bluuebunny/crossref_metadata_2025 huggingface dataset:
Measuring the Utility Cost of Temporary Employment Contracts Before Adaptation: A Conjoint Analysis Approach
Authors: POULIAKAS KONSTANTINOS , THEODOSSIOU IOANNIS
Published: April 2009

This study attempts to estimate the ‘utility cost’ of temporary employment contracts purged of the psychological effects of adaptation. A conjoint analysis experiment is used that examines the ex ante contract preferences of a unique sample of low‐skilled employees from seven European countries. It is shown that permanent contract holders request a significant wage premium to move to a temporary job. In contrast, temporary workers are indifferent between permanent and temporary contracts, ceteris paribus. The evidence suggests that individuals have a psychological immune system which neutralizes events that challenge their sense of wellbeing, such as job insecurity.
Internalizing Team Production Externalities through Delegation: The British Passenger Rail Sector as an Example
Authors: HORTALA‐VALLVE RAFAEL , SANCHEZ VILLALBA MIGUEL
Published: April 2009

We show that in situations of team production, the associated externality between workers can be partially internalized via the delegation of authority of contracting rights, thus improving the overall efficiency of organizations. A delegated structure provides further incentives to individuals in higher tiers of the hierarchy because it makes them residual claimants. Our model sheds light on recent debates about the organization of the British passenger rail sector.
Defining Economics: The Long Road to Acceptance of the Robbins Definition
Authors: BACKHOUSE ROGER E. , MEDEMA STEVE G.
Published: April 2009

Robbins' Essay gave economics a definition that came to dominate the professional literature. This definition laid a foundation that could be seen as justifying both the narrowing of economic theory to the theory of constrained maximization or rational choice and economists' ventures into other social science fields. Though often presented as self‐evidently correct, both the definition itself and the developments that it has been used to support were keenly contested. This paper traces the reception, diffusion and contesting of the Robbins definition, arguing that this process took around three decades and that even then there was still significant dissent.
Effective Tension in Robbins' Economic Methodology
Authors: HANDS D. WADE
Published: April 2009

Lionel Robbins'Essayis one of the most influential methodological works in twentieth century economics. This said, theEssayis not philosophically seamless; it exhibits certain tensions that are not easily reconciled within any specific philosophical characterization of scientific knowledge. This paper discusses these issues, but also emphasizes that these tensions did not inhibit the influence of theEssaywithin economics. In fact, it is argued that these philosophical tensions actually contributed to its influence. It was a methodology for economics, not for philosophers, and its influence needs to be understood within the context of 1930s marginalist economics.
Nurses' Pay Formation in Swedish Health Call Centres
Authors: Bäck Monica Andersson
Published: April 2009

This article analyses the pay formation process for nurses in the new organizational form of health call centres (HCCs) in Sweden. It finds that HCC tele‐nurses have gained a better labour market position than both the average call centre employees in other sectors and some other nurses. This specialization of the nursing occupation may thus have importance for gendered pay formation in public healthcare. In evaluating pay formation, the article draws on case studies carried out by the author. It analyses the shift from centralized bargaining towards more decentralized and individualized pay formation and the importance of union organization, economic and professional factors that have contributed to relatively higher pay for these workers. The article concludes with a discussion of the implications of this process for the gender pay gap in the state sector and limitations to future gains.
Migraine and the Hypothalamus
Authors: Alstadhaug KB
Published: April 2009

Migraine is a complex brain disorder where several neuronal pathways and neurotransmitters are involved in the pathophysiology. To search for a specific anatomical or physiological defect in migraine may be futile, but the hypothalamus, with its widespread connections with other parts of the central nervous system and its paramount control of the hypophysis and the autonomic nervous system, is a suspected locus in quo. Several lines of evidence support involvement of this small brain structure in migraine. However, whether it plays a major or minor role is unclear. The most convincing support for a pivotal role so far is the activation of the hypothalamus shown by positron emission tomography (PET) scanning during spontaneous migraine attacks. A well-known theory is that the joint effect of several triggers may cause temporary hypothalamic dysfunction, resulting in a migraine attack. If PET scanning had consistently confirmed hypothalamic activation prior to migraine headache, this hypothesis would have been supported. However, such evidence has not been provided, and the role of the hypothalamus in migraine remains puzzling. This review summarizes and discusses some of the clues.
Changes in Functional Vasomotor Reactivity in Migraine With Aura
Authors: Wolf ME , Jäger T , Bäzner H , Hennerici M
Published: April 2009

Migraine with aura (MA) is associated with cerebral hyper- and hypoperfusion during and after the attacks. Several attempts to estimate individual perfusion changes and asymmetries in patients with MA using transcranial Doppler (TCD) have not been consistent. In 70 patients with MA and 40 controls with migraine without aura (MoA) or without any history of migraine, interictally recorded TCD sequences were prospectively analysed. Formal curve analysis of the visually evoked flow response (VEFR) was performed semiautomatically. As a main parameter for functional vasomotor reactivity (fVMR), the visually evoked flow rate (VEFR%) was calculated. The VEFR% showed a significantly higher mean difference of 14.7 ± 12% in MA patients vs. 5.8 ± 4.4% ( P < 0.001) in controls. The significant asymmetry of fVMR in MA patients is suggested to reflect interattack persisting vasomotor changes which are of pathophysiological interest and may be used as a monitoring tool under prophylactic medication.
Weight Change and Clinical Markers of Cardiovascular Disease Risk During Preventive Treatment of Migraine
Authors: Bigal ME , Lipton RB , Biondi DM , Xiang J , Hulihan J
Published: April 2009

