology. Taken together, our data suggest that FANCM can specifically bind to replication forks and Holliday junctions in vitro, and that its DEAH box helicase domain is associated with a potent branch migration activity. We propose that FANCM might have a direct role in the processing of DNA replication intermediates. This is consistent with the current view that FA proteins coordinate DNA repair at stalled replication forks. Our findings provide a first hint as to the context in which FANCM might play a role in the cell. We are optimistic that they might be key to further elucidate the function of a pathway which is far from being understood.