Contractile performance of adult ventricular rat cardiomyocytes is not directly jeopardized by NO/cGMP-dependent induction of pro-apoptotic pathways

The activation of NO/cGMP pathways can induce pro-apoptotic pathways in cardiomyocytes although only a small number of cardiomyocytes fulfill the criteria of apoptosis. The same pathways reduce the contractile performance of cardiomyocytes. In the present study, we tested the hypothesis that exposure of cells to NO/cGMP for 24 h decrease their contractile performance due to an activation of pro-apoptotic pathways. Experiments were performed on freshly isolated and cultured adult ventricular rat cardiomyocytes. Cells were incubated with 8-bromo-cyclo-GMP (100 nmol/L-1 micromol/L), the NO donor SNAP (1 nmol/L-100 micromol/L), or the guanylyl cyclase activator YC-1 (3 micromol/L). Cell shortening, contraction and relaxation velocities, and diastolic cell lengths were determined at beating frequencies of 0.5, 1, and 2 Hz 24 h later. The activation of pro-apoptotic pathways was determined by staining of cardiomyocytes with an antibody directed against active caspase-3 and quantification of the number of apoptotic cells (annexin staining). Caspase-3 activation and an increase in the number of apoptotic cells was observed, but only at the highest concentrations tested (8-bromo-cyclo-GMP: 1-10 mmol/L; SNAP: 1-100 micromol/L). At these concentrations, none of the drugs decreased the mean cell shortening of cardiomyocytes. However, at concentrations lower than those required for induction of apoptotic cell death, the diastolic cell lengths and sarcomere lengths increased but cell shortening decreased. In conclusion, low concentrations of either NO or cGMP cause a desensitization of myofibrils, as indicated by elongated cell shapes, increased sarcomere lengths and reduced load-free cell shortening. High concentrations of NO/cGMP induce caspase-3 activation and increase the number of cells fulfilling the criteria of apoptotic cell death but did not impair cell function. Therefore, induction of apoptotic cell death per se seems not to contribute to the loss of contractile efficiency on the cellular level.

Inactivity of nitric oxide synthase gene in the atherosclerotic human carotid artery

OBJECTIVE: Nitric oxide (NO) inhibits thrombus formation, vascular contraction, and smooth muscle cell proliferation. We investigated whether NO release is enhanced after endothelial NO synthase (eNOS) gene transfer in atherosclerotic human carotid artery ex vivo. METHODS AND RESULTS: Western blotting and immunohistochemistry revealed that transduction enhanced eNOS expression; however, neither nitrite production nor NO release measured by porphyrinic microsensor was altered. In contrast, transduction enhanced NO production in non-atherosclerotic rat aorta and human internal mammary artery. In transduced carotid artery, calcium-dependent eNOS activity was minimal and did not differ from control conditions. Vascular tetrahydrobiopterin concentrations did not differ between the experimental groups.Treatment of transduced carotid artery with FAD, FMN, NADPH, L-arginine, and either sepiapterin or tetrahydrobiopterin did not alter NO release. Superoxide formation was similar in transduced carotid artery and control. Treatment of transduced carotid artery with superoxide dismutase (SOD), PEG-SOD, PEG-catalase did not affect NO release. CONCLUSIONS: eNOS transduction in atherosclerotic human carotid artery results in high expression without any measurable activity of the recombinant protein. The defect in the atherosclerotic vessels is neither caused by cofactor deficiency nor enhanced NO breakdown. Since angioplasty is performed in atherosclerotic arteries,eNOS gene therapy is unlikely to provide clinical benefit.

Effect of discharge desynchronization on the size of motor evoked potentials: an analysis

