bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of familial hypercholesterolaemia in children and adolescents
Authors: Justo Robert N
Published: October 2011

Familial hypercholesterolaemia is a disorder of low‐density lipoprotein (LDL) cholesterol metabolism, which is associated with the onset of vascular changes associated with coronary heart disease in childhood. This disorder has co‐dominant transmission with a prevalence of one in 500 in the general population. Cascade screening is the most effective method of identifying children. Children in the at‐risk group should have their cholesterol levels checked between the age of 2 and 10 years. Children with LDL cholesterol levels ≥ 3.4 mmol/L are likely to suffer from this disorder, although at this level there is a significant false positive rate. Molecular genetic testing is available for the LDL receptor gene, APOB gene and the PCSK9 gene. This is the most specific test for familial hypercholesterolaemia but has a false negative rate of 20–50%. Once diagnosed, treatment should be considered in children with an LDL cholesterol level ≥ 4.9 mmol/L. If the child has two other risk factors or a positive family history, this threshold should be lowered to ≥4.1 mmol/L. Guidelines recommend that treatment should be commenced by the age of 10 years, although some advise waiting until menarche in females. Statin therapy is currently recommended as first line treatment. Randomised placebo trials have shown that statin therapy reduces LDL cholesterol levels by 25% and is not associated with increased risk of adverse events. These are short‐term studies, and longer follow‐up will be required to definitively prove efficacy and safety.
Conjunctival dacryops in two golden retrievers
Authors: Lamagna Barbara , Peruccio Claudio , Guardascione Anna , Paciello Orlando , Costagliola Alessandro , Giudice Chiara , Rondena Marco , Saccone Maurizio , Uccello Valeria , Lamagna Francesco
Published: October 2011

Two 5‐month‐old golden retriever dogs were referred for the evaluation of a mass arising from the left ventrolateral conjunctiva of the lower eyelid. The masses were externally located, deemed to be cystic in nature, and were surgically removed, and in one case, 0.15 mL of clear fluid was collected. Cytological examination of the aspirated fluid revealed proteinaceous, basophilic amorphous material, and few epithelial cells with foamy cytoplasm and small nuclei. No micro‐organisms were detected. Histological examination of the cysts showed a wall composed of single to double cell layers. The cells were cuboidal to flattened, nonciliated, lined with mild submucosal connective tissues and slight inflammation composed of lymphocytes, plasma cells, and rare macrophages. In some areas, lobules of acinar glandular tissue were observed. To the authors’ knowledge, this is the first case report of conjunctival dacryops in dogs. The complete surgical removal of the cysts was curative in both cases.
Phylogenetic relationships of the Rhacophorus everetti‐group and implications for the evolution of reproductive modes in Philautus (Amphibia: Anura: Rhacophoridae)
Authors: Hertwig Stefan T. , Das Indraneil , Schweizer Manuel , Brown Rafe , Haas Alexander
Published: October 2011

Hertwig, S., Das, I., Schweizer, M., Brown, R., & Haas, A. (2011). Phylogenetic relationships of the Rhacophorus everetti‐group and implications for the evolution of reproductive modes in Philautus (Amphibia: Anura: Rhacophoridae). —Zoologica Scripta, 41, 29–46.

This study presents the first phylogenetic analysis of the enigmatic Rhacophorus everetti species group and the first description of its unique tadpole. A total sample of 95 12S and 16S mitochondrial rDNA sequences were compiled including new sequence data from 28 rhacophorid species. Based on 1332 and 1407 bp, respectively, and on the gap coding method applied, a new hypothesis about the phylogeny of rhacophorid tree frogs from Sundaland was obtained. While Rhacophorus was uncovered as a polyphyletic assemblage, the monophyly of the Bush Frogs of the genus Philautus, including the Rhacophorus everetti‐group, is robustly supported. We, therefore, transfer the everetti‐group to the genus Philautus. As a second step, we recognise Philautus macroscelis (comb. nov.) from Borneo and P. everetti (comb. nov.) from Palawan as distinct allopatric species. Molecular and morphological evidence clearly indicates that each is a distinct lineage with a unique ancestry and discrete evolutionary fate. Moreover, close phylogenetic relationships of several Philautus species from Borneo to taxa from outside Borneo were recovered; P. everetti and P. macroscelis being the only one example. These findings indicate a complex biogeographical history of Sundaland Bush Frogs, which can only be explained by repeated dispersal and vicariance events between the Asian mainland and the Sunda islands. Finally, a single tadpole discovered on Gunung Kinabalu was matched genetically to P. macroscelis. Features of its peculiar external morphology suggest that this larva is endotrophic and possibly nidicolous. A comparable reproductive biology was formerly unknown in rhacophorid tree frogs. The presence of a free‐swimming tadpole in Philautus challenges the notion that terrestrial direct development represents an apomorphic character unambiguously shared by all members of this genus. The implications for the evolution of reproductive modes in Bush Frogs are discussed in a phylogenetic context.
Demonstrating online teaching in the disciplines. A systematic approach to activity design for online synchronous tuition
Authors: Macdonald Janet , Campbell Anne
Published: October 2011

