Evidence from glut2-null mice that glucose is a critical physiological regulator of feeding.

A role for glucose in the control of feeding has been proposed, but its precise physiological importance is unknown. Here, we evaluated feeding behavior in glut2-null mice, which express a transgenic glucose transporter in their beta-cells to rescue insulin secretion (ripglut1;glut2-/- mice). We showed that in the absence of GLUT2, daily food intake was increased and feeding initiation and termination following a fasting period were abnormal. This was accompanied by suppressed regulation of hypothalamic orexigenic and anorexigenic neuropeptides expression during the fast-to-refed transition. In these conditions, however, there was normal regulation of the circulating levels of insulin, leptin, or glucose but a loss of regulation of plasma ghrelin concentrations. To evaluate whether the abnormal feeding behavior was due to suppressed glucose sensing, we evaluated feeding in response to intraperitoneal or intracerebroventricular glucose or 2-deoxy-D-glucose injections. We showed that in GLUT2-null mice, feeding was no longer inhibited by glucose or activated by 2-deoxy-D-glucose injections and the regulation of hypothalamic neuropeptide expression by intracerebroventricular glucose administration was lost. Together, these data demonstrate that absence of GLUT2 suppressed the function of central glucose sensors, which control feeding probably by regulating the hypothalamic melanocortin pathway. Furthermore, inactivation of these glucose sensors causes overeating.

Morphological and physiological species-dependent characteristics of the rodent Grueneberg ganglion.

In the mouse, the Grueneberg ganglion (GG) is an olfactory subsystem implicated both in chemo- and thermo-sensing. It is specifically involved in the recognition of volatile danger cues such as alarm pheromones and structurally-related predator scents. No evidence for these GG sensory functions has been reported yet in other rodent species. In this study, we used a combination of histological and physiological techniques to verify the presence of a GG and investigate its function in the rat, hamster, and gerbil comparing with the mouse. By scanning electron microscopy (SEM) and transmitted electron microscopy (TEM), we found isolated or groups of large GG cells of different shapes that in spite of their gross anatomical similarities, display important structural differences between species. We performed a comparative and morphological study focusing on the conserved olfactory features of these cells. We found fine ciliary processes, mostly wrapped in ensheating glial cells, in variable number of clusters deeply invaginated in the neuronal soma. Interestingly, the glial wrapping, the amount of microtubules and their distribution in the ciliary processes were different between rodents. Using immunohistochemistry, we were able to detect the expression of known GG proteins, such as the membrane guanylyl cyclase G and the cyclic nucleotide-gated channel A3. Both the expression and the subcellular localization of these signaling proteins were found to be species-dependent. Calcium imaging experiments on acute tissue slice preparations from rodent GG demonstrated that the chemo- and thermo-evoked neuronal responses were different between species. Thus, GG neurons from mice and rats displayed both chemo- and thermo-sensing, while hamsters and gerbils showed profound differences in their sensitivities. We suggest that the integrative comparison between the structural morphologies, the sensory properties, and the ethological contexts supports species-dependent GG features prompted by the environmental pressure.

NCoR1 is a conserved physiological modulator of muscle mass and oxidative function.

Transcriptional coregulators control the activity of many transcription factors and are thought to have wide-ranging effects on gene expression patterns. We show here that muscle-specific loss of nuclear receptor corepressor 1 (NCoR1) in mice leads to enhanced exercise endurance due to an increase of both muscle mass and of mitochondrial number and activity. The activation of selected transcription factors that control muscle function, such as MEF2, PPARβ/δ, and ERRs, underpins these phenotypic alterations. NCoR1 levels are decreased in conditions that require fat oxidation, resetting transcriptional programs to boost oxidative metabolism. Knockdown of gei-8, the sole C. elegans NCoR homolog, also robustly increased muscle mitochondria and respiration, suggesting conservation of NCoR1 function. Collectively, our data suggest that NCoR1 plays an adaptive role in muscle physiology and that interference with NCoR1 action could be used to improve muscle function.