OBJECTIVE: Motor evoked potentials (MEPs) after transcranial magnetic brain stimulation (TMS) are smaller than CMAPs after peripheral nerve stimulation, because desynchronization of the TMS-induced motor neurone discharges occurs (i.e. MEP desynchronization). This desynchronization effect can be eliminated by use of the triple stimulation technique (TST; Brain 121 (1998) 437). The objective of this paper is to study the effect of discharge desynchronization on MEPs by comparing the size of MEP and TST responses. METHODS: MEP and TST responses were obtained in 10 healthy subjects during isometric contractions of the abductor digiti minimi, during voluntary background contractions between 0% and 20% of maximal force, and using 3 different stimulus intensities. Additional data from other normals and from multiple sclerosis (MS) patients were obtained from previous studies. RESULTS: MEPs were smaller than TST responses in all subjects and under all stimulating conditions, confirming the marked influence of desynchronization on MEPs. There was a linear relation between the amplitudes of MEPs vs. TST responses, independent of the degree of voluntary contraction and stimulus intensity. The slope of the regression equation was 0.66 on average, indicating that desynchronization reduced the MEP amplitude on average by one third, with marked inter-individual variations. A similar average proportion was found in MS patients. CONCLUSIONS: The MEP size reduction induced by desynchronization is not influenced by the intensity of TMS and by the level of facilitatory voluntary background contractions. It is similar in healthy subjects and in MS patients, in whom increased desynchronization of central conduction was previously suggested to occur. Thus, the MEP size reduction observed may not parallel the actual amount of desynchronization.

Mechanical signals regulating extracellular matrix gene expression in fibroblasts

Mechanical forces are essential for connective tissue homeostasis. The extracellular matrix (ECM) plays a key role in the transmission of forces generated by the organism (e.g. muscle contraction) and externally applied (e.g. gravity). The expression of specific ECM proteins such as collagens and tenascin-C, as well as of matrix metalloproteinases, involved in their turnover, is influenced by mechanical stimuli. The precise mechanisms by which mechanical strains are translated into chemical signals and lead to differential gene expression are however not fully understood. Cell-matrix adhesion sites are good candidates for hosting a "mechanosensory switch", as they transmit forces from the ECM to the cytoskeleton and vice versa by physically linking the cytoskeleton to the ECM. Integrins, transmembrane proteins located to these adhesion sites, have been shown to trigger a set of internal signaling cascades after mechanical stimulation. We have shown that the expression level of tenascin-C directly correlates with externally applied mechanical stress, as well as with RhoA/RhoA-dependent kinase-mediated cytoskeletal tension. Presumably other genes are regulated in a similar manner. The changes in ECM composition and mechanical properties derived from mechanical stress are relevant in medical intervention after ligament and tendon injury.

Locational policies in secondary capital cities: constructing a dynamic framework

Capital cities that are not the economic centers of their nations – so-called secondary capital cities (SSCs) – tend to be overlooked in the field of political science. Consequentially, there is a lack of research and resulting theory describing their local economy and their public policies. This paper analyzes how SCCs try to develop and position themselves through the formulation of locational policies. By linking three different theoretical strands – the Regional Innovation System (RIS) approach, the concept of locational policies, and the regime perspective – this paper aims for constructing a framework to study the economic and political dynamics in SCCs.

Tracks of immigrant political incorporation

Models of Immigrant Political Incorporation brings together a multidisciplinary group of scholars to consider pathways by which immigrants may be incorporated into the political processes of western democracies. It builds on a rich tradition of studying immigrant incorporation, but each chapter innovates by moving beyond singular accounts of particular groups and locations toward a general causal model with the scope and breadth to apply across groups, places, and time. Models of Immigrant Political Incorporation addresses three key analytic questions: what, if anything, are the distinctive features of immigrants or immigrant groups? How broadly should one define and study politics? What are the initial premises for analyzing pathways toward incorporation; does one learn more by starting from an assumption of racialization and exclusion or from an assumption of engagement and inclusion? While all models engage with all three key analytic questions, chapters vary in their relative focus on one or another, and in the answers they provide. Most include graphical illustrations of the model, as well as extended examples applying the model to one or more immigrant populations. At a time when research on immigrant political incorporation is rapidly accumulating - and when immigrants are increasingly significant political actors in many democratic polities — this volume makes a timely and valuable intervention by pushing researchers to articulate causal dynamics, provide clear definitions and measurable concepts, and develop testable hypotheses. Furthermore, the wide array of frameworks examining how immigrants become part of a polity or are shunted aside ensure that activists and analysts alike will find useful insights. By including historians, sociologists, and political scientists, by ranging across North America and Western Europe, by addressing successful and failed incorporative efforts, this handbook offers guides for anyone seeking to develop a dynamic, unified, and supple model of immigrant political incorporation.

