Electrical colonic stimulation reduces mean transit time in a porcine model.

Abstract Electrical stimulation is a new way to treat digestive disorders such as constipation. Colonic propulsive activity can be triggered by battery operated devices. This study aimed to demonstrate the effect of direct electrical colonic stimulation on mean transit time in a chronic porcine model. The impact of stimulation and implanted material on the colonic wall was also assessed. Three pairs of electrodes were implanted into the caecal wall of 12 anaesthetized pigs. Reference colonic transit time was determined by radiopaque markers for each pig before implantation. It was repeated 4 weeks after implantation with sham stimulation and 5 weeks after implantation with electrical stimulation. Aboral sequential trains of 1-ms pulse width (10 V; 120 Hz) were applied twice daily for 6 days, using an external battery operated stimulator. For each course of markers, a mean value was computed from transit times obtained from individual pig. Microscopic examination of the caecum was routinely performed after animal sacrifice. A reduction of mean transit time was observed after electrical stimulation (19 +/- 13 h; mean +/- SD) when compared to reference (34 +/- 7 h; P = 0.045) and mean transit time after sham stimulation (36 +/- 9 h; P = 0.035). Histological examination revealed minimal chronic inflammation around the electrodes. Colonic transit time measured in a chronic porcine model is reduced by direct sequential electrical stimulation. Minimal tissue lesion is elicited by stimulation or implanted material. Electrical colonic stimulation could be a promising approach to treat specific disorders of the large bowel.

Three essays on internationalization and firm entrepreneurial behavior

PAPER 1: A THEORY ON THE EFFECTS OF INTERNATIONALIZATION ON FIRM ENTREPRENEURIAL BEHAVIOR AND GROWTH Abstract This article addresses the relationship. Past findings reveal that the direct effects of internationalization on performance are mixed and inconclusive. Our framework integrates firm entrepreneurial behavior as a mediating force of the troublesome Drawing on the tension between the entrepreneurship literature and the organizational inertia theory, we argue that internationalization is key to minimizing the stifling effects of inertia and in engendering entrepreneurial behavior towards growth. We suggest that firms that internationalize at a young age and enjoy an intense degree of internationalization tend to become more entrepreneurial than do late and weakly internationalized firms. As a consequence, early and intense internationalizers experience superior growth. Aware of the inherent endogeneity of our propositions, we also discuss how consistent estimates can be obtained when testing the model empirically. PAPER 2: DOES INTERNATIONALIZATION MATTER FOR GROWTH? THE CASE OF SWISS SOFTWARE FIRMS. Abstract This paper seeks to address the issue of whether early and intense internationalization leads to superior firm growth. We revisit the hypotheses of previous studies within the emerging research domain of international entrepreneurship. Empirical analyses on the performance implications of internationalization have so far been limited and inconsistent. Our paper intends to make two contributions to the international entrepreneurship literature. First, we bring additional empirical evidence as to the inconclusive firm performance endogeneity in our causal model, using a sample of 103 Swiss international small and medium-sized enterprises (SMEs). On one hand, we find that the degree of internationalization significantly increases perceived firm growth (i.e., relative firm performance in a market); however, age at internationalization was unrelated to perceived firm growth. On the other hand, we reproduced the causal path of a highly cited study that showed how age at internationalization was significantly and negatively associated with objective firm growth (i.e., sales). Interestingly, our results support the study similar setting (OLS regression with comparable control variables); however, the effect for age at internationalization reverses when we correct for endogeneity. PAPER 3: EFFECT OF INTERNATIONALIZATION ON FIRM ENTREPRENEURIAL ORIENTATION AND PERFORMANCE: THE CASE OF SWISS SOFTWARE FIRMS. Abstract How does internationalization influence a firm orientation (EO) and is this related to firm growth? This paper inquires into the performance theorizing, we test a process model in which EO plays a mediating role in accounting for the relationship between internationalization and growth. We position this paper on the tension zone between the entrepreneurship literature and the organizational inertia theory. We lay out the argument that internationalization is source of opportunities that drives a firm and thus mitigates inertial pressure. Using a sample of Swiss software small and medium-sized enterprises (SMEs), we found that degree of internationalization (but not age of internationalization) increases EO, which subsequently increased firm growth.

