Metabolomic insights into the intricate gut microbial-host interaction in the development of obesity and type 2 diabetes.

Gut microbiota has recently been proposed as a crucial environmental factor in the development of metabolic diseases such as obesity and type 2 diabetes, mainly due to its contribution in the modulation of several processes including host energy metabolism, gut epithelial permeability, gut peptide hormone secretion, and host inflammatory state. Since the symbiotic interaction between the gut microbiota and the host is essentially reflected in specific metabolic signatures, much expectation is placed on the application of metabolomic approaches to unveil the key mechanisms linking the gut microbiota composition and activity with disease development. The present review aims to summarize the gut microbial-host co-metabolites identified so far by targeted and untargeted metabolomic studies in humans, in association with impaired glucose homeostasis and/or obesity. An alteration of the co-metabolism of bile acids, branched fatty acids, choline, vitamins (i.e., niacin), purines, and phenolic compounds has been associated so far with the obese or diabese phenotype, in respect to healthy controls. Furthermore, anti-diabetic treatments such as metformin and sulfonylurea have been observed to modulate the gut microbiota or at least their metabolic profiles, thereby potentially affecting insulin resistance through indirect mechanisms still unknown. Despite the scarcity of the metabolomic studies currently available on the microbial-host crosstalk, the data-driven results largely confirmed findings independently obtained from in vitro and animal model studies, putting forward the mechanisms underlying the implication of a dysfunctional gut microbiota in the development of metabolic disorders.

Cutaneous leishmaniasis mimicking a pyogenic granuloma.

The Leishmania genus is formed by parasitic protozoa which are transmitted by the bite of infected female sand flies. Cases of sexual, vertical or transfusional transmission or via infected needles have also been described. In humans, 4 forms of this disease have been described: localised cutaneous (LC), diffuse cutaneous, mucocutaneous and visceral (1). LC counts for 50–75% of all cases (2), it is the mildest form of the disease and can be caused by any species of Leishmania. In Spain, the most frequent form is the oriental sore caused by L. infantum (2). Most cases resolve spontaneously within one year. In United States and Europe, the incidence is increasing due to tourism and co-infection with HIV. The morphological spectrum of LC is very wide; multiple forms of clinical presentation have been described, although the most characteristic one is the nodular ulcerative lesion, characterised by painless crater-like ulcers with a necrotic base and covered by an adhesive crust. The main complication of LC is its progression in some strains towards the other 3 forms of the disease (3). In patients with AIDS and other diseases associated with immunosuppression the risk of dissemination is much higher than in the immunocompetent. We present a case of LC with clinical and histopathological features similar to a pyogenic granuloma.

Patients' and physicians' preferences for type 2 diabetes mellitus treatments in Spain and Portugal: a discrete choice experiment.

OBJECTIVE To assess Spanish and Portuguese patients' and physicians' preferences regarding type 2 diabetes mellitus (T2DM) treatments and the monthly willingness to pay (WTP) to gain benefits or avoid side effects. METHODS An observational, multicenter, exploratory study focused on routine clinical practice in Spain and Portugal. Physicians were recruited from multiple hospitals and outpatient clinics, while patients were recruited from eleven centers operating in the public health care system in different autonomous communities in Spain and Portugal. Preferences were measured via a discrete choice experiment by rating multiple T2DM medication attributes. Data were analyzed using the conditional logit model. RESULTS Three-hundred and thirty (n=330) patients (49.7% female; mean age 62.4 [SD: 10.3] years, mean T2DM duration 13.9 [8.2] years, mean body mass index 32.5 [6.8] kg/m(2), 41.8% received oral + injected medication, 40.3% received oral, and 17.6% injected treatments) and 221 physicians from Spain and Portugal (62% female; mean age 41.9 [SD: 10.5] years, 33.5% endocrinologists, 66.5% primary-care doctors) participated. Patients valued avoiding a gain in bodyweight of 3 kg/6 months (WTP: €68.14 [95% confidence interval: 54.55-85.08]) the most, followed by avoiding one hypoglycemic event/month (WTP: €54.80 [23.29-82.26]). Physicians valued avoiding one hypoglycemia/week (WTP: €287.18 [95% confidence interval: 160.31-1,387.21]) the most, followed by avoiding a 3 kg/6 months gain in bodyweight and decreasing cardiovascular risk (WTP: €166.87 [88.63-843.09] and €154.30 [98.13-434.19], respectively). Physicians and patients were willing to pay €125.92 (73.30-622.75) and €24.28 (18.41-30.31), respectively, to avoid a 1% increase in glycated hemoglobin, and €143.30 (73.39-543.62) and €42.74 (23.89-61.77) to avoid nausea. CONCLUSION Both patients and physicians in Spain and Portugal are willing to pay for the health benefits associated with improved diabetes treatment, the most important being to avoid hypoglycemia and gaining weight. Decreased cardiovascular risk and weight reduction became the third most valued attributes for physicians and patients, respectively.