Orthotropic active strain models for the numerical simulation of cardiac biomechanics

An active strain formulation for orthotropic constitutive laws arising in cardiac mechanics modeling is introduced and studied. The passive mechanical properties of the tissue are described by the Holzapfel-Ogden relation. In the active strain formulation, the Euler-Lagrange equations for minimizing the total energy are written in terms of active and passive deformation factors, where the active part is assumed to depend, at the cell level, on the electrodynamics and on the specific orientation of the cardiac cells. The well-posedness of the linear system derived from a generic Newton iteration of the original problem is analyzed and different mechanical activation functions are considered. In addition, the active strain formulation is compared with the classical active stress formulation from both numerical and modeling perspectives. Taylor-Hood and MINI finite elements are employed to discretize the mechanical problem. The results of several numerical experiments show that the proposed formulation is mathematically consistent and is able to represent the main key features of the phenomenon, while allowing savings in computational costs.

Fatty acid ketodienes and fatty acid ketotrienes: Michael addition acceptors that accumulate in wounded and diseased Arabidopsis leaves.

Physical damage and disease are known to lead to changes in the oxylipin signature of plants. We searched for oxylipins produced in response to both wounding and pathogenesis in Arabidopsis leaves. Linoleic acid 9- and 13-ketodienes (KODEs) were found to accumulate in wounded leaves as well as in leaves infected with the pathogen Pseudomonas syringae pv. tomato (Pst). Quantification of the compounds showed that they accumulated to higher levels during the hypersensitive response to Pst avrRpm1 than during infection with a Pst strain lacking an avirulence gene. KODEs are Michael addition acceptors, containing a chemically reactive alpha,beta-unsaturated carbonyl group. When infiltrated into leaves, KODEs were found to induce expression of the GST1 gene, but vital staining indicated that these compounds also damaged plant cells. Several molecules typical of lipid oxidation, including malonaldehyde, also contain the alpha,beta-unsaturated carbonyl reactivity feature, and, when delivered in a volatile form, powerfully induced the expression of GST1. The results draw attention to the potential physiological importance of naturally occurring Michael addition acceptors in plants. In particular, these compounds could act directly, or indirectly via cell damage, as powerful gene activators and might also contribute to host cell death.

Sentinel lymph node involvement and a high Breslow index are independent factors of risk for early relapse of melanoma

Rapport de synthèse : Le ganglion sentinelle (GS) se défini comme le premier ganglion de la chaîne ganglionnaire qui draine le territoire anatomique où siège une tumeur et, par conséquent, celui ayant le plus de possibilités de recevoir des métastases. La combinaison des deux techniques de détection du GS existantes, lymphoscintigraphie et coloration, permettent de déceler le GS dans 95-100% des cas. Le taux d'attente métastatique du GS varie entre 16 et 21 % des patients. Dans 50 à 87% des cas, le GS est le seul site de métastase et la probabilité de trouver des micro-métastases dans des ganglions appartenant aux relais supérieurs sans atteinte du GS est estimée à moins de 2%. Ces chiffres relèvent l'importance de la détection du GS. L'emploi de cette technique offre de nombreux avantages par rapport à la lymphadénéctomie élective que nous décrirons. Selon Rousseau et al., il existe une probable association entre le statut du GS et la survie de la maladie. Cette interprétation et celles d'autres auteurs soulignent la pertinence clinique du statut du GS dans le mélanome. En ce qui concerne la survie sans maladie (DFS) et la survie globale (OS), aucune différence significative n'a été observée entre les patients ayant subi une résection complète immédiate des ganglions lymphatiques et ceux qui d'abord ont subi une résection chirurgicale et analyse du GS secondaire, suivies par une dissection élective en cas de positivité. L'objectif de cette étude prospective était d'évaluer la pertinence de la positivité tumorale du GS dans l'évaluation des risques de rechute du mélanome. Cette étude a confirmé l'intérêt de la scintigraphie des ganglions lymphatiques (associée à la technique de coloration par bleu et celle de détection par sonde portable) dans l'identification du GS comme approche thérapeutique au stade précoce du mélanome. Elle a montré, en autre, que le statut du GS et l'indice de Breslow sont des facteurs de risque indépendants importants de rechute chez des patients atteints d'un mélanome au stade précoce. La combinaison de ces deux paramètres a permis de créer des groupes de patients à risque de rechute différents qui pourraient conduire à l'adaptation des protocoles de thérapie en fonction de ces risques.