Effects of the PPAR-beta agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination.

BACKGROUND: Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS). Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). Peroxisome proliferator-associated receptor (PPAR) pathways are involved in the control of the inflammatory processes, and PPAR-beta seems to play an important role in the regulation of central inflammation. In addition, PPAR-beta agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-beta agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-gamma and LPS. METHODS: Aggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-gamma and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG). The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), inducible NO synthase (i-NOS), PPAR-beta, PPAR-gamma, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and high molecular weight neurofilament protein (NF-H). GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4) and ED1 labeling. RESULTS: GW 501516 decreased the IFN-gamma-induced up-regulation of TNF-alpha and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-beta agonist. However, it increased IL-6 m-RNA expression. In demyelinating cultures, reactivity of both microglial cells and astrocytes was observed, while the expression of the inflammatory cytokines and iNOS remained unaffected. Furthermore, GW 501516 did not protect against the demyelination-induced changes in gene expression. CONCLUSION: Although GW 501516 showed anti-inflammatory activity, it did not protect against antibody-mediated demyelination. This suggests that the protective effects of PPAR-beta agonists observed in vivo can be attributed to their anti-inflammatory properties rather than to a direct protective or trophic effect on oligodendrocytes.

Three-dimensional radiobiological dosimetry of kidneys for treatment planning in peptide receptor radionuclide therapy.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) delivers high absorbed doses to kidneys and may lead to permanent nephropathy. Reliable dosimetry of kidneys is thus critical for safe and effective PRRT. The aim of this work was to assess the feasibility of planning PRRT based on 3D radiobiological dosimetry (3D-RD) in order to optimize both the amount of activity to administer and the fractionation scheme, while limiting the absorbed dose and the biological effective dose (BED) to the renal cortex. METHODS: Planar and SPECT data were available for a patient examined with (111)In-DTPA-octreotide at 0.5 (planar only), 4, 24, and 48 h post-injection. Absorbed dose and BED distributions were calculated for common therapeutic radionuclides, i.e., (111)In, (90)Y and (177)Lu, using the 3D-RD methodology. Dose-volume histograms were computed and mean absorbed doses to kidneys, renal cortices, and medullae were compared with results obtained using the MIRD schema (S-values) with the multiregion kidney dosimetry model. Two different treatment planning approaches based on (1) the fixed absorbed dose to the cortex and (2) the fixed BED to the cortex were then considered to optimize the activity to administer by varying the number of fractions. RESULTS: Mean absorbed doses calculated with 3D-RD were in good agreement with those obtained with S-value-based SPECT dosimetry for (90)Y and (177)Lu. Nevertheless, for (111)In, differences of 14% and 22% were found for the whole kidneys and the cortex, respectively. Moreover, the authors found that planar-based dosimetry systematically underestimates the absorbed dose in comparison with SPECT-based methods, up to 32%. Regarding the 3D-RD-based treatment planning using a fixed BED constraint to the renal cortex, the optimal number of fractions was found to be 3 or 4, depending on the radionuclide administered and the value of the fixed BED. Cumulative activities obtained using the proposed simulated treatment planning are compatible with real activities administered to patients in PRRT. CONCLUSIONS: The 3D-RD treatment planning approach based on the fixed BED was found to be the method of choice for clinical implementation in PRRT by providing realistic activity to administer and number of cycles. While dividing the activity in several cycles is important to reduce renal toxicity, the clinical outcome of fractionated PRRT should be investigated in the future.

