The interconnection of somatic and mental issues within a multidisciplinary adolescent health unit. [L'intrication des problématiques somatiques et psychiques dans une unité multidisciplinaire de santé des adolescents.]

Les aspects physiques et psychiques sont étroitement intriqués à l'adolescence, et le corps représente un lieu privilégié d'expression des conflits. C'est dire l'importance de donner une place de choix au versant psychologique au sein d'une consultation de santé des adolescents, pour tenter de discerner la souffrance psychique souvent cachée derrière la plainte somatique.

Wound infection after excision and primary midline closure for pilonidal disease: risk factor analysis to improve patient selection.

BACKGROUND: Excision and primary midline closure for pilonidal disease (PD) is a simple procedure; however, it is frequently complicated by infection and prolonged healing. The aim of this study was to analyze risk factors for surgical site infection (SSI) in this context. METHODS: All consecutive patients undergoing excision and primary closure for PD from January 2002 through October 2008 were retrospectively assessed. The end points were SSI, as defined by the Center for Disease Control, and time to healing. Univariable and multivariable risk factor analyses were performed. RESULTS: One hundred thirty-one patients were included [97 men (74%), median age = 24 (range 15-66) years]. SSI occurred in 41 (31%) patients. Median time to healing was 20 days (range 12-76) in patients without SSI and 62 days (range 20-176) in patients with SSI (P < 0.0001). In univariable and multivariable analyses, smoking [OR = 2.6 (95% CI 1.02, 6.8), P = 0.046] and lack of antibiotic prophylaxis [OR = 5.6 (95% CI 2.5, 14.3), P = 0.001] were significant predictors for SSI. Adjusted for SSI, age over 25 was a significant predictor of prolonged healing. CONCLUSION: This study suggests that the rate of SSI after excision and primary closure of PD is higher in smokers and could be reduced by antibiotic prophylaxis. SSI significantly prolongs healing time, particularly in patients over 25 years.

La définition des interfaces pour améliorer la qualité: l'exemple de l'anorexie en hospitalisation somatique [Defining interfaces to improve quality of care: the example of anorexia nervosa in acute somatic hospitalisation]

Specialisation in medicine requires multidisciplinary approaches, and hence coordination in collaborations of the different partners involved. These integrated approaches, sometimes called "disease management", fit particularly well to chronic diseases. Our institution introduced an integrated approach for taking care of the acute somatic hospitalisation of patients suffering from anorexia nervosa. Interfaces with the different partners were defined, specifying tasks, rights, and duties of each person, care givers or patients. This initiative allows now to identify any deviation occurring in the process of care or hole in the care system, so that it can be corrected and recurrence prevented. This model will be extended to other complex and multidisciplinary care processes and other services in our institution.

Evaluation of somatic cell variants deficient in glycosylphosphatidyl-inositol anchoring as candidates for genetic correction.

Many cell surface glycoproteins are anchored in the lipid bilayer by a glycosylphosphatidyl-inositol (GPI) structure. Recently, a number of cell lines which are deficient in the biosynthesis and/or addition of this anchor have been described. In this report, we summarize the current knowledge on these lines and discuss their potential use to isolate the genes involved in the GPI anchor biosynthetic pathway with a specific emphasis on L cell fibroblasts.

Psychothérapie en milieu somatique--quelles spécificités [Psychotherapy in the somatic field--what specificities?].

This article illustrates some of the specific aspects of the psychotherapeutic approach with medically ill patients. Our considerations are based on our daily work in CL Psychiatry and refer to the psychodynamic model, rooted in Freudian's thought. Characteristics are the setting, as well as the relationship with the patient and the interactions with the physicians as the "emergence" of the suffering body within the therapy. We therefore adopt specific approaches such as the work with the Auxiliary Ego and the narrative reconstruction. This paper illustrates our experiences applying the mentioned tools with patients suffering from chronic pain and cancer.

Incomplete excision of basal cell carcinoma in the subunits of the nose.

Reconstructive procedures after resection of nasal basal cell carcinoma (BCC) vary depending on the subunit involved. The aim of the present study was to assess the influence of the location of the BCC on the rate of incomplete excisions, so we made a retrospective analysis of all nasal BCC excised at our hospital between 2002 and 2005. The incomplete excision rate was 24/148 (16%). More incomplete excision occurred on the alae (n=13) when compared to the dorsum (n=2) of the nose (p<0.05). Eight two-staged procedures resulted in incomplete resection, whereas 9 (6%) frozen section analyses were false-negative. BCC were most likely to be incompletely excised on the nasal tip and alae, and both subunits required more elaborate reconstructions. This, however, was not the result of poor estimation of the extent of the tumour and reluctance to excise more challenging areas widely for reconstruction, but to the method chosen to eradicate the tumour.