Migraine, particularly migraine with aura, and increased body weight are independent risk factors for cardiovascular disease (CVD). The association of weight change and clinical markers of CVD risk was evaluated in subjects participating in a randomized double-blind, parallel-group study of migraine-preventive treatment comparing 100 mg/day of topiramate and amitriptyline. Individuals from both treatment groups were pooled and stratified into three groups. The ‘major weight gain’ group gained ≥ 5% of their baseline body weight at the conclusion of the study; the ‘major weight loss’ group lost ≥ 5% of their baseline body weight. The third group had < 5% of weight change. The influence of weight change in headache outcomes, as well as in markers of CVD (blood pressure, cholesterol, C-reactive protein), was assessed using analysis of covariance. Of 331 subjects, 52 (16%) experienced major weight gain and 56 (17%) experienced major weight loss. Weight change was not associated with differential efficacy for the treatment of headache. However, contrasted with those with major weight loss, those who gained weight experienced elevations in mean diastolic blood pressure (+2.5 vs. -1.2 mmHg), heart rate (+7.6 vs. -1.3 beats per minute), glycosylated haemoglobin (+0.09% vs. -0.04%), total cholesterol (+6.4 vs. -6.3 mg/dl), low-density lipoprotein cholesterol (+7.0 vs. -4.4 mg/ dl) and triglycerides (+15.3 vs. -10.4 mg/dl) and an increase in high-sensitivity C-reactive protein (+1.8 vs. -1.9 mg/l). Both groups experienced decreases in systolic blood pressure (-4.0 vs. -1.3 mmHg) and high-density lipoprotein cholesterol (-3.7 vs. -0.8 mg/dl). Increased weight during migraine treatment is not associated with poor headache treatment outcomes, but is associated with deterioration of CVD risk markers.
Genetic Association Study of Endothelin-1 and Its Receptors EDNRA and EDNRB in Migraine with Aura
Authors: Tikka-Kleemola P , Kaunisto MA , Hämäläinen E , Todt U , Göbel H , Kaprio J , Kubisch C , Färkkilä M , Palotie A , Wessman M , Kallela M
Published: April 2009

The effect of endothelin-1 and its receptors EDNRA and EDNRB in migraine with aura (MA) susceptibility is not established yet. We studied the association between the MA end-diagnosis and three migraine trait components and 32 single nucleotide polymorphisms (SNPs) capturing the variation of endothelin genes in 850 Finnish migraine patients and 890 non-migrainous individuals. The SNPs showing evidence of association were further studied in 648 German migraine patients and 651 non-migrainous individuals. No significant association was detected. However, the homozygous minor genotype (5% in cases) of the EDNRA SNP rs2048894 showed nominal association with MA both in the Finnish sample ( P = 0.015) and in the pooled sample [odds ratio (OR) 1.61, 95% confidence interval (CI) 1.12-2.32, P = 0.010] when adjusted for gender and sample origin. The trait age of onset < 20 years was also associated with rs2048894 (OR 1.69, 95% CI 1.13-2.54, P = 0.011) in the pooled sample. To confirm this finding studies on even larger samples are required.
Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice
Authors: Garcia‐Alloza Monica , Prada Claudia , Lattarulo Carli , Fine Sara , Borrelli Laura A. , Betensky Rebecca , Greenberg Steven M. , Frosch Matthew P. , Bacskai Brian J.
Published: April 2009

Cerebral amyloid angiopathy (CAA), characterized by extracellular β‐amyloid peptide (Aβ) deposits in vessel walls, is present in the majority of cases of Alzheimer’s disease and is a major cause of hemorrhagic stroke. Although the molecular pathways activated by vascular Aβ are poorly understood, extracellular matrix metalloproteinases (MMP) and Aβ‐induced oxidative stress appear to play important roles. We adapted fluorogenic assays for MMP activity and reactive oxygen species generation for use in vivo. Using multiphoton microcopy in APPswe/PS1dE9 and Tg‐2576 transgenic mice, we observed strong associations between MMP activation, oxidative stress, and CAA deposition in leptomeningeal vessels. Antioxidant treatment with α‐phenyl‐N‐tert‐butyl‐nitrone reduced oxidative stress associated with CAA (∼50% reduction) without affecting MMP activation. Conversely, a selection of agents that inhibit MMP by different mechanisms of action, including minocycline, simvastatin, and GM6001, reduced not only CAA‐associated MMP activation (∼30–40% reduction) but also oxidative stress (∼40% reduction). The inhibitors of MMP did not have direct antioxidant effects. Treatment of animals with α‐phenyl‐N‐tert‐butyl‐nitrone or minocycline did not have a significant effect on CAA progression rates. These data suggest a close association between Aβ‐related MMP activation and oxidative stress in vivo and raise the possibility that treatment with MMP inhibitors may have beneficial effects by indirectly reducing the oxidative stress associated with CAA.
Sod2 overexpression preserves myoblast mitochondrial mass and function, but not muscle mass with aging
Authors: Lee Sukkyoo , Van Remmen Holly , Csete Marie
Published: April 2009

