Fetal Diagnosis of Cardiac Rhabdomyoma, its Management and Outcome : P71

Objectives: This study analyses the long term cardiac and neurological outcome of patients with cardiac rhabdomyoma (CR) in order to allow comprehensive prenatal counselling. Because of the relative rarity of the disease, there is paucity of data concerning the outcome of patients with CR. Methods: A retrospective study including all cases with echocardiographic diagnosis of CR encountered between April 1986 and August 2006. Results: Of 24 CR patients identified, 7 were diagnosed in-utero at a gestational age (GA) between 28-35 weeks and 17 postnatally between 10 days and 5 years. 14 had multiple CR and 10 had one/two CR. The CRs were situated predominantly in the LV (70%), RV (52%) and IVS (48%) and to a lesser extent in the atria (13%) and pericardium (4%). Follow-up echocardiography in. 18'show\'ld complete postnatal regression of CR in 3, partial regression in 13 and no change in 2. Cardiac complications were encountered in 5 patients, 1 with WPW syndrome and SVT requiring anti-arrhythmic therapy, 1 with sub-aortic obstruction needing surgical intervention and 3 with occasional bouts of paroxysmal SVT. Long-term follow-up revealed tuberous sclerosis of Bourneville (TSB) as definite diagnosIs in 22 (92%), complicated by epilepsy in 16 (67%) and developmental delay in 14 (64%). Conclusions: CR generally regresses after birth and after the high risk perinatal period cardiac related problems are rare. The relatively poor neurodevelopmental outcome of the almost always associated TSB however should form a dominating aspect of the prenatal counselling of parents whose fetuses are diagnosed with this rare disease.

Educational expansion, intergenerational mobility and over-education

[eng] There is a vast literature on intergenerational mobility in sociology and economics. Similar interest has emerged for the phenomenon of over-education in both disciplines. There are no studies, however, linking these two research lines. We study the relationship between social mobility and over-education in a context of educational expansion. Our framework allows for the evaluation of several policies, including those affecting social segregation, early intervention programs and the power of unions. Results show the evolution of social mobility, over-education, income inequality and equality of opportunity under each scenario.

Availability of soil water under tillage systems, mulch management and citrus rootstocks

The increased availability of soil water is important for the management of non-irrigated orange orchards. The objective of this study was to evaluate the availability of soil water in a Haplorthox (Rhodic Ferralsol) under different tillage systems used for orchard plantation, mulch management and rootstocks in a "Pêra" orange orchard in northwest Paraná, Brazil. An experiment in a split-split-plot design was established in 2002, in an area cultivated with Brachiaria brizantha grass in which three tillage systems (no tillage, conventional tillage and strip-tillage) were used for orchard plantation. This grass was mowed twice a year between the rows, representing two mulch managements in the split plots (no mulching and mulching in the plant rows). The split-split-plots were represented by two rootstocks ("Rangpur" lime and "Cleopatra" mandarin). The soil water content in the plant rows was evaluated in the 0-20 cm layer in 2007 and at 0-20 and 20-40 cm in 2008-2009. The effect of soil tillage systems prior to implantation of orange orchards on soil water availability was less pronounced than mulching and the rootstocks. The soil water availability was lower when "Pêra" orange trees were grafted on "Cleopatra" mandarin than on "Rangpur" lime rootstocks. Mulching had a positive influence on soil water availability in the sandy surface layer (0-20 cm) and sandy clay loam subsurface (20-40 cm) of the soil in the spring. The production of B. brizantha between the rows and residue disposal in the plant rows as mulch increased water availability to the "Pêra" orange trees.

Cheminformatic studies of molecular properties and their influence on bioactivity in the context of drug discovery

