Neuroendocrine deregulation of food intake, adipose tissue and the gastrointestinal system in obesity and metabolic syndrome.

Obesity is an excess of fat mass. Fat mass is an energy depot but also an endocrine organ. A deregulation of the sympathetic nervous system (SNS) might produce obesity. Stress exaggerates diet-induced obesity. After stress, SNS fibers release neuropeptide Y (NPY) which directly increases visceral fat mass producing a metabolic syndrome (MbS)-like phenotype. Adrenergic receptors are the main regulators of lipolysis. In severe obesity, we demonstrated that the adrenergic receptor subtypes are differentially expressed in different fat depots. Liver and visceral fat share a common sympathetic pathway, which might explain the low-grade inflammation which simultaneously occurs in liver and fat of the obese with MbS. The neuroendocrine melanocortinergic system and gastric ghrelin are also greatly deregulated in obesity. A specific mutation in the type 4 melanocortin receptor induces early obesity onset, hyperphagia and insulin-resistance. Nonetheless, it was recently discovered that a mutation in the prohormone convertase 1/3 simultaneously produces severe gastrointestinal dysfunctions and obesity.

Quantitative comparison between simulations of seismic wave propagation in heterogeneous poro-elastic media and equivalent visco-elastic solids for marine-type environments

There is increasing evidence to suggest that the presence of mesoscopic heterogeneities constitutes an important seismic attenuation mechanism in porous rocks. As a consequence, centimetre-scale perturbations of the rock physical properties should be taken into account for seismic modelling whenever detailed and accurate responses of specific target structures are desired, which is, however, computationally prohibitive. A convenient way to circumvent this problem is to use an upscaling procedure to replace each of the heterogeneous porous media composing the geological model by corresponding equivalent visco-elastic solids and to solve the visco-elastic equations of motion for the inferred equivalent model. While the overall qualitative validity of this procedure is well established, there are as of yet no quantitative analyses regarding the equivalence of the seismograms resulting from the original poro-elastic and the corresponding upscaled visco-elastic models. To address this issue, we compare poro-elastic and visco-elastic solutions for a range of marine-type models of increasing complexity. We found that despite the identical dispersion and attenuation behaviour of the heterogeneous poro-elastic and the equivalent visco-elastic media, the seismograms may differ substantially due to diverging boundary conditions, where there exist additional options for the poro-elastic case. In particular, we observe that at the fluid/porous-solid interface, the poro- and visco-elastic seismograms agree for closed-pore boundary conditions, but differ significantly for open-pore boundary conditions. This is an important result which has potentially far-reaching implications for wave-equation-based algorithms in exploration geophysics involving fluid/porous-solid interfaces, such as, for example, wavefield decomposition.

Religious coping in schizophrenia patients : spiritual support in medical care and pastoral counselling

Following an introduction focusing on the role of religion in the treatment of psychosis, the first part of this paper describes an initial study in which the role of spirituality and religiosity was assessed in 115 patients with schizophrenia in Geneva (Switzerland) and 126 in Trois-Rivières (Quebec). These themes have been shown to be highly prevalent for these patients, though their clinicians are often unaware of this prevalence. The following part of the paper presents a second study where religious supervision was offered to clinicians in Geneva. Comparison between forty patients who received spiritual assessment and opportunities to work on religious topics with their clinicians was made with thirty patients without religious intervention. In the supervisory sessions, six different types of religious interventions were suggested. Outcomes at three months show that patients of the intervention group maintain their interest for help in religious matters while clinicians' interest in integrating religious topics in discussions with their patients has decreased. The third and main part of the paper is devoted to an analysis of the suggested interventions from the viewpoint of the study of religions. Five aspects of religion are distinguished, and explanations of the reasons some of them are easier to manage for clinicians are proposed. The paper concludes with proposals for the education of clinicians to help them to differentiate different kinds of religious coping and to recognize when it could be helpful to refer the patient to a pastoral counsellor.