The introduction of new online technologies in Higher Education brings many challenges for staff, not only in learning new functionality, but in deciding how to use tools in pedagogically effective ways. This case study describes an initiative at the Open University (UK), which set out to provide professional development in the use of an online synchronous tool. It focuses on the teaching potential in a number of different disciplines. The account describes the development of this resource, together with the perspectives of those engaged in producing it. We have illustrated a systematic approach to activity design inspired by threshold concepts and troublesome knowledge. We found that the demonstrators appreciated both the approach and the peer support available. The approach helped with identification of appropriate areas for intervention as well as in the design of activities and authentic use of tools. We suggest that the protocol adopted here is of great relevance to those adopting a blended approach, when deciding what tutor‐student interventions should take place, and when.

Practitioner Notes

What is already known about this topic

A wide range of factors influence the way a discipline is taught.

Professional development needs to integrate these factors if it is to be relevant.

Teachers need to understand why they should use online tools before they are likely to adopt them.

Theories of threshold concepts and troublesome knowledge can help to identify significant or difficult areas of curriculum. This can be helpful in deciding when to intervene and facilitate learning.

What this paper adds

It highlights the teaching potential of an online synchronous tool using example activities within various disciplines.

It illustrates a systematic approach to identifying areas of student need, before planning appropriate times in the course for facilitation using online activities.

It highlights the potential for a community approach to online activity development and for sharing activities amongst tutors.

Implications for practice and/or policy

In blended learning strategies staff need to shift their thinking from presenting content in a lecture to putting content online and devoting their time to facilitation.

This paper provides a systematic approach to deciding at what stages staff may need to facilitate understanding of significant concepts or skills in the course. It also helps in identifying the aims of any learning activities.

Online activities for synchronous tools are time consuming to develop and benefit from collaborative effort in the development and sharing of resources.
Standardising antisocial personality disorder: the social shaping of a psychiatric technology
Authors: Pickersgill Martyn
Published: October 2011

The Diagnostic and Statistical Manual of Mental Disorders (DSM) is one of the most influential and controversial terminological standards ever produced. As such, it continues to provide a valuable case study for sociologists of health and illness. In this article I take as my focus one particular DSM category: antisocial personality disorder (ASPD). The analysis charts the shifting understandings of personality disorders associated with antisocial behaviour in the DSM and in US psychiatry more broadly from 1950 to the present day. Memos, letters and minutes produced by the DSM‐III committee and held in the American Psychiatric Association (APA) archives ground the discussion. Finally, the article explores more recent constructions of antisocial personality disorder and examines the anticipatory discourse pertaining to the rewriting of this category expected in the forthcoming DSM‐5. In presenting an in‐depth socio‐historical narrative of the development – and potential future – of standards for pathological antisociality, this analysis casts new light on the ASPD construct. In particular, by considering it as a technology, I elaborate how processes of path dependency constrain innovation and how imaginaries of users and publics are implicated in the APA debates constitutive of this.
The meanings and practices of barebacking among Brazilian internet users
Authors: da Silva Luís Augusto Vasconcelos , Iriart Jorge Alberto Bernstein
Published: October 2011