Leadership at the upper echelons : three essays

"IT'S THE ECONOMY STUPID", BUT CHARISMA MATTERS TOO: A DUAL PROCESS MODEL OF PRESIDENTIAL ELECTION OUTCOMES. ABSTRACT Because charisma is assumed to be an important determinant of effective leadership, the extent to which a presidential nominee is more charismatic than his opponent should be an important determinant of voter choices. We computed a composite measure of the rhetorical richness of acceptances speeches given by U.S. presidential candidates at their national party convention. We added this marker of charisma to Ray C. Fair's presidential vote-share equation (1978; 2009). We theorized that voters decide using psychological attribution (i.e., due to macroeconomics and incumbency) as well as inferential processes (i.e., due to leader charismatic behavior) when voting. Controlling for the macro-level variables and incumbency in the Fair model, our results indicated that difference between nominees' charisma is a significant determinant of electoral success, particularly in close elections. This extended model significantly improves the precision of the Fair model and correctly predicts 23 out of the last 24 U.S. presidential elections. Paper 2: IT CEO LEADERSHIP, CORPORATE SOCIAL AND FINANCIAL PERFORMANCE. ABSTRACT We investigated whether CEO leadership predicted corporate financial performance (CFP) and corporate social performance (CSP). Using longitudinal data on 258 CEOs from 117 firms across 19 countries and 10 industry sectors, we found that determinants of CEO leadership (i.e., implicit motives) significantly predicted both CFP and CSP. As expected, the most consistent positive predictor was Responsibility Disposition when interacting with n (need for) Power. n Achievement and n Affiliation were generally negatively related or unrelated to outcomes. CSP was positively related to accounting measures of CFP. Our findings suggest that executive leader characteristics have important consequences for corporate level outcomes. Paper 3. PUNISHING THE POWERFUL: ATTRIBUTIONS OF BLAME AND LEADERSHIP ABSTRACT We propose that individuals are more lenient in attributing blame to leaders than to nonleaders. We advance a motivational explanation building on the perspective of punishment and on system justification theory. We conducted two scenario experiments which supported our proposition. In study 1, wrongdoer leader status was negatively related to blame and the perceived seriousness of the wrongdoing. In study 2, controlling for the Big-Five personality factor and individual differences in moral evaluation (i.e., moral foundations), wrongdoer leader status was negatively related with desired severity of punishment, and fair punishments were perceived as more just for non-leaders than for leaders.

Hierarchy of interactive functions in father-mother-baby three-way games

In developmental research, the family has mainly been studied through dyadic interaction. Three-way interactions have received less attention, partly because of their complexity. This difficulty may be overcome by distinguishing between four hierarchically embedded functions in three-way interactions: (1) participation (inclusion of all participants), (2) organization (partners keeping to their roles), (3) focalization (sharing a common focus) and (4) affective contact (being in tune). We document this hierarchical model on a sample of 80 families observed in the Lausanne Trilogue Play situation across four different sites. Hierarchy between functions was demonstrated by means of Guttman scalability coefficient. Given the importance of the child's development in a threesome, the pertinence of this model for family assessment is discussed.

The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model.

Isolated limb perfusion (ILP) with melphalan and tumor necrosis factor (TNF)-α is used to treat bulky, locally advanced melanoma and sarcoma. However, TNF toxicity suggests a need for better-tolerated drugs. Cilengitide (EMD 121974), a novel cyclic inhibitor of alpha-V integrins, has both anti-angiogenic and direct anti-tumor effects and is a possible alternative to TNF in ILP. In this study, rats bearing a hind limb soft tissue sarcoma underwent ILP using different combinations of melphalan, TNF and cilengitide in the perfusate. Further groups had intra-peritoneal (i.p.) injections of cilengitide or saline 2 hr before and 3 hr after ILP. A 77% response rate (RR) was seen in animals treated i.p. with cilengitide and perfused with melphalan plus cilengitide. The RR was 85% in animals treated i.p. with cilengitide and ILP using melphalan plus both TNF and cilengitide. Both RRs were significantly greater than those seen with melphalan or cilengitide alone. Histopathology showed that high RRs were accompanied by disruption of tumor vascular endothelium and tumor necrosis. Compared with ILP using melphalan alone, the addition of cilengitide resulted in a three to sevenfold increase in melphalan concentration in tumor but not in muscle in the perfused limb. Supportive in vitro studies indicate that cilengitide both inhibits tumor cell attachment and increases endothelial permeability. Since cilengitide has low toxicity, these data suggest the agent is a good alternative to TNF in the ILP setting.