Repolitisations féministes et queer du cerveau

L’histoire des relations entre biologie et politique féministe est tendue et contradictoire. Cela paraît d’autant plus flagrant aujourd’hui à l’âge d’or des neurosciences qui ramènent les arguments de supériorité masculine, le caractère inéluctable des différences de genre et la prédominance de l’hétérosexualité à une affaire de cerveau. Dans cet article, nous analysons les points d’intersection propres aux sciences du cerveau et du féminisme. Ces deux champs de recherche entretiennent selon nous des rapports conflictuels mais parfois aussi productifs, y compris dans leurs rapports à l’activisme politique. Ces rapports peuvent être caractérisés en référence à trois directions de recherche principales : des « déstabilisations », des « reconstructions » et des « recontextualisations ». En guise de conclusion, nous terminons par quelques réflexions sur les conditions sociologiques de l’engagement dans une économie politique des neurosciences.[1] [1]Traduit de l’anglais par Marc Gagnepain. Pour une brève présentation de l’article et du dossier thématique dans lequel il s’inscrit, nous renvoyons le/la lecteur/trice à l’article introductif de Bovet, Kraus, Panese, Pidoux et Stücklin, « Les neurosciences à l’épreuve de la clinique et des sciences sociales. Regards croisés ».

A Preliminary Impact Assessment of Doha Round Results on Agricultural Policies in Turkey

Turkish agriculture has been experiencing a period of unique policy experiment over the last couple years. A World Bank-initiated project, called the Agricultural Reform Implementation Project (ARIP), has been at the forefront of policy change. It was initially promoted by the Bank as an exemplary reform package which could also be adopted by other developing countries. It was introduced in 2001 as part of a major International Monetary Fund (IMF)/World Bank-imposed program of “structural adjustment” after the country had been hit by a major financial crisis. The project has finally come to an end in 2009, and there is now an urgent need for a retrospective assessment of its overall impact on the agricultural sector. Has it fulfilled its ambitious objective of reforming and restructuring Turkish agriculture? Or should it be recorded as a failure of the neo-liberal doctrine? This book aims at finding answers to these questions by investigating the legacy of ARIP from a multi-disciplinary perspective.

Dein Gott ist ein Esel. Griechische und römische Tierkarikaturen als Spiegel antiker Wertvorstellungen

Die Doktorarbeit “Dein Gott ist ein Esel. Griechische und römische Tierkarikaturen als Spiegel antiker Wertvorstellungen” hat sowohl die lange und intensive Beziehung zwischen Mensch und Tier als auch das antike Humorverständnis zum Thema. Trotz seiner verschiedenen Rollen als Helfer und Freund blieb (und bleibt) das Tier der Stereotyp des ‚Anderen’, das Gegenbild, das alle Menschen teilen. Das Lachen und damit die Karikatur wiederum helfen uns, zu reflektieren und Distanz zu den Dingen und vielleicht zu uns selbst zu gewinnen. Tierkarikaturen sind deshalb besonders geeignet, ein Spiegel menschlicher Fehler und Schwächen zu sein. In der Regel handelt es sich bei den antiken Tierkarikaturen um Bilder von Menschen, die tiergestaltig ‚verzerrt’ sind, zum Beispiel ein Lehrer mit dem Äusseren eines Esels. Solche Darstellungen sind ab dem 6. Jh. v. Chr. zu finden und werden in hellenistischer und römischer Zeit häufiger, wo der Fokus der Arbeit liegt. Meist sind es Terrakotta- oder Bronzefiguren, die verschiedenen gesellschaftlichen Bereichen zugeordnet werden können wie Religion, Politik, Freizeit usw. Unter Berücksichtigung des spezifischen kulturellen und funktionalen Kontextes jedes Stückes sowie zeitgenössischen schriftlichen Quellen wird die Bedeutung dieser Karikaturen erarbeitet.