Rivascolarizzazione miocardica con arteria radiale: tecniche chirurgiche a confronto e risultati a breve termine [Myocardial revascularization and radial artery: different surgical strategies and short-term results]

BACKGROUND: The radial artery is routinely used as a graft for surgical arterial myocardial revascularization. The proximal radial artery anastomosis site remains unknown. In this study, we analyzed the short-term results and the operative risk determinants after having used four different common techniques for radial artery implantation. METHODS: From January 2000 to December 2004, 571 patients underwent coronary artery bypass grafting with radial arteries. Data were analyzed for the entire population and for subgroups following the proximal radial artery anastomosis site: 140 T-graft with the mammary artery (group A), 316 free-grafts with the proximal anastomosis to the ascending aorta (group B), 55 mammary arteries in situ elongated with the radial artery (group C) and 60 radial arteries elongated with a piece of mammary artery and anastomosed to the ascending aorta (group D). RESULTS: The mean age was 53.8 +/- 7.7 years; 55.5% of patients had a previous myocardial infarction and 73% presented with a satisfactory left ventricular function. A complete arterial myocardial revascularization was achieved in 532 cases (93.2%) and 90.2% of the procedures were performed under cardiopulmonary bypass and cardioplegic arrest. The operative mortality rate was 0.9%, a postoperative myocardial infarction was diagnosed in 19 patients (3.3%), an intra-aortic balloon pump was used in 10 patients (1.7%) and a mechanical circulatory device was implanted in 2 patients. The radial artery harvesting site remained always free from complications. The proximal radial artery anastomosis site was not a determinant of early hospital mortality. Group C showed a higher risk of postoperative myocardial infarction (p = 0.09), together with female gender (p = 0.003), hypertension (p = 0.059) and a longer cardiopulmonary bypass time. CONCLUSIONS: The radial artery and the mammary artery can guarantee multiple arterial revascularization also for patients with contraindications to double mammary artery use. The four most common techniques for proximal radial artery anastomosis are not related to a higher operative risk and they can be used alternatively to reach the best surgical results

Clinical and molecular characteristics of HNSCC patients with brain metastases: a retrospective study.

Among the metastasis patterns of head and neck squamous cell carcinoma (HNSCC), intracranial spread is a rare but dreaded event. To date only very few cases have been reported and clinical and molecular data are sparse. We screened our archives for HNSCC patients from 1992 to 2005 who were diagnosed with brain metastases (BM). For retrospective analysis, all clinico-pathological data including disease-free survival (DFS), local progression-free survival (LPFS), and overall survival (OS) were compiled. Additionally, we assessed the mutational status of the TP53 gene and the prevalence of HPV serotypes by PCR and Sanger sequencing. Immunohistochemistry was applied to detect p16INK4A expression levels as surrogate marker for HPV infection. The prevalence rate of BM in our cohort comprising 193 patients with advanced HNSCC was 5.7 %. Of 11 patients with BM, 3 were female and 9 were male. Seven of the primary tumors were of oropharyngeal origin (OPSCC). LPFS of the cohort was 11.8 months, DFS was 12.1 months and OS was 36.0 months. After the diagnosis of BM, survival was 10.5 months. Five tumors showed a mutation in the TP53 gene, while five of the seven OPSCC tumors had a positive HPV status displaying infection with serotype 16 in all cases. Compared with patients who harbored TP53wt/HPV-positive tumors, patients with TP53 mutations showed a poor prognosis. Compared with the whole cohort, the interval between diagnosis of the primary and the detection of BM was prolonged in the HPV-infected OPSCC subgroup (26.4 vs. 45.6 months). The prognosis of HNSCC patients with BM is poor. In our cohort, most tumors were OPSCC with the majority being HPV positive. Our study points toward a putatively unusual metastatic behavior of HPV-positive OPSCC.

In vivo reprogramming of circuit connectivity in postmitotic neocortical neurons.

The molecular mechanisms that control how progenitors generate distinct subtypes of neurons, and how undifferentiated neurons acquire their specific identity during corticogenesis, are increasingly understood. However, whether postmitotic neurons can change their identity at late stages of differentiation remains unknown. To study this question, we developed an electrochemical in vivo gene delivery method to rapidly manipulate gene expression specifically in postmitotic neurons. Using this approach, we found that the molecular identity, morphology, physiology and functional input-output connectivity of layer 4 mouse spiny neurons could be specifically reprogrammed during the first postnatal week by ectopic expression of the layer 5B output neuron-specific transcription factor Fezf2. These findings reveal a high degree of plasticity in the identity of postmitotic neocortical neurons and provide a proof of principle for postnatal re-engineering of specific neural microcircuits in vivo.