Psychometrics of the Dyadic Coping Inventory in three language groups

This article introduces the Dyadic Coping Inventory (DCI; Bodenmann, 2008) and aims (1) to investigate the reliability and aspects of the validity of the Italian and French versions of the DCI, and (2) to replicate its factor structure and reliabilities using a new Swiss German sample. Based on 216 German-, 378 Italian-, and 198 French-speaking participants, the factor structure of the original German inventory was able to be replicated by using principal components analysis in all three groups after excluding two items in the Italian and French versions. The latter were shown to be as reliable as the German version with the exception of the low reliabilities of negative dyadic coping in the French group. Confirmatory factor analyses provided additional support for delegated dyadic coping and evaluation of dyadic coping. Intercorrelations among scales were similar across all three languages groups with a few exceptions. Previous findings could be replicated in all three groups, showing that aspects of dyadic coping were more strongly related to marital quality than to dyadic communication. The use of the dyadic coping scales in the actor-partner interdependence model, the common fate model, and the mutual influence model is discussed.

A comparison of three methods of Mendelian randomization when the genetic instrument, the risk factor and the outcome are all binary.

The method of instrumental variable (referred to as Mendelian randomization when the instrument is a genetic variant) has been initially developed to infer on a causal effect of a risk factor on some outcome of interest in a linear model. Adapting this method to nonlinear models, however, is known to be problematic. In this paper, we consider the simple case when the genetic instrument, the risk factor, and the outcome are all binary. We compare via simulations the usual two-stages estimate of a causal odds-ratio and its adjusted version with a recently proposed estimate in the context of a clinical trial with noncompliance. In contrast to the former two, we confirm that the latter is (under some conditions) a valid estimate of a causal odds-ratio defined in the subpopulation of compliers, and we propose its use in the context of Mendelian randomization. By analogy with a clinical trial with noncompliance, compliers are those individuals for whom the presence/absence of the risk factor X is determined by the presence/absence of the genetic variant Z (i.e., for whom we would observe X = Z whatever the alleles randomly received at conception). We also recall and illustrate the huge variability of instrumental variable estimates when the instrument is weak (i.e., with a low percentage of compliers, as is typically the case with genetic instruments for which this proportion is frequently smaller than 10%) where the inter-quartile range of our simulated estimates was up to 18 times higher compared to a conventional (e.g., intention-to-treat) approach. We thus conclude that the need to find stronger instruments is probably as important as the need to develop a methodology allowing to consistently estimate a causal odds-ratio.

Phylogenetic relationships and divergence times among dormice (Rodentia, Gliridae) based on three nuclear genes

We examined phylogenetic relationships among six species representing three subfamilies, Glirinae, Graphiurinae and Leithiinae with sequences from three nuclear protein-coding genes (apolipoprotein B, APOB; interphotoreceptor retinoid-binding protein, IRBP; recombination-activating gene 1, RAG1). Phylogenetic trees reconstructed from maximum-parsimony (MP), maximum-likelihood (ML) and Bayesian-inference (BI) analyses showed the monophyly of Glirinae (Glis and Glirulus) and Leithiinae (Dryomys, Eliomys and Muscardinus) with strong support, although the branch length maintaining this relationship was very short, implying rapid diversification among the three subfamilies. Divergence time estimates were calculated from ML (local clock model) and Bayesian-dating method using a calibration point of 25 Myr (million years) ago for the divergence between Glis and Glirulus, and 55 Myr ago for the split between lineages of Gliridae and Sciuridae on the basis of fossil records. The results showed that each lineage of Graphiuros, Glis, Glirulus and Muscardinus dates from the Late Oligocene to the Early Miocene period, which is mostly in agreement with fossil records. Taking into account that warm climate harbouring a glirid-favoured forest dominated from Europe to Asia during this period, it is considered that this warm environment triggered the prosperity of the glirid species through the rapid diversification. Glirulus japonicas is suggested to be a relict of this ancient diversification during the warm period.