Mice lacking superoxide dismutase‐2 (SOD2 or MnSOD) die during embryonic or early neonatal development, with diffuse superoxide‐induced mitochondrial damage. Although stem and progenitor cells are exquisitely sensitive to oxidant stress, they have not been well studied in MnSOD2‐manipulated mouse models. Patterns of proliferation and differentiation of cultured myoblasts (muscle progenitor cells), PI3‐Akt signaling during differentiation, and the maintenance of mitochondrial mass with aging using myoblasts from young (3–4 week old) and aged (27–29 months old) MnSOD2‐overexpressing (Sod2‐Tg) and heterozygote (Sod2+/−) mice were characterized by us. Overexpression of MnSOD2 in myoblasts had a protective effect on mitochondrial DNA abundance and some aspects of mitochondrial function with aging, and preservation of differentiation potential. Sod2 deficiency resulted in defective signaling in the PI3‐Akt pathway, specifically impaired phosphorylation of Akt at Ser473 and Thr308 in young myoblasts, and decreased differentiation potential. Compared with young myoblasts, aged myoblast Akt was constitutively phosphorylated, unresponsive to mitogen signaling, and indifferent to MnSOD2 levels. These data suggest that specific sites in the PI3K‐Akt pathway are more sensitive to increased superoxide levels than to the increased hydrogen peroxide levels generated in Sod2‐transgenic myoblasts. In wild‐type myoblasts, aging was associated with significant loss of mitochondrial DNA relative to chromosomal DNA, but MnSOD2 overexpression was associated with maintained myoblast mitochondrial DNA with aging.
Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels
Authors: Yuan Rong , Tsaih Shirng‐Wern , Petkova Stefka B. , De Evsikova Caralina Marin , Xing Shuqin , Marion Michael A. , Bogue Molly A. , Mills Kevin D. , Peters Luanne L. , Bult Carol J. , Rosen Clifford J. , Sundberg John P. , Harrison David E. , Churchill Gary A. , Paigen Beverly
Published: April 2009

To better characterize aging in mice, the Jackson Aging Center carried out a lifespan study of 31 genetically‐diverse inbred mouse strains housed in a specific pathogen‐free facility. Clinical assessments were carried out every 6 months, measuring multiple age‐related phenotypes including neuromuscular, kidney and heart function, body composition, bone density, hematology, hormonal levels, and immune system parameters. In a concurrent cross‐sectional study of the same 31 strains at 6, 12, and 20 months, more invasive measurements were carried out followed by necropsy to assess apoptosis, DNA repair, chromosome fragility, and histopathology. In this report, which is the initial paper of a series, the study design, median lifespans, and circulating insulin‐like growth factor 1 (IGF1) levels at 6, 12, and 18 months are described for the first cohort of 32 females and 32 males of each strain. Survival curves varied dramatically among strains with the median lifespans ranging from 251 to 964 days. Plasma IGF1 levels, which also varied considerably at each time point, showed an inverse correlation with a median lifespan at 6 months (R = −0.33, P = 0.01). This correlation became stronger if the short‐lived strains with a median lifespan < 600 days were removed from the analysis (R = −0.53, P < 0.01). These results support the hypothesis that the IGF1 pathway plays a key role in regulating longevity in mice and indicates that common genetic mechanisms may exist for regulating IGF1 levels and lifespan.
Lifespan extension by dietary restriction is not linked to protection against somatic DNA damage in Drosophila melanogaster
Authors: Edman Ursula , Garcia Ana Maria , Busuttil Rita A. , Sorensen Dylan , Lundell Martha , Kapahi Pankaj , Vijg Jan
Published: April 2009

Dietary restriction (DR) has been shown to robustly extend lifespan in multiple species tested so far. The pro‐longevity effect of DR is often ascribed to an increase in cellular defense against somatic damage, most notably damage by reactive oxygen species (ROS), considered a major cause of aging. Especially irreversible damage to DNA, the carrier of genetic information, is considered a critical causal factor in aging. Using a recently developed transgenic Drosophila melanogaster model system harboring a lacZ‐plasmid construct that can be recovered in E. coli, spontaneous DNA mutation frequency in flies under DR and ad libitum conditions are measured. Three different DR conditions, imposed by manipulating levels of different types of yeast sources, were tested in females and males of two lacZ reporter gene lines. Feeding with the ROS producer paraquat at 1 mM resulted in a rapid accumulation of somatic mutations, indicating that the frequency of mutations at the lacZ locus is a reliable marker for increased oxidative stress. However, none of the DR conditions altered the accumulation of spontaneous mutations with age. These results suggest that the beneficial effects of DR are unlikely to be linked to protection against oxidative somatic DNA damage.
East‐Central Europe's changing energy landscapes: a place for geography
Authors: Bouzarovski Stefan
Published: April 2009

Energy developments in the post‐Communist states of Eastern and Central Europe (ECE) have a major impact on global energy security and sustainability, thanks to this region's key geographical position between the energy‐exporting states of the former Soviet Union, on the one hand, and the energy‐importing states of Western and Southern Europe, on the other. At the same time, post‐socialist reforms of energy industries in this region provide unique insights into the complex relations of power, economic transformation and spatial inequality that govern energy production and consumption. This paper therefore aims to provide an initial look at some of the theoretical and policy issues that underpin the emergent ‘geographies’ of energy reform in ECE, as well as their embeddedness in relations of power stemming from organisational, infrastructural and economic inequalities in the region. It employs an analysis of local news reports, policy papers and statistical data to examine the intricate institutional networks and spatial formations that have governed the energy transformation process. In broader terms, the paper aims to emphasise the important role that human geography can play in making sense of the territorial differences and frictions that have emerged during the post‐socialist reform process, while challenging the idea of a ‘neat’ neoliberal transition from a centrally planned to a market‐based mode of energy regulation.
On the Structure of Analyst Research Portfolios and Forecast Accuracy
Authors: KINI OMESH , MIAN SHEHZAD , REBELLO MICHAEL , VENKATESWARAN ANAND
Published: April 2009