A Lower Olfactory Capacity Is Related to Higher Circulating Concentrations of Endocannabinoid 2-Arachidonoylglycerol and Higher Body Mass Index in Women.

The endocannabinoid (eCB) system can promote food intake by increasing odor detection in mice. The eCB system is over-active in human obesity. Our aim is to measure circulating eCB concentrations and olfactory capacity in a human sample that includes people with obesity and explore the possible interaction between olfaction, obesity and the eCB system. The study sample was made up of 161 females with five groups of body mass index sub-categories ranging from under-weight to morbidly obese. We assessed olfactory capacity with the "Sniffin´Sticks" test, which measures olfactory threshold-discrimination-identification (TDI) capacity. We measured plasma concentrations of the eCBs 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine or anandamide (AEA), and several eCB-related compounds, 2-acylglycerols and N-acylethanolamines. 2-AG and other 2-acylglycerols fasting plasma circulating plasma concentrations were higher in obese and morbidly obese subjects. AEA and other N-acylethanolamine circulating concentrations were lower in under-weight subjects. Olfactory TDI scores were lower in obese and morbidly obese subjects. Lower TDI scores were independently associated with higher 2-AG fasting plasma circulating concentrations, higher %body fat, and higher body mass index, after controlling for age, smoking, menstruation, and use of contraceptives. Our results show that obese subjects have a lower olfactory capacity than non-obese ones and that elevated fasting plasma circulating 2-AG concentrations in obesity are linked to a lower olfactory capacity. In agreement with previous studies we show that eCBs AEA and 2-AG, and their respective congeners have a distinct profile in relation to body mass index. The present report is the first study in humans in which olfactory capacity and circulating eCB concentrations have been measured in the same subjects.

A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

BACKGROUND Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown. METHODS AND FINDINGS The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed. CONCLUSIONS These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.

Insuffisance rénale terminale d'origine lithiasique : fréquence, causes et prévention [Nephrolithiasis-induced ESRD: frequency, causes and prevention].

Nephrolithiasis still remains a too frequent - and under-appreciated - cause of end-stage renal disease (ESRD), and this is all the most unfortunate since such an untoward course is now preventable in most cases. Among 1391 patients who started maintenance dialysis at Necker hospital between 1989 and 2000, nephrolithiasis was identified as the cause of ESRD in 45 of them, an overall prevalence of 3.2%. Infection stones accounted for 42.2% of cases, calcium stones for 26.7%, uric acid stones for 17.8% and hereditary diseases for 13.3%. The proportion of nephrolithiasis-associated ESRD declined from 4.7% to 2.2% from the 1989-1991 to the 1998-2000 period, as a result of the decreased incidence of ESRD in patients with infection and calcium nephrolithiasis. Based on our observations and on published reports, it emerges that most cases of nephrolithiasis-associated ESRD were due to sub-optimal management (especially in the case of infection or cystine stones) or to late (or erroneous) etiologic diagnosis, precluding early institution of appropriate therapeutic measures. In particular, several patients with primary hyperoxaluria or 2,8-dihydroxyadeninuria were diagnosed while already on dialysis or after unsuccessful kidney transplantation, due to wrong initial diagnosis. In conclusion, thanks to recent advances in diagnosis and management of stone formers, ESRD should now be prevented in the great majority of patients, at the condition of early etiologic diagnosis based on accurate morphoconstitutional analysis of calculi and metabolic evaluation, and early implementation of appropriate preventive medical treatment.

