Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1.

Prostaglandins (PG) are known to induce pain perception indirectly by sensitizing nociceptors. Accordingly, the analgesic action of nonsteroidal anti-inflammatory drugs (NSAIDs) results from inhibition of cyclooxygenases and blockade of PG biosynthesis. Cyclopentenone PGs, 15-d-PGJ(2), PGA(2), and PGA(1), formed by dehydration of their respective parent PGs, PGD(2), PGE(2), and PGE(1), possess a highly reactive alpha,beta-unsaturated carbonyl group that has been proposed to gate the irritant transient receptor potential A1 (TRPA1) channel. Here, by using TRPA1 wild-type (TRPA1(+/+)) or deficient (TRPA1(-/-)) mice, we show that cyclopentenone PGs produce pain by direct stimulation of nociceptors via TRPA1 activation. Cyclopentenone PGs caused a robust calcium response in dorsal root ganglion (DRG) neurons of TRPA1(+/+), but not of TRPA1(-/-) mice, and a calcium-dependent release of sensory neuropeptides from the rat dorsal spinal cord. Intraplantar injection of cyclopentenone PGs stimulated c-fos expression in spinal neurons of the dorsal horn and evoked an instantaneous, robust, and transient nociceptive response in TRPA1(+/+) but not in TRPA1(-/-) mice. The classical proalgesic PG, PGE(2), caused a slight calcium response in DRG neurons, increased c-fos expression in spinal neurons, and induced a delayed and sustained nociceptive response in both TRPA1(+/+) and TRPA1(-/-) mice. These results expand the mechanism of NSAID analgesia from blockade of indirect nociceptor sensitization by classical PGs to inhibition of direct TRPA1-dependent nociceptor activation by cyclopentenone PGs. Thus, TRPA1 antagonism may contribute to suppress pain evoked by PG metabolites without the adverse effects of inhibiting cyclooxygenases.

Foreign credit: travel writing and authenticity in the dutch translation of The memoirs and travels of Mauritius Augustus, Count de Benyowsky (1790)

This article explores the translation and reception of the Memoirs and Travels (1790) of Count Mauritius Augustus Benyowsky (1746-86) in the Netherlands, and examines the complications, tensions and problems that transfer between a major and a more minor European language involves. I analyse how the Dutch translator Petrus Loosjes Adriaanszoon positioned himself as a mediator between these very different source and target cultures and ask how he dealt with the problems of plausibility and ‘credit’ which had beleaguered the reception of the Memoirs and Travels from the outset. In this article I am concerned to restore minority languages to the discussion of how travel literature circulated in Western Europe at the close of the eighteenth century and to demonstrate how major/minor language translation was central to the construction of Dutch-language culture in the Low Countries in this period.

The Cold War in retrospect : 25 years after its end

This special issue of Cold War History offers a retrospective on the end of the Cold War, 25 years after its peaceful conclusion. This peaceful conclusion is an achievement that cannot be celebrated enough, and we must continue to build international relations in conflict and co-operation on this awareness of our common humanity and our common human fallibility.

Low-level Laser Therapy Improves Skeletal Muscle Performance, Decreases Skeletal Muscle Damage and Modulates mRNA Expression of COX-1 and COX-2 in a Dose-dependent Manner

We tested if modulation in mRNA expression of cyclooxygenase isoforms (COX-1 and COX-2) can be related to protective effects of phototherapy in skeletal muscle. Thirty male Wistar rats were divided into five groups receiving either one of four laser doses (0.1, 0.3, 1.0 and 3.0 J) or a no-treatment control group. Laser irradiation (904 nm, 15 mW average power) was performed immediately before the first contraction for treated groups. Electrical stimulation was used to induce six tetanic tibial anterior muscle contractions. Immediately after sixth contraction, blood samples were collected to evaluate creatine kinase activity and muscles were dissected and frozen in liquid nitrogen to evaluate mRNA expression of COX-1 and COX-2. The 1.0 and 3.0 J groups showed significant enhancement (P < 0.01) in total work performed in six tetanic contractions compared with control group. All laser groups, except the 3.0 J group, presented significantly lower post-exercise CK activity than control group. Additionally, 1.0 J group showed increased COX-1 and decreased COX-2 mRNA expression compared with control group and 0.1, 0.3 and 3.0 J laser groups (P < 0.01). We conclude that pre-exercise infrared laser irradiation with dose of 1.0 J enhances skeletal muscle performance and decreases post-exercise skeletal muscle damage and inflammation.