European genetic diversity and susceptibility to pathogens.

Infectious diseases, both in their endemic and epidemic forms, have shaped the human genome. Ecology has also contributed to geographically constrained pressures on human populations. There are now multiple examples of population-specific genetic variants that modulate susceptibility to infection - several of which have been observed solely in Europeans. The pathogen genome also mutates and adapts to individuals and common alleles in populations. The current understanding has benefited from genome-wide association studies as well as from rapid progress in the genetic characterization of Mendelian immunodeficiencies that are defined by susceptibility to specific pathogens. It is expected that current efforts to characterize rare human genetic variants will contribute to the understanding of severe manifestations of common infections in European and other human groups.

Epigenetic regulatory elements associate with specific histone modifications to prevent silencing of telomeric genes.

In eukaryotic cells, transgene expression levels may be limited by an unfavourable chromatin structure at the integration site. Epigenetic regulators are DNA sequences which may protect transgenes from such position effect. We evaluated different epigenetic regulators for their ability to protect transgene expression at telomeres, which are commonly associated to low or inconsistent expression because of their repressive chromatin environment. Although to variable extents, matrix attachment regions (MARs), ubiquitous chromatin opening element (UCOE) and the chicken cHS4 insulator acted as barrier elements, protecting a telomeric-distal transgene from silencing. MARs also increased the probability of silent gene reactivation in time-course experiments. Additionally, all MARs improved the level of expression in non-silenced cells, unlike other elements. MARs were associated to histone marks usually linked to actively expressed genes, especially acetylation of histone H3 and H4, suggesting that they may prevent the spread of silencing chromatin by imposing acetylation marks on nearby nucleosomes. Alternatively, an UCOE was found to act by preventing deposition of repressive chromatin marks. We conclude that epigenetic DNA elements used to enhance and stabilize transgene expression all have specific epigenetic signature that might be at the basis of their mode of action.

Closed loop electrical muscle stimulation in spinal cord injured rehabilitation

The effect of motor training using closed loop controlled Functional Electrical Stimulation (FES) on motor performance was studied in 5 spinal cord injured (SCI) volunteers. The subjects trained 2 to 3 times a week during 2 months on a newly developed rehabilitation robot (MotionMaker?). The FES induced muscle force could be adequately adjusted throughout the programmed exercises by the way of a closed loop control of the stimulation currents. The software of the MotionMaker? allowed spasms to be detected accurately and managed in a way to prevent any harm to the SCI persons. Subjects with incomplete SCI reported an increased proprioceptive awareness for motion and were able to achieve a better voluntary activation of their leg muscles during controlled FES. At the end of the training, the voluntary force of the 4 incomplete SCI patients was found increased by 388% on their most affected leg and by 193% on the other leg. Active mobilisation with controlled FES seems to be effective in improving motor function in SCI persons by increasing the sensory input to neuronal circuits involved in motor control as well as by increasing muscle strength.

Mouse Grueneberg ganglion neurons share molecular and functional features with C. elegans amphid neurons.

The mouse Grueneberg ganglion (GG) is an olfactory subsystem located at the tip of the nose close to the entry of the naris. It comprises neurons that are both sensitive to cold temperature and play an important role in the detection of alarm pheromones (APs). This chemical modality may be essential for species survival. Interestingly, GG neurons display an atypical mammalian olfactory morphology with neurons bearing deeply invaginated cilia mostly covered by ensheathing glial cells. We had previously noticed their morphological resemblance with the chemosensory amphid neurons found in the anterior region of the head of Caenorhabditis elegans (C. elegans). We demonstrate here further molecular and functional similarities. Thus, we found an orthologous expression of molecular signaling elements that was furthermore restricted to similar specific subcellular localizations. Calcium imaging also revealed a ligand selectivity for the methylated thiazole odorants that amphid neurons are known to detect. Cellular responses from GG neurons evoked by chemical or temperature stimuli were also partially cGMP-dependent. In addition, we found that, although behaviors depending on temperature sensing in the mouse, such as huddling and thermotaxis did not implicate the GG, the thermosensitivity modulated the chemosensitivity at the level of single GG neurons. Thus, the striking similarities with the chemosensory amphid neurons of C. elegans conferred to the mouse GG neurons unique multimodal sensory properties.