Patients presenting with somatic complaints in general practice: depression, anxiety and somatoform disorders are frequent and associated with psychosocial stressors.

BACKGROUND: Mental disorders in primary care patients are frequently associated with physical complaints that can mask the disorder. There is insufficient knowledge concerning the role of anxiety, depression, and somatoform disorders in patients presenting with physical symptoms. Our primary objective was to determine the prevalence of depression, anxiety, and somatoform disorders among primary care patients with a physical complaint. We also investigated the relationship between cumulated psychosocial stressors and mental disorders. METHODS: We conducted a multicentre cross-sectional study in twenty-one private practices and in one academic primary care centre in Western Switzerland. Randomly selected patients presenting with a spontaneous physical complaint were asked to complete the self-administered Patient Health Questionnaire (PHQ) between November 2004 and July 2005. The validated French version of the PHQ allowed the diagnosis of mental disorders (DSM-IV criteria) and the analyses of exposure to psychosocial stressors. RESULTS: There were 917 patients exhibiting at least one physical symptom included. The rate of depression, anxiety, and somatoform disorders was 20.0% (95% confidence interval [CI] = 17.4% to 22.7%), 15.5% (95% CI = 13.2% to 18.0%), and 15.1% (95% CI = 12.8% to 17.5%), respectively. Psychosocial stressors were significantly associated with mental disorders. Patients with an accumulation of psychosocial stressors were more likely to present anxiety, depression, or somatoform disorders, with an increase of 2.2 fold (95% CI = 2.0 to 2.5) for each additional stressor. CONCLUSIONS: The investigation of mental disorders and psychosocial stressors among patients with physical complaints is relevant in primary care. Psychosocial stressors should be explored as potential epidemiological causes of mental disorders.

Patients presenting with somatic complaints in general practice : dépression, anxiety and somatoform disorders are frequent and associated with psychosocial stressors

RAPPORT DE SYNTHÈSE Introduction En médecine de premier recours, les plaintes physiques sont fréquemment associées à des troubles dépressifs, anxieux et somatoformes et peuvent les masquer. Il est fréquemment reporté que ces troubles mentaux ont tendance à être insuffisamment diagnostiqués. Par ailleurs, peu d'études ont été conduites en médecine de premier recours concernant la possible association entre facteurs de stress psychosociaux et troubles dépressifs, anxieux et somatoformes. Objectifs Les objectifs étaient de déterminer la prévalence des troubles dépressifs, anxieux et somatoformes chez des patients consultant avec une plainte physique en médecine de premier recours, ainsi que d'explorer la possible association entre ces troubles mentaux et des facteurs de stress psychosociaux. Méthodes Nous avons conduit une étude transversale, multicentrique parmi vingt et un cabinets médicaux en Suisse Romande et la Policlinique Médicale Universitaire de Lausanne. Les sujets étaient sélectionnés aléatoirement parmi des patients qui avaient présenté spontanément au moins une plainte physique et qui avaient consulté lors d'une demi- journée de consultation considérée pour l'étude. Les patients inclus ont rempli l'auto- questionnaire Patient Health Questionnaire (PHQ) entre novembre 2004 et juillet 2005. Nous avons utilisé la version française et validée du PHQ qui permet le diagnostic des principaux troubles mentaux selon les critères du DSM-IV et l'analyse de l'exposition aux facteurs de stress psychosociaux. Résultats Neuf cent dix-sept patients se présentant avec au moins une plainte physique ont été inclus. Le taux de troubles dépressifs, anxieux et somatoformes a été de 20,0% (intervalle de confiance [IC] à 95% = 17,4%-22,7%), 15,5% (IC 95% = 13,2%- 18,0%) et 15,1% (IC 95% = 12,8%~17,5%), respectivement. Les facteurs de stress psychosociaux ont été significativement associés aux troubles mentaux. Les patients avec une accumulation de facteurs de stress psychosociaux ont été le plus souvent déprimés, anxieux ou ont manifesté des troubles somatoformes, avec une augmentation par un facteur 2,2 (IC 95% = 2,0-2,5) pour chaque facteur additionnel. Conclusions Bien que la relation entre facteurs de stress psychosociaux et trouble dépressif soit bien établie, cette étude montre qu'il existe un lien entre ces facteurs de stress et les troubles dépressifs, anxieux et somatoformes. L'investigation de ces troubles mentaux chez des patients consultant avec un symptôme physique en médecine de premier recours est pertinente. D'autres explorations sont nécessaires pour investiguer le bénéfice potentiel d'une prise en charge intégrée des facteurs de stress psychosociaux sur la diminution des plaintes physiques et des troubles mentaux chez les patients que suivent les médecins de premier recours.