This study provides insights into the forces and constraints that shape analyst research coverage along country and sector dimensions and the impact of the structure of an analyst's portfolio on forecast accuracy. We find that analyst specialization by country and sector is sensitive to the extent to which firms within a country or sector and firms across country‐sectors are exposed to common economic forces, the potential for revenue generation, and broker culture. Our tests indicate that existing research on the relation between analyst portfolio structure and forecast accuracy may suffer from an endogeneity bias. We use our analysis of analyst specialization to develop controls for this bias. Once we employ these controls, we find that country diversification is associated with superior forecast accuracy. However, the relation between sector diversification and forecast accuracy is context‐specific. Specifically, sector diversification enhances forecast accuracy in an international context, while it detracts from forecast accuracy in a domestic U.S. context.
Delegation to Encourage Communication of Problems
Authors: NEWMAN D. PAUL , NOVOSELOV KIRILL E.
Published: April 2009

We study a principal's choice to centralize or delegate decisions to an agent when delegation can be used to encourage the agent to communicate potential problems. We find that the principal may choose centralization either to exercise better control over the agent's actions or to provide stronger incentives. Delegation emerges in equilibrium only if the costs of effort to acquire information for both the principal and the agent are sufficiently high. We find that increases in the principal's penalties for an incorrect decision may increase the principal's expected payoff, owing to optimal organizational responses. In addition, catastrophic risk, the risk of incorrectly accepting a defective audit (or product), may be greater under centralization than under delegation. Furthermore, catastrophic risk can be increased by well‐intentioned legislative efforts to decrease such risk by, for example, increasing the agent's penalties for failing to take a corrective action, because the organizational structure may change.
Transcriptional regulation of monocyte chemotactic protein‐1 release by endothelin‐1 in human airway smooth muscle cells involves NF‐κB and AP‐1
Authors: Sutcliffe Amy M , Clarke Deborah L , Bradbury Dawn A , Corbett Lisa M , Patel Jamie A , Knox Alan J
Published: April 2009

Background and purpose: Endothelin‐1 (ET‐1) is implicated in airway inflammation in asthma, but the mechanisms of its effects are poorly understood. We studied the effect of ET‐1 on expression of the chemokine, monocyte chemotactic protein‐1 (MCP‐1), in primary cultures of human airway smooth muscle cells.

Experimental approach: MCP‐1 release was measured byelisa. Pharmacological antagonists/inhibitors, reverse transcriptase‐polymerase chain reaction (RT‐PCR) and Western blotting were used to study ET receptors and kinase cascades. Transcriptional regulation was studied by real‐time RT‐PCR, transient transfection studies and chromatin immunoprecipitation assay. Major findings were confirmed in cells from three donors and mechanistic studies in cells from one donor.

Key results: ET‐1 increased MCP‐1 release through an ETAand ETBreceptor‐dependent mechanism. ET‐1 increased MCP‐1 mRNA levels but not mRNA stability suggesting it was acting transcriptionally. ET‐1 increased the activity of an MCP‐1 promoter–reporter construct. Serial deletions of the MCP‐1 promoter mapped ET‐1 effects to a region between −213 and −128 base pairs upstream of the translation start codon, containing consensus sequences for activator protein‐1 (AP‐1) and nuclear factor‐κB (NF‐κB). ET‐1 promoted binding of AP‐1 c‐Jun subunit and NF‐κB p65 subunit to the MCP‐1 promoter. Blocking the inhibitor of κB kinase‐2 with 2‐[(aminocarbonyl)amino]‐5‐[4‐fluorophenyl]‐3‐thiophenecarboxamide (TPCA‐1) decreased ET‐1‐stimulated MCP‐1 production. p38 and p44/p42 mitogen‐activated protein kinases were involved in upstream signalling.

Conclusions and implications: ET‐1 regulated MCP‐1 transcriptionally, via NF‐κB and AP‐1. The upstream signalling involved ETA, ETBreceptors, p38 and p44/p42 mitogen‐activated protein kinases. These may be targets for novel asthma therapies.
Increased endothelin‐1 reactivity and endothelial dysfunction in carotid arteries from rats with hyperhomocysteinemia
Authors: De Andrade CR , Leite PF , Montezano AC , Casolari DA , Yogi A , Tostes RC , Haddad R , Eberlin MN , Laurindo FRM , De Souza HP , Corrêa FMA , De Oliveira AM
Published: April 2009

Background and purpose:  There are interactions between endothelin‐1 (ET‐1) and endothelial vascular injury in hyperhomocysteinemia (HHcy), but the underlying mechanisms are poorly understood. Here we evaluated the effects of HHcy on the endothelin system in rat carotid arteries.

Experimental approach:  Vascular reactivity to ET‐1 and ETA and ETB receptor antagonists was assessed in rings of carotid arteries from normal rats and those with HHcy. ETA and ETB receptor expression was assessed by mRNA (RT‐PCR), immunohistochemistry and binding of [125I]‐ET‐1.