This article originates from an online ethnography on barebacking (intentional unprotected anal sex) in Brazil, between the years 2004 and 2008. More specifically, some elements or conceptual dimensions present in discussions on barebacking will be examined. Based on internet discussion forums and 23 open online interviews, using the Windows Live Messenger program, it was possible to organise the practice of barebacking into two principal modalities: more extensive and involving greater contact and partial or involving reduced risks. The individuals who practise bareback sex may experience situations that include various forms of barebacking during their lives, such as the men who contract HIV and try to develop strategies to reduce the risks in their sexual interactions by, for example, avoiding ejaculating inside their partner or trying to establish sexual relationships with men of the same serological status. Therefore, in general, the different motivations for barebacking constitute a frontier region (of tension) between the pleasure of sensory contact and the risk of infection. Beyond producing a dichotomy between pleasure and risk, the various meanings described by the potential barebackers must be taken into account.
Bounding endogenous regressor coefficients using moment inequalities and generalized instruments
Authors: Choi Jin‐young , Lee Myoung‐jae
Published: October 2011

The main approach to deal with regressor endogeneity is instrumental variable estimator (IVE), where an instrumental variable (IV) m is required to be uncorrelated to the regression model error term u (COR(m,u)=0) and correlated to the endogenous regressor. If COR(m,u)≠0 is likely, then m gets discarded. But even when COR(m,u)≠0, often one has a good idea on the sign of COR(m,u). This article shows how to make use of the sign information on COR(m,u) to obtain an one‐sided bound on the endogenous regressor coefficient, calling m a ‘generalized instrument’ or ‘generalized instrumental variable (GIV)’. If there are two GIV's m1 and m2, then a two‐sided bound or an improved one‐sided bound can be obtained. Our approach is simple, needing only IVE; no non‐parametrics, nor any ‘tuning constants’. Specifically, the usual IVE is carried out, and the only necessary modification is that the estimate for the endogenous regressor coefficient is interpreted as a lower/upper bound depending on the prior notion on the sign of COR(m,u) and some estimable moment. A real data application is done to Korean household data with two or more children to illustrate our approach for the issue of child quantity–quality trade‐off.
INCOME DISPARITIES IN THE ENLARGED EU: SOCIO‐ECONOMIC, SPECIALISATION AND GEOGRAPHICAL CLUSTERS
Authors: CHAPMAN SHEILA A. , MELICIANI VALENTINA
Published: October 2011

The paper contains a non‐parametric analysis of regional convergence in the enlarged EU over the period 1998–2005. It finds overall convergence but growing within country disparities, especially due to the behaviour of newcomer regions. It also finds strong (but falling) spatial correlation of per‐capita income. Starting from this evidence, the paper considers the role of socio‐economic features, specialisation patterns and geographical factors in explaining within countries disparities. Overall we find that partly specialisation but more evidently socio‐economic clusters have a good explanatory power while simple geographical factors do not explain within countries divergence. This does not mean that spatial factors are not important: rather it means that agglomeration alone cannot explain a complex and variegated pattern of growth where structural and socio‐economic factors appear to be playing an important and increasing role.
The Encroachment of Value Pragmatism on Pluralism: The Practice of the Valuation of Urban Green Space Using Stated‐preference Approaches
Authors: LO ALEX Y.
Published: October 2011

Monetary valuation of urban green space using stated‐preference approaches has gained prominence among pragmatic urban researchers, but the resultant reduced potential for value pluralism has gone unnoticed. There is confusion on value concepts. Public‐social values have been treated as private‐economic ones. The potential for reflecting the multiple values and social roles of urban nature is thus reduced. Being method‐driven, the practice fails to relate to the claimed objective of comprehensively portraying it. There is inadequate understanding of the philosophy and psychology of the values associated with urban green space, despite its multi‐faceted role being widely recognized. This results in an unreflective acceptance of economic techniques. More work is needed to clarify issues concerning the manifestation and theoretical foundation of value pluralism. Deliberative approaches may be a potential complementary or alternative valuation method.