Passive modernization? the new human development index and its components in Italy’s regions (1871-2007)

The article presents and discusses estimates of social and economic indicators for Italy’s regions in benchmark years roughly from Unification to the present day: life expectancy, education, GDP per capita at purchasing power parity, and the new Human Development Index (HDI). A broad interpretative hypothesis, based on the distinction between passive and active modernization, is proposed to account for the evolution of regional imbalances over the long-run. In the lack of active modernization, Southern Italy converged thanks to passive modernization, i.e., State intervention: however, this was more effective in life expectancy, less successful in education, expensive and as a whole ineffective in GDP. As a consequence, convergence in the HDI occurred from the late XIX century to the 1970s, but came to a sudden halt in the last decades of the XX century.

Colaniella, foraminifère index du Permien tardif téthysien: propositions pour une taxonomie simplifiée, répartition géographique et environnements

Une classification simplifiee du genre Colaniella LIKHAREV est proposee: Colaniella ex gr. parva, Colaniella ex gr. lepida, Colaniella ex gr. minima. Elle correspond a la division du taxon en trois groupes morphologiques. La repartition geographique de ce taxon est inventoriée de meme que les environnements sedimentaires et les microfaunes associees. Les nouvelles decouvertes de C. ex gr. parva dans Ie Permien superieur des coupes de Mesagros (ile d'Egine, Grece), d'Emarat (N Elbourz, Iran) et du Wadi Wasil dans les montagnes centrales d'Oman sont decrites en detail. L'importance des Colanielles dans la biostratigraphie du Permien superieur tethysien est analysee et clarifiee au vu des travaux recents et Ie problème des migrations est abordé. A simplified taxonomic classification in 3 groups of the genus Colaniella LIKHAREV is proposed: Colaniella ex gr. parva, Colaniella ex gr. lepida, Colaniella ex gr. minima. The repartition of the eight main Colaniella biofacies is given and the paleogeographic distribution of this genus is presented on a late Permian map configuration. New late Permian localities with Colaniella ex gr. parva have been found: Aegina island (Greece), Emmarat in the northern Alborz (Iran) and Wadi Wasit in the central Oman Mountains. The stratigraphic range of Colaniella ex gr. parva is much longer than previously accepted even by specialists. This range begins in the early Midian (Abadehian) and ends in the late Changhsingian (Dorashamian), very close to the range of the genus. For environmental reasons and slow eastward migration we have apparent shorter ranges in the Eastern part of the Tethyan domain.

Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index.

BACKGROUND: Cigarette smoking is associated with lower body mass index (BMI), and a commonly cited reason for unwillingness to quit smoking is a concern about weight gain. Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region (chromosome 15q25) is robustly associated with smoking quantity in smokers, but its association with BMI is unknown. We hypothesized that genotype would accurately reflect smoking exposure and that, if smoking were causally related to weight, it would be associated with BMI in smokers, but not in never smokers. METHODS: We stratified nine European study samples by smoking status and, in each stratum, analysed the association between genotype of the 15q25 SNP, rs1051730, and BMI. We meta-analysed the results (n = 24 198) and then tested for a genotype × smoking status interaction. RESULTS: There was no evidence of association between BMI and genotype in the never smokers {difference per T-allele: 0.05 kg/m(2) [95% confidence interval (95% CI): -0.05 to 0.18]; P = 0.25}. However, in ever smokers, each additional smoking-related T-allele was associated with a 0.23 kg/m(2) (95% CI: 0.13-0.31) lower BMI (P = 8 × 10(-6)). The effect size was larger in current [0.33 kg/m(2) lower BMI per T-allele (95% CI: 0.18-0.48); P = 6 × 10(-5)], than in former smokers [0.16 kg/m(2) (95% CI: 0.03-0.29); P = 0.01]. There was strong evidence of genotype × smoking interaction (P = 0.0001). CONCLUSIONS: Smoking status modifies the association between the 15q25 variant and BMI, which strengthens evidence that smoking exposure is causally associated with reduced BMI. Smoking cessation initiatives might be more successful if they include support to maintain a healthy BMI.