Celecoxib prevents tumor growth in an animal model by a COX-2 independent mechanism

Nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to reduce cell growth in several tumors. Among these possible antineoplastic drugs are cyclooxygenase-2 (COX-2)-selective drugs, such as celecoxib, in which antitumoral mechanisms were evaluated in rats bearing Walker-256 (W256) tumor. W256 carcinosarcoma cells were inoculated subcutaneously (10(7) cells/rat) in rats submitted to treatment with celecoxib (25 mg kg(-1)) or vehicle for 14 days. Tumor growth, body-weight gain, and survival data were evaluated. The mechanisms, such as COX-2 expression and activity, oxidative stress, by means of enzymes and lipoperoxidation levels, and apoptosis mediators were also investigated. A reduction in tumor growth and an increased weight gain were observed. Celecoxib provided a higher incidence of survival compared with the control group. Cellular effects are probably COX-2 independent, because neither enzyme expression nor its activity, measured by tumoral PGE(2), showed significant difference between groups. It is probable that this antitumor action is dependent on an apoptotic way, which has been evaluated by the expression of the antiapoptotic protein Bcl-xL, in addition to the cellular changes observed by electronic microscopy. Celecoxib has also a possible involvement with redox homeostasis, because its administration caused significant changes in the activity of oxidative enzymes, such as catalase and superoxide dismutase. These results confirm the antitumor effects of celecoxib in W256 cancer model, contributing to elucidating its antitumoral mechanism and corroborating scientific literature about its effect on other types of cancer.

Insulin suppresses LPS-induced iNOS and COX-2 expression and NF-kappa B activation in alveolar macrophages

The development of septic shock is a common and frequently lethal consequence of gram-negative infection. Mediators released by lung macrophages activated by bacterial products such as lipopolysaccharide (LPS) contribute to shock symptoms. We have shown that insulin downregulates LPS-induced TNF production by alveolar macrophages (AMs). In the present study, we investigated the effect of insulin on the LPS-induced production of nitric oxide (NO) and prostaglandin (PG)-E(2), on the expression of inducible nitric oxide synthase ( iNOS) and cyclooxygenase (COX)-2, and on nuclear factor kappa B (NF-kappa B) activation in AMs. Resident AMs from male Wistar rats were stimulated with LPS (100 ng/mL) for 30 minutes. Insulin (1 mU/mL) was added 10 min before LPS. Enzymes expression, NF-kappa B p65 activation and inhibitor of kappa B (I-kappa B) a phosphorylation were assessed by immunobloting; NO by Griess reaction and PGE(2) by enzyme immunoassay (EIA). LPS induced in AMs the expression of iNOS and COX-2 proteins and production of NO and PGE(2), and, in parallel, NF-kappa B p65 activation and cytoplasmic I-kappa B alpha phosphorylation. Administration of insulin before LPS suppressed the expression of iNOS and COX-2, of NO and PGE(2) production and Nuclear NF-kappa B p65 activation. Insulin also prevented cytoplasmic I-kappa Ba phosphorylation. These results show that in AMs stimulated by LPS, insulin prevents nuclear translocation of NF-kappa B, possibly by blocking I-kappa Ba degradation, and supresses the production of NO and PGE(2), two molecules that contribute to septic shock. Copyright (C) 2008 S. Karger AG, Basel.

Improved likelihood inference for the shape parameter in Weibull regression

We obtain adjustments to the profile likelihood function in Weibull regression models with and without censoring. Specifically, we consider two different modified profile likelihoods: (i) the one proposed by Cox and Reid [Cox, D.R. and Reid, N., 1987, Parameter orthogonality and approximate conditional inference. Journal of the Royal Statistical Society B, 49, 1-39.], and (ii) an approximation to the one proposed by Barndorff-Nielsen [Barndorff-Nielsen, O.E., 1983, On a formula for the distribution of the maximum likelihood estimator. Biometrika, 70, 343-365.], the approximation having been obtained using the results by Fraser and Reid [Fraser, D.A.S. and Reid, N., 1995, Ancillaries and third-order significance. Utilitas Mathematica, 47, 33-53.] and by Fraser et al. [Fraser, D.A.S., Reid, N. and Wu, J., 1999, A simple formula for tail probabilities for frequentist and Bayesian inference. Biometrika, 86, 655-661.]. We focus on point estimation and likelihood ratio tests on the shape parameter in the class of Weibull regression models. We derive some distributional properties of the different maximum likelihood estimators and likelihood ratio tests. The numerical evidence presented in the paper favors the approximation to Barndorff-Nielsen`s adjustment.