A novel animal model for external anal sphincter insufficiency

Abstract PURPOSE: Reliable animal models are essential to evaluate future therapeutic options like cell-based therapies for external anal sphincter insufficiency. The goal of our study was to describe the most reliable model for external sphincter muscle insufficiency by comparing three different methods to create sphincter muscle damage. METHODS: In an experimental animal study, female Lewis rats (200-250 g) were randomly assigned to three treatment groups (n = 5, each group). The external sphincter muscle was weakened in the left dorsal quadrant by microsurgical excision, cryosurgery, or electrocoagulation by diathermy. Functional evaluation included in vivo measurements of resting pressure, spontaneous muscle contraction, and contraction in response to electrical stimulation of the afferent nerve at baseline and at 2, 4, and 6 weeks after sphincter injury. Masson's trichrome staining and immunofluorescence for skeletal muscle markers was performed for morphological analysis. RESULTS: Peak contraction after electrical stimulation was significantly decreased after sphincter injury in all groups. Contraction forces recovered partially after cryosurgery and electrocoagulation but not after microsurgical excision. Morphological analysis revealed an incomplete destruction of the external sphincter muscle in the cryosurgery and electrocoagulation groups compared to the microsurgery group. CONCLUSIONS: For the first time, three different models of external sphincter muscle insufficiency were directly compared. The animal model using microsurgical sphincter destruction offers the highest level of consistency regarding tissue damage and sphincter insufficiency, and therefore represents the most reliable model to evaluate future therapeutic options. In addition, this study represents a novel model to specifically test the external sphincter muscle function.

Evaluating Esophageal Bolus Transit by Impedance Monitoring

The function of the esophagus is transporting nutrients from the oropharyngeal cavity to the stomach. This is achieved by coordinated contractions and relaxation of the tubular esophagus and the upper and lower esophageal sphincter. Multichannel intraluminal impedance monitoring offers quantification of esophageal bolus transit and/or retention without the use of ionizing radiation. Combined with conventional or high-resolution manometry, impedance measurements complement the quantification of esophageal body contraction and sphincter relaxation, offering a more comprehensive evaluation of esophageal function. Further studies evaluating the utility of quantifying bolus transit will help clarify the role and position of impedance measurements.

Stabilisation of precipitates of pedogenic dissolved organic matter by multivalent cations

Purpose Precipitation of dissolved organic matter (DOM) by multivalent cations is important for biogeochemical cycling of organic carbon. We investigated to which extent cation bridges are involved in DOM precipitation and how cross-links by cations and water molecule bridges (WaMB) stabilise the matrix of precipitated DOM. Materials and methods DOM was precipitated from the aqueous extract of a forest floor layer adding solutions of Ca(NO3)2, Al(NO3)3 and Pb(NO3)2 with different initial metal cation/C (Me/C) ratios. Precipitates were investigated by differential scanning calorimetry before and after ageing to detect cation bridges, WaMB and restructuring of supramolecular structure. Results and discussion Twenty-five to sixty-seven per cent of the dissolved organic carbon was precipitated. The precipitation efficiency of cations increased in the order Ca < Al < Pb, while the cation content of precipitates increased in the order Pb < Ca < Al. The different order and the decrease in the WaMB transition temperature (T*) for Al/C > 3 is explained by additional formation of small AlOOH particles. Thermal analysis indicated WaMB and their disruption at T* of 53–65 °C. Like cation content, T* increased with increasing Me/C ratio and in the order Ca < Pb < Al for low Me/C. This supports the general assumption that cross-linking ability increases in the order Ca < Pb < Al. The low T* for high initial Me/C suggests less stable and less cross-linked precipitates than for low Me/C ratios. Conclusions Our results suggest a very similar thermal behaviour of OM bound in precipitates compared with soil organic matter and confirms the relevance of WaMB in stabilisation of the supramolecular structure of cation-DOM precipitates. Thus, stabilisation of the supramolecular structure of the DOM precipitates is subjected to dynamics in soils.

The impact of associational life on trust in local institutions: a comparison of 57 Swiss municipalities

In this paper, we evaluate the impact of associational life on individual political trust in 57 Swiss municipalities. Our hierarchical regression models show that individual political trust is not only affected by individual associational membership but also by the exchange between associations and local political authorities in a community. In other words, if political authorities and associations are linked at the community level, citizens will place more trust in their local institutions. Furthermore, we find clear evidence for the rainmaker hypothesis: our results show that the positive effect of a vibrant connection between associational life and local politics on political trust is not solely confined to the associational members themselves, but rather indicate that the structure of the local civic culture fosters political trust among members and non-members at the same time. However, the internal democratic processes of associations have no effect on individuals’ trust in local political institutions.