Key results:  HHcy enhanced ET‐1‐induced contractions of carotid rings with intact endothelium. Selective antagonism of ETA or ETB receptors produced concentration‐dependent rightward displacements of ET‐1 concentration response curves. Antagonism of ETA but not of ETB receptors abolished enhancement in HHcy tissues. ETA and ETB receptor gene expressions were not up‐regulated. ETA receptor expression in the arterial media was higher in HHcy arteries. Contractions to big ET‐1 served as indicators of endothelin‐converting enzyme activity, which was decreased by HHcy, without reduction of ET‐1 levels. ET‐1‐induced Rho‐kinase activity, calcium release and influx were increased by HHcy. Pre‐treatment with indomethacin reversed enhanced responses to ET‐1 in HHcy tissues, which were reduced also by a thromboxane A2 receptor antagonist. Induced relaxation was reduced by BQ788, absent in endothelium‐denuded arteries and was decreased in HHcy due to reduced bioavailability of NO.

Conclusions and implications:  Increased ETA receptor density plays a fundamental role in endothelial injury induced by HHcy. ET‐1 activation of ETA receptors in HHcy changed the balance between endothelium‐derived relaxing and contracting factors, favouring enhanced contractility.

British Journal of Pharmacology (2009) 157, 568–580; doi:10.1111/j.1476‐5381.2009.00165.x; published online 9 April 2009

This article is part of a themed section on Endothelium in Pharmacology. For a list of all articles in this section see the end of this paper, or visit: http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009
Opportunities for the replacement of animals in the study of nausea and vomiting
Authors: Holmes AM , Rudd JA , Tattersall FD , Aziz Q , Andrews PLR
Published: April 2009

Nausea and vomiting are among the most common symptoms encountered in medicine as either symptoms of disease or side effects of treatments. Developing novel anti‐emetics and identifying emetic liability in novel chemical entities rely on models that can recreate the complexity of these multi‐system reflexes. Animal models (especially the ferret and dog) are the current gold standard; however, the selection of appropriate models is still a matter of debate, especially when studying the subjective human sensation of nausea. Furthermore, these studies are associated with animal suffering. Here, following a recent workshop held to review the utility of animal models in nausea and vomiting research, we discuss the limitations of some of the current models in the context of basic research, anti‐emetic development and emetic liability detection. We provide suggestions for how these limitations may be overcome using non‐animal alternatives, including greater use of human volunteers,in silicoandin vitrotechniques and lower organisms.
The long‐acting β‐adrenoceptor agonist, indacaterol, inhibits IgE‐dependent responses of human lung mast cells
Authors: Scola Anne‐Marie , Loxham Matthew , Charlton Steven J , Peachell Peter T
Published: April 2009

Background and purpose: The long‐acting β2‐adrenoceptor agonist, indacaterol, has been developed as a bronchodilator for the therapeutic management of respiratory diseases. The aim of the present study was to determine whether indacaterol has any anti‐inflammatory activity. To this end, the effects of indacaterol on human lung mast cell responses were investigated.

Experimental approach: The effects of indacaterol, and the alternative long‐acting β‐agonists formoterol and salmeterol, were investigated on the IgE‐dependent release and generation of histamine, cysteinyl‐leukotrienes and prostaglandin D2from human lung mast cells. Moreover, the extent to which long‐term (24–72 h) incubation of mast cells with long‐acting β‐agonists impaired the subsequent ability of β‐agonists to inhibit mast cell responses was assessed.

Key results: Indacaterol was as potent and as efficacious as the full agonist, isoprenaline (EC50, ∼4 nmol·L−1), at inhibiting the IgE‐dependent release of histamine from mast cells. Formoterol was a full agonist whereas salmeterol was a partial agonist as inhibitors of histamine release. All three long‐acting β‐agonists were effective inhibitors of the IgE‐dependent generation of cysteinyl‐leukotrienes and prostaglandin D2. Long‐term incubation of mast cells with long‐acting β‐agonists led to a reduction in the subsequent ability of β‐agonists to stabilize mast cell responses. This tendency to induce functional desensitization was least evident for indacaterol.

Conclusions and implications: Indacaterol is an effective inhibitor of the release of mediators from human lung mast cells. This suggests that, as well as bronchodilation, mast cell stabilization may constitute an additional therapeutic benefit of indacaterol.
Therapeutically targeting protein–glycan interactions
Authors: Rek A , Krenn E , Kungl AJ
Published: April 2009

Glycosylation is the most common form of post‐translational modifications by which oligosaccharide side chains are covalently attached to specific residues of the core protein. Especially O‐linked glycan structures like the glycosaminoglycans were found to contribute significantly to many (patho‐)biological processes like inflammation, coagulation, cancer and viral infections. Glycans exert their function by interacting with proteins thereby changing the structure of the interacting proteins and consequently modulating their function. Given the complex nature of cell‐surface and extracellular matrix glycan structures, this therapeutic site has been neglected for a long time, the only exception being the antithrombin III‐glycan interaction which has been sucessfully targeted by unfractionated and low‐molecular weight heparins for many decades. Due to the recent breakthrough in the ‘–ome’ sciences, among them proteomics and glycomics, protein–glycan interactions became more amenable for therapeutic approaches so that novel inhibitors of this interaction are currently in preclinical and clinical studies. An overview of current approaches, their advantages and disadvantages, is given and the promising potential of pharmacologically interfering with protein–glycan interactions is highlighted here.
Drug targets for traumatic brain injury from poly(ADP‐ribose)polymerase pathway modulation
Authors: Besson Valerie C
Published: April 2009