Molecular shape has long been known to be an important property for the process of molecular recognition. Previous studies postulated the existence of a drug-like shape space that could be used to artificially bias the composition of screening libraries, with the aim to increase the chance of success in Hit Identification. In this work, it was analysed to which extend this assumption holds true. Normalized Principal Moments of Inertia Ratios (NPRs) have been used to describe the molecular shape of small molecules. It was investigated, whether active molecules of diverse targets are located in preferred subspaces of the NPR shape space. Results illustrated a significantly stronger clustering than could be expected by chance, with parts of the space unlikely to be occupied by active compounds. Furthermore, a strong enrichment of elongated, rather flat shapes could be observed, while globular compounds were highly underrepresented. This was confirmed for a wide range of small molecule datasets from different origins. Active compounds exhibited a high overlap in their shape distributions across different targets, making a purely shape­ based discrimination very difficult. An additional perspective was provided by comparing the shapes of protein binding pockets with those of their respective ligands. Although more globular than their ligands, it was observed that binding sites shapes exhibited a similarly skewed distribution in shape space: spherical shapes were highly underrepresented. This was different for unoccupied binding pockets of smaller size. These were on the contrary identified to possess a more globular shape. The relation between shape complementarity and exhibited bioactivity was analysed; a moderate correlation between bioactivity and parameters including pocket coverage, distance in shape space, and others could be identified, which reflects the importance of shape complementarity. However, this also suggests that other aspects are of relevance for molecular recognition. A subsequent analysis assessed if and how shape and volume information retrieved from pocket or respective reference ligands could be used as a pre-filter in a virtual screening approach. ln Lead Optimization compounds need to get optimized with respect to a variety of pararneters. Here, the availability of past success stories is very valuable, as they can guide medicinal chemists during their analogue synthesis plans. However, although of tremendous interest for the public domain, so far only large corporations had the ability to mine historical knowledge in their proprietary databases. With the aim to provide such information, the SwissBioisostere database was developed and released during this thesis. This database contains information on 21,293,355 performed substructural exchanges, corresponding to 5,586,462 unique replacements that have been measured in 35,039 assays against 1,948 molecular targets representing 30 target classes, and on their impact on bioactivity . A user-friendly interface was developed that provides facile access to these data and is accessible at http//www.swissbioisostere.ch. The ChEMBL database was used as primary data source of bioactivity information. Matched molecular pairs have been identified in the extracted and cleaned data. Success-based scores were developed and integrated into the database to allow re-ranking of proposed replacements by their past outcomes. It was analysed to which degree these scores correlate with chemical similarity of the underlying fragments. An unexpectedly weak relationship was detected and further investigated. Use cases of this database were envisioned, and functionalities implemented accordingly: replacement outcomes are aggregatable at the assay level, and it was shawn that an aggregation at the target or target class level could also be performed, but should be accompanied by a careful case-by-case assessment. It was furthermore observed that replacement success depends on the activity of the starting compound A within a matched molecular pair A-B. With increasing potency the probability to lose bioactivity through any substructural exchange was significantly higher than in low affine binders. A potential existence of a publication bias could be refuted. Furthermore, often performed medicinal chemistry strategies for structure-activity-relationship exploration were analysed using the acquired data. Finally, data originating from pharmaceutical companies were compared with those reported in the literature. It could be seen that industrial medicinal chemistry can access replacement information not available in the public domain. In contrast, a large amount of often-performed replacements within companies could also be identified in literature data. Preferences for particular replacements differed between these two sources. The value of combining different endpoints in an evaluation of molecular replacements was investigated. The performed studies highlighted furthermore that there seem to exist no universal substructural replacement that always retains bioactivity irrespective of the biological environment. A generalization of bioisosteric replacements seems therefore not possible. - La forme tridimensionnelle des molécules a depuis longtemps été reconnue comme une propriété importante pour le processus de reconnaissance moléculaire. Des études antérieures ont postulé que les médicaments occupent préférentiellement un sous-ensemble de l'espace des formes des molécules. Ce sous-ensemble pourrait être utilisé pour biaiser la composition de chimiothèques à cribler, dans le but d'augmenter les chances d'identifier des Hits. L'analyse et la validation de cette assertion fait l'objet de cette première partie. Les Ratios de Moments Principaux d'Inertie Normalisés (RPN) ont été utilisés pour décrire la forme tridimensionnelle de petites molécules de type médicament. Il a été étudié si les molécules actives sur des cibles différentes se co-localisaient dans des sous-espaces privilégiés de l'espace des formes. Les résultats montrent des regroupements de molécules incompatibles avec une répartition aléatoire, avec certaines parties de l'espace peu susceptibles d'être occupées par des composés actifs. Par ailleurs, un fort enrichissement en formes allongées et plutôt plates a pu être observé, tandis que les composés globulaires étaient fortement sous-représentés. Cela a été confirmé pour un large ensemble de compilations de molécules d'origines différentes. Les distributions de forme des molécules actives sur des cibles différentes se recoupent largement, rendant une discrimination fondée uniquement sur la forme très difficile. Une perspective supplémentaire a été ajoutée par la comparaison des formes des ligands avec celles de leurs sites de liaison (poches) dans leurs protéines respectives. Bien que plus globulaires que leurs ligands, il a été observé que les formes des poches présentent une distribution dans l'espace des formes avec le même type d'asymétrie que celle observée pour les ligands: les formes sphériques sont fortement sous­ représentées. Un résultat différent a été obtenu pour les poches de plus petite taille et cristallisées sans ligand: elles possédaient une forme plus globulaire. La relation entre complémentarité de forme et bioactivité a été également analysée; une corrélation modérée entre bioactivité et des paramètres tels que remplissage de poche, distance dans l'espace des formes, ainsi que d'autres, a pu être identifiée. Ceci reflète l'importance de la complémentarité des formes, mais aussi l'implication d'autres facteurs. Une analyse ultérieure a évalué si et comment la forme et le volume d'une poche ou de ses ligands de référence pouvaient être utilisés comme un pré-filtre dans une approche de criblage virtuel. Durant l'optimisation d'un Lead, de nombreux paramètres doivent être optimisés simultanément. Dans ce contexte, la disponibilité d'exemples d'optimisations réussies est précieuse, car ils peuvent orienter les chimistes médicinaux dans leurs plans de synthèse par analogie. Cependant, bien que d'un extrême intérêt pour les chercheurs dans le domaine public, seules les grandes sociétés pharmaceutiques avaient jusqu'à présent la capacité d'exploiter de telles connaissances au sein de leurs bases de données internes. Dans le but de remédier à cette limitation, la base de données SwissBioisostere a été élaborée et publiée dans le domaine public au cours de cette thèse. Cette base de données contient des informations sur 21 293 355 échanges sous-structuraux observés, correspondant à 5 586 462 remplacements uniques mesurés dans 35 039 tests contre 1948 cibles représentant 30 familles, ainsi que sur leur impact sur la bioactivité. Une interface a été développée pour permettre un accès facile à ces données, accessible à http:/ /www.swissbioisostere.ch. La base de données ChEMBL a été utilisée comme source de données de bioactivité. Une version modifiée de l'algorithme de Hussain et Rea a été implémentée pour identifier les Matched Molecular Pairs (MMP) dans les données préparées au préalable. Des scores de succès ont été développés et intégrés dans la base de données pour permettre un reclassement des remplacements proposés selon leurs résultats précédemment observés. La corrélation entre ces scores et la similarité chimique des fragments correspondants a été étudiée. Une corrélation plus faible qu'attendue a été détectée et analysée. Différents cas d'utilisation de cette base de données ont été envisagés, et les fonctionnalités correspondantes implémentées: l'agrégation des résultats de remplacement est effectuée au niveau de chaque test, et il a été montré qu'elle pourrait également être effectuée au niveau de la cible ou de la classe de cible, sous réserve d'une analyse au cas par cas. Il a en outre été constaté que le succès d'un remplacement dépend de l'activité du composé A au sein d'une paire A-B. Il a été montré que la probabilité de perdre la bioactivité à la suite d'un remplacement moléculaire quelconque est plus importante au sein des molécules les plus actives que chez les molécules de plus faible activité. L'existence potentielle d'un biais lié au processus de publication par articles a pu être réfutée. En outre, les stratégies fréquentes de chimie médicinale pour l'exploration des relations structure-activité ont été analysées à l'aide des données acquises. Enfin, les données provenant des compagnies pharmaceutiques ont été comparées à celles reportées dans la littérature. Il a pu être constaté que les chimistes médicinaux dans l'industrie peuvent accéder à des remplacements qui ne sont pas disponibles dans le domaine public. Par contre, un grand nombre de remplacements fréquemment observés dans les données de l'industrie ont également pu être identifiés dans les données de la littérature. Les préférences pour certains remplacements particuliers diffèrent entre ces deux sources. L'intérêt d'évaluer les remplacements moléculaires simultanément selon plusieurs paramètres (bioactivité et stabilité métabolique par ex.) a aussi été étudié. Les études réalisées ont souligné qu'il semble n'exister aucun remplacement sous-structural universel qui conserve toujours la bioactivité quel que soit le contexte biologique. Une généralisation des remplacements bioisostériques ne semble donc pas possible.

