bluuebunny/crossref_metadata_2025 huggingface dataset:
Methodology to improve epidermal barrier homeostasis: How to accelerate the barrier recovery?
Authors: Denda M.
Published: January 2009

Synopsis

Good water‐impermeable barrier function is vital for healthy skin. Abnormality of the barrier function is observed in a variety of skin diseases, such as atopic dermatitis, psoriasis and contact dermatitis. Moreover, repeated barrier disruption induces epidermal hyperplasia and inflammation. On the other hand, acceleration of the barrier recovery prevents epidermal hyperplasia induced by barrier disruption in a dry environment. Thus, methods to improve the barrier function are very important for clinical dermatology. Recently, we have been searching for new reagents and/or new materials to improve barrier homeostasis. In this review, I will describe our recent findings and show how they provide the basis for a new perspective for clinical dermatology.
Treatment of Cluster Headache in Pregnancy and Lactation
Authors: Jügens TP , Schaefer C , May A
Published: January 2009

Cluster headache is a rare disorder in women, but has a serious impact on the affected woman's life, especially on family planning. Women with cluster headache who are pregnant need special support, including the expertise of an experienced headache centre, an experienced gynaecologist and possibly a teratology information centre. The patient should be seen through all stages of the pregnancy. A detailed briefing about the risks and safety of various treatment options is mandatory. In general, both the number of medications and the dosage should be kept as low as possible. Preferred treatments include oxygen, subcutaneous or intranasal sumatriptan for acute pain and verapamil and prednisone/ prednisolone as preventatives. If there is a compelling reason to treat the patient with another preventative, gabapentin is the drug of choice. While breastfeeding, oxygen, sumatriptan and lidocaine for acute pain and prednisone/prednisolone, verapamil, and lithium as preventatives are the drugs of choice. As the individual pharmacokinetics differ substantially, adverse drug effects should be considered if unexplained symptoms occur in the newborn.
Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders
Authors: Whitney Nicholas P. , Eidem Tess M. , Peng Hui , Huang Yunlong , Zheng Jialin C.
Published: January 2009

Brain inflammation is a complex cellular and molecular response to stress, injury or infection of the CNS in attempt to defend against insults, clear dead and damaged neurons and return the CNS to a normal state. Inflammation in the CNS is driven by the activation of resident microglia, astrocytes and infiltrating peripheral macrophages, which release a plethora of anti‐ and pro‐inflammatory cytokines, chemokines, neurotransmitters and reactive oxygen species. This inflammatory state inadvertently causes further bystander damage to neurons and produces both detrimental and favorable conditions for neurogenesis. Inflammatory factors have varying effects on neural progenitor cell proliferation, migration, differentiation, survival and incorporation of newly born neurons into the CNS circuitry. The unique profile of inflammatory factors, which depends on the severity of inflammation, can have varying consequences on neurogenesis. Inflammatory factors released during mild acute inflammation usually stimulate neurogenesis; where as the factors released by uncontrolled inflammation create an environment that is detrimental to neurogenesis. This review will provide a summary of current progress in this emerging field and examine the potential mechanisms through which inflammation affects neurogenesis during neurological complications.
A reappraisal of the central effects of botulinum neurotoxin type A: by what mechanism?
Authors: Caleo Matteo , Antonucci Flavia , Restani Laura , Mazzocchio Riccardo
Published: January 2009

Botulinum neurotoxin A (BoNT/A) is a metalloprotease that enters peripheral motor nerve terminals and blocks the release of acetylcholine via the specific cleavage of the synaptosomal‐associated protein of 25‐kDa. Localized injections of BoNT/A are widely employed in clinical neurology to treat several human diseases characterized by muscle hyperactivity. It is generally assumed that the effects of BoNT/A remain localized to the injection site. However, several neurophysiological studies have provided evidence for central effects of BoNT/A, raising the issue of how these actions arise. Here we review these data and discuss the possibility that retrograde axonal transport of catalytically active BoNT/A may explain at least some of its effects at the level of central circuits.
Different climatic envelopes among invasive populations may lead to underestimations of current and future biological invasions
Authors: Beaumont Linda J. , Gallagher Rachael V. , Thuiller Wilfried , Downey Paul O. , Leishman Michelle R. , Hughes Lesley
Published: January 2009

Aim  We explore the impact of calibrating ecological niche models (ENMs) using (1) native range (NR) data versus (2) entire range (ER) data (native and invasive) on projections of current and future distributions of three Hieracium species.

Location  H. aurantiacum, H. murorum and H. pilosella are native to Europe and invasive in Australia, New Zealand and North America.

Methods  Differences among the native and invasive realized climatic niches of each species were quantified. Eight ENMs in BIOMOD were calibrated with (1) NR and (2) ER data. Current European, North American and Australian distributions were projected. Future Australian distributions were modelled using four climate change scenarios for 2030.

Results  The invasive climatic niche of H. murorum is primarily a subset of that expressed in its native range. Invasive populations of H. aurantiacum and H. pilosella occupy different climatic niches to those realized in their native ranges. Furthermore, geographically separate invasive populations of these two species have distinct climatic niches. ENMs calibrated on the realized niche of native regions projected smaller distributions than models incorporating data from species’ entire ranges, and failed to correctly predict many known invasive populations. Under future climate scenarios, projected distributions decreased by similar percentages, regardless of the data used to calibrate ENMs; however, the overall sizes of projected distributions varied substantially.

Main conclusions  This study provides quantitative evidence that invasive populations of Hieracium species can occur in areas with different climatic conditions than experienced in their native ranges. For these, and similar species, calibration of ENMs based on NR data only will misrepresent their potential invasive distribution. These errors will propagate when estimating climate change impacts. Thus, incorporating data from species’ entire distributions may result in a more thorough assessment of current and future ranges, and provides a closer approximation of the elusive fundamental niche.
Contrasting patterns of genetic variation and structure in plant invasions of mountains
Authors: Alexander Jake M. , Poll Myriam , Dietz Hansjörg , Edwards Peter J.
Published: January 2009

Aim  To assess the population genetic consequences of the colonization of two species with contrasting mating systems, Solidago canadensis and Lactuca serriola, along altitudinal gradients in both their native and introduced ranges.

Location  Allegheny Mountains, West Virginia and Wallowa Mountains, Oregon, USA; Valais, southern Switzerland.

Methods  Leaf material was collected from populations along altitudinal gradients and genotyped at seven microsatellite loci for each species. Differences in variability between native and introduced areas and in relation to altitude were analysed using linear models. Differences in the genetic, geographical and altitudinal structure of populations between areas were analysed by AMOVA, cluster analysis and Mantel tests.

Results  Genetic variation within and across populations of S. canadensis was significantly reduced, while populations of L. serriola were significantly more variable, in the introduced area. Genetic diversity decreased significantly with altitude for S. canadensis but not L. serriola. Genetic structure of S. canadensis was similar in both areas, and populations were isolated by geographical but not altitudinal distance. By contrast, population structure of L. serriola was much weaker in the introduced area, and populations were not isolated by distance in either area.

Main conclusions  Solidago canadensis has experienced a strong genetic bottleneck on introduction to the Valais, but this has not prevented it from colonizing a wide altitudinal range. Variation in neutral markers is therefore not necessarily a good measure for judging the ecological behaviour of a species. By contrast, the greater variability of L. serriola in the introduced area, where it also occurs over a greater altitudinal range, can be explained by increased outcrossing among admixed populations. This suggests that the ecological amplitude of alien species might be enhanced after population admixture in the new range, especially for species with highly structured native populations. However, even genetically depauperate introduced populations can be expected to colonize the same environmental range that they occupy in the native area.
Incomplete dissociation of glibenclamide from wild‐type and mutant pancreatic KATPchannels limits their recovery from inhibition
Authors: Russ U , Kühner P , Prager R , Stephan D , Bryan J , Quast U
Published: January 2009

Background and purpose: The antidiabetic sulphonylurea, glibenclamide, acts by inhibiting the pancreatic ATP‐sensitive K+(KATP) channel, a tetradimeric complex of KIR6.2 and sulphonylurea receptor 1 (KIR6.2/SUR1)4. At room temperature, recovery of channel activity following washout of glibenclamide is very slow and cannot be measured. This study investigates the relation between the recovery of channel activity from glibenclamide inhibition and the dissociation rate of [3H]‐glibenclamide from the channel at 37°C.

Experimental approach: KIR6.2, KIR6.2ΔN5 or KIR6.2ΔN10 (the latter lacking amino‐terminal residues 2–5 or 2–10 respectively) were coexpressed with SUR1 in HEK cells. Dissociation of [3H]‐glibenclamide from the channel and recovery of channel activity from glibenclamide inhibition were determined at 37°C.

Key results: The dissociation kinetics of [3H]‐glibenclamide from the wild‐type channel followed an exponential decay with a dissociation half‐time,t1/2(D) = 14 min; however, only limited and slow recovery of channel activity was observed.t1/2(D) for KIR6.2ΔN5/SUR1 channels was 5.3 min and recovery of channel activity exhibited a sluggish sigmoidal time course with a half‐time,t1/2(R) = 12 min.t1/2(D) for the ΔN10 channel was 2.3 min; recovery kinetics were again sigmoidal witht1/2(R) ∼4 min.

Conclusions and implications: The dissociation of glibenclamide from the truncated channels is the rate‐limiting step of channel recovery. The sigmoidal recovery kinetics are in quantitative agreement with a model where glibenclamide must dissociate from all four (or at least three) sites before the channel reopens. It is argued that these conclusions hold also for the wild‐type (pancreatic) KATPchannel.
The effect of ‘two hit’ neonatal and young‐adult stress on dopaminergic modulation of prepulse inhibition and dopamine receptor density
Authors: Choy Kwok Ho Christopher , De Visser Yvonne P. , Van Den Buuse Maarten
Published: January 2009

Background and purpose: A combination of early neurodevelopmental insult(s) and young‐adult stress exposure may be involved in the development of schizophrenia. We studied prepulse inhibition (PPI) regulation in rats after an early stress, maternal deprivation, combined with a later stress, simulated by chronic corticosterone treatment, and also determined whether changes in brain dopamine receptor density were involved.

Experimental approach: Rats were subjected to either 24 h maternal deprivation on postnatal day 9, corticosterone treatment from 8 to 10 weeks of age, or both. At 12 weeks of age, the rats were injected with 0.1, 0.3 or 1.0 mg·kg−1of apomorphine or 0.5 or 2.5 mg·kg−1of amphetamine and PPI was determined using automated startle boxes. Dopamine D1and D2receptor levels were assessed in the nucleus accumbens and caudate nucleus using receptor autoradiography.

Key results: Young‐adult treatment with corticosterone resulted in attenuated disruption of PPI by apomorphine and amphetamine. In some rats, maternal deprivation resulted in reduced baseline PPI which added to the effect of corticosterone treatment. There was no down‐regulation of dopamine D1or D2receptors.

Conclusions and implications: These results confirm and extend our finding of an inhibitory interaction of developmental stress on dopaminergic regulation of PPI. No corresponding changes in dopamine receptor density were observed in brain regions with a major involvement in PPI regulation, suggesting long‐lasting desensitization of dopamine receptor signalling or indirect changes in PPI regulation.
Pharmacokinetic optimization of four soluble epoxide hydrolase inhibitors for use in a murine model of inflammation
Authors: Liu Jun‐Yan , Tsai Hsing‐Ju , Hwang Sung Hee , Jones Paul D , Morisseau Christophe , Hammock Bruce D
Published: January 2009

Background and purpose:  Early soluble epoxide hydrolase inhibitors (sEHIs) such as 12‐(3‐adamantan‐1‐yl‐ureido)‐dodecanoic acid (AUDA) are effective anti‐hypertensive and anti‐inflammatory agents in various animal models. However, their poor metabolic stability and limited water solubility make them difficult to use pharmacologically. Here we present the evaluation of four sEHIs for improved pharmacokinetic properties and the anti‐inflammatory effects of one sEHI.

Experimental approach:  The pharmacokinetic profiles of inhibitors were determined following p.o. (oral) administration and serial bleeding in mice. Subsequently the pharmacokinetics of trans‐4‐[4‐(3‐adamantan‐1‐yl‐ureido)‐cyclohexyloxy]‐benzoic acid (t‐AUCB), the most promising inhibitor, was further studied following s.c. (subcutaneous), i.v. (intravenous) injections and administration in drinking water. Finally, the anti‐inflammatory effect of t‐AUCB was evaluated by using a lipopolysaccharide (LPS)‐treated murine model.

Key results:  Better pharmacokinetic parameters (higher Cmax, longer t1/2 and greater AUC) were obtained from the tested inhibitors, compared with AUDA. Oral bioavailability of t‐AUCB (0.1 mg·kg−1) was 68 ± 22% (n = 4), and giving t‐AUCB in drinking water is recommended as a feasible, effective and easy route of administration for chronic studies. Finally, t‐AUCB (p.o.) reversed the decrease in plasma ratio of lipid epoxides to corresponding diols (a biomarker of soluble epoxide hydrolase inhibition) in lipopolysaccharide‐treated mice. The in vivo potency of 1 mg·kg−1 of t‐AUCB (p.o.) was better in this inflammatory model than that of 10 mg·kg−1 of AUDA‐butyl ester (p.o) at 6 h after treatment.

Conclusions and implications:  t‐AUCB is a potent sEHI with improved pharmacokinetic properties. This compound will be a useful tool for pharmacological research and a promising starting point for drug development.
Selective noradrenaline reuptake inhibitor atomoxetine directly blocks hERG currents
Authors: Scherer Daniel , Hassel David , Bloehs Ramona , Zitron Edgar , Von Löwenstern Katharina , Seyler Claudia , Thomas Dierk , Konrad Franziska , Bürgers Heiner F. , Seemann Gunnar , Rottbauer Wolfgang , Katus Hugo A. , Karle Christoph A. , Scholz Eberhard P.
Published: January 2009

Background and purpose:  Atomoxetine is a selective noradrenaline reuptake inhibitor, recently approved for the treatment of attention‐deficit/hyperactivity disorder. So far, atomoxetine has been shown to be well tolerated, and cardiovascular effects were found to be negligible. However, two independent cases of QT interval prolongation, associated with atomoxetine overdose, have been reported recently. We therefore analysed acute and subacute effects of atomoxetine on cloned human Ether‐à‐Go‐Go‐Related Gene (hERG) channels.

Experimental approach:  hERG channels were heterologously expressed in Xenopus oocytes and in a human embryonic kidney cell line and hERG currents were measured using voltage clamp and patch clamp techniques. Action potential recordings were made in isolated guinea‐pig cardiomyocytes. Gene expression and channel surface expression were analysed using quantitative reverse transcriptase polymerase chain reaction, Western blot and the patch clamp techniques.

Key results:  In human embryonic kidney cells, atomoxetine inhibited hERG current with an IC50 of 6.3 µmol·L−1. Development of block and washout were fast. Channel activation and inactivation were not affected. Inhibition was state‐dependent, suggesting an open channel block. No use‐dependence was observed. Inhibitory effects of atomoxetine were attenuated in the pore mutants Y652A and F656A. In guinea‐pig cardiomyocytes, atomoxetine lengthened action potential duration without inducing action potential triangulation. Overnight incubation with high atomoxetine concentrations resulted in a decrease of channel surface expression.

Conclusions and implications:  Whereas subacute effects of atomoxetine seem negligible under therapeutically relevant concentrations, hERG channel block should be considered in cases of atomoxetine overdose and when administering atomoxetine to patients at increased risk for the development of acquired long‐QT syndrome.
P‐selectin glycoprotein‐ligand‐1 regulates pulmonary recruitment of neutrophils in a platelet‐independent manner in abdominal sepsis
Authors: Asaduzzaman Muhammad , Rahman Milladur , Jeppsson Bengt , Thorlacius Henrik
Published: January 2009

Background and purpose:  Neutrophil‐mediated lung injury is an insidious feature in sepsis although the mechanisms regulating pulmonary recruitment of neutrophils remain elusive. Here, we investigated the role of P‐selectin glycoprotein‐ligand‐1 (PSGL‐1) in sepsis‐induced neutrophil recruitment and tissue injury in the lung.

Experimental approach:  Bronchoalveolar infiltration of neutrophils, levels of myeloperoxidase, oedema formation and CXC chemokines were determined 24 h after caecal ligation and puncture (CLP) in mice. Animals were pretreated with a control antibody, monoclonal antibodies directed against PSGL‐1 and P‐selectin as well as a platelet‐depleting antibody directed against GP1bα.

Key results:  CLP caused pulmonary damage characterized by oedema formation, neutrophil infiltration and increased levels of CXC chemokines in the lung. Immunoneutralization of PSGL‐1 or P‐selectin reduced CLP‐induced neutrophil recruitment in the bronchoalveolar space by more than 56% and lung myeloperoxidase activity by 62%. Notably, the inhibitory effect of the anti‐PSGL‐1 antibody on sepsis‐induced neutrophil infiltration was also observed in platelet‐depleted mice. Moreover, inhibition of PSGL‐1 and P‐selectin abolished CLP‐induced oedema formation and tissue damage in the lung. CLP‐induced formation of CXC chemokines was not changed in mice pretreated with the anti‐PSGL‐1 and anti‐P‐selectin antibodies.

Conclusions and implications:  These data demonstrate that PSGL‐1 plays a key role in pulmonary infiltration of neutrophils as well as lung oedema associated with abdominal sepsis. Moreover, our findings suggest that PSGL‐1‐dependent neutrophil recruitment is independent of circulating platelets. Thus, these novel findings indicate that PSGL‐1 may be a useful target to protect against sepsis‐induced accumulation of neutrophils and tissue damage in the lung.
Levosimendan induces NO production through p38 MAPK, ERK and Akt in porcine coronary endothelial cells: role for mitochondrial KATPchannel
Authors: Grossini E , Molinari C , Caimmi PP , Uberti F , Vacca G
Published: January 2009

Background and purpose: Levosimendan acts as a vasodilator through the opening of ATP‐sensitive K+channels (KATP) channels. Moreover, the coronary vasodilatation caused by levosimendan in anaesthetized pigs has recently been found to be abolished by the nitric oxide synthase (NOS) inhibitor Nω‐nitro‐L‐arginine methyl ester, indicating that nitric oxide (NO) has a role in the vascular effects of levosimendan. However, the intracellular pathway leading to NO production caused by levosimendan has not yet been investigated. Thus, the purpose of the present study was to examine the effects of levosimendan on NO production and to evaluate the intracellular signalling pathway involved.

Experimental approach: In porcine coronary endothelial cells (CEC), the release of NO in response to levosimendan was examined in the presence and absence of Nω‐nitro‐L‐arginine methyl ester, an adenylyl cyclase inhibitor, KATPchannel agonists and antagonists, and inhibitors of intracellular protein kinases. In addition, the role of Akt, ERK, p38 and eNOS was investigated through Western blot analysis.

Key results: Levosimendan caused a concentration‐dependent and K+‐related increase of NO production. This effect was amplified by the mitochondrial KATPchannel agonist, but not by the selective plasma membrane KATPchannel agonist. The response of CEC to levosimendan was prevented by the KATPchannel blockers, the adenylyl cyclase inhibitor and the Akt, ERK, p38 inhibitors. Western blot analysis showed that phosphorylation of the above kinases lead to eNOS activation.

Conclusions and implications: In CEC levosimendan induced eNOS‐dependent NO production through Akt, ERK and p38. This intracellular pathway is associated with the opening of mitochondrial KATPchannels and involves cAMP.
Accelerated inactivation of cardiac L‐type calcium channels triggered by anaesthetic‐induced preconditioning
Authors: Tampo A , Hogan CS , Sedlic F , Bosnjak ZJ , Kwok WM
Published: January 2009

Mandarin translation of abstract

Background and purpose:  Cardioprotection against ischaemia by anaesthetic‐induced preconditioning (APC) is well established. However, the mechanism underlying Ca2+ overload attenuation by APC is unknown. The effects of APC by isoflurane on the cardiac L‐type Ca channel were investigated.

Experimental approach:  In a model of in vivo APC, Wistar rats were exposed to isoflurane (1.4%), delivered via a vaporizer in an enclosure, prior to thoracotomy. The Dahl S rats were similarly preconditioned to determine strain‐dependent effects. Whole‐cell patch clamp using cardiac ventricular myocytes was used to determine the L‐type Ca2+ current (ICa,L) characteristics and calmodulin (CaM) levels were determined by Western blot analysis. Cytosolic Ca2+ levels were monitored using fluo‐4‐AM. Action potential (AP) simulations examined the effects of APC.

Key results:  In Wistar rats, APC significantly accelerated ICa,L inactivation kinetics. This was abolished when external Ca2+ was replaced with Ba2+, suggesting that Ca2+‐dependent inactivation of ICa,L was modulated by APC. Expression levels of CaM, a determinant of ICa,L inactivation, were not affected. Attenuation of cytosolic Ca2+ accumulation following oxidative stress was observed in the APC group. Simulations showed that the accelerated inactivation of ICa,L resulted in a shortening of the AP duration. The Dahl S rat strain was resistant to APC and changes in ICa,L inactivation were not observed in cardiomyocytes prepared from these rats.

Conclusions and implications:  APC triggered persistent changes in the inactivation of cardiac L‐type Ca channels. This can potentially lead to a reduction in Ca2+ influx and attenuation of Ca2+ overload during ischaemia/reperfusion.

Mandarin translation of abstract
Tachykinin receptor modulation of cyclooxygenase‐2 expression in human polymorphonuclear leucocytes
Authors: Gallicchio M , Benetti E , Rosa AC , Fantozzi R
Published: January 2009

Mandarin translation of abstract

Background and purpose: We investigated the ability of natural and synthetic selective NK receptors agonists and antagonists to modulate cyclooxygenase‐2 (COX‐2) expression in human polymorphonuclear leucocytes (PMNs).

Experimental approach: The presence of all three tachykinin in PMNs was assessed by Western blot and PCR techniques. Natural and synthetic ligands selective for the tachykinin receptors were used to modulate COX‐2 protein (measured with Western blotting) and activity [as prostaglandin E2(PGE2) output]. Effects of substance P (SP) on phosphorylation of mitogen‐activated protein kinases (MAPKs) and nuclear factor‐kappa B (NF‐κB) activation were studied to analyse the signalling pathway involved in COX‐2 up‐regulation mediated by SP.

Key results: Stimulation of NK receptors with the natural ligands SP, neurokinin A (NKA) and neurokinin B, in the pmol·L−1‐µmol·L−1concentration range, modulated COX‐2 expression and PGE2release in a concentration‐ and time‐dependent manner. Experiments with synthetic selective agonists [Sar9, Met(O2)11]SP, [β‐Ala8] NKA(4‐10), senktide or selective antagonists L703,606, SR48,968 or SR142801, confirmed that COX‐2 up‐regulation was mediated by NK receptors. We found that mainly p38, p42 and p46 MAPKs were phosphorylated by SP and SB202190, PD98059 and SP600125, which are selective inhibitors of these kinases, blocked SP‐induced COX‐2 expression. SP also induced nuclear translocation of NF‐κB concentration‐dependently, with a maximum effect at 1 nmol·L−1.

Conclusions and implications: Human PMNs possess functional NK1, NK2and NK3receptors, which mediate the induction of COX‐2 expression and NF‐κB activation by SP.

Mandarin translation of abstract
Pharmacological characterization of recombinant NR1/NR2A NMDA receptors with truncated and deleted carboxy termini expressed inXenopus laevisoocytes
Authors: Puddifoot CA , Chen PE , Schoepfer R , Wyllie DJA
Published: January 2009

Mandarin translation of abstract

Background and purpose: The carboxy terminal domain (CTD) of NR2N‐methyl‐d‐aspartate receptor (NMDAR) subunits interacts with numerous scaffolding and signal transduction proteins. Mutations of this region affect trafficking and downstream signalling of NMDARs. This study determines to what extent characteristic pharmacological properties of NR2A‐containing NMDARs are influenced by this key functional domain.

Experimental approach: Using recombinant receptor expression inXenopus laevisoocytes and two electrode voltage clamp recordings we characterized pharmacological properties of rat NR1/NR2A NMDARs with altered CTDs. We assessed the effects of truncating [at residue Iso1098; NR2A(trunC)] and deleting [from residue Phe822; NR2A(delC)] the CTD of NR2A NMDAR subunits on agonist potencies, channel block by Mg2+and memantine and potentiation of NMDAR‐mediated responses by chelating contaminating divalent cations.

Key results: Truncation or deletion of the CTD of NR2A NMDAR subunits did not affect glutamate potency [EC50 = 2.2 µmol·L−1, NR2A(trunC); 2.7 µmol·L−1, NR2A(delC) compared with 3.3 µmol·L−1, NR2A(WT)] but did significantly increase glycine potency [EC50 = 500 nmol·L−1, NR2A(trunC); 900 nmol·L−1, NR2A(delC) compared with 1.3 µmol·L−1, NR2A(WT)]. Voltage‐dependent Mg2+block of NR2A(WT)‐ and NR2A(trunC)‐containing NMDARs was similar but low concentrations of Mg2+(1 µmol·L−1) potentiated NR1/NR2A(delC) NMDARs. Memantine block was not affected by changes to the structure of the NR2A CTD. EDTA‐induced potentiation was similar at each of the three NMDAR constructs.

Conclusions and implications: Of the parameters studied only minor influences of the CTD were observed; these are unlikely to compromise interpretation of studies that make use of CTD‐mutated recombinant receptors or transgenic mice in investigations of the role of the CTD in NMDAR signalling.

Mandarin translation of abstract
Simvastatin protects against cholestasis‐induced liver injury
Authors: Dold S , Laschke MW , Lavasani S , Menger MD , Jeppsson B , Thorlacius H
Published: January 2009

Mandarin translation of abstract

Background:  Bile duct obstruction is associated with hepatic accumulation of leukocytes and liver injury. The aim of this study was to evaluate the effect of simvastatin on cholestasis‐induced liver inflammation and tissue damage.

Experimental approach:  C57BL/6 mice were treated with simvastatin (0.02 and 0.2 mg·kg−1) and vehicle before and after undergoing bile duct ligation (BDL) for 12 h. Leukocyte recruitment and microvascular perfusion in the liver were analysed using intravital fluorescence microscopy. CXC chemokines in the liver were determined by enzyme‐linked immunosorbent assay. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic levels of myeloperoxidase (MPO) were also determined.

Key results:  Administration of 0.2 mg·kg−1 simvastatin decreased ALT and AST by 87% and 83%, respectively, in BDL mice. This dose of simvastatin reduced hepatic formation of CXC chemokines by 37–82% and restored sinusoidal perfusion in cholestatic animals. Moreover, BDL‐induced leukocyte adhesion in sinusoids and postsinusoidal venules, as well as MPO levels in the liver, was significantly reduced by simvastatin. Notably, administration of 0.2 mg·kg−1 simvastatin 2 h after BDL induction also decreased cholestatic liver injury and inflammation.

Conclusions and implications:  These findings show that simvastatin protects against BDL‐induced liver injury. The hepatoprotective effect of simvastatin is mediated, at least in part, by reduced formation of CXC chemokines and leukocyte recruitment. Thus, our novel data suggest that the use of statins may be an effective strategy to protect against the hepatic injury associated with obstructive jaundice.

Mandarin translation of abstract
Actors of the tyrosine kinase receptor downstream signaling pathways in amphioxus
Authors: Bertrand Stéphanie , Campo‐Paysaa Florent , Camasses Alain , García‐Fernàndez Jordi , Escrivà Héctor
Published: January 2009

SUMMARY
One of the major goals of evo‐developmentalists is to understand how the genetic mechanisms controlling embryonic development have evolved to create the current diversity of bodyplans that we encounter in the animal kingdom. Tyrosine kinase receptors (RTKs) are transmembrane receptors present in all metazoans known to control several developmental processes. They act via the activation of various cytoplasmic signaling cascades, including the mitogen‐activated protein kinase (MAPK), the PI3K/Akt, and the phospholipase C‐γ (PLCγ)/protein kinase C (PKC) pathways. In order to address the evolution of these three pathways and their involvement during embryogenesis in chordates, we took advantage of the complete genome sequencing of a key evolutionarily positioned species, the cephalochordate amphioxus, and searched for the complete gene set of the three signaling pathways. We found that the amphioxus genome contains all of the most important modules of the RTK‐activated cascades, and looked at the embryonic expression of two genes selected from each cascade. Our data suggest that although the PI3K/Akt pathway may have ubiquitous functions, the MAPK and the PLCγ/PKC cascades may play specific roles in amphioxus development. Together with data known in vertebrates, the expression pattern of PKC in amphioxus suggests that the PLCγ/PKC cascade was implicated in neural development in the ancestor of all chordates.
Comparative gene expression in the heads of Drosophila melanogaster and Tribolium castaneum and the segmental affinity of the Drosophila hypopharyngeal lobes
Authors: Economou Andrew D. , Telford Maximilian J.
Published: January 2009

SUMMARY
Drosophila melanogaster has long played an important role in debates surrounding insect and arthropod head segmentation. It is surprising, therefore, that one important feature of Drosophila head segmentation has remained controversial: namely the position of the boundary between the intercalary and mandibular segments. The Drosophila embryonic head has a pair of structures lying behind the stomodeum known as the hypopharyngeal lobes. Traditionally they have been seen as part of the intercalary segment. More recent work looking at the position of the lobes relative to various marker genes has been somewhat equivocal: segment polarity gene expression has been used to argue for a mandibular affinity of these lobes, while the expression of the anterior‐most hox gene labial (lab) has supported an intercalary affinity. We have addressed the question of the segmental affinity of the hypopharyngeal lobes by conducting a detailed comparison of gene expression patterns between Drosophila and the red flour beetle Tribolium castaneum, in which the intercalary segment is unambiguously marked out by lab. We demonstrate that there is a large degree of conservation in gene expression patterns between Drosophila and Tribolium, and this argues against an intercalary segment affinity for the hypopharyngeal lobes. The lobes appear to be largely mandibular in origin, although some gene expression attributed to them appears to be associated with the stomodeum. We propose that the difficulties in interpreting the Drosophila head result from a topological shift in the Drosophila embryonic head, associated with the derived process of head involution.
Division Manager Lobbying Power and the Allocation of Capital
Authors: McNeil Chris R. , Smythe Thomas I.
Published: January 2009

We investigate whether division manager lobbying power affects the allocation of capital in multi‐divisional firms. We find that firm‐level disparities in division manager lobbying power (measured by tenure, time‐in‐position, board membership, and top executive status) affect capital allocation in expected ways. Managers with greater relative lobbying power compete for capital expenditures from a position of strength. Evidence is also provided which suggests that division manager ownership mitigates lobbying efforts. Furthermore, disparity in division manager lobbying power is associated with lower firm excess value. These results support the view that division manager influence activities impact the operation of internal capital markets.
The Diversification Discount Puzzle: Evidence for a Transaction‐Cost Resolution
Authors: Aggarwal Raj , Zhao Shelly
Published: January 2009

The literature on the corporate diversification discount and the relative efficiency of internal versus external capital markets provides mixed results. We argue that transaction‐cost economics is useful in understanding this puzzle. According to transaction‐cost economics, diversified firms should outperform single segment firms in industries with higher external transaction costs (e.g., emergent industries) and under‐perform in industries with low external transaction costs and high agency and other internal costs (e.g., some mature industries). This paper provides evidence supporting these contentions.
Anti‐inflammatory effects of low molecular weight heparin derivative in a rat model of carrageenan‐induced pleurisy
Authors: Ceccarelli Matteo , Bani Daniele , Cinci Lorenzo , Nistri Silvia , Uliva Caterina , Ragazzo Elena , Vannacci Alfredo , Manoni Marco , Gori Anna Maria , Abbate Rosanna , Gensini Gian Franco , Masini Emanuela
Published: January 2009

Low molecular weight heparin derivatives are characterized by low anti‐coagulant activity and marked anti‐inflammatory effects that allow for these molecules to be viewed as a new class of non‐steroidal anti‐inflammatory drugs (NSAIDs). We show here that K5NOSepiLMW, an O‐sulphated heparin‐like semi‐synthetic polymer of the D‐glucuronic acid–N‐acetyleparoson disaccharide unit with low molecular weight, has marked anti‐inflammatory effects in a rat model of acute inflammation, the carrageenan‐induced pleurisy, commonly used to test NSAID efficacy. A 30‐min. pre‐treatment with K5NOSepiLMW (0.1, 0.5 and 1 mg/kg b.wt., given intrapleurally) attenuated the recruitment of leucocytes in the lung tissue and the pleural exudate, inhibited the induction of inducible nitric oxide synthase and cyclooxygenase‐2 (COX‐2), thereby abating the generation of nitric oxide and pro‐inflammatory prostaglandins such as PgE2 and PGF1α, reduced the inflammation‐induced nitroxidative lung tissue injury, as shown by tissue thiobarbituric acid‐reactive substances and nitrotyrosine, and blunted the local generation of cytokines such as interleukin‐1β and tumour necrosis factor‐α. All these parameters were markedly increased by intrapleural carrageenan in the absence of any pre‐treatment. The anti‐inflammatory action of K5NOSepiLMW is specific, as judged by the lack of therapeutic effects of B4/110, a biologically inactive cognate polysaccharide, given in the place of the authentic molecule. Moreover, K5NOSepiLMW showed similar effects as celecoxib (1 mg/kg b.wt), a COX‐2 inhibitor and well‐known NSAID. This study provides further insight into the mechanisms underlying the beneficial effects of heparin derivatives in inflammation and identifies K5NOSepiLMW as a novel, promising anti‐inflammatory drug.
Prospective analysis of the incidence of autoimmune bullous disorders in Lower Franconia, Germany
Authors: Bertram Franziska , Bröcker Eva‐B. , Zillikens Detlef , Schmidt Enno
Published: January 2009

Background: Only limited epidemiologic data are available on autoimmune bullous diseases. Improved diagnostic tools should have led to an increased incidence. To test this hypothesis, all patients with autoimmune bullous disorders who were treated in the Department of Dermatology at the University of Würzburg, Germany, between January 2001 and June 2002 were analysed prospectively.

Patients and Methods: Epidemiologic data of patients diagnosed with an autoimmune bullous disease during this time period were registered and statistically evaluated. Diagnosis was based on the clinical picture and specific immunopathological findings. Only patients from Lower Franconia, a well‐defined administrative region of Southern Germany, were included into this study.

Results: During the study period, 41 patients with an autoimmune bullous disease were diagnosed, including 27 with bullous pemphigoid, 4 with pemphigoid gestationis and mucous membrane pemphigoid, 2 with dermatitis herpetiformis and linear IgA disease, and 1 with epidermolysis bullosa acquisita and pemphigus vulgaris, respectively. The highest incidence was calculated for bullous pemphigoid (13.4 per 1 million inhabitants per year) followed by pemphigoid gestationis (2.0) and mucous membrane pemphigoid (2.0). Patients with mucous membrane pemphigoid were found to have the highest mean age at disease onset (76 years) followed by patients with bullous pemphigoid (74 years).

Conclusions: This is the first prospective study on the incidence of autoimmune bullous disorders. Subepidermal blistering autoimmune diseases were shown to be more frequent than previously reported for Central Europe. This is most likely due to improved diagnostic tools for and increased awareness of these diseases.
Skin diseases and sexually transmitted diseases in HIV‐infected patients on HAART compared to a non‐infected population – results of a retrospective study
Authors: Rothengatter Sonja , Sehr Tanja , Gholam Patrick , Durani Hendrike , Hartmann Martin
Published: January 2009

Background: The prevalence of skin diseases and sexually transmitted diseases has always played a special role in studying HIV infections, both because of immunosuppression and simultaneous transmission. In the early years of the HIV epidemic, skin diseases were often a pathognomonic sign in heavily immunosuppressed patients. With highly active antiretroviral therapy (HAART), HIV infection has become a treatable chronic disease. For this reason the spectrum as well as the prevalence of skin diseases has changed. Pathognomonic skin diseases have become rare and the wide spectrum today ranges from infectious to iatrogenic skin diseases.

Patients and methods: From April to October 2007 166 HIV‐infected patients and 173 patients of a comparison group were surveyed in retrospect by means of a questionnaire about skin diseases and sexually transmitted diseases that appeared over the entire year 2006.

Results and conclusions: The study confirmed the shift to a wide variety of mostly trivial skin diseases and away from severe opportunistic skin diseases. HIV‐infected patients today have more numerous skin problems than the non‐infected population and thus need regular dermatologic control examinations.
Pulse oximetry screening as a complementary strategy to detect critical congenital heart defects
Authors: Meberg Alf , Andreassen Andreas , Brunvand Leif , Markestad Trond , Moster Dag , Nietsch Lutz , Silberg Inger Elisabeth , Skålevik Jan Einar
Published: January 2009

Objective: To compare strategies with and without first‐day of life pulse oximetry screening to detect critical congenital heart defects (CCHDs).

Study design: Population based study including all live born infants in Norway in 2005 and 2006 (n = 116 057). Postductal (foot) arterial oxygen saturation (SpO2) was measured in apparently healthy newborns after transferral to the nursery, with SpO2 < 95% as cut‐off point. Out of 57 959 live births in the hospitals performing pulse oximetry screening, 50 008 (86%) were screened.

Results: A total of 136 CCHDs (1.2 per 1000) were diagnosed, 38 (28%) of these prenatally. Of the CCHDs detected after birth, 44/50 (88%) were detected before discharge in the population offered pulse oximetry screening (25 by pulse oximetry), compared to 37/48 (77%) in the non‐screened population (p = 0.15). Median times for diagnosing CCHDs in‐hospital before discharge were 6 and 16 h after birth respectively (p < 0.0001). In the screened population 6/50 (12%) CCHDs were missed and recognized after discharge because of symptoms. Two of the six missed cases failed the pulse oximetry screening, but were overlooked (echocardiography not performed before discharge). If these cases had been recognized, 4/50 (8%) would have been missed compared to 11/48 (23%) in the non‐screened population (p = 0.05). Of the cases missed, 14/17 (82%) had left‐sided obstructive lesions.

Conclusion: First‐day of life pulse oximetry screening provides early in‐hospital detection of CCHDs and may reduce the number missed and diagnosed after discharge.
Early working memory and maternal communication in toddlers born very low birth weight
Authors: Lowe Jean , Erickson Sarah J , MacLean Peggy , Duvall Susanne W
Published: January 2009

Aim: Early working memory is emerging as an important indicator of developmental outcome predicting later cognitive, behavioural and academic competencies. The current study compared early working memory in a sample of toddlers (18–22 months) born very low birth weight (VLBW; n = 40) and full term (n = 51) and the relationship between early working memory, mental developmental index (MDI), and maternal communication in both samples.

Methods: Early working memory, measured by object permanence; Bayley mental developmental index; and maternal communication, coded during mother‐toddler play interaction, were examined in 39 toddlers born VLBW and 41 toddlers born full term.

Results: Toddlers born VLBW were found to be 6.4 times less likely to demonstrate attainment of object permanence than were toddlers born full term, adjusting for age at testing. MDI and maternal communication were found to be positively associated with attainment of object permanence in the VLBW group only.

Conclusion: The difference found in the early working memory performance of toddlers born VLBW, compared with those born full term, emphasizes the importance of assessing early working memory in at‐risk populations, while the maternal communication finding highlights potential targets of intervention for improving working memory in toddlers born VLBW.
X‐ray crystallographic and enzymatic analyses of shikimate dehydrogenase from Staphylococcus epidermidis
Authors: Han Cong , Hu Tiancen , Wu Dalei , Qu Su , Zhou Jiahai , Ding Jianping , Shen Xu , Qu Di , Jiang Hualiang
Published: January 2009

Shikimate dehydrogenase (SDH) catalyzes the NADPH‐dependent reduction of 3‐dehydroshikimate to shikimate in the shikimate pathway. In this study, we determined the kinetic properties and crystal structures of Staphylococcus epidermidis SDH (SeSDH) both in its ligand‐free form and in complex with shikimate. SeSDH has a kcat of 22.8 s−1 and a Km of 73 μm towards shikimate, and a Km of 100 μm towards NADP. The overall folding of SeSDH comprises the N‐terminal α/β domain for substrate binding and the C‐terminal Rossmann fold for NADP binding. The active site is within a large groove between the two domains. Residue Tyr211, normally regarded as important for substrate binding, does not interact with shikimate in the binary SeSDH–shikimate complex structure. However, the Y211F mutation leads to a significant decrease in kcat and a minor increase in the Km for shikimate. The results indicate that the main function of Tyr211 may be to stabilize the catalytic intermediate during catalysis. The NADP‐binding domain of SeSDH is less conserved. The usually long helix specifically recognizing the adenine ribose phosphate is substituted with a short 310 helix in the NADP‐binding domain. Moreover, the interdomain angle of SeSDH is the widest among all known SDH structures, indicating an inactive ‘open’ state of the SeSDH structure. Thus, a ‘closing’ process might occur upon NADP binding to bring the cofactor close to the substrate for catalysis.
Modified C‐Reactive Protein Is Expressed by Stroke Neovessels and Is a Potent Activator of Angiogenesis In Vitro
Authors: Slevin Mark , Matou‐Nasri Sabine , Turu Marta , Luque Ana , Rovira Norma , Badimon Lina , Boluda Susana , Potempa Lawrence , Sanfeliu Coral , De Vera Nuria , Krupinski Jerzy
Published: January 2009

Native C‐reactive protein (nCRP) is a pentameric oligo‐protein and an acute phase reactant whose serum expression is increased in patients with inflammatory disease. We have identified by immunohistochemistry, significant expression of a tissue‐binding insoluble modified version or monomeric form of CRP (mCRP) associated with angiogenic microvessels in peri‐infarcted regions of patients studied with acute ischaemic stroke. mCRP, but not nCRP was expressed in the cytoplasm and nucleus of damaged neurons. mCRP co‐localized with CD105, a marker of angiogenesis in regions of revascularisation. In vitro investigations demonstrated that mCRP was preferentially expressed in human brain microvessel endothelial cells following oxygen‐glucose deprivation and mCRP (but not column purified nCRP) associated with the endothelial cell surface, and was angiogenic to vascular endothelial cells, stimulating migration and tube formation in matrigel more strongly than fibroblast growth factor‐2. The mechanism of signal transduction was not through the CD16 receptor. Western blotting showed that mCRP stimulated phosphorylation of the key down‐stream mitogenic signalling protein ERK1/2. Pharmacological inhibition of ERK1/2 phosphorylation blocked the angiogenic effects of mCRP. We propose that mCRP may contribute to the neovascularization process and because of its abundant presence, be important in modulating angiogenesis in both acute stroke and later during neuro‐recovery.
Leveling the Playing Field: Negotiating Opportunities and Recognition in Gendered Jobs
Authors: Roth Louise Marie
Published: January 2009

In gendered jobs, how do women and men negotiate opportunities to perform and receive recognition for their accomplishments? Women face disadvantages negotiating the workplace, especially in male‐dominated positions, while men receive advantages even in female‐dominated jobs. This article uses research on gender inequality on Wall Street to illustrate how gender schemas sustain gender inequality in career opportunities, access to networks and mentors, and evaluations of performance. Women on Wall Street faced exclusionary networks and assumptions that men were more competent at finance. The article then focuses on strategies that some women on Wall Street have used to successfully negotiate career opportunities and recognition. These strategies include developing expertise, specializing in financial products, and seeking positions with objective performance criteria.