Caractérisation phénotypique et génotypique de la néphropathie liée aux mutations du facteur de transcription HNF-1Beta : rôle d'HNF-1Beta dans l'insuffisance rénale aiguë expérimentale

Le gène HNF1B code pour le facteur de transcription HNF-1bêta (hepatocyte nuclear factor-1bêta). Chez l'homme, les mutations d'HNF1B sont associées à une maladie à transmission autosomique dominante touchant à des degrés divers le rein, le pancréas, le foie et l'appareil génital. Dans le rein, HNF-1bêta régule la néphrogenèse précoce et tardive, la tubulogenèse, la polarisation planaire des cellules tubulaires (division orientée dans l'espace) et plus tardivement l'homéostasie des cellules tubulaires. Les objectifs de ce travail de thèse étaient de trois ordres : mieux caractériser le phénotype associé aux mutations d'HNF1B en particulier à l'âge adulte (partie clinique), mieux définir le génotype des patients HNF1B (partie génétique) et caractériser le rôle d'HNF-1bêta au cours de la régénération suivant une agression épithéliale aiguë (partie fondamentale). (1) Caractérisation phénotypique. Outre la publication de deux phénotypes originaux (atrésie de l'œsophage - anomalies rénales ; néphropathie kystique mimant une polykystose autosomique dominante), nous avons pu colliger les données d'une cohorte de 27 patients adultes porteurs d'une mutation d'HNF1B et rapporter les faits suivants : à l'âge adulte, la néphropathie est de type tubulo-interstitielle chronique et associe fréquemment une hypomagnésémie et une hypokaliémie. Nous avons également pu réaliser une analyse génotype-phénotype précise d'une large cohorte d'individus mutés (majoritairement d'âge pédiatrique). (2) Caractérisation Génétique. En plus de participer à une étude de corrélation génotype - phénotype, nous avons entrepris de mieux définir la population pouvant bénéficier d'une exploration du gène HNF1B. L'étude d'une large cohorte de 433 patients testés dans le laboratoire de Génétique du CHU de Toulouse nous a permis de définir un score prédictif de mutation d'HNF1B utile à la fois aux cliniciens et aux généticiens. (3) Caractérisation du rôle d'HNF-1bêta chez l'homme et en pathologie. Dans un premier temps, le rôle d' HNF-1bêta dans le rein humain post-natal a été appréhendé par l'analyse de l'expression de ses gènes cibles dans le sédiment urinaire de patients HNF1B (succédané du tissu rénal habituellement non disponible dans cette pathologie) et de leurs apparentés au 1er degré indemnes de la mutation. Nous avons pu confirmer par cette approche indirecte les données parcellaires disponibles chez la souris : l'expression des cystogènes cibles d'HNF-1bêta après la phase du développement rénal n'est pas différente de celle des patients témoins. Dans un second temps, nous avons tenté d'appréhender le rôle d'HNF-1bêta au cours des phases de régénération épithéliale suivant une agression rénale aiguë. L'étude d'un modèle murin de choc hémorragique contrôlé nous a permis de définir la cinétique d'expression d'HNF-1bêta et de la rapporter à celle de ses cibles géniques, dont SOCS3, acteur clé de la réparation de l'épithélium rénal et de la réponse épithéliale aux stimuli extra-cellulaires (IL-6, HGF, EGF...). In vitro, l'impact de l'hypoxie et du facteur induit par l'hypoxie Hif-1a sur l'expression d'HNF-1bêta a également pu être détaillée. L'expression d'HNF-1bêta n'étant pas limitée au rein, nous faisons l'hypothèse que ce facteur pourrait également être impliqué dans la régénération d'autres épithélia, comme le foie ou le tube digestif. Enfin, afin de mieux caractériser l'impact d'une agression épithéliale sur l'expression d'HNF-1bêta et en déduire les mécanismes moléculaires de sa régulation, nous détaillons actuellement l'impact d'un choc endotoxinique (injection de lipopolysaccharide) sur l'expression d'HNF-1bêta et de ses gènes cibles dans les différents organes sus-cités. L'étude in vitro de cellules rénales soumises au même stress nous a également permis de définir une nouvelle voie