Intracellular excision and reintegration dynamics of the ICEclc genomic island of Pseudomonas knackmussii sp. strain B13.

Genomic islands are DNA elements acquired by horizontal gene transfer that are common to a large number of bacterial genomes, which can contribute specific adaptive functions, e.g. virulence, metabolic capacities or antibiotic resistances. Some genomic islands are still self-transferable and display an intricate life-style, reminiscent of both bacteriophages and conjugative plasmids. Here we studied the dynamical process of genomic island excision and intracellular reintegration using the integrative and conjugative element ICEclc from Pseudomonas knackmussii B13 as model. By using self-transfer of ICEclc from strain B13 to Pseudomonas putida and Cupriavidus necator as recipients, we show that ICEclc can target a number of different tRNA(Gly) genes in a bacterial genome, but only those which carry the GCC anticodon. Two conditional traps were designed for ICEclc based on the attR sequence, and we could show that ICEclc will insert with different frequencies in such traps producing brightly fluorescent cells. Starting from clonal primary transconjugants we demonstrate that ICEclc is excising and reintegrating at detectable frequencies, even in the absence of recipient. Recombination site analysis provided evidence to explain the characteristics of a larger number of genomic island insertions observed in a variety of strains, including Bordetella petri, Pseudomonas aeruginosa and Burkholderia.

Excision of the Staphylococcal Cassette Chromosome mec (SCCmec) and its crucial role in the horizontal transfer of methicillin resistance in staphylococci.