The deleterious pathophysiological cascade induced after traumatic brain injury (TBI) is initiated by an excitotoxic process triggered by excessive glutamate release. Activation of the glutamatergic N‐methyl‐D‐aspartate receptor, by increasing calcium influx, activates nitric oxide (NO) synthases leading to a toxic production of NO. Moreover, after TBI, free radicals are highly produced and participate to a deleterious oxidative stress. Evidence has showed that the major toxic effect of NO comes from its combination with superoxide anion leading to peroxynitrite formation, a highly reactive and oxidant compound. Indeed, peroxynitrite mediates nitrosative stress and is a potent inducer of cell death through its reaction with lipids, proteins and DNA. Particularly DNA damage, caused by both oxidative and nitrosative stresses, results in activation of poly(ADP‐ribose) polymerase (PARP), a nuclear enzyme implicated in DNA repair. In response to excessive DNA damage, massive PARP activation leads to energetic depletion and finally to cell death. Since 10 years, accumulating data have showed that inactivation of PARP, either pharmacologically or using PARP null mice, induces neuroprotection in experimental models of TBI. Thus TBI generating NO, oxidative and nitrosative stresses promotes PARP activation contributing in post‐traumatic motor, cognitive and histological sequelae. The mechanisms by which PARP inhibitors provide protection might not entirely be related to the preservation of cellular energy stores, but might also include other PARP‐mediated mechanisms that needed to be explored in a TBI context. Ten years of experimental research provided rational basis for the development of PARP inhibitors as treatment for TBI.
The Silver Curtain: Representations of the West in the Soviet Cold War Films
Authors: Dobrynin Sergei
Published: April 2009

The image of the West in Soviet cinema is a subject suffused with ambivalence. On the one hand, most of the Soviet films with an international setting and/or foreign characters clearly had an ideological agenda. By claiming a high moral ground for the Soviet or a ‘progressive’ Western protagonist, they served as a weapon in the ongoing cultural Cold War. On the other, the subject matter presented an opportunity to attract the audiences (a major concern for the late‐Soviet film industry) with lurid depictions of Western ‘decadence’ and ‘decay’, as well as a chance to exploit the attractiveness of Western popular genres. This seemingly uneasy combination was typical of the Soviet film industry for most of its history but became especially pronounced in its later stages, during the Détente and after, as the fast‐changing political demands had to be reconciled with the growing commercialization of Soviet cinema. The resulting body of work has rarely had artistic value but remains a useful and largely untapped source for cultural historians looking for reflections of social change in the former USSR.
Understanding Medieval Manuscripts: St. Gall's Virtual Library
Authors: Grotans Anna , Hendrix Julian , Kaczynski Bernice
Published: April 2009

In 2005, the Stiftsbibliothek St. Gallen began digitizing its collection of medieval manuscripts. The creation of such virtual libraries available via the Internet is gaining in popularity with libraries, a trend that will radically ease the logistical constraints of studying medieval texts in their original context. While critical editions will continue to be an important tool for certain types of research, virtual libraries enable a wider community of scholars to engage with texts that are not amenable to critical editions or to ask questions that critical editions obscure. This article reviews the range of research that has centered around the study of manuscripts held at St. Gall, including school books, liturgical books, and patristic authors, and outlines the kinds of questions and insights that manuscript studies can provide for medieval history.
Writing the History of the Modern Copts: From Victims and Symbols to Actors
Authors: Sedra Paul
Published: April 2009

Scholars of Egyptian history and politics face a dearth of analytical studies of the modern Coptic Church and community. This state of affairs is due to various factors of a methodological, theoretical, and practical nature. In practical terms, both the Egyptian state and the Coptic Orthodox Church have discouraged exploration of Coptic identity given the political taboo of sectarianism. In theoretical terms, Edward Said's Orientalism led to concerns among scholars about overemphasizing faith in their analyses of Middle Eastern history and politics. In methodological terms, modern Coptic historiography remains hobbled by an ‘enlightenment paradigm’ which discounts the political potential and action of subaltern and clerical forces within the community. This article urges a concern with the ways in which these subaltern and clerical forces shaped the Coptic ‘discursive tradition’ in the course of the twentieth century, as a means by which to restore Copts to modern Egyptian historiography, not as victims or symbols, but as actors in their own right.
Australian Aboriginal Activism in Interwar Britain and Europe: Anthony Martin Fernando
Authors: Paisley Fiona
Published: April 2009

This article reflects on the limits of the archives in the recovery of indigenous lives. An Australian Aboriginal activist and traveller in interwar Britain and Europe, Anthony Martin Fernando was an outspoken protestor of Aboriginal conditions while in Australia but mostly from overseas. He demonstrated outside Australia House in the 1920s, planned to approach the League of Nations, and was an advocate of a form of direct international mandate over land reserved for Aboriginal occupation in Australia. Much is still unknown about his life, but new information shows that he was also, among other things, a labourer in Trieste, Vienna, and Rome, a manservant in London, a civilian internee in Austria during the First World War, an interviewee of the Swiss progressive press in the interwar years, and a speaker at Hyde Park Corner. Information about his life story has been gained through wide‐ranging archival research, and, perhaps most remarkably, recent contact with two families that employed him in England. More than a life shaped by tragedy, yet it was the tragic nature of colonisation and its genocidal effects that drove his life's work.
Childhood Pityriasis Rosea
Authors: GÜNDÜZ ÖZGE , ERSOY‐EVANS SIBEL , KARADUMAN AYŞEN
Published: April 2009

Abstract:  Pityriasis rosea (PR) is an acute, self‐limiting papulosquamous disorder of unknown etiology. Published studies of childhood PR are scarce and most are reviews. The aim of this study was to determine the demographic and clinical features of childhood PR.
Onychomadesis: A Rare Side‐Effect of Valproic Acid Medication?
Authors: PORETTI ANDREA , LIPS ULRICH , BELVEDERE MARCO , SCHMITT BERNHARD
Published: April 2009

Abstract:  Valproic acid (VPA) is frequently used as an antiepileptic drug. Several side effects are known. We report on a child with onychomadesis as a possible side‐effect of treatment with VPA. Normal nail growth was observed after stopping VPA. The pathomechanism of onychomadesis due to VPA treatment remains unclear.
Retrospective Analysis of 32 Pediatric Patients with Anticonvulsant Hypersensitivity Syndrome (ACHSS)
Authors: Newell Brandon D. , Moinfar Maryam , Mancini Anthony J. , Nopper Amy Jo
Published: April 2009

Abstract: Objectıve: To review 32 pediatric patients with anticonvulsant hypersensitivity syndrome.

Design: Retrospectively, data and photographs were collected on 32 patients who had been diagnosed with anticonvulsant hypersensitivity syndrome.

Setting: The sections of dermatology at Children’s Memorial Hospital in Chicago, Illinois, and Children’s Mercy Hospitals and Clinics in Kansas City, Missouri.

Main Outcome Measures: Presentation, implicated medications, laboratory evaluations, complications, treatment and outcome.

Results: The mean age of all patients with anticonvulsant hypersensitivity syndrome (ACHSS) was 8.9 years. The mean duration of anticonvulsant therapy before onset of symptoms was 3 weeks. Phenytoin, carbamazepine, and phenobarbital were the most commonly implicated medications. Lamotrigine, oxcarbamazepine, and primidone were implicated in some of our patients. Fever and rash were seen in all patients, while lymphadenopathy was found in 84.4% of patients. Hematologic abnormalities were seen in 93.8% and hepatic involvement was seen in 90.4% of cases, representing the two most commonly involved systems. Atypical lymphocytosis and eosinophilia was seen in 72% and 56% of patients, respectively. Renal and pulmonary involvement were each seen in 15.6% of cases. Systemic steroids were used in 59.4% of ACHSS patients; 16% of patients received intravenous immunoglobulin. No deaths were reported in our group of pediatric patients.

Conclusions: The ACHSS is a distinct clinical entity which may occur in pediatric patients treated with anticonvulsants, and may have potentially life‐threatening consequences. Involvement of multiple organ systems, including the hematologic, hepatic, renal, and pulmonary systems was common. Treatment varied widely, but ranged from supportive care to systemic corticosteroids.
The Glycine Reuptake Inhibitor Org 25935 Interacts With Basal and Ethanol‐Induced Dopamine Release in Rat Nucleus Accumbens
Authors: Lidö Helga Höifödt , Stomberg Rosita , Fagerberg Anne , Ericson Mia , Söderpalm Bo
Published: April 2009

Background:  The mesolimbic dopamine (DA) projection from the ventral tegmental area to nucleus accumbens (nAc), a central part of the reward system, is activated by ethanol (EtOH) and other drugs of abuse. We have previously demonstrated that the glycine receptor in the nAc and its amino acid agonists may be implicated in the DA activation and reinforcing properties of EtOH. We have also reported that the glycine transporter 1 inhibitor, Org 25935, produces a robust and dose‐dependent decrease in EtOH consumption in Wistar rats. The present study explores the interaction between EtOH and Org 25935 with respect to DA levels in the rat nAc.

Methods:  The effects of Org 25935 (6 mg/kg, i.p.) and/or EtOH (2.5 g/kg, i.p.) on accumbal DA levels were examined by means of in vivo microdialysis (coupled to HPLC‐ED) in freely moving male Wistar rats. The effect of Org 25935 on accumbal glycine output was also investigated.

Results:  Systemic Org 25935 increased DA output in a subpopulation of rats (52% in Experiment 1 and 38% in Experiment 2). In Experiment 2, EtOH produced a significant increase in DA levels in vehicles (35%) and in Org 25935 nonresponders (19%), whereas EtOH did not further increase the DA level in rats responding to Org 25935 (2%). The same dose of Org 25935 increased glycine levels by 87% in nAc.

Conclusions:  This study demonstrates that Org 25935, probably via increased glycine levels, (i) counteracts EtOH‐induced increases of accumbal DA levels and (ii) increases basal DA levels in a subpopulation of rats. The results are in line with previous findings and it is suggested that the effects observed involve interference with accumbal GlyRs and are related to the alcohol consumption modulating effect of Org 25935.
MitochondrialS‐Adenosyl‐l‐Methionine Transport is Insensitive to Alcohol‐Mediated Changes in Membrane Dynamics
Authors: Fernández Anna , Colell Anna , Caballero Francisco , Matías Nuria , García‐Ruiz Carmen , Fernández‐Checa José C.
Published: April 2009

Background: Alcohol‐induced liver injury is associated with decreasedS‐adenosyl‐l‐methionine (SAM)/S‐adenosyl‐l‐homocysteine (SAH) ratio and mitochondrial glutathione (mGSH) depletion, which has been shown to sensitize hepatocytes to tumor necrosis factor (TNF).