Kolerahanteringen i Falun år 1834 & 1853 : En studie av sundhetsnämndens agerande

Syftet med uppsatsen är att undersöka vilka åtgärder som Falu stad, genom sundhetsnämnden, vidtog när farsoten kolera spreds i Sverige år 1834 respektive år 1853 samt om dessa åtgärder skiljer sig över tid. Frågeställningarna som används är: Vilka förebyggande åtgärder mot kolera vidtog staden genom sundhetsnämnden år 1834 och år 1853? Hur agerade läkarna i Falun mot kolerahotet? Skiljer sig Falu sundhetsnämnds åtgärder i jämförelse med andra städers sundhetsnämnder? Skiljer sig sundhetsnämndens åtgärder mellan åren 1834 och 1853? Materialet som används består av sundhetsnämndens mötesprotokoll från åren 1834 och år 1853, kolerakungörelser från de båda tidpunkterna, stadsläkare- och gruvläkarapporter samt utdrag från Tidning för Falu län och stad. Resultatet visar, att Falun vid båda tillfällena spärrades av genom att vaktstationer upprättades vid vägarna och vid stadens gräns. En karantänsstation upprättades vid stadens hälsobrunn för att ta om hand personer som inte vistats på kolerafri ort de 10 senaste dagarna. Staden delades in i tio distrikt som bemannades med en distriktschef samt några uppsyningsmän, som kontrollerade att staden hölls ren och att invånarna var rena. Stadens läkare var väldigt aktiva under sundhetsnämndens möten år 1834 och gav flera förslag på vad som behövdes göras medan de år 1853 intog en mer passiv roll. Åtgärderna i Stockholm år 1834 är snarlika de åtgärder som genomfördes i Falun samma år, huvudstaden delades också in i distrikt och det tillsattes även distriktschefer och uppsyningsmän. En annan likhet är att både Falun och Stockholm beställde färdiga likkistor för att ha i beredskap. Såväl sundhetsnämnderna i Karlskrona, Ystad och Arboga liksom Falun år 1853 vidtog i stort sett samma åtgärder som gjordes redan år 1834 t ex spärrningsåtgärder, karantänsskydd, införandet av kolerasjukhus och extra insatser för de mest utsatta i samhället.

Crafting organization

The recent shift in attention away from organization studies as science has allowed for consideration of new ways of thinking about both organization and organizing and has led to several recent attempts to 'bring down' organizational theorizing. In this paper, we extend calls for organization to be represented as a creative process by considering organization as craft. Organizational craft, we argue, is attractive, accessible, malleable, reproducible, and marketable. It is also a tangible way of considering organization studies with irreverence. We draw on the hierarchy of distinctions among fine art, decorative art, and craft to suggest that understanding the organization of craft assists in complicating our understanding of marginality. We illustrate our argument by drawing on the case of a contemporary Australian craftworks and marketplace known initially as the Meat Market Craft Centre ('MMCC') and then, until its recent closure, as Metro! &Dagger; Stella Minahan was a board member and then the Chief Executive Officer of the Metro! Craft Centre.

Excess and mimesis in organization theory: emancipation from within?

In organizational analysis it can be argued that 'radical separatism'&mdash;in the guise of the original 'agenda' for Radical Organization Theory (see Benson, 1977a; Burrell and Morgan, 1979; Clegg and Dunkerley, 1980) or more recently that for Critical Management Studies (see Alvesson and Willmott, 1992; Fournier and Grey, 2000; Casey, 2002; Grey, 2004)&mdash;has failed to breach the hegemony of functionalist orthodoxy, and notably so when it comes to practice. Given this failure, we speculate, upon the potential for a different emancipatory approach, one based theoretically on the fluid process of 'undecidability'. Unusually our approach attempts to undermine the conventions of functionalist organization theory from within. In brief, we speculate upon the adoption and enactment of Luce Irigaray's (1985, 1991) strategy of mimicry as a means to illuminate the notion of 'excess' in organization theory. To liberate the feminine, Irigaray mimics the symbolic representation of the female body to excess so as to expose the contradictions of phallocentric discourse. When applied to organization theory, this sees a deliberate mimicking of critiques of radical separatism so as to make explicit the latter's imprisonment within functionalism. Through excessive mimicking of the functionalists' critique, the radical/critical organization theorist may become cognizant of, but perhaps not so subjugated by, the hegemony of functionalist discourse.