Distribution of free and liposomal doxorubicin after isolated lung perfusion in a sarcoma model.

BACKGROUND: Isolated lung perfusion (ILP) with free and a novel liposomal-encapsulated doxorubicin (Liporubicin, CT Sciences SA, Lausanne, Switzerland) was compared with respect to drug uptake and distribution in rat lungs bearing a sarcomatous tumor. METHODS: A single sarcomatous tumor was generated in the left lung of 39 Fischer rats, followed 10 days later by left-sided ILP (n = 36) with free and equimolar-dosed liposomal doxorubicin at doses of 100 microg (n = 9) and 400 microg (n = 9) for each doxorubicin formulation. In each perfused lung, the drug concentration and distribution were assessed in the tumor and in three areas of normal lung parenchyma by high-performance liquid chromatography (n = 6) and fluorescence microscopy (n = 3). Histologic assessment and immunostaining with von Willebrand factor was performed in 3 animals with untreated tumors. RESULTS: The sarcomatous tumors in controls were well vascularized with fine branching capillaries present throughout the tumors. Isolated lung perfusion resulted in a heterogeneous drug distribution within the perfused lung and a consistently lower drug uptake in tumors than in lung parenchyma for both doxorubicin formulations and both drug doses applied. Isolated lung perfusion with free doxorubicin resulted in a significantly higher drug uptake than Liporubicin in both the tumor and lung tissue for both drug doses applied (p < 0.01). However, the tumor/normal tissue drug ratio was lower for free than for liposomal doxorubicin at a drug dose of 100 microg (0.27 +/- 0.1 vs 0.53 +/- 0.5; p = 0.225) and similar for both doxorubicin formulations at a drug dose of 400 microg (0.67 +/- 0.2 vs 0.54 +/- 0.2; p = 0.335). Both doxorubicin formulations resulted in fluorescence signaling emerging from all tissue compartments of normal lung parenchyma but only in weak and sporadic signaling from the tumors confined to the tumor periphery and vessels situated within the tumor for both drug doses assessed. CONCLUSIONS: Isolated lung perfusion with free and liposomal doxorubicin resulted in a heterogeneous drug distribution within the perfused lung and in a lower drug uptake in tumors than in lung tissue for both doxorubicin formulations and drug doses applied.

Genetic polymorphisms of the main transcription factors for adiponectin gene promoter in regulation of adiponectin levels: association analysis in three European cohorts.

Adiponectin serum concentrations are an important biomarker in cardiovascular epidemiology with heritability etimates of 30-70%. However, known genetic variants in the adiponectin gene locus (ADIPOQ) account for only 2%-8% of its variance. As transcription factors are thought to play an under-acknowledged role in carrying functional variants, we hypothesized that genetic polymorphisms in genes coding for the main transcription factors for the ADIPOQ promoter influence adiponectin levels. Single nucleotide polymorphisms (SNPs) at these genes were selected based on the haplotype block structure and previously published evidence to be associated with adiponectin levels. We performed association analyses of the 24 selected SNPs at forkhead box O1 (FOXO1), sterol-regulatory-element-binding transcription factor 1 (SREBF1), sirtuin 1 (SIRT1), peroxisome-proliferator-activated receptor gamma (PPARG) and transcription factor activating enhancer binding protein 2 beta (TFAP2B) gene loci with adiponectin levels in three different European cohorts: SAPHIR (n = 1742), KORA F3 (n = 1636) and CoLaus (n = 5355). In each study population, the association of SNPs with adiponectin levels on log-scale was tested using linear regression adjusted for age, sex and body mass index, applying both an additive and a recessive genetic model. A pooled effect size was obtained by meta-analysis assuming a fixed effects model. We applied a significance threshold of 0.0033 accounting for the multiple testing situation. A significant association was only found for variants within SREBF1 applying an additive genetic model (smallest p-value for rs1889018 on log(adiponectin) = 0.002, β on original scale = -0.217 µg/ml), explaining ∼0.4% of variation of adiponectin levels. Recessive genetic models or haplotype analyses of the FOXO1, SREBF1, SIRT1, TFAPB2B genes or sex-stratified analyses did not reveal additional information on the regulation of adiponectin levels. The role of genetic variations at the SREBF1 gene in regulating adiponectin needs further investigation by functional studies.

Navigator-gated free-breathing 3D balanced FFE projection renal MRA: Comparison with contrast-enhanced breath-hold 3D MRA in a swine model.

A cardiac-triggered, free-breathing, 3D balanced FFE projection renal MR angiography (MRA) technique with a 2D pencil beam aortic labeling pulse for selective aortic spin tagging was developed. For respiratory motion artifact suppression during free breathing, a prospective real-time navigator was implemented for renal MRA. Images obtained with the new approach were compared with standard contrast-enhanced (CE) 3D breath-hold MRA in seven swine. Signal properties and vessel visualization were analyzed. With the presented technique, high-resolution, high-contrast renal projection MRA with superior vessel length visualization (including a greater visible number of distal branches of the renal arteries) compared to standard breath-hold CE-MRA was obtained. The present results warrant clinical studies in patients with renal artery disease.

Model development for capercaillie (Tetrao urogallus) habitat in the Jura Mountains (Western Switzerland)

Capercaillie, Tetrao urogallus, is a threatened species in central Europe, and Swiss populations declined 40 to 50 % between 1970 and 1985. Capercaillie are sensitive to forest structure, and loss of habitat is a major cause of their decline. Knowledge of habitat characteristics is therefore essential for capercaillie conservation. Here, we present models predicting capercaillie probability of occurrence, based on relevant structural habitat variables. Models were built using multiple logistic regression analyses on capercaillie presence/absence data. Vegetation survey was carried out in July 1999 in a 170-km2 forested area (Jura mountains, canton de Vaud, western Switzerland) inhabited by capercaillie and presence/absence of the species was assessed according to dropping presence/absence. The survey was based on 10-m-radius sample plots each in a 1-km2 forest patch (n = 76 with capercaillie droppings, n = 80 without). A first model included seven out of 27 measured habitat variables and a second model only four. The latter model best represents practical needs. It includes three variables which had a negative impact on capercaillie presence: tree and shrub covers and spruce, Picea excelsa, shrub cover, and one which had a positive effect: bilberry, Vaccinium myrtillus, cover, highlighting that capaercaillie selected open forest with high bilberry abundance. The model can be used to map potential capercaillie habitat distribution and to manage the habitat in favour of capercaillie (protection and adapted forestry practices) in the Swiss Jura mountains.

Prospective sampling based on model ensembles improves the detection of rare species

Identifying the geographic distribution of populations is a basic, yet crucial step in many fundamental and applied ecological projects, as it provides key information on which many subsequent analyses depend. However, this task is often costly and time consuming, especially where rare species are concerned and where most sampling designs generally prove inefficient. At the same time, rare species are those for which distribution data are most needed for their conservation to be effective. To enhance fieldwork sampling, model-based sampling (MBS) uses predictions from species distribution models: when looking for the species in areas of high habitat suitability, chances should be higher to find them. We thoroughly tested the efficiency of MBS by conducting an important survey in the Swiss Alps, assessing the detection rate of three rare and five common plant species. For each species, habitat suitability maps were produced following an ensemble modeling framework combining two spatial resolutions and two modeling techniques. We tested the efficiency of MBS and the accuracy of our models by sampling 240 sites in the field (30 sitesx8 species). Across all species, the MBS approach proved to be effective. In particular, the MBS design strictly led to the discovery of six sites of presence of one rare plant, increasing chances to find this species from 0 to 50%. For common species, MBS doubled the new population discovery rates as compared to random sampling. Habitat suitability maps coming from the combination of four individual modeling methods predicted well the species' distribution and more accurately than the individual models. As a conclusion, using MBS for fieldwork could efficiently help in increasing our knowledge of rare species distribution. More generally, we recommend using habitat suitability models to support conservation plans.