L'évaluation monétaire de l'espace vert urbain à l'aide de modèles basés sur les préférences déclarées a pris de l'importance chez les auteurs pragmatiques de la recherche urbaine, mais le fait qu'elle affaiblit le potentiel du pluralisme des valeurs est passé inaperçu. Les concepts de valeur se mélangent. Les valeurs publiques sociales ont été traitées comme des valeurs privées économiques. La capacité de refléter les multiples valeurs et rôles sociaux de la nature urbaine a donc été réduite. La pratique, mue par la méthode, ne rejoint pas l'objectif exprimé de représenter intégralement cet espace. Bien que les différentes facettes de son rôle soient généralement reconnues, il se crée une compréhension inadéquate de la philosophie et de la psychologie des valeurs associées à l'espace vert urbain. C'est ainsi que les techniques économiques sont acceptées sans discernement. Il faut envisager d'autres études pour clarifier les aspects liés à la manifestation et au fondement théorique du pluralisme des valeurs. Des approches délibératives pourraient constituer une méthode d'évaluation complémentaire ou alternative.
A survey of the physicochemical and microbiological quality of ultra‐heat‐treated whole milk in Brazil during their shelf life
Authors: DE LONGHI ROSANA , SPINARDI NATALÍ , NISHIMURA MARLISE TALISSA , MIYABE MARCIA YUKARI , ARAGON‐ALEGRO LINA CASALE , DE REZENDE COSTA MARCELA , DE SANTANA ELSA HELENA WALTER
Published: October 2011

The objective was to evaluate the quality of important brands of ultra‐heat‐treated (UHT) milk marketed in the northern of Parana State, Brazil, during the shelf life of the product. Five brands were analysed at 30, 60, 90 and 120 days after UHT milk production. The physicochemical quality of the milk was assessed in terms of fat content, titratable acidity, density, freezing point depression, total solids, solids‐not‐fat, proteolysis and alcohol stability. Microbiological quality was assessed by the enumeration of aerobic mesophilic micro‐organisms. None of the brands complied with all the physicochemical standards. Two brands met all applicable microbiological requirements. Gelation was observed from 90 days of storage onwards in all brands.
Lifestyle intervention on diet and exercise reduced excessive gestational weight gain in pregnant women under a randomised controlled trial
Authors: Hui A , Back L , Ludwig S , Gardiner P , Sevenhuysen G , Dean H , Sellers E , McGavock J , Morris M , Bruce S , Murray R , Shen GX
Published: October 2011

Please cite this paper as: Hui A, Back L, Ludwig S, Gardiner P, Sevenhuysen G, Dean H, Sellers E, McGavock J, Morris M, Bruce S, Murray R, Shen G. Lifestyle intervention on diet and exercise reduced excessive gestational weight gain in pregnant women under a randomised controlled trial. BJOG 2012;119:70–77.

Objective  To examine the effect of an exercise and dietary intervention during pregnancy on excessive gestational weight gain (EGWG), dietary habit and physical activity in pregnant women.

Design  Randomised controlled trial.

Setting  Community‐based study.

Population  Nondiabetic urban‐living pregnant women (<26 weeks of gestation).

Methods  Participants in the intervention group were provided with community‐based group exercise sessions, instructed home exercise and dietary counselling between 20 and 36 weeks of gestation. Participants in both groups received physical activity and food intake surveys at enrolment and 2 months after the enrolment.

Main outcome measures  Prevalence of EGWG and measures of physical activity and food intakes between the two groups.

Results  A total of 190 pregnant women, 88 in the control group and 102 in the intervention group, completed the study. Decreased daily intakes of calorie, fat, saturated fat and cholesterol were detected in participants in the intervention group at 2 months after enrolment compared with the control group (P < 0.01). Participants in the intervention group had higher physical activity 2 months after enrolment compared with the control group (P < 0.01). The lifestyle intervention during pregnancy reduced the prevalence of EGWG in the intervention group compared with the control group (P < 0.01) according to the guidelines of the Institute of Medicine.

Conclusion  The findings suggest that lifestyle intervention during pregnancy increased physical activity, improved dietary habits and reduced EGWG in urban‐living pregnant women.
Modulatory effects of the CCR5 antagonist maraviroc on microglial pro‐inflammatory activation elicited by gp120
Authors: Lisi Lucia , Tramutola Antonella , De Luca Andrea , Navarra Pierluigi , Dello Russo Cinzia
Published: October 2011

