Prostacyclins have no direct inotropic effect on isolated atrial strips from the normal and pressure-overloaded human right heart

Prostacyclins are vasodilatory agents used in the treatment of pulmonary arterial hypertension. The direct effects of prostacyclins on right heart function are still not clarified. The aim of this study was to investigate the possible direct inotropic properties of clinical available prostacyclin mimetics in the normal and the pressure-overloaded human right atrium. Trabeculae from the right atrium were collected during surgery from chronic thromboembolic pulmonary hypertension (CTEPH) patients with pressure-overloaded right hearts, undergoing pulmonary thromboendarterectomy (n = 10) and from patients with normal right hearts operated by valve replacement or coronary bypass surgery (n = 9). The trabeculae were placed in an organ bath, continuously paced at 1 Hz. They were subjected to increasing concentrations of iloprost, treprostinil, epoprostenol, or MRE-269, followed by isoprenaline to elicit a reference inotropic response. The force of contraction was measured continuously. The expression of prostanoid receptors was explored through quantitative polymerase chain reaction (qPCR). Iloprost, treprostinil, epoprostenol, or MRE-269 did not alter force of contraction in any of the trabeculae. Isoprenaline showed a direct inotropic response in both trabeculae from the pressure-overloaded right atrium and from the normal right atrium. Control experiments on ventricular trabeculae from the pig failed to show an inotropic response to the prostacyclin mimetics. qPCR demonstrated varying expression of the different prostanoid receptors in the human atrium. In conclusion, prostacyclin mimetics did not increase the force of contraction of human atrial trabeculae from the normal or the pressure-overloaded right heart. These data suggest that prostacyclin mimetics have no direct inotropic effects in the human right atrium

How do firms comply with international sustainability standards? Processes and consequences of adopting the global reporting initiative

This paper addresses the issue of the influence of global governance institutions, particularly international sustainability standards, on a firm’s intra-organizational practices. More precisely, we provide an exploratory empirical view of the impact of the Global Reporting Initiative (GRI) on a multinational corporation’s (MNC) corporate social responsibility (CSR) management practices. We investigate standard compliance by comparing the stated intention of the use of the GRI with its actual use and the consequent effects within the firm. Based on an in-depth case study, our findings illustrate the processes and consequences of the translation of the GRI within the organization. We show that substantive standard adoption can lead to unintended consequences on CSR management practices, specifically it can influence the management structure and CSR committee function; the choice of CSR activities, the relationships between subsidiaries, the temporal dimension of CSR management, and the interpretation of CSR performance. We also highlight the need to look at the relationship dynamics (or lack of) between standards. Finally we illustrate and discuss the role of reporting and its influence on management in order to better understand the internal issues arising from compliance with standards

Effect of hypoxia and Beraprost sodium on human pulmonary arterial smooth muscle cell proliferation: the role of p27kip1

<p>Abstract</p> <p>Background</p> <p>Hypoxia induces the proliferation of pulmonary arterial smooth muscle cell (PASMC) <it>in vivo </it>and <it>in vitro</it>, and prostacyclin analogues are thought to inhibit the growth of PASMC. Previous studies suggest that p27^kip1, a kind of cyclin-dependent kinase inhibitor, play an important role in the smooth muscle cell proliferation. However, the mechanism of hypoxia and the subcellular interactions between p27^kip1and prostacyclin analogues in human pulmonary arterial smooth muscle cell (HPASMC) are not fully understood.</p> <p>Methods</p> <p>We investigated the role of p27^kip1in the ability of Beraprost sodium (BPS; a stable prostacyclin analogue) to inhibit the proliferation of HPASMC during hypoxia. To clarify the biological effects of hypoxic air exposure and BPS on HPASMC, the cells were cultured in a hypoxic chamber under various oxygen concentrations (0.1–21%). Thereafter, DNA synthesis was measured as bromodeoxyuridine (BrdU) incorporation, the cell cycle was analyzed by flow cytometry with propidium iodide staining. The p27^kip1mRNA and protein expression and it's stability was measured by real-time RT-PCR and Western blotting. Further, we assessed the role of p27^kip1in HPASMC proliferation using p27^kip1gene knockdown using small interfering RNA (siRNA) transfection.</p> <p>Results</p> <p>Although severe hypoxia (0.1% oxygen) suppressed the proliferation of serum-stimulated HPASMC, moderate hypoxia (2% oxygen) enhanced proliferation in accordance with enhanced p27^kip1protein degradation, whereas BPS suppressed HPASMC proliferation under both hypoxic and normoxic conditions by suppressing p27^kip1degradation with intracellular cAMP-elevation. The 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP), a cAMP analogue, had similar action as BPS in the regulation of p27^kip1. Moderate hypoxia did not affect the stability of p27^kip1protein expression, but PDGF, known as major hypoxia-induced growth factors, significantly decreased p27^kip1protein stability. We also demonstrated that BPS and 8-Br-cAMP suppressed HPASMC proliferation under both hypoxic and normoxic conditions by blocking p27^kip1mRNA degradation. Furthermore, p27^kip1gene silencing partially attenuated the effects of BPS and partially restored hypoxia-induced proliferation.</p> <p>Conclusion</p> <p>Our study suggests that moderate hypoxia induces HPASMC proliferation, which is partially dependent of p27^kip1down-regulation probably <it>via </it>the induction of growth factors such as PDGF, and BPS inhibits both the cell proliferation and p27^kip1mRNA degradation through cAMP pathway.</p

Oxytocin Signaling in Mouse Taste Buds

The neuropeptide, oxytocin (OXT), acts on brain circuits to inhibit food intake. Mutant mice lacking OXT (OXT knockout) overconsume salty and sweet (i.e. sucrose, saccharin) solutions. We asked if OXT might also act on taste buds via its receptor, OXTR.Using RT-PCR, we detected the expression of OXTR in taste buds throughout the oral cavity, but not in adjacent non-taste lingual epithelium. By immunostaining tissues from OXTR-YFP knock-in mice, we found that OXTR is expressed in a subset of Glial-like (Type I) taste cells, and also in cells on the periphery of taste buds. Single-cell RT-PCR confirmed this cell-type assignment. Using Ca2+ imaging, we observed that physiologically appropriate concentrations of OXT evoked [Ca2+]i mobilization in a subset of taste cells (EC50 approximately 33 nM). OXT-evoked responses were significantly inhibited by the OXTR antagonist, L-371,257. Isolated OXT-responsive taste cells were neither Receptor (Type II) nor Presynaptic (Type III) cells, consistent with our immunofluorescence observations. We also investigated the source of OXT peptide that may act on taste cells. Both RT-PCR and immunostaining suggest that the OXT peptide is not produced in taste buds or in their associated nerves. Finally, we also examined the morphology of taste buds from mice that lack OXTR. Taste buds and their constituent cell types appeared very similar in mice with two, one or no copies of the OXTR gene.We conclude that OXT elicits Ca2+ signals via OXTR in murine taste buds. OXT-responsive cells are most likely a subset of Glial-like (Type I) taste cells. OXT itself is not produced locally in taste tissue and is likely delivered through the circulation. Loss of OXTR does not grossly alter the morphology of any of the cell types contained in taste buds. Instead, we speculate that OXT-responsive Glial-like (Type I) taste bud cells modulate taste signaling and afferent sensory output. Such modulation would complement central pathways of appetite regulation that employ circulating homeostatic and satiety signals

“Working the System”—British American Tobacco's Influence on the European Union Treaty and Its Implications for Policy: An Analysis of Internal Tobacco Industry Documents

Katherine Smith and colleagues investigate the ways in which British American Tobacco influenced the European Union Treaty so that new EU policies advance the interests of major corporations, including those that produce products damaging to health

30(+) years of exercise in pregnancy

In 1980 I came to Loma Linda to study maternal exercise, with Dr. Longo as my mentor. For millennia strenuous exercise was considered harmful for the fetus. Early studies reinforced that idea, by showing that exercise reduced uterine blood flow and fetal PO2 by up to 40 and 29 %, respectively. But utero-placental reserve is ~50 %. So why was fetal PO2 so much reduced during exercise?Methods proved to be important. It took chronically instrumented animals accustomed to the laboratory environment, experiments standardized to fitness of the individual (%VO2max), measurement of total uterine blood flow, and blood gas values corrected for body temperature. The results were simple and hold till this day. Uterine blood flow decreases linearly with maternal heart rate increase, which depends on exercise intensity and duration. Maximal reduction in uterine blood flow is ~20 % and uterine O2-uptake remains unaltered because blood flow reduction is compensated by increases in hematocrit and uterine O2-extraction. Fetal body temperature increases with that of the mother by ~2 degrees C at maximal exercise and fetal blood gas values are little affected by exhaustive maternal exercise, if properly corrected for temperature. So I left Loma Linda knowing that pregnant sheep can exercise to exhaustion without harm to the fetus, thanks to effective compensatory mechanisms.After returning to Erasmus University Rotterdam further studies in humans showed that physical fitness is unaffected by pregnancy, weight-gain affects performance, and strenuous exercise in healthy pregnant women does not harm the fetus. Thus, the millennia-old perspective has changed