Radioimmuno positron emission tomography with monoclonal antibodies: a new approach to quantifying in vivo tumour concentration and biodistribution for radioimmunotherapy.

Radioimmunodetection of tumours with monoclonal antibodies is becoming an established procedure. Positron emission tomography (PET) shows better resolution than normal gamma camera single photon emission tomography and can provide more precise quantitative data. Thus, in the present study, these powerful methods have been combined to perform radioimmuno PET (RI-PET). Monoclonal antibodies directed against carcinoembryonic antigen (CEA) an IgG, its F(ab')2 and a mouse-human chimeric IgG derived from it were labelled with 124I, a positron-emitting radionuclide with a convenient physical half-life of four days. Mice, xenografted with a CEA-producing human colon carcinoma, were injected with the 124I-MAb and the tumours were visualized using PET. The concentrations of 124I in tumour and normal tissue were determined by both PET and direct radioactivity counting of the dissected animals, with very good agreement. To allow PET quantification, a procedure was established to account for the presence of radioactivity during the absorption correction measurement (transmission scan). Comparison of PET and tissue counting indicates that this novel combination of radioimmunolocalization and PET (RI-PET) will provide, in addition to more precise diagnosis, more accurate radiation dosimetry for radioimmunotherapy.

A new approach to accurate measurement of uniaxial joint angles based on a combination of accelerometers and gyroscopes.

A new method of measuring joint angle using a combination of accelerometers and gyroscopes is presented. The method proposes a minimal sensor configuration with one sensor module mounted on each segment. The model is based on estimating the acceleration of the joint center of rotation by placing a pair of virtual sensors on the adjacent segments at the center of rotation. In the proposed technique, joint angles are found without the need for integration, so absolute angles can be obtained which are free from any source of drift. The model considers anatomical aspects and is personalized for each subject prior to each measurement. The method was validated by measuring knee flexion-extension angles of eight subjects, walking at three different speeds, and comparing the results with a reference motion measurement system. The results are very close to those of the reference system presenting very small errors (rms = 1.3, mean = 0.2, SD = 1.1 deg) and excellent correlation coefficients (0.997). The algorithm is able to provide joint angles in real-time, and ready for use in gait analysis. Technically, the system is portable, easily mountable, and can be used for long term monitoring without hindrance to natural activities.

Multi-dimensional approach to bullying

RÉSUMÉ : Le bullying est un type de comportement agressif qu'un élève (ou plusieurs) fait subir à un autre et qui se manifeste par des agressions verbales, physiques et/ou psychologiques. Les caractéristiques du bullying sont la répétitivité d'actions négatives sur le long terme et une relation de pouvoir asymétrique. Pour la victime, ce type de comportement peut avoir des conséquences graves telles qu'échec scolaire, dépression, troubles alimentaires, ou idées suicidaires. De plus, les auteurs de bullying commettent plus de comportements déviants au sein de l'école ou à l'extérieur de cette dernière. La mise en place d'actions ciblées auprès des auteurs de bullying pourrait donc non seulement prévenir une victimisation, mais aussi réduire les actes de délinquance en général. Hormis quelques études locales ou cantonales, aucune recherche nationale auprès d'adolescents n'existait dans le domaine. Ce travail propose de combler cette lacune afin d'obtenir une compréhension suffisante du phénomène qui permet de donner des pistes pour définir des mesures de prévention appropriées. Afin d'appréhender la problématique du bullying dans les écoles secondaires suisses, deux sondages de délinquance juvénile autoreportée ont été effectués. Le premier a eu lieu entre 2003 et 2005 dans le canton de Vaud auprès de plus de 4500 écoliers. Le second a été administré en 2006 dans toute la Suisse et environ 3600 jeunes y ont participé. Les jeunes ont répondu au sondage soit en classe (questionnaire papier) soit en salle d'informatique (questionnaire en ligne). Les jeunes ayant répondu avoir sérieusement harcelé un autre élève est d'environ 7% dans le canton de Vaud et de 4% dans l'échantillon national. Les analyses statistiques ont permis tout d'abord de sélectionner les variables les plus fortement liées au bullying. Les résultats montrent que les jeunes avec un bas niveau d'autocontrôle et ayant une attitude positive envers la violence sont plus susceptibles de commettre des actes de bullying. L'importance des variables environnementales a aussi été démontrée: plus le jeune est supervisé et encadré par des adultes, plus les autorités (école, voisinage) jouent leur rôle de contrôle social en faisant respecter les règles et en intervenant de manière impartiale, moins le jeune risque de commettre des actes de bullying. De plus, l'utilisation d'analyses multiniveaux a permis de montrer l'existence d'effets de l'école sur le bullying. En particulier, le taux de bullying dans une école donnée augmente lorsque les avis des jeunes divergent par rapport à leur perception du climat scolaire. Un autre constat que l'on peut mettre en évidence est que la réaction des enseignants lors de bagarres a une influence différente sur le taux de bullying en fonction de l'établissement scolaire. ABSTRACT : Bullying is the intentional, repetitive or persistent hurting of one pupil by another (or several), where the relationship involves an imbalance of power. Bullying is a type of aggressive behaviour and the act can be verbal, physical and/or psychological. The consequences on the victims are serious: school failure, depressive symptomatology, eating disorders, or suicidal ideation. Moreover, the authors of bullying display more delinquent behaviour within or outside the school. Thus, preventive programmes targeting bullying could not only prevent victimisation, but also reduce delinquency in general. Very little data concerning bullying had been collected in Switzerland and, except some local or cantonal studies, no national research among teenagers existed in the field. This work intends to fill the gap in order to provide sufficient understanding of the phenomenon and to suggest some tracks for defining appropriate measures of prevention. In order to understand the problems of bullying in Swiss secondary schools better, two surveys of self-reported juvenile delinquency were carried out. The first one took place between 2003 and 2005 in the canton Vaud among more than 4500 pupils, the second in 2006 across Switzerland with about 3600 youths taking part. The pupils answered to the survey either in the classroom (paper questionnaire) or in the computer room (online questionnaire). The youths that answered having seriously bullied another pupil are about 7% in canton Vaud and 4% in the national sample. Statistical analyses have selected the variables most strongly related to bullying. The results show that the youths with a low level of self-control and adopting a positive attitude towards violence are more likely to bully others. The importance of the environmental variables was also shown: the more that youth is supervised and monitored by adults, and the more the authorities (school, neighbourhood) play their role of social control by making the rules be respected through intervening in an impartial way, the less the youth bully. Moreover, the use of multilevel analyses permitted to show the existence of effects of the school on bullying. In particular, the rate of bullying in a given school increases when there is a wide variation among students of the same school in their perception of their school climate. Another important aspect concerns teachers' reactions when pupils fight: this variable does not influence the bullying rate to the same extent, and depends on the school.