Staphylococcus aureus est un pathogène humain majeur ayant développé des résistances contre la quasi totalité des antibiotiques disponibles, incluant la très importante famille des β- lactamines. La résistance à cette classe d'antibiotiques est conférée par la « Staphylococcal Cassette Chromosome mec » (SCCmec), qui est un élément génétique mobile capable de s'insérer dans le chromosome bactérien et capable d'être transféré horizontalement chez d'autres staphylocoques. Le mécanisme moléculaire impliqué dans ce transfert horizontal demeure largement inconnu. L'une des premières étapes du transfert est l'excision du SCC mec du chromosome bactérien. Cette excision est promue par des enzymes codées par l'élément SCCmec lui- même et appelées de ce fait « Cassette Chromosome Recombinases » (Ccr). L'un des buts de ce travail de thèse a été de comprendre la régulation de l'expression des gènes codant pour les Ccr recombinases. En utilisant des outils moléculaires originaux, nous avons été en mesure de démontrer en premier lieu que les Ccr recombinases étaient exprimées de façon « bistable », c'est à dire qu'uniquement quelques pourcents de cellules dans une population exprimaient ces gènes à un temps donné. Dans un deuxième temps, nous avons également démontré que l'expression de ces gènes était régulée par des facteurs étrangers au SCC mec. L'expression bistable des recombinases est un concept important. Effectivement, cela permet à la majorité des cellules d'une population de conserver l'élément SCC mec, alors que seulement une petite fraction le perd afin de le rendre disponible pour un transfert. Ainsi, alors que l'élément SCC mec continue de se propager avec la multiplication des bactéries Staphylococcus aureus résistant à la méticilline (SARM), il peut être simultanément transmis à des souches susceptibles (Staphylococcus aureus susceptible à la méticilline, SASM), entraînant l'apparition de nouveaux SARM. De façon très intéressante, le fait que cette bistabilité est contrôlée par les bactéries, et non le SCCmec lui-même, montre que la décision de transférer ou non la cassette SCC mec appartient à la bactérie. En conséquence, il doit exister dans la nature des souches qui sont plus ou moins aptes à effectuer ce transfert. En nous appuyant sur ces observations, nous avons montré que l'excision du SCC mec était effectivement régulée de façon très étroite au cours de la division cellulaire, et ne se passait que pendant un temps limité au début de la croissance. Ce résultat est compatible avec une régulation génétique commandée par la densité cellulaire, qui pourrait être dépendante de la production de signaux extracellulaires, du type que l'on rencontre dans le quorum sensing. Les signaux hypothétiques entraînant l'excision du SCC mec restent inconnus à l'heure actuelle. La connaissance de ces signaux pourrait se révéler très importante afin de développer des stratégies pour interférer avec la dissémination de la résistance au β-lactamines. Deux sujets additionnels ont été logiquement investigués au vu de ces premiers résultats. Premièrement, si certaines souches de SARM sont plus ou moins aptes à déclencher l'excision du SCC mec, de même certaines souches de SASM devraient être plus ou moins aptes à acquérir cet élément. Deuxièmement, afin d'étudier ces mécanismes de transfert au niveau épidémiologique, il nous a été nécessaire de développer des outils nous permettant d'explorer le phénomène à une plus large échelle. Concernant le premier point, il a été postulé que certains SASM seraient réfractaires à l'intégration génomique d'un SCC mec en raison de polymorphismes particuliers à proximité du site d'insertion chromosomique (attB). En étudiant plus de 40 isolais de S. aureus, provenant de porteurs sains, nous avons confirmé ce polymorphisme dans l'environnement à'attB. De plus, nous avons pu montrer que ces régions polymorphiques ont évolué parallèlement à des groupes phylogénétiques bien connus. Ainsi, si des telles régions réfractaires à l'intégration de SCC mec existent, celles-ci devraient ségréger dans des complexes clonaux bien définis qui devraient être facilement identifiables au niveau épidémiologique. Concernant le second point, nous avons été capables de construire un système rapporteur de l'excision du SCCmec, en utilisant un plasmide à faible copie. Ce système consistait en un promoteur fort et un gène codant pour une protéine verte fluorescente (GFP) sous le contrôle d'un promoteur fort séparés à l'aide d'un élément SCC artificiel portant trois terminateurs de transcription. Ainsi, la fluorescence ne s'exprime que si l'élément SCC est excisé du plasmide. Ce système a été testé avec succès dans plusieurs types de staphylocoques, et est actuellement évalué dans d'autres souches et conditions stimulant ou inhibant l'excision. De manière générale, cette dissertation représente parcours scientifique à travers plusieurs aspects d'un problème de santé publique majeur en rapport avec la résistance bactérienne aux antibiotiques. Ce travail s'attaque à des problèmes fondamentaux concernant le transfert horizontal de l'élément SCC mec. De plus, il s'intéresse à des aspects plus généraux de cet élément génétique mobile qui pourraient se révéler très importants en terme de mouvement de gènes au sein des staphylocoques, voir d'autres bactéries gram-positives. Finalement ce travail de thèse met en place le fondamentaux requis pour des recherches futures visant à interférer avec le transfert horizontal de la résistance aux β-lactamines. - Staphylococcus aureus is a major human pathogen. Moreover, S. aureus have developed resistance to almost all available antibiotics, including the important family of β-lactam molecules. Intrinsic resistance to β-lactams is conferred by the Staphylococcal Cassette Chromosome mec (SCCmec), which is a mobile genomic island that inserts into the staphylococcal chromosome and can be horizontally transferred into other staphylococci. However, little is known about the molecular mechanisms involved in this horizontal transfer into naïve strains. One of the first steps in SCC mec horizontal transfer is its excision from the chromosome. Excision is mediated by recombinase enzymes that are encoded by SCC mec itself, and named accordingly Ccr recombinases - for Cassette Chromosome recombinases. One goal of this thesis was to understand the regulation these recombinase genes. By using original molecular tools we could demonstrate first that the Ccr recombinases were expressed in a "bistable" manner, i.e. in only few percentages of the bacterial cells at a given time, and second that they were regulated by determinants that were not encoded on the SCC mec element, but elsewhere on the staphylococcal genome. "Bistable" expression Ccr recombinases is an important concept. It allows SCC mec to be excised and thus available for horizontal transfer, while ensuring that only some cells, but not the whole population, loose their valuable SCC mec genes. Thus, while the SCC mec element expands with the multiplication of the MRSA colony, it can simultaneously be transmitted into methicillin-susceptible S. aureus (MSSA), which convert into new MRSA. Most interestingly, the fact that bistability was regulated by the cells, rather than by SCC mec, indicates that it was the choice of the bacteria to trigger or not SCC mec transfer. As a consequence, there must be, in nature, staphylococcal strains that are more or less prone to sustain SCC mec transfer. Following these seminal observations we found that excision was indeed tightly regulated during bacterial division, and occurred only during a limited period of time at the beginning of bacterial growth. This is compatible with cell-density mediated gene regulation, and may depend on the production of extracellular signal molecules that transmit appropriate orders to neighboring cells, such as in quorum sensing. The potential signal triggering SCCmec excision is as yet unknown. However, it could be critical in promoting the horizontal transfer of methicillin resistance, or for the possible development of means to interfere with it. Two additional hypothesis were logically investigated in the view of these first results. First, if some strains of MRSA might be more prone than others to promote SCC mec excision, then some strains of MS SA might be more or less prone to acquire the element as well. Second, to investigate these multiple mechanisms at an epidemiological level, one would need to develop tools amenable to explore S. aureus strains at a larger scale. Regarding the first issue, it was postulated by others that some MSSA might be refractory to SCC mec integration because they had peculiar DNA polymorphisms in the vicinity of the site-specific chromosomal entry point {attB) of SCC mec. By studying >40 S. aureus isolates from healthy carriers, we confirmed the polymorphism of the attB environment. Moreover, we could show that these polymorphic regions co-evolved with well-known phylogenic clonal clusters. Therefore, if SCCwec-refractory attB environments exist, then they would segregate in well- defined S. aureus clonal clusters that would be easy to identify at the epidemiological level. Regarding the second issue, we were able to construct a new excision reporter system in a low copy number S. aureus plasmid. The reporter system consists in a strong promoter driving a green fluorescent protein {gfp) gene, separated by an artificial SCC-like element carrying three transcriptional terminators. Thus, fluorescence is not expressed unless the SCC-like element is excised. The system has been successfully tested in several aureus and non- aureus staphylococci, and is now being applied to more strains and various excision- triggering or inhibiting conditions. Altogether the dissertation is a scientific journey through various aspects of a salient medical problem with regard to antibiotic resistance and public health threat. The research work tackles fundamental issues about the mechanisms of horizontal transfer of the SCC mec element. Moreover, it also addresses more general features of this mobile element, which could be of larger importance with regard to gene trafficking in staphylococci, and maybe other gram-positive bacteria. Finally, the dissertation sets the fundamentals for future work and possible new ways to interfere with the horizontal transfer of methicillin resistance.