Aims: As the effect of alcohol on mitochondrial SAM (mSAM) has been poorly characterized, our aim was to examine the status and transport of mSAM in relation to that of mGSH during alcohol intake.

Methods: Sprague–Dawley rats were pair fed Lieber–DeCarli diets containing alcohol for 1 to 4 weeks and liver fractionated into cytosol and mitochondria to examine the mSAM transport and its sensitivity to membrane dynamics.

Results: We found that cytosol SAM was depleted from the first week of alcohol feeding, with mSAM levels paralleling these changes. Cytosol SAH, however, increased during the first 3 weeks of alcohol intake, whereas its mitochondrial levels remained unchanged. mGSH depletion occurred by 3 to 4 weeks of alcohol intake due to cholesterol‐mediated impaired transport from the cytosol. In contrast to this outcome, the transport of SAM into hepatic mitochondria was unaffected by alcohol intake and resistant to cholesterol‐mediated perturbations in membrane dynamics; furthermore cytosolic SAH accumulation in primary hepatocytes by SAH hydrolase inhibition reproduced the mSAM depletion by alcohol due to the competition of SAH with SAM for mitochondrial transport. However, alcohol feeding did not potentiate the sensitivity to inhibition by SAH accumulation.

Conclusions: Alcohol‐induced mSAM depletion precedes that of mGSH and occurs independently of alcohol‐mediated perturbations in membrane dynamics, disproving an inherent defect in the mSAM transport by alcohol. These findings suggest that the early mSAM depletion may contribute to the alterations of mitochondrial membrane dynamics and the subsequent mGSH down‐regulation induced by alcohol feeding.
Protective Effect of Vitamin E Against Ethanol‐Induced Hyperhomocysteinemia, DNA Damage, and Atrophy in the Developing Male Rat Brain
Authors: Shirpoor Alireza , Salami Siamak , Khadem‐Ansari Mohammad Hassan , Minassian Syranush , Yegiazarian Marine
Published: April 2009

Background: Chronic alcoholism leads to elevated plasma and brain homocysteine (Hcy) levels, as demonstrated by clinical investigations and animal experiments. It has been posited that elevated levels of Hcy mediate DNA damage, brain atrophy, and excitotoxicity. The current study sought to elucidate the effect of vitamin E on ethanol‐induced hyperhomocysteinemia, DNA damage, and atrophy in the developing hippocampus and cerebellum of rats.

Methods: Pregnant Wistar rats received ethanol with or without vitamin E from gestation day 7 throughout lactation. Weight changes in the brain, hippocampus and cerebellum, DNA damage, and Hcy levels in the plasma, hippocampus, and cerebellum of male offspring were measured at the end of lactation.

Results: The results revealed that along with a significant decrease in brain, cerebellum, and hippocampus weights in animals that received alcohol, the levels of DNA damage and Hcy significantly increased. Significant amelioration of brain atrophy and DNA damage as well as restoration of the elevated level of Hcy to that of controls were found in vitamin E‐treated rats.

Conclusions: These findings strongly support the idea that ethanol intake by dams during pregnancy and lactation induces Hcy‐mediated oxidative stress in the developing hippocampus and cerebellum of offspring rats, and that these effects can be alleviated by vitamin E as an antioxidant.
N‐Acetylcysteine Improves Group B Streptococcus Clearance in a Rat Model of Chronic Ethanol Ingestion
Authors: Tang Sonja M. , Gabelaia Levan , Gauthier Theresa W. , Brown Lou Ann S.
Published: April 2009

Background:  Sepsis is the most common risk factor associated with acute respiratory distress syndrome (ARDS) and results in a 40–60% mortality rate due to respiratory failure. Furthermore, recent epidemiological studies have demonstrated that a history of alcohol abuse increases the risk of ARDS by 3.6‐fold. More recently, group B streptococcus (GBS) infections in nonpregnant adults have been increasing, particularly in alcoholics where there is an increased risk of lobular invasion and mortality. We have shown in an established rat model that chronic ethanol ingestion impaired macrophage internalization of inactivated infectious particles in vitro and enhanced bidirectional protein flux across the alveolar epithelial‐endothelial barriers, both of which were attenuated when glutathione precursors were added to the diet. We hypothesized that chronic ethanol ingestion would increase the risk of infection even though GBS is less pathogenic but that dietary N‐acetylcysteine (NAC), a glutathione precursor, would improve in vivo clearance of infectious particles and reduce systemic infection.

Methods:  After 6 weeks of ethanol feeding, rats were given GBS intratracheally and sacrificed 24 hours later. GBS colony‐forming units were counted in the lung, liver, spleen, and bronchoalveolar lavage fluid. Acute lung injury in response to GBS was also assessed.

Results:  Chronic ethanol exposure decreased GBS clearance from the lung indicating an active lung infection. In addition, increased colonies formed within the liver and spleen indicated that ethanol increased the risk of systemic infection. Ethanol also exacerbated the acute lung injury induced by GBS. NAC supplementation normalized GBS clearance by the lung, prevented the appearance of GBS systemically, and attenuated acute lung injury.

Conclusions:  These data suggested that chronic alcohol ingestion increased the susceptibility of the lung to bacterial infections from GBS as well as systemic infections. Furthermore, dietary NAC improved in vivo clearance of GBS particles, attenuated acute lung injury, and disseminated infection.