Building energy saving techniques and indoor air quality : a dilemma

In European countries and North America, people spend 80 to 90% of time inside buildings and thus breathe indoor air. In Switzerland, special attention has been devoted to the 16 stations of the national network of observation of atmospheric pollutants (NABEL). The results indicate a reduction in outdoor pollution over the last ten years. With such a decrease in pollution over these ten years the question becomes: how can we explain an increase of diseases? Indoor pollution can be the cause. Indoor contaminants that may create indoor air quality (IAQ) problems come from a variety of sources. These can include inadequate ventilation, temperature and humidity dysfunction, and volatile organic compounds (VOCs). The health effects from these contaminants are varied and can range from discomfort, irritation and respiratory diseases to cancer. Among such contaminants, environmental tobacco smoke (ETS) could be considered the most important in terms of both health effects and engineering controls of ventilation. To perform indoor pollution monitoring, several selected ETS tracers can be used including carbon monoxide (CO), carbon dioxide (CO2), respirable particles (RSP), condensate, nicotine, polycyclic aromatic hydrocarbons (PAHs), nitrosamines, etc. In this paper, some examples are presented of IAQ problems that have occurred following the renewal of buildings and energy saving concerns. Using industrial hygiene sampling techniques and focussing on selected priority pollutants used as tracers, various problems have been identified and solutions proposed. [Author]

A model for physical activity, bahaviour and energy expenditure assessment in real-life condition

RésuméL'origine de l'obésité, qui atteint des proportions épidémiques, est complexe. Elle est liée au mode de vie et au comportement des individus par rapport à l'activité physique, expression des choix individuels et de l'interaction avec l'environnement. Les mesures du comportement au niveau de l'activité physique des individus face à leur environnement, la répartition des types d'activité physique, la durée, la fréquence, l'intensité, et la dépense énergétique sont d'une grande importance. Aujourd'hui, il y a un manque de méthodes permettant une évaluation précise et objective de l'activité physique et du comportement des individus. Afin de compléter les recherches relatives à l'activité physique, à l'obésité et à certaines maladies, le premier objectif du travail de thèse était de développer un modèle pour l'identification objective des types d'activité physique dans des conditions de vie réelles et l'estimation de la dépense énergétique basée sur une combinaison de 2 accéléromètres et 1 GPS. Le modèle prend en compte qu'une activité donnée peut être accomplie de différentes façons dans la vie réelle. Les activités quotidiennes ont pu être classées en 8 catégories, de sédentaires à actives, avec une précision de 1 min. La dépense énergétique a pu peut être prédite avec précision par le modèle. Après validation du modèle, le comportement des individus de l'activité physique a été évalué dans une seconde étude. Nous avons émis l'hypothèse que, dans un environnement caractérisé par les pentes, les personnes obèses sont tentées d'éviter les pentes raides et de diminuer la vitesse de marche au cours d'une activité physique spontanée, ainsi que pendant les exercices prescrits et structurés. Nous avons donc caractérisé, par moyen du modèle développé, le comportement des individus obèses dans un environnement vallonné urbain. La façon dont on aborde un environnement valloné dans les déplacements quotidiens devrait également être considérée lors de la prescription de marche supplémentaire afin d'augmenter l'activité physique.SummaryOrigin of obesity, that reached epidemic proportion, is complex and may be linked to different lifestyle and physical activity behaviour. Measurement of physical activity behaviour of individuals towards their environment, the distribution of physical activity in terms of physical activity type, volume, duration, frequency, intensity, and energy expenditure is of great importance. Nowadays, there is a lack of methods for accurate and objective assessment of physical activity and of individuals' physical activity behaviour. In order to complement the research relating physical activity to obesity and related diseases, the first aim of the thesis work was to develop a model for objective identification of physical activity types in real-life condition and energy expenditure based on a combination of 2 accelerometers and 1 GPS device. The model takes into account that a given activity can be achieved in many different ways in real life condition. Daily activities could be classified in 8 categories, as sedentary to active physical activity, within 1 min accuracy, and physical activity patterns determined. The energy expenditure could be predicted accurately with an accuracy below 10%. Furthermore, individuals' physical activity behaviour is expression of individual choices and their interaction with the neighbourhood environment. In a second study, we hypothesized that, in an environment characterized by inclines, obese individuals are tempted to avoid steep positive slopes and to decrease walking speed during spontaneous outdoor physical activity, as well as during prescribed structured bouts of exercise. Finally, we characterized, by mean of the developed model, the physical activity behaviour of obese individuals in a hilly urban environment. Quantifying how one tackles hilly environment or avoids slope in their everyday displacements should be also considered while prescribing extra walking in free-living conditions in order to increase physical activity.

Assessment of particulate exposure and surface characteristics in association with urinary levels of 8-hydroxy-2'-deoxyguanosine, considered as marker of oxidative stress

Epidemiological studies have demonstrated that exposure to fine particles is associated to adverse health effects, including cancer, respiratory and cardiovascular diseases. However, mechanisms by which particles induce health effects remain unclear. According to one of the most investigated hypotheses, particles cause adverse effects through the production of reactive oxygen species (ROS), which are very hazardous compounds able to attack directly biological structures, including the DNA strand or the lipid bilayer of the cells. If the defense mechanisms, constituted of antioxidants, are not able to counter ROS, then these compounds will cause in the body a range of oxidation reactions called "oxidative stress". The aim of the present research project was to better understand mechanisms by which exposure to fine particles induces oxidative stress. The first point of this project was to check whether exposure to high levels of fine particles is directly linked to oxidative stress, and whether this oxidative stress is accompanied by the activation of the defense mechanisms (antioxidants). The second point was to study the role played by the particle surface characteristics in the oxidative stress process. For that purpose, a study was conducted in bus depots with the participation of 40 mechanics. First, occupational exposure to particles (PM4) and to other pollutants (NOx, O3) was measured over a two-day period. Then, urine samples of mechanics were collected in order to measure levels of 8-hydroxy-2'-deoxyguanosine (8OHdG) and antioxidants. 8OHdG is a molecule formed by the oxidation of DNA and allowing to assess the oxidative stress status of the mechanics. Finally, particles were collected on filters, and functional groups located on the particle surface were analyzed in the laboratory using a Knudsen flow reactor. This technique allows not only to quantify functional groups on the particle surface, but also to measure the reaction kinetics. Results obtained during the field campaign in bus depots showed that mechanics were exposed to rather low levels of PM4 (20-85 μg/m3) and of pollutants (NOx: 100-1000 ppb; O3: <15 ppb). However, despite this low exposure, urinary levels of the oxidative stress biomarker (8OHdG) increased significantly for non-smoking workers over a two-day period of shift. This oxidative stress was accompanied by an increase of antioxidants, indicating the activation of defense mechanisms. On the other hand, the analysis of functional groups on the particle surface showed important differences, depending on the workplace, the date and the activities of workers. The particle surface contained simultaneously antagonistic functional groups which did not undergo internal reactions (such as acids and bases), and was usually characterized by a high density of carbonyl functions and a low density of acidic sites. Reaction kinetics measured using the Knudsen flow reactor pointed out fast reactions of oxidizable groups and slow reactions of acidic sites. Several exposure parameters were significantly correlated with the increase of the oxidative stress status: the presence of acidic sites, carbonyl functions and oxidizable groups on the particle surface; reaction kinetics of functional groups on the particle surface; particulate iron and copper concentrations; and NOx concentration.

Identification, using a siRNA screen approach, and molecular characterization of a new Fas pathway modulator: STK11/

Abstract : Apoptosis is an evolutionarily conserved cellular suicide mechanism that can be triggered by activation of various pathways, such as the Fas-Pathway. Upon stimulation by its specific ligand (FasL), present at the surface of Cytotoxic Τ lymphocytes, the death receptor Fas initiates a signaling cascade culminating in the activation of cellular caspases, leading thus to cell death of the target cell (e.g. transformed cell). Dysregulation of apoptosis in general, and of Fas pathway in particular, was shown to contribute to pathogenesis of cancers and many human diseases. Even though, during the last decades the molecular mechanisms of apoptosis have been widely studied, it is important to better understand the mechanisms leading to apoptosis, to improve our understanding of pathological processes, and generate more subtle apoptosis-modulating therapies to fight cancer and other diseases. In order to identify new components of the Fas signaling pathway, a screen based on the mechanism of RNA interference was undertaken. After a first and a second manual whole-kinome screen, we identified several strong positive hits that showed a protection against Fas ligand-induced apoptosis with distinct siRNAs, notably STK11, an interesting tumor suppressor mutated in several sporadic and inherited cancers. The STK11 functional characterization reveals that this kinase represents an apically acting general pro-apoptotic modulator of the extrinsic pathway (FasL, TRAIL, TNF-induced apoptosis), but not of the intrinsic apoptotic pathway. The STK11 action on the Fas pathway was shown to be dependent on its kinase activity, but independent of AMPK, a well-characterized STK11 downstream substrate. Furthermore, STK11 was shown to interact with caspase-8, a major mediator of the extrinsic pathway, and modulate its activity through an unclear mechanism that may involve an STK11-dependant caspase-8 phosphorylation. This modification may allow a proper caspase-8 polyubiquitination and activation in p62 sequestosmes aggregates, but may also increase the activation of caspase-8 at the DISC level. In addition, we observed that STK11 modulate not only the apoptotic pathway induced by Fas engagement, but also FasL-induced JNK and NF- KB, sustaining an upstream role of this kinase in the pathway. In conclusion, our report reveals that STK11 is an important pro-apoptotic modulator of the Fas pathway in particular, and extrinsic pathway in general. Our finding could explain, at least partially, why inactivating mutations of the kinase leads to cancer, by allowing resistance to apoptosis and accordingly evasion of immune surveillance. Résumé : L'apoptose est un mécanisme de suicide cellulaire, conservé dans diverses espèces, et qui au niveau moléculaire est déclenché par différentes voies de signalisation, comme par exemple lors de l'activation du récepteur Fas. La liaison du ligand FasL au récepteur de la mort Fas, induit une cascade de signalisation qui conduit à l'activation des caspases. Les lymphocytes Τ cytotoxiques peuvent utiliser la voie Fas pour induire la mort et se débarrasser de cellules dangereuses pour le reste de l'organisme, tel que les cellules transformées. La dysrégulation de l'apoptose en général, et de la voie Fas en particulier, peut contribuer à diverses maladies telles que le cancer. Même si ces dernières décennies, les mécanismes moléculaires conduisant à l'apoptose ont été extensivement étudiés, il reste néanmoins important de mieux comprendre le phénomène d'apoptose, pour améliorer notre compréhension des processus pathologiques, mais surtout dans le but de développer de nouvelles thérapies ciblant l'apoptose contre le cancer et d'autres pathologies. Pour identifier de nouveau constituants de la voie Fas, un criblage génétique basé sur l'interférence à l'ARN a été entrepris. Après un premier et un deuxième criblage d'une librairie du kinome, nous avons identifié différentes protéines qui pourraient jouer un rôle positif dans la voie Fas, et en particulier la protéine suppresseur de tumeur STK11, qui est fréquemment mutée dans divers cancers sporadiques et héréditaires. La caractérisation fonctionnelle de STK11 a révélé que cette kinase était un modulateur apical de la voie extrinsèque de l'apoptose en général (Fas, TNF, TRAIL), mais pas de la voie intrinsèque. L'action de STK11 sur la voie Fas est dépendante de sa fonction kinase, mais indépendante de l'AMPK, un substrat bien caractérisé de STK11. De plus, STK11 interagît avec la caspase-8, un constituant majeur de la voie Fas, et module son activité, par un mécanisme encore peu clair qui pourrait impliquer une phosphorylation de la caspase-8 par STK11. Cette modification pourrait permettre une activation optimale de la caspase-8 en jouant un rôle dans le processus de polyubiquitination de la caspase-8, phénomène qui semble être important pour l'activation de la caspase-8 dans des agrégats protéiques avec p62, mais qui pourrait aussi augmenter son activation au niveau du DISC. Finalement, nous avons observé que STK11 modulait non seulement la voie apoptotique déclenchée par l'activation de Fas, mais aussi les voies non-apoptotiques de Fas, comme JNK et NF-KB. En conclusion notre étude, révèle que STK11 est un important modulateur pro- apoptotique de la voie Fas, et de la voie extrinsèque en général. Cette découverte pourrait expliquer, du moins partiellement, pourquoi les mutations inactivatrices de STK11 conduisent au cancer, par une augmentation de la résistance à l'apoptose et donc par l'évasion de la surveillance immunitaire.

Phacomatoses et tumeurs génétiquement déterminées: la transition enfant-adulte [Phacomatosis and genetically determined tumors: the transition from childhood to adulthood]

Les phacomatoses regroupent des maladies du développement du neurectoderme, engendrant des manifestations cutanées ou du système nerveux central. Les symptômes de ces maladies peuvent affecter les individus atteints à différents moments de leur vie. Il s'agit de maladies, héréditaires ou congénitales, qui sont transmises de façon variable. Effectivement, certaines, telles que la neurofibromatose, la sclérose tubéreuse ou la maladie de von Hippel-Lindau sont autosomiques dominantes, alors que d'autres, telles que la maladie de Sturge-Weber sont sporadiques. Des transmissions autosomiques récessives liées à X ou des formes mosaïques existent également. Une revue de la littérature, comprenant les cinq phacomatoses les plus fréquemment vues par un neurochirurgien (neurofibromatose de type I et II, sclérose tubéreuse de Bourneville, maladie de Sturge-Weber-Krabbe, maladie de von Hippel-Lindau) a été effectuée en se centrant sur le diagnostic, la variabilité de la symptomatologie selon l'âge du patient et son traitement. Les cas de patients adultes et pédiatriques vus aux consultations de neurologie et neurochirurgie de l'hôpital de Lille (France) et Lausanne (Suisse), de 1961 à nos jours, ont été revus pour illustrer les différentes pathologies rencontrées, selon l'âge des patients atteints. Le phénotype de ces maladies se modifie avec l'âge, car les gènes incriminés sont des gènes impliqués dans la différentiation tissulaire et sont activés à des âges différents suivant les tissus. Le rôle du neurochirurgien sera variable selon l'âge et le syndrome du patient. Il importe de connaître les variations du phénotype de ces maladies avec l'âge ainsi que les conséquences à long terme des traitements pour proposer au patient un suivi neurochirurgical personnalisé. Phacomatoses, or neurocutaneous disorders, are a group of congenital and hereditary diseases characterized by developmental lesions of the neuroectoderm, leading to pathologies affecting the skin and the central nervous system. There is a wide range of pathologies affecting individuals at different moments of life. The genetics is variable: while neurofibromatosis 1 and 2, tuberous sclerosis and von Hippel-Lindau disease are all inherited as autosomal dominant traits, Sturge-Weber syndrome is sporadic. Other neurocutaneous disorders can be inherited as autosomal recessive traits (i.e., ataxia-telangiectasia), X-linked (i.e., incontinentia pigmenti) or explained by mosaicism (i.e., hypomelanosis of Ito, McCune-Albright syndrome). In this review, we discuss the major types of neurocutaneous disorders most frequently encountered by the neurosurgeon and followed beyond childhood. They include neurofibromatosis types 1 and 2, tuberous sclerosis, Sturge-Weber syndrome and von Hippel-Lindau disease. In each case, a review of the literature, including diagnosis, genetics and treatment will be presented. The lifespan of the disease with the implications for neurosurgeons will be emphasized. A review of cases, including both pediatric and adult patients, seen in neurosurgical practices in the Lille, France and Lausanne, Switzerland hospitals between 1961 and 2007 is presented to illustrate the pathologies seen in different age-groups. Because the genes mutated in most phacomatoses are involved in development and are activated following a timed schedule, the phenotype of these diseases evolves with age. The implication of the neurosurgeon varies depending on the patient's age and pathology. While neurosurgeons tend to see pediatric patients affected with neurofibromatosis type 1, tuberous sclerosis and Sturge-Weber syndrome, there will be a majority of adult patients with von Hippel-Lindau disease or neurofibromatosis type 2

Hypolipidemic therapeutics and muscle metabolism

Summary : Lipid metabolism disorders, leading to obesity and cardiovascular diseases, are a major public health issue worldwide. These diseases have been treated by drugs and surgery, leading to tremendous costs and secondary morbidity. The aim of this thesis work is to investigate the mechanisms of actions of a new, micronutrition-based, approach to prevent obesity and cardiovascular diseases. This specific combination of micronutrients, Lipistase, incorporated into any dietary ail can be used in the daily food. Micronutrients are substances used by the living organism in small quantities to maintain physiological homeostasis. However, the human body is not able to produce them and has to obtain them from dietary sources. The combination of micronutrients investigated here, is composed of 26 compounds including trace elements, vitamins, minerals, ails and plant extracts, known to have individually a beneficial effect on lipid metabolism regulation. These specific micronutrients are used for the first time in a combinatorial mode targeting several metabolic pathways for better homeostasis control as opposed to a single target treatment, either chemical or natural. Short and long term studies, in different mouse strains, showed a significant decrease in plasma triglycerides, body weight gain and body fat mass in animals that were fed with a standard diet containing Lipistase. Additionally, a greatly reduced fat accumulation was observed in adipose tissue and liver of Lipistase-treated animals, while lipid and glucose utilization by skeletal muscle was enhanced. Moreover, the size of atherosclerotic plaques was significantly reduced in mice whose masher was treated during pregnancy and suckling, without showing any adverse effect. Finally, Lipistase has been shown to increase longevity by 20%. The control mice that did not receive Lipistase in their diet did not show all these beneficial effects. These micronutrients are used at the lowest dosage ever reported for treating Lipid disorders, resulting in far much lower costs as well as probably a higher safety. This is the first approach being very suitable for an effective large scale prevention policy for obesity and cardiovascular diseases, like iodine in dietary salt has been for goiter. Résumé : Les dysrégulations du métabolisme des lipids, à l'origine d'obésité et de maladies cardiovasculaires, sont un problème de santé publique majeur et mondial. Ces maladies impliquent des traitements médicamenteux et chirurgicaux dont le coût la morbidité secondaire sont très important. Le but de ce travail de thèse est d'étudier les mécanismes d'action d'une nouvelle approche préventive, basée sur la micronutrition. Cette combinaison spécifique de micronutriments, Lipistase, peut être incorporée dans n'importe quelle huile alimentaire et utilisée dans l'alimentation quotidienne. Les micronutrirnents sont des substances essentielles, à très faibles doses, pour le maintien de l'homéostasie physiologique des organismes vivants. Cependant, étant incapable de les synthétiser, le corps humain est dépendant en cela de l'apport alimentaire. La combinaison de micronutriments que nous avons étudié contient 26 composants, incluant des extraits de plantes, des huiles, des vitamines, des métaux et des minéraux, tous connus pour avoir individuellement des effets bénéfiques sur la régulation du métabolisme des lipides. Ces micronutriments spécifiques sont utilisés pour la première fois en mode combinatoire, ciblant ainsi plusieurs voies métaboliques pour un meilleur control de l'homéostasie, par opposition monothérapies chimiques ou naturelles. Des expériences de court et long terme, avec divers modèles de souris, ont montré une diminution significative des taux de triglycérides plasmatiques, de la prise de poids et de la masse graisseuse corporelle chez les animaux qui ont reçu Lipistase dans la nourriture standard. Une accumulation significativement moins importante des graisses a été observée dans le tissu adipeux et hépatique des souris traitées, alors que l'utilisation des lipides et glucose a été favorisée dans le muscle. En outre, la taille des plaques d'athérosclérose aété significativement réduite chez les souris dont la mère a été traitée pendant la grossesse et l'allaitement, sans montrer aucun effet indésirable. Enfin, les souris traitées par Lipistase ont vécu 20% plus longtèmps. Les souris contrôles qui n'ont pas reçu Lipistase dans la nourriture n'ont montré aucun de ces effets bénéfiques. Ces micronutriments sont utilisés au dosage le plus faible jamais rapporté pour le traitement des maladies du métabolisme lipidique, permettant ainsi un coût plus faible et surtout une meilleure sécurité. C'est une approche adéquate pour une politique de prévention de santé publique à large échelle de l'obésité et des maladies cardiovasculaires. C'est en cela et sous bien d'autres aspects, une première dans la prise en charge des maladies du métabolisme lipidique et pourrait même être pour ces dernières ce que l'iode du sel de cuisine a été pour le goitre.