de régulation d'HNF-1bêta. En résumé, ce travail aborde un ensemble de problématiques attenant au facteur de transcription HNF-1bêta (manifestions phénotypiques et génotypiques de ses mutations, caractérisation du rôle d'HNF-1bêta en situation d'agression épithéliale aiguë). Par extension, la caractérisation du rôle d'HNF-1bêta dans la réparation épithéliale et de ses modes de régulation pourrait ouvrir un nouveau champ de recherche sur son éventuelle capacité à prévenir la dédifférenciation tubulaire, prémisse à l'apparition d'une fibrose rénale.The HNF1B gene encodes for the HNF-1beta transcription factor (hepatocyte nuclear factor-1beta). In human, HNF1B-related disease is a highly heterogeneous dominantly inherited multi-organ disease, which encompasses renal, pancreas, liver and genital tract abnormalities. In the kidney, HNF-1beta controls all the steps of the nephrogenesis (tubulogenesis, planar cell polarity (oriented mitotic division) and tubular segment specification and maintenance. Aims of this thesis were to better detail the phenotype associated with HNF1B mutations (clinical part), to better define the genotype of the HNF1B patients (genetic part) and to assess the role of HNF-1beta in acute kidney injury (scientific part). 1. Clinical part. First, we reported two atypical presentations of HNF1B mutation (cystic kidney disease mimicking an autosomal polycystic kidney disease ; esophageal atresia and urinary tract/renal abnormalities). We also reported the clinical charts of 27 adult patients with HNF1B mutation and highlighted the following data : in adult patients, HNF1B nephropathy has the characteristics of a chronic tubulo-interstitial nephritis with frequent hypomagnesemia and hypokaliemia. Last, we could perform a genotype-phenotype analysis in a large cohort of HNF1B individuals (mostly lower than 18 years of age). 2. Genetic part. In addition to the genotype-phenotype correlation study, we tried to better define the individuals that could beneficiate from HNF1B analysis. Studying a large cohort of 433 patients tested in the Genetic department of the University hospital of Toulouse, we could establish a predictive score of HNF1B mutation in order to help both clinicians and geneticist. 3. Scientific part. First, role of HNF-1 beta in post-natal human kidney was assessed by studying the expression of its target genes in the urinary cells pellets of HNF1B patients and their first-degree relatives free of mutation. With this indirect approach, we could confirm preliminary data observed in mouse models : in post-natal kidney, expression of HNF-1 beta target cystogenes was similar in individuals with and without HNF1B mutation. Then, we aimed at better delineate the role of HNF-1beta in acute kidney injury. Studying a mouse model of hemorrhagic shock, we could characterize the kinetic of HNF-1beta expression in injured kidney and to correlate it to the expression of its target genes, like Socs3, a key actor of epithelial repair which control an adaptative response of the epithelium to extra-cellular signals (IL-6, EGF, HGF...). In vitro, respective roles of the hypoxia-inducible factor HIF-1a and hypoxia per se were detailed. Given the expression of HNF-1beta in many epithelial cells, we hypothesized that this transcription factor may also be involved in the reparation of other organ (liver, gut...). Last, in order to better decipher the consequences of an epithelial injury on HNF-1beta expression, experiments in a mouse model of endotoxinic shock (lipopolysaccharide infusion) are currently on going. In summary, this work aimed at better delineate the genotype and phenotype of HNF1B mutations and decipher the role of this transcription factor in acute (ischemic and septic) kidney injury. Characterization of the role of HNF-1beta in epithelial repair and identification of its regulatory factors could open a new field of research : may HNF-1beta prevent epithelial dedifferentiation, a well-known trigger of renal fibrosis

Early presentation of primary glioblastoma

Background Clinical and neuroimaging findings of glioblastomas (GBM) at an early stage have rarely been described and those tumors are most probably under-diagnosed. Furthermore, their genetic alterations, to our knowledge, have never been previously reported. Methods We report the clinical as well as neuroimaging findings of four early cases of patients with GBM. Results In our series, early stage GBM occurred at a mean age of 57 years. All patients had seizures as their first symptom. In all early stages, MRI showed a hyperintense signal on T2-weighted sequences and an enhancement on GdE-T1WI sequences. A hyperintense signal on diffusion sequences with a low ADC value was also found. These early observed occurrences of GBM developed rapidly and presented the MRI characteristics of classic GBM within a few weeks. The GBM size was multiplied by 32 in one month. Immunohistochemical analysis indicated the de novo nature of these tumors, i.e. absence of mutant IDH1 R132H protein expression, which is a diagnostic marker of low-grade diffuse glioma and secondary GBM. Conclusions A better knowledge of early GBM presentation would allow a more suitable management of the patients and may improve their prognosis

Una nueva forma de gestión: la evaluación

Actualmente, el control permanente de los desempeños se tiende a instaurar en todos los lugares de trabajo, en las fábricas, en las oficinas, en los supermercados y también en los empleos subalternos de la actividad intelectual. La incertidumbre, asociada con frecuencia a estas formas de actividad, que obliga a invertir y “desinvertir” continuamente, moviliza, al mismo tiempo, la creencia en el futuro y la amenaza de perder el empleo. La disponibilidad y la flexibilidad suscitan auto-evaluación y reconversión. Las relaciones de trabajo son inseparablemente relaciones de dominación, donde cada puesto, al mismo tiempo que implica el dominio de una competencia técnica específica, requiere las cualidades exigidas ordinariamente al personal. Así, con la informática, hasta del personal subalterno se exige una parte cada vez más importante de actividad de servicio y de “comunicación”. Tomándose aparentemente más autónomo, cada asalariado debe acumular las cualidades contradictorias implicadas en el dominio técnico del puesto y en la consideración de las relaciones entre colegas, asumiendo inclusive tareas de encuadramiento. Cada uno debe saber negociar su trabajo, autoevaluarse, “venderse”

Sociólogo de campo

La sociología empírica, a comienzos de los años 1960 en Francia, no tenía una existencia institucional susceptible de estructurar un proyecto en común, si por esto se entiende la existencia de un verdadero curso de formación, modelos a imitar dejados por las generaciones precedentes y, finalmente, salidas profesionales cuyos criterios de reclutamiento y de éxito se apoyan precisamente sobre una deontología profesional específica. Este débil grado de institucionalización de la profesión de sociólogo puede explicar a la vez la poca homogeneidad en las formaciones de los investigadores, la diversidad de sus trayectorias así como la gran heterogeneidad de las “producciones científicas”. Este artículo, que se apoya en los testimonios de miembros del “equipo Bourdieu”, despeja tres modelos de reconversion hacia la sociología: filósofos reconvertidos en investigadores autodidactas en ciencias sociales, militantes políticos y, finalmente, profesores de disciplinas literarias que buscaban en el modelo “artista” los esquemas de una ruptura con una visión académica de las ciencias sociales: la noción.de “intelectual colectivo” tiende a conciliar en un proyecto común de socioanálisis las contradicciones de estos modelos vocacionales diferentes.Empirical sociology, in the early 1960s,in France, had no institutional existence capable of structuring a common project, in terms of the existence of a real course of training, role models left by previous generations, and finally, career and recruitment criteria of success based precisely on a specific professional ethics. This slight degree of institutionalization of the profession of sociologist can explain both the lack of uniformity in the training of researchers, the diversity of their paths and the large heterogeneity of the «scientific productions». This article, which is based on the testimonies of members of the «Bourdieu group”, shows three models for conversion to sociology: self-taught philosopher-turned-social science researchers, political activists, and finally, teachers seeking literary disciplines in the model of artists with the aim of breaking the schemes of an academic view of social science: the notion of «collective intellectual» tends to reconcile in a joint project of socio-analysis of the contradictions of these different vocational models.Traducción: Matilde Balduzzi (NEES

Optic nerve and visual pathways primary glioblastoma treated with radiotherapy and temozolomide chemotherapy

PURPOSE: Primary malignant gliomas of the optic nerves are rare tumors of adulthood, progressing rapidly to blindness and to death within several months, regardless of the type of treatment. Recently, treatments associating radiotherapy and temozolomide have been used in other types of glioblastomas, but their impact on optic nerve malignant gliomas is not known. METHODS: This was a retrospective case series of 2 patients diagnosed with primary optic nerve and chiasm glioblastoma (GBM), treated with radiotherapy and concomitant temozolomide. RESULTS: A 74-year-old man presented with visual loss caused by an infiltrative and enhancing lesion, affecting the left optic nerve and the chiasm, subsequently confirmed as GBM World Health Organization (WHO) grade IV. The patient was treated with external conformal radiotherapy (54 Gy over 42 days) and concomitant chemotherapy with temozolomide (75 mg/m2/day), followed by 6 monthly cycles of adjuvant treatment (250 mg/day for 5 days). The second patient was a 74-year-old woman diagnosed with bilateral visual loss due to pathologically confirmed GBM (WHO grade IV). She was treated with temozolomide (220 mg/day) for 1 month, followed by radiotherapy (54 Gy over 42 days) and temozolomide chemotherapy (75 mg/m2/day). There was no adjuvant regimen. This treatment resulted in disease stabilization and partial preservation of vision during 12 months for patient 1, 8 months for patient 2. Survival after first examination was 15 and 11 months, respectively. CONCLUSIONS: Combined radiotherapy and temozolomide may be an alternative treatment in optic nerve and visual pathways primary GBM, potentially providing a longer survival

Effects of comorbidities on quality of life in Filipino people with tuberculosis.

BACKGROUND: We investigated health-related quality of life (HrQoL) in Filipino people undergoing TB treatment, and whether HrQoL was negatively impacted by comorbidity with undernutrition, diabetes (DM) and anaemia.METHODS: Adult participants were enrolled in public facilities in Metro Manila (three sites) and Negros Occidental (two sites). Multivariate linear regression was used to model the four correlated domain scores from a WHOQOL-BREF questionnaire (physical, psychological, social, environmental). A forward-stepwise approach was used to select a final multivariable model with inclusion based on global tests of significance at P < 0.1.RESULTS: In 446 people on drug-susceptible TB treatment, DM and moderate/severe anaemia were not associated with HrQoL. After adjustment for age, sex, education, food insecurity, treatment adherence, inflammation, Category I or II TB treatment, treatment phase, current side effects and inhibited ability to work, moderate/severe undernutrition (body mass index < 17 kg/m²) was associated with lower HrQoL (P = 0.003) with reduced psychological (coefficient: -1.02, 95% CI -1.54 to -0.51), physical (-0.62, 95% CI -1.14 to -0.09) and environmental domain scores (-0.45, 95% CI -0.88 to -0.01). In 225 patients with known HIV status in Metro Manila, HIV was associated with modestly reduced HrQoL (P = 0.014).CONCLUSION: Nutritional status and food insecurity represent modifiable risk factors for poor HrQoL that may be alleviated through interventions

Patterns and predictors of co-morbidities in Tuberculosis: A cross-sectional study in the Philippines.

Diabetes and undernutrition are common risk factors for TB, associated with poor treatment outcomes and exacerbated by TB. We aimed to assess non-communicable multimorbidity (co-occurrence of two or more medical conditions) in Filipino TB outpatients, focusing on malnutrition and diabetes. In a cross-sectional study, 637 adults (70% male) from clinics in urban Metro Manila (N = 338) and rural Negros Occidental (N = 299) were enrolled. Diabetes was defined as HbA1c of ≥6.5% and/or current diabetes medication. Study-specific HIV screening was conducted. The prevalence of diabetes was 9.2% (54/589, 95%CI: 7.0-11.8%) with 52% newly diagnosed. Moderate/severe undernutrition (body mass index (BMI) <17 kg/2) was 20.5% (130/634, 95%CI: 17.4-23.9%). Forty percent of participants had at least one co-morbidity (diabetes, moderate/severe undernutrition or moderate/severe anaemia (haemoglobin <11 g/dL)). HIV infection (24.4%, 74/303) was not associated with other co-morbidities (but high refusal in rural clinics). Central obesity assessed by waist-to-hip ratio was more strongly associated with diabetes (Adjusted Odds Ratio (AOR) = 6.16, 95%CI: 3.15-12.0) than BMI. Undernutrition was less common in men (AOR = 0.44, 95%CI: 0.28-0.70), and associated with previous history of TB (AOR = 1.97, 95%CI: 1.28-3.04) and recent reduced food intake. The prevalence of multimorbidity was high demonstrating a significant unmet need. HIV was not a risk factor for increased non-communicable multimorbidity