Network-guided analysis of genes with altered somatic copy number and gene expression reveals pathways commonly perturbed in metastatic melanoma.

Cancer genomes frequently contain somatic copy number alterations (SCNA) that can significantly perturb the expression level of affected genes and thus disrupt pathways controlling normal growth. In melanoma, many studies have focussed on the copy number and gene expression levels of the BRAF, PTEN and MITF genes, but little has been done to identify new genes using these parameters at the genome-wide scale. Using karyotyping, SNP and CGH arrays, and RNA-seq, we have identified SCNA affecting gene expression ('SCNA-genes') in seven human metastatic melanoma cell lines. We showed that the combination of these techniques is useful to identify candidate genes potentially involved in tumorigenesis. Since few of these alterations were recurrent across our samples, we used a protein network-guided approach to determine whether any pathways were enriched in SCNA-genes in one or more samples. From this unbiased genome-wide analysis, we identified 28 significantly enriched pathway modules. Comparison with two large, independent melanoma SCNA datasets showed less than 10% overlap at the individual gene level, but network-guided analysis revealed 66% shared pathways, including all but three of the pathways identified in our data. Frequently altered pathways included WNT, cadherin signalling, angiogenesis and melanogenesis. Additionally, our results emphasize the potential of the EPHA3 and FRS2 gene products, involved in angiogenesis and migration, as possible therapeutic targets in melanoma. Our study demonstrates the utility of network-guided approaches, for both large and small datasets, to identify pathways recurrently perturbed in cancer.

Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma.

We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.

Anorexie: évaluation et prise en charge somatiques [Anorexia: somatic assessment and management].

Anorexia nervosa, which affects about 2-3% of the general population, is the psychiatric illness with the highest rate of mortality. The management is often complex, requiring multiple stakeholders on the patient's physical and psychiatric. The new specialized centre "abC" (anorexia-bulimia, Centre vaudois) was created with the objective of providing quality services to patients involved and to provide a network facilitating the interaction between physicians and specialized institutions. This is an inter-institutional and interdisciplinary collaboration born of the CHUV and the eHnv (Hospitalized Institutions in Nord Vaudois). The abC includes an outpatient pole (CHUV) and a hospital unit on the site of Saint Loup. At term, it will include a day centre (CHUV).

Pial and arachnoid welding for restoration of normal cord anatomy after excision of intramedullary spinal cord tumors.

A significant postoperative problem in patients undergoing excision of intramedullary tumors is painful dysesthesiae, attributed to various causes, including edema, arachnoid scarring and cord tethering. The authors describe a technique of welding the pia and arachnoid after the excision of intramedullary spinal cord tumors used in seven cases. Using a fine bipolar forcep and a low current, the pial edges of the myelotomy were brought together and welded under saline irrigation. A similar method was used for closing the arachnoid while the dura was closed with a running 5-0 vicryl suture. Closing the pia and arachnoid restores normal cord anatomy after tumor excision and may reduce the incidence of postoperative painful dysesthesiae.