Soil microbial biomass under different management and tillage systems of permanent intercropped cover species in an orange orchard

To mitigate soil erosion and enhance soil fertility in orange plantations, the permanent protection of the inter-rows by cover species has been suggested. The objective of this study was to evaluate alterations in the microbial biomass, due to different soil tillage systems and intercropped cover species between rows of orange trees. The soil of the experimental area previously used as pasture (Brachiaria humidicola) was an Ultisol (Typic Paleudult) originating from Caiuá sandstone in the northwestern part of the State of Paraná, Brazil. Two soil tillage systems were evaluated: conventional tillage (CT) in the entire area and strip tillage (ST) (strip width 2 m), in combination with different ground cover management systems. The citrus cultivar 'Pera' orange (Citrus sinensis) grafted onto 'Rangpur' lime rootstock was used. Soil samples were collected after five years of treatment from a depth of 0-15 cm, under the tree canopy and in the inter-row, in the following treatments: (1) CT and an annual cover crop with the leguminous species Calopogonium mucunoides; (2) CT and a perennial cover crop with the leguminous peanut Arachis pintoi; (3) CT and an evergreen cover crop with Bahiagrass Paspalum notatum; (4) CT and a cover crop with spontaneous Brachiaria humidicola grass vegetation; and (5) ST and maintenance of the remaining grass (pasture) of Brachiaria humidicola. Soil tillage and the different cover species influenced the microbial biomass, both under the tree canopy and in the inter-row. The cultivation of brachiaria increased C and N in the microbial biomass, while bahiagrass increased P in the microbial biomass. The soil microbial biomass was enriched in N and P by the presence of ground cover species and according to the soil P content. The grass species increased C, N and P in the soil microbial biomass from the inter-row more than leguminous species.