Différences induites par la définition des périodes diurnes et nocturnes sur la pression artérielle et le dipping lors d'une mesure ambulatoire de la pression artérielle [Effects of nighttime and daytime interval definition on blood pressure and dipping in patients referred for ambulatory blood pressure measurement].

Ambulatory blood pressure monitoring (ABPM) has become indispensable for the diagnosis and control of hypertension. However, no consensus exists on how daytime and nighttime periods should be defined. OBJECTIVE: To compare daytime and nighttime blood pressure (BP) defined by an actigraph and by body position with BP resulting from arbitrary daytime and nighttime periods. PATIENTS AND METHOD: ABPM, sleeping periods and body position were recorded simultaneously using an actigraph (SenseWear Armband(®)) in patients referred for ABPM. BP results obtained with the actigraph (sleep and position) were compared to the results obtained with fixed daytime (7a.m.-10p.m.) and nighttime (10p.m.-7a.m.) periods. RESULTS: Data from 103 participants were available. More than half of them were taking antihypertensive drugs. Nocturnal BP was lower (systolic BP: 2.08±4.50mmHg; diastolic BP: 1.84±2.99mmHg, P<0.05) and dipping was more marked (systolic BP: 1.54±3.76%; diastolic BP: 2.27±3.48%, P<0.05) when nighttime was defined with the actigraph. Standing BP was higher (systolic BP 1.07±2.81mmHg; diastolic BP: 1.34±2.50mmHg) than daytime BP defined by a fixed period. CONCLUSION: Diurnal BP, nocturnal BP and dipping are influenced by the definition of daytime and nighttime periods. Studies evaluating the prognostic value of each method are needed to clarify which definition should be used.

MRE11-RAD50-NBS1 is a critical regulator of FANCD2 stability and function during DNA double-strand break repair.

Monoubiquitination of the Fanconi anaemia protein FANCD2 is a key event leading to repair of interstrand cross-links. It was reported earlier that FANCD2 co-localizes with NBS1. However, the functional connection between FANCD2 and MRE11 is poorly understood. In this study, we show that inhibition of MRE11, NBS1 or RAD50 leads to a destabilization of FANCD2. FANCD2 accumulated from mid-S to G2 phase within sites containing single-stranded DNA (ssDNA) intermediates, or at sites of DNA damage, such as those created by restriction endonucleases and laser irradiation. Purified FANCD2, a ring-like particle by electron microscopy, preferentially bound ssDNA over various DNA substrates. Inhibition of MRE11 nuclease activity by Mirin decreased the number of FANCD2 foci formed in vivo. We propose that FANCD2 binds to ssDNA arising from MRE11-processed DNA double-strand breaks. Our data establish MRN as a crucial regulator of FANCD2 stability and function in the DNA damage response.

Le trouble somatoforme douloureux et le syndrome de fatigue chronique, des nouvelles expressions de la médicalisation de la souffrance

Résumé Le trouble somatoforme douloureux persistant et le syndrome de fatigue chronique constituent des entités cliniques qui incarnent la position particulière du corps dans notre société actuelle. Tous les deux se situent dans un carrefour entre le psychique et le somatique, en interaction étroite avec l'entourage socioculturel, soulignant ainsi la nécessité de considérer l'être humain dans son intégralité. La société actuelle, pauvre en repères collectifs, où l'exaltation de l'individualité est un critère primordial et où le corps social réparateur n'existe pas, provoque une grand mal être. Le sentiment de ne pas être reconnu dans son intériorité est incorporé et après s'exprime ensuite sous la forme d'une plainte douloureuse. Le contexte de l'émigration et celui des systèmes de prévoyance sociale dans les pays occidentaux, sont des exemples de conditions qui favorisent le changement dans la dynamique de la maladie. En s'appuyant sur la représentation du corps dans un moment historique précis, l'homme cherche à exprimer une souffrance profonde dans le vécu de soi-même, qui n'a pas accès à d'autres voies d'expression. Le contexte social, culturel, médical, professionnel, lui facilite les moyens d'obtenir la reconnaissance de son affliction sans être exclu du groupe d'appartenance sociale. Les deux symptômes, douleur et fatigue, rassemblent les conditions nécessaires, dans la conception actuelle du corps, sociale et médicale, pour transporter le désir et la demande d'une partie de la société qui ne peut pas exprimer sa souffrance.