J. Neurochem. (2012) 120, 106–114.

Despite important clinical benefits of the highly active antiretroviral therapy, neurological disorders affect approximately 50% of AIDS patients. In the brain, infected microglia release pro‐inflammatory mediators as well as human immunodeficiency virus type 1 (HIV‐1) proteins, like the envelope protein gp120, that sustain inflammation and mediate neuronal damage. Gp120 allows the virus entry in the host cells via binding to the CD4 receptor together with a specific co‐receptor (CCR5/CXCR4). The antiretroviral drug maraviroc is a CCR5 receptor antagonist, approved for the treatment of HIV‐experienced patients. By interfering with a chemokine receptor, highly expressed in microglia, maraviroc has the potential to modulate their activation during HIV‐1 infection. To test this hypothesis, primary cultures of rat cortical microglia were activated by gp120. Gp120CN54, a protein derived by macrophage (M)‐tropic viruses, showed strong pro‐inflammatory action, thus it was used to test the effects of maraviroc. The latter displayed opposite effects, depending on whether or not interferon‐γ (IFNγ) was also present in the system. IFNγ significantly enhanced gp120 proinflammatory activity, possibly via up‐regulation of CCR5 receptor expression. In this experimental paradigm, maraviroc significantly increased microglial activation, thus suggesting that its chronic use can exacerbate neuronal pathology, especially in HIV‐experienced patients with higher cerebral IFNγ levels.
Identifying priority areas for reducing species vulnerability to climate change
Authors: Crossman Neville D. , Bryan Brett A. , Summers David M
Published: October 2011

Aim The dimensions of species vulnerability to climate change are complex, and this impedes efforts to provide clear advice for conservation planning. In this study, we used a formal framework to assess species vulnerability to climate change quantifying exposure, sensitivity and adaptive capacity and then used this information to target areas for reducing vulnerability at a regional scale.

Location The 6500‐km2Mount Lofty Ranges region in South Australia.

Methods We quantified the vulnerability of 171 plant species in a fragmented yet biologically important agro‐ecological landscape, typical of many temperate zones globally. We specified exposure, using three climate change scenarios; sensitivity, as the adverse impact of climate change on species’ spatial distribution; and adaptive capacity, as the ability of species to migrate calculated using dispersal kernels. Priority areas for reducing vulnerability were then identified by incorporating these various components into a single priority index.

Results Climate change had a variable impact on species distributions. Those species whose range decreased or shifted geographically were attributed higher sensitivity than those species that increased geographic range or remained unchanged. The ability to adapt to range changes in response to shifting climates varies both spatially and between species. Areas of highest priority for reducing vulnerability were found at higher altitudes and lower latitudes with increasing severity of climate change.

Main conclusions Our study demonstrates the use of a single spatially explicit index that identifies areas in the landscape for targeting specific conservation and restoration actions to reduce species vulnerability to climate change. Our index can be transferred to other regions around the world in which climate change poses an increasing threat to native species.
Satellite surface reflectance improves habitat distribution mapping: a case study on heath and shrub formations in the Cantabrian Mountains (NW Spain)
Authors: Morán‐Ordóñez Alejandra , Suárez‐Seoane Susana , Elith Jane , Calvo Leonor , de Luis Estanislao
Published: October 2011

Aim  We aim to map the distribution of four heath and shrub formations constituting habitats of high conservation priority in Europe, whose occurrence is strongly dependent on human activities. Specifically, we assess whether the use of LANDSAT data in habitat distribution modelling may account for land use management, allowing accurate mapping of real distribution patterns. In particular, we explore whether reflectance values may be a better alternative to other remote sensing data traditionally used in modelling approaches (i.e. spectral vegetation indices and classified land cover maps). Finally, we test whether modelling performance is affected by the ecological traits of the dominant species of the target formations.

Location  Cantabrian Mountains (NW Spain).

Methods  We generated maps for the four formations (two specialists vs. two generalists) using MaxEnt. First, we ran the models with environmental predictors only (topography, climate, lithology and human disturbances). Then, we compared the advantages of including, in turn, different data derived from LANDSAT imagery: reflectance values (corresponding to different wavelength channels of the multispectral image), a spectral index and a land cover map. We assessed changes in explanatory power and also in the formation’s predicted distribution patterns.

Results  Formations dominated by specialist species were accurately mapped on a base of environmental variables only, whereas those dominated by generalists were overpredicted. Average mean temperature, southness and distance to urban areas were the variables contributing most in predictions of environmental models. LANDSAT channels increased the accuracy of all models, but mainly those for formations dominated by generalist species. They showed advantages against other remote sensing data traditionally used in modelling approaches.

Main conclusions  Habitat distribution models allowed accurate mapping of heath and shrub formations. The use of reflectance values as predictors improved the accuracy of the models, particularly for formations dominated by generalist species, supