Nox2 NADPH Oxidase Promotes Pathologic Cardiac Remodeling Associated with Doxorubicin Chemotherapy

Doxorubicin is a highly effective cancer treatment whose use is severely limited by dose-dependent cardiotoxicity. It is well established that doxorubicin increases reactive oxygen species (ROS) production. In this study, we investigated contributions to doxorubicin cardiotoxicity from Nox2 NADPH oxidase, an important ROS source in cardiac cells, which is known to modulate several key processes underlying the myocardial response to injury. Nox2-deficient mice (Nox2(-/-)) and wild-type (WT) controls were injected with doxorubicin (12 mg/kg) or vehicle and studied 8 weeks later. Echocardiography indicated that doxorubicin-induced contractile dysfunction was attenuated in Nox2(-/-) versus WT mice (fractional shortening: 29.5 +/- 1.4 versus 25.7 +/- 1.0%; P

Taking the Next Step? Achieving another Bill of Rights

The aim of this article is to explore the recent Bill of Rights debate in the UK. This is deliberately located in the UK’s complex ‘national question’ because of the obsessive focus on achieving a proper grounding for human rights. A new form of national human rights protectionism appears to be emerging and merits careful consideration. The article suggests that it is better to acknowledge and accept the existence of a plurality of nationalisms in the UK in these discussions and understand how an essentially ‘British nationalist’ discourse sounds and works in that overall context. The concern is that the Bill of Rights debate is becoming an inadequate surrogate for the more challenging constitutional conversations that are required, and human rights discourse thus invested with expectations of national renewal that it can never meet and does not have the internal resources to resolve. If the process does go forward it may be better to prepare the ground for a deeper and wider constitutional dialogue across these islands than stumble clumsily and divisively into this territory simply via ‘another’ UK Bill of Rights.

Polyopes lancifolius (Halymeniales, Rhodophyta), a new component of the Japanese marine flora introduced to Europe

Polyopes lancifolius (Harvey) S. Kawaguchi & H.W. Wang has been recorded for the first time in Europe, during the summer or 2008. A small population was discovered in the Gulf of Morbihan (northeast Atlantic, France). This is the first observation of P. lancifolius outside its native range. Vegetative and reproductive morphological features are compared with previous descriptions. rbcL sequences show no divergence from Japanese populations. Imports of Pacific oysters Crassostrea gigas (Thunberg 1793) are likely to be responsible for its accidental introduction into the Gulf of Morbihan, either directly from northwest Pacific regions or indirectly (secondary dispersal) by transfers from another European oyster farming site. The history of previous algal introductions from Japan suggests that if it becomes successfully established at Morbihan, the species is likely to spread to other European coastal areas.

Benzylguanidines and Other Galegine Analogues Inducing Weight Loss in Mice

Dimethylallylguanidine, also known as galegine, isolated from Galega officinalis, has been shown to have weight reducing properties in vivo. Substitution of the guanidine group with an N-cyano group and replacement of guanidine with amidine, pyrimidine, pyridine, or the imidazole moieties removed the weight reducing properties when evaluated in BALB/c mice. However, retention of the guanidine and replacement of the dimethylallyl group by a series of functionalized benzyl substituents was shown to exhibit, and in some cases significantly improve, the weight reducing properties of these molecules in BALB/c, ob/ob, and diet induced obesity (DIO) mice models. The lead compound identified, across all models, was 1-(4-chlorobenzyl)guanidine hemisulfate, which gave an average daily weight difference (% from time-matched controls; +/- SEM) of -19.7 +/- 1.0, -11.0 +/- 0.7, and -7.3 +/- 0.8 in BALB/c, ob/ob, and DIO models, respectively.

Mechanisms underlying the metabolic actions of galegine that contribute to weight loss in mice

Background and purpose: Galegine and guanidine, originally isolated from Galega officinalis, led to the development of the biguanides. The weight-reducing effects of galegine have not previously been studied and the present investigation was undertaken to determine its mechanism(s) of action.

Experimental approach: Body weight and food intake were examined in mice. Glucose uptake and acetyl-CoA carboxylase activity were studied in 3T3-L1 adipocytes and L6 myotubes and AMP activated protein kinase (AMPK) activity was examined in cell lines. The gene expression of some enzymes involved in fat metabolism was examined in 3T3-L1 adipocytes.

Key results: Galegine administered in the diet reduced body weight in mice. Pair-feeding indicated that at least part of this effect was independent of reduced food intake. In 3T3-L1 adipocytes and L6 myotubes, galegine (50 µm-3 mm) stimulated glucose uptake. Galegine (1–300 µm) also reduced isoprenaline-mediated lipolysis in 3T3-L1 adipocytes and inhibited acetyl-CoA carboxylase activity in 3T3-L1 adipocytes and L6 myotubes. Galegine (500 µm) down-regulated genes concerned with fatty acid synthesis, including fatty acid synthase and its upstream regulator SREBP. Galegine (10 µm and above) produced a concentration-dependent activation of AMP activated protein kinase (AMPK) in H4IIE rat hepatoma, HEK293 human kidney cells, 3T3-L1 adipocytes and L6 myotubes.

Conclusions and implications: Activation of AMPK can explain many of the effects of galegine, including enhanced glucose uptake and inhibition of acetyl-CoA carboxylase. Inhibition of acetyl-CoA carboxylase both inhibits fatty acid synthesis and stimulates fatty acid oxidation, and this may to contribute to the in vivo effect of galegine on body weight.

Contextualised Equality and the Politics of Legal Mobilisation: Affirmative Action in Northern Ireland

This article examines the development of affirmative action and equality policies targeted at the two main ethno-national communities in Northern Ireland, as an example of ‘contextualised equality’. The argument places particular weight on a politics of legal mobilisation. The article suggests that the ability to connect post-1998 reforms, in practical and symbolic ways, to overriding inter-communal narratives was often a determining factor in identifying those elements of the Good Friday Agreement which advanced, or were constructed as achievable. The argument has implications for understanding how equality debates will progress, and explaining why certain agendas appear to ‘succeed’ and others ‘fail’.

The Gastrointestinal Peptide Obestatin Induces Vascular Relaxation Via Specific Activation of Endothelium-Dependent Nitric Oxide Signalling.

Background and purpose: Obestatin is a recently-discovered gastrointestinal peptide with established metabolic actions, which is linked to diabetes and may exert cardiovascular benefits. Here we aimed to investigate the specific effects of obestatin on vascular relaxation. Experimental approach: Cumulative relaxation responses to obestatin peptides were assessed in isolated rat aorta and mesenteric artery (n=8) in the presence/absence of selective inhibitors. Complementary studies were performed in cultured bovine aortic endothelial cells (BAEC). Key results: Obestatin peptides elicited concentration-dependent relaxation in both aorta and mesenteric artery. Responses to full-length obestatin(1-23) were greater than those to obestatin(1-10) and obestatin(11-23). Obestatin(1-23)-induced relaxation was attenuated by endothelial denudation, L-NAME (NO synthase inhibitor), high extracellular K(+) , GDP-ß-S (G protein inhibitor), MDL-12,330A (adenylate cyclase inhibitor), wortmannin (PI3K inhibitor), KN-93 (CaMKII inhibitor), ODQ (guanylate cyclase inhibitor) and iberiotoxin (BK(Ca) blocker), suggesting that it is mediated by an endothelium-dependent NO signalling cascade involving an adenylate cyclase-linked G protein-coupled receptor, PI3K/Akt, Ca(2+) -dependent eNOS activation, soluble guanylate cyclase and modulation of vascular smooth muscle K(+) . Supporting data from BAEC indicated that nitrite production, intracellular Ca(2+) and Akt phosphorylation were increased after exposure to obestatin(1-23). Relaxations to obestatin(1-23) were unaltered by inhibitors of candidate endothelium-derived hyperpolarising factors (EDHFs) and combined SK(Ca) /IK(Ca) blockade, suggesting that EDHF-mediated pathways were not involved. Conclusions and Implications: Obestatin produces significant vascular relaxation via specific activation of endothelium-dependent NO signalling. These actions may be important in normal regulation of vascular function and are clearly relevant to diabetes, a condition characterised by endothelial dysfunction and cardiovascular complications.

Referral to an Extracorporeal Membrane Oxygenation Center and Mortality Among Patients With Severe 2009 Influenza A(H1N1)

Context Extracorporeal membrane oxygenation (ECMO) can support gas exchange in patients with severe acute respiratory distress syndrome (ARDS), but its role has remained controversial. ECMO was used to treat patients with ARDS during the 2009 influenza A(H1N1) pandemic.

Ceramium Roth (Ceramiales, Rhodophyta) from Venice lagoon (Adriatic Sea, Italy): Comparative studies of Mediterranean and Atlantic taxa

The cosmopolitan genus Ceramium (Ceramiaceae, Rhodophyta) is a large and systematically complex group. The taxonomy of this genus remains in a chaotic state due to the high degree of morphological variation. Culture studies, suggesting a strong influence of environment on phenotype, and the use of molecular tools have recently questioned the validity of morphological features used in species recognition. Here we compare three Ceramium taxa from Venice lagoon with samples from northwest Europe using the plastid ribulose-1,5-bisphosphate carboxylase/oxygenase gene (rbcL) and the rbcL-rbcS intergenic spacer combined with morphological observations. A strongly banded species, previously identified as member of a poorly understood and misnamed group, the Ceramium diaphanum complex sensu Feldmann-Mazoyer, is probably conspecific with British samples of Ceramium diaphanum sensu Harvey, for which no valid name has been identified up to now. We show that Ceramium polyceras (Kutzing) Zanardini is a valid name for this species. A fully corticated Ceramium species morphologically resembling C. secundatum differs at the species level from Atlantic C. secundatum; a valid name for this entity is Ceramium derbesii Solier ex Kutzing, described from Mediterranean France. A third species characterized by cortical spines, previously listed as Ceramium ciliation var. robustum (J. Agardh) Mazoyer, is shown to be Ceramium nudiusculum (Kutzing) Rabenhorst, originally described from Venice.

Eosinophil peroxidase induces the expression and function of acid-sensing ion channel-3 in allergic rhinitis:in vitro evidence in cultured epithelial cells

BACKGROUND:
Acid-sensing ion channels (ASIC) are a family of acid-activated ligand-gated cation channels. As tissue acidosis is a feature of inflammatory conditions, such as allergic rhinitis (AR), we investigated the expression and function of these channels in AR.
OBJECTIVES:
The aim of the study was to assess expression and function of ASIC channels in the nasal mucosa of control and AR subjects.
METHODS:
Immunohistochemical localization of ASIC receptors and functional responses to lactic acid application were investigated. In vitro studies on cultured epithelial cells were performed to assess underlying mechanisms of ASIC function.
RESULTS:
Lactic acid at pH 7.03 induced a significant rise in nasal fluid secretion that was inhibited by pre-treatment with the ASIC inhibitor amiloride in AR subjects (n = 19). Quantitative PCR on cDNA isolated from nasal biopsies from control and AR subjects demonstrated that ASIC-1 was equally expressed in both populations, but ASIC-3 was significantly more highly expressed in AR (P < 0.02). Immunohistochemistry confirmed significantly higher ASIC-3 protein expression on nasal epithelial cells in AR patients than controls (P < 0.01). Immunoreactivity for EPO+ eosinophils in both nasal epithelium and submucosa was more prominent in AR compared with controls. A mechanism of induction of ASIC-3 expression relevant to AR was suggested by the finding that eosinophil peroxidase (EPO), acting via ERK1/2, induced the expression of ASIC-3 in epithelial cells. Furthermore, using a quantitative functional measure of epithelial cell secretory function in vitro, EPO increased the air-surface liquid depth via an ASIC-dependent chloride secretory pathway.
CONCLUSIONS:
This data suggests a possible mechanism for the observed association of eosinophils and rhinorrhoea in AR and is manifested through enhanced ASIC-3 expression.

Fracture surface, impact energy and hardness of Ni-free high-Mn steels

Two manganese steels were investigated: Fe-19.7%Mn (VM339A) and Fe-19.7%Mn stabilized with 0.056%C, 0.19%Ti and 0.083%Al (VM339B). The toughness of VM339A was higher than VM339B, but VM339B had higher hardness. Tempering does not affect the toughness of the alloys. SEM images of the fracture surface for both the alloys revealed ductile fractures. A further alloy with a lower manganese content, Fe-8.46%Mn-0.24%Nb-0.038%C, and thus even lower cost than the conventional 3.5Ni cryogenic steel, was tested for its impact toughness after heat treatment at 600°C, giving promising results.