Secondary Aural Symptoms in Relation to Cranio-Cervical and General Disorders

The present thesis comprises two study populations. The first study sample (SS1) consisted of 411 adults examined and interviewed at three annual visits. The second study sample (SS2) consisted of 1720 adults who filled in a mailed questionnaire about secondary otalgia, tinnitus and fullness of ears. In the second phase of the SS2, 100 subjects with otalgia were examined and interviewed by specialist in stomatognathic physiology and otorhinolaryngology. In the third phase, 36 subjects participated in a randomized, controlled and blinded trial of effectiveness of occlusal appliance on secondary otalgia, facial pain, headache and treatment need of temporomandibular disorders (TMD). The standardized prevalence of recurrent secondary otalgia was 6%, tinnitus 15% and fullness of ears 8%. Aural symptoms were more frequent among young than old subjects. They were associated with other, simultaneous aural symptoms, TMD pain, head and neck region pain, and visits to a physician. The subjects with aural symptoms more often had tenderness on palpation of masticatory muscles and clinical signs of temporomandibular joint than the subjects without. 85% of the subjects reporting secondary otalgia had cervical spine or temporomandibular disorder or both. In SS1, the final model of secondary otalgia included active need treatment for TMD, elevated level of stress symptoms, and bruxism. In SS2, the final models of aural symptoms included associated aural symptoms, young age, TMD pain, headache and shoulder ache. Stabilization splint more effectively alleviated secondary otalgia and active treatment need for TMD than a palatal control splint. In patients with aural pain, tinnitus or fullness of ears, it is important to first rule out otologic and nasopharyngeal diseases that may cause the symptoms. If no explanation for aural symptoms is found, temporomandibular and cervical spine disorders should be rouled out to minimize unnecessary visits to a physician.