Biomechanical wall properties of human intracranial aneurysms resected following surgical clipping (IRRAs Project)

Background and purpose: Individual rupture risk assessment of intracranial aneurysms is a major issue in the clinical management of asymptomatic aneurysms. Aneurysm rupture occurs when wall tension exceeds the strength limit of the wall tissue. At present, aneurysmal wall mechanics are poorly understood and thus, risk assessment involving mechanical properties is inexistent. Aneurysm computational hemodynamics studies make the assumption of rigid walls, an arguable simplification. We therefore aim to assess mechanical properties of ruptured and unruptured intracranial aneurysms in order to provide the foundation for future patient-specific aneurysmal risk assessment. This work also challenges some of the currently held hypotheses in computational flow hemodynamics research. Methods: A specific conservation protocol was applied to aneurysmal tissues following clipping and resection in order to preserve their mechanical properties. Sixteen intracranial aneurysms (11 female, 5 male) underwent mechanical uniaxial stress tests under physiological conditions, temperature, and saline isotonic solution. These represented 11 unruptured and 5 ruptured aneurysms. Stress/strain curves were then obtained for each sample, and a fitting algorithm was applied following a 3-parameter (C(10), C(01), C(11)) Mooney-Rivlin hyperelastic model. Each aneurysm was classified according to its biomechanical properties and (un)rupture status.Results: Tissue testing demonstrated three main tissue classes: Soft, Rigid, and Intermediate. All unruptured aneurysms presented a more Rigid tissue than ruptured or pre-ruptured aneurysms within each gender subgroup. Wall thickness was not correlated to aneurysmal status (ruptured/unruptured). An Intermediate subgroup of unruptured aneurysms with softer tissue characteristic was identified and correlated with multiple documented risk factors of rupture. Conclusion: There is a significant modification in biomechanical properties between ruptured aneurysm, presenting a soft tissue and unruptured aneurysms, presenting a rigid material. This finding strongly supports the idea that a biomechanical risk factor based assessment should be utilized in the to improve the therapeutic decision making.

Temporal diffeomorphic free-form deformation: application to motion and strain estimation from 3D echocardiography

This paper presents a new registration algorithm, called Temporal Di eomorphic Free Form Deformation (TDFFD), and its application to motion and strain quanti cation from a sequence of 3D ultrasound (US) images. The originality of our approach resides in enforcing time consistency by representing the 4D velocity eld as the sum of continuous spatiotemporal B-Spline kernels. The spatiotemporal displacement eld is then recovered through forward Eulerian integration of the non-stationary velocity eld. The strain tensor iscomputed locally using the spatial derivatives of the reconstructed displacement eld. The energy functional considered in this paper weighs two terms: the image similarity and a regularization term. The image similarity metric is the sum of squared di erences between the intensities of each frame and a reference one. Any frame in the sequence can be chosen as reference. The regularization term is based on theincompressibility of myocardial tissue. TDFFD was compared to pairwise 3D FFD and 3D+t FFD, bothon displacement and velocity elds, on a set of synthetic 3D US images with di erent noise levels. TDFFDshowed increased robustness to noise compared to these two state-of-the-art algorithms. TDFFD also proved to be more resistant to a reduced temporal resolution when decimating this synthetic sequence. Finally, this synthetic dataset was used to determine optimal settings of the TDFFD algorithm. Subsequently, TDFFDwas applied to a database of cardiac 3D US images of the left ventricle acquired from 9 healthy volunteers and 13 patients treated by Cardiac Resynchronization Therapy (CRT). On healthy cases, uniform strain patterns were observed over all myocardial segments, as physiologically expected. On all CRT patients, theimprovement in synchrony of regional longitudinal strain correlated with CRT clinical outcome as quanti ed by the reduction of end-systolic left ventricular volume at follow-up (6 and 12 months), showing the potential of the proposed algorithm for the assessment of CRT.

Characterization of myocardial deformation in patients with different etiologies of left ventricular hypertrophy by using strain distribution from Magnetic Resonance Imaging

Introducción y objetivos. Se ha señalado que, en la miocardiopatía hipertrófica (MCH), la desorganización de las fibras regionales da lugar a segmentos en los que la deformación es nula o está gravemente reducida, y que estos segmentos tienen una distribución no uniforme en el ventrículo izquierdo (VI). Esto contrasta con lo observado en otros tipos de hipertrofia como en el corazón de atleta o la hipertrofia ventricular izquierda hipertensiva (HVI-HT), en los que puede haber una deformación cardiaca anormal, pero nunca tan reducida como para que se observe ausencia de deformación. Así pues, proponemos el empleo de la distribución de los valores de strain para estudiar la deformación en la MCH. Métodos. Con el empleo de resonancia magnética marcada (tagged), reconstruimos la deformación sistólica del VI de 12 sujetos de control, 10 atletas, 12 pacientes con MCH y 10 pacientes con HVI-HT. La deformación se cuantificó con un algoritmo de registro no rígido y determinando los valores de strain sistólico máximo radial y circunferencial en 16 segmentos del VI. Resultados. Los pacientes con MCH presentaron unos valores medios de strain significativamente inferiores a los de los demás grupos. Sin embargo, aunque la deformación observada en los individuos sanos y en los pacientes con HVI-HT se concentraba alrededor del valor medio, en la MCH coexistían segmentos con contracción normal y segmentos con una deformación nula o significativamente reducida, con lo que se producía una mayor heterogeneidad de los valores de strain. Se observaron también algunos segmentos sin deformación incluso en ausencia de fibrosis o hipertrofia. Conclusiones. La distribución de strain caracteriza los patrones específicos de deformación miocárdica en pacientes con diferentes etiologías de la HVI. Los pacientes con MCH presentaron un valor medio de strain significativamente inferior, así como una mayor heterogeneidad de strain (en comparación con los controles, los atletas y los pacientes con HVI-HT), y tenían regiones sin deformación.

Body mass index and health-related quality of life among young Swiss men.

BACKGROUND: Studies about the association between body mass index (BMI) and health-related quality of life (HRQOL) are often limited, because they 1) did not include a broad range of health-risk behaviors as covariates; 2) relied on clinical samples, which might lead to biased results; and 3) did not incorporate underweight individuals. Hence, this study aims to examine associations between BMI (from being underweight through obesity) and HRQOL in a population-based sample, while considering multiple health-risk behaviors (low physical activity, risky alcohol consumption, daily cigarette smoking, frequent cannabis use) as well as socio-demographic characteristics. METHODS: A total of 5 387 young Swiss men (mean age = 19.99; standard deviation = 1.24) of a cross-sectional population-based study were included. BMI was calculated (kg/m²) based on self-reported height and weight and divided into 'underweight' (<18.5), 'normal weight' (18.5-24.9), 'overweight' (25.0-29.9) and 'obese' (≥30.0). Mental and physical HRQOL was assessed via the SF-12v2. Self-reported information on physical activity, substance use (alcohol, cigarettes, and cannabis) and socio-demographic characteristics also was collected. Logistic regression analyses were conducted to study the associations between BMI categories and below average mental or physical HRQOL. Substance use variables and socio-demographic variables were used as covariates. RESULTS: Altogether, 76.3% were normal weight, whereas 3.3% were underweight, 16.5% overweight and 3.9% obese. Being overweight or obese was associated with reduced physical HRQOL (adjusted OR [95% CI] = 1.58 [1.18-2.13] and 2.45 [1.57-3.83], respectively), whereas being underweight predicted reduced mental HRQOL (adjusted OR [95% CI] = 1.49 [1.08-2.05]). Surprisingly, obesity decreased the likelihood of experiencing below average mental HRQOL (adjusted OR [95% CI] = 0.66 [0.46-0.94]). Besides BMI, expressed as a categorical variable, all health-risk behaviors and socio-demographic variables were associated with reduced physical and/or mental HRQOL. CONCLUSIONS: Deviations from normal weight are, even after controlling for important health-risk behaviors and socio-demographic characteristics, associated with compromised physical or mental HRQOL among young men. Hence, preventive programs should aim to preserve or re-establish normal weight. The self-appraised positive mental well-being of obese men noted here, which possibly reflects a response shift, might complicate such efforts.