Management and prognosis of status epilepticus according to hospital setting: a prospective study.

BACKGROUND: The treatment of status epilepticus (SE) is based on relatively little evidence although several guidelines have been published. A recent study reported a worse SE prognosis in a large urban setting as compared to a peripheral hospital, postulating better management in the latter. The aim of this study was to analyse SE episodes occurring in different settings and address possible explanatory variables regarding outcome, including treatment quality. METHODS: Over six months we prospectively recorded consecutive adults with SE (fit lasting five or more minutes) at the Centre Hospitalier Universitaire Vaudois (CHUV) and in six peripheral hospitals (PH) in the same region. Demographical, historical and clinical variables were collected, including SE severity estimation (STESS score) and adherence to Swiss SE treatment guidelines. Outcome at discharge was categorised as "good" (return to baseline), or "poor" (persistent neurological sequelae or death). RESULTS: Of 54 patients (CHUV: 36; PH 18), 33% had a poor outcome. Whilst age, SE severity, percentage of SE episodes lasting less than 30 minutes and total SE duration were similar, fewer patients had a good outcome at the CHUV (61% vs 83%; OR 3.57; 95% CI 0.8-22.1). Mortality was 14% at the CHUV and 5% at the PH. Most treatments were in agreement with national guidelines, although less often in PH (78% vs 97%, P = 0.04). CONCLUSION: Although not statistically significant, we observed a slightly worse SE prognosis in a large academic centre as compared to smaller hospitals. Since SE severity was similar in the two settings but adherence to national treatment guidelines was higher in the academic centre, further investigation on the prognostic role of SE treatment and outcome determinants is required.

Clinical management and outcome of histologically verified adult brainstem gliomas in Switzerland: a retrospective analysis of 21 patients.

Because of low incidence, mixed study populations and paucity of clinical and histological data, the management of adult brainstem gliomas (BSGs) remains non-standardized. We here describe characteristics, treatment and outcome of patients with exclusively histologically confirmed adult BSGs. A retrospective chart review of adults (age >18 years) was conducted. BSG was defined as a glial tumor located in the midbrain, pons or medulla. Characteristics, management and outcome were analyzed. Twenty one patients (17 males; median age 41 years) were diagnosed between 2004 and 2012 by biopsy (n = 15), partial (n = 4) or complete resection (n = 2). Diagnoses were glioblastoma (WHO grade IV, n = 6), anaplastic astrocytoma (WHO grade III, n = 7), diffuse astrocytoma (WHO grade II, n = 6) and pilocytic astrocytoma (WHO grade I, n = 2). Diffuse gliomas were mainly located in the pons and frequently showed MRI contrast enhancement. Endophytic growth was common (16 vs. 5). Postoperative therapy in low-grade (WHO grade I/II) and high-grade gliomas (WHO grade III/IV) consisted of radiotherapy alone (three in each group), radiochemotherapy (2 vs. 6), chemotherapy alone (0 vs. 2) or no postoperative therapy (3 vs. 1). Median PFS (24.1 vs. 5.8 months; log-rank, p = 0.009) and mOS (30.5 vs. 11.5 months; log-rank, p = 0.028) was significantly better in WHO grade II than in WHO grade III/IV tumors. Second-line therapy considerably varied. Histologically verification of adult BSGs is feasible and has an impact on postoperative treatment. Low-grade gliomas can simple be followed or treated with radiotherapy alone. Radiochemotherapy with temozolomide can safely be prescribed for high-grade gliomas without additional CNS toxicities.

Educational expansion, intergenerational mobility and over-education

[eng] There is a vast literature on intergenerational mobility in sociology and economics. Similar interest has emerged for the phenomenon of over-education in both disciplines. There are no studies, however, linking these two research lines. We study the relationship between social mobility and over-education in a context of educational expansion. Our framework allows for the evaluation of several policies, including those affecting social segregation, early intervention programs and the power of unions. Results show the evolution of social mobility, over-education, income inequality and equality of opportunity under each scenario.