Evaluation of an online, case-based interactive approach to teaching pathophysiology

Rapport de synthèse : L'article qui fait l'objet de ma thèse évalue une nouvelle approche pédagogique pour l'apprentissage de certains chapitres de physiopathologie. Le dispositif pédagogique se base sur l'alternance d'apprentissage ex-cathedra et de l'utilisation d'un site web comprenant des vignettes cliniques. Lors de la consultation de ces-dernières, l'étudiant est invité à demander des examens de laboratoire dont il pourrait justifier la pertinence selon le cas clinique étudié. La nouveauté du procédé réside dans le fait que, préalablement à son cours ex-cathedra, l'enseignant peut consulter les statistiques de demandes de laboratoire et ainsi orienter son cours selon les éléments mal compris par les étudiants. A la suite du cours ex-cathedra, les étudiants peuvent consulter sur internet la vignette clinique complète avec des explications. A l'issue de tout le cours, une évaluation auprès des étudiants a été conduite. Le procédé a été mis en place durant deux années consécutives et l'article en discute notamment les résultats. Nous avons pu conclure que cette méthode innovatrice d'enseignement amène les étudiants à mieux se préparer pour les cours ex-cathedra tout en permettant à l'enseignant d'identifier plus précisément quelles thématiques étaient difficiles pour les étudiants et donc d'ajuster au mieux son cours. Mon travail de thèse a consisté à créer ce dispositif d'apprentissage, à créer l'application web des vignettes cliniques et à l'implanter durant deux années consécutives. J'ai ensuite analysé les données des évaluations et écrit l'article que j'ai présenté à la revue 'Medical Teacher'. Après quelques corrections et précisions demandées par le comité de lecture, l'article a été accepté et publié. Ce travail a débouché sur une seconde version de l'application web qui est actuellement utilisée lors du module 3.1 de 3è année à l'Ecole de Médecine à Lausanne. Summary : Since the early days of sexual selection, our understanding of the selective forces acting on males and females during reproduction has increased remarkably. However, despite a long tradition of experimental and theoretical work in this field and relentless effort, numerous questions remain unanswered and many results are conflicting. Moreover, the interface between sexual selection and conservation biology has to date received little attention, despite existing evidence for its importance. In the present thesis, I first used an empirical approach to test various sexual selection hypotheses in a population of whitefish of central Switzerland. This precise population is characterized by a high prevalence of gonadal alterations in males. In particular, I challenged the hypothesis that whitefish males displaying peculiar gonadal features are of lower genetic quality than other seemingly normal males. Additionally, I also worked on identifying important determinant of sperm behavior. During a second theoretical part of my work, which is part of a larger project on the evolution of female mate preferences in harvested fish populations, I developed an individual-based simulation model to estimate how different mate discrimination costs affect the demographical behavior of fish populations and the evolutionary trajectories of female mate preferences. This latter work provided me with some insight on a recently published article addressing the importance of sexual selection for harvesting-induced evolution. I built upon this insight in a short perspective paper. In parallel, I let some methodological questions drive my thoughts, and wrote an essay about possible synergies between the biological, the philosophical and the statistical approach to biological questions.

A surface-based approach to quantify local cortical gyrification.

The high complexity of cortical convolutions in humans is very challenging both for engineers to measure and compare it, and for biologists and physicians to understand it. In this paper, we propose a surface-based method for the quantification of cortical gyrification. Our method uses accurate 3-D cortical reconstruction and computes local measurements of gyrification at thousands of points over the whole cortical surface. The potential of our method to identify and localize precisely gyral abnormalities is illustrated by a clinical study on a group of children affected by 22q11 Deletion Syndrome, compared to control individuals.

Current developments in the radiotherapy approach to elderly and frail patients with glioblastoma multiforme.

The benefit of postoperative radiotherapy (RT) has been demonstrated in elderly patients aged 65 years or older with glioblastoma multiforme. Hypofractionated RT schedules can reduce the time and morbidity of treatment while maintaining comparable survival outcomes to lengthy conventional RT. Current international randomized clinical trials are studying the optimized hypofractionated RT regimens, hypofractionated RT in comparison with temozolomide chemotherapy and hypofractionated RT in comparison with the same RT plus temozolomide. Given the guarded prognosis of the elderly and frail patients, quality of life and side effects of treatment should be closely examined. As more than half of cancers in the world occur in developing countries, hypofractionated RT could be better utilized as a cost-effective treatment for this group of patients.

Diffusion-weighted spectroscopy: a novel approach to determine macromolecule resonances in short-echo time 1H-MRS.

Quantification of short-echo time proton magnetic resonance spectroscopy results in >18 metabolite concentrations (neurochemical profile). Their quantification accuracy depends on the assessment of the contribution of macromolecule (MM) resonances, previously experimentally achieved by exploiting the several fold difference in T(1). To minimize effects of heterogeneities in metabolites T(1), the aim of the study was to assess MM signal contributions by combining inversion recovery (IR) and diffusion-weighted proton spectroscopy at high-magnetic field (14.1 T) and short echo time (= 8 msec) in the rat brain. IR combined with diffusion weighting experiments (with δ/Δ = 1.5/200 msec and b-value = 11.8 msec/μm(2)) showed that the metabolite nulled spectrum (inversion time = 740 msec) was affected by residuals attributed to creatine, inositol, taurine, choline, N-acetylaspartate as well as glutamine and glutamate. While the metabolite residuals were significantly attenuated by 50%, the MM signals were almost not affected (< 8%). The combination of metabolite-nulled IR spectra with diffusion weighting allows a specific characterization of MM resonances with minimal metabolite signal contributions and is expected to lead to a more precise quantification of the neurochemical profile.

Chest pulse-wave velocity: a novel approach to assess arterial stiffness.

Pulse-wave velocity (PWV) is considered as the gold-standard method to assess arterial stiffness, an independent predictor of cardiovascular morbidity and mortality. Current available devices that measure PWV need to be operated by skilled medical staff, thus, reducing the potential use of PWV in the ambulatory setting. In this paper, we present a new technique allowing continuous, unsupervised measurements of pulse transit times (PTT) in central arteries by means of a chest sensor. This technique relies on measuring the propagation time of pressure pulses from their genesis in the left ventricle to their later arrival at the cutaneous vasculature on the sternum. Combined thoracic impedance cardiography and phonocardiography are used to detect the opening of the aortic valve, from which a pre-ejection period (PEP) value is estimated. Multichannel reflective photoplethysmography at the sternum is used to detect the distal pulse-arrival time (PAT). A PTT value is then calculated as PTT = PAT - PEP. After optimizing the parameters of the chest PTT calculation algorithm on a nine-subject cohort, a prospective validation study involving 31 normo- and hypertensive subjects was performed. 1/chest PTT correlated very well with the COMPLIOR carotid to femoral PWV (r = 0.88, p < 10 (-9)). Finally, an empirical method to map chest PTT values onto chest PWV values is explored.

Fatigue: revue et approche diagnostique [Fatigue: review and systematic approach to potential causes]

Fatigue is defined as a sensation of exhaustion during or after usual activities. As much as one third of patients consulting a primary care physician report this complaint. After investigation, two-thirds of the patients have a somatic or psychiatric diagnosis. This review presents a seven-step approach to the patient who complains of fatigue.

New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations.

Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.

Organometallic anticancer agents that interfere with cellular energy processes: a subtle approach to inducing cancer cell death.

Two hybrid compounds comprising an antimetastatic ruthenium-arene fragment tethered to an indazole-3-carboxylic acid derivative that inhibits aerobic glycolysis in cancer cells have been prepared and evaluated in a variety of cancer cell lines, including highly relevant human glioblastoma cells, with an apparent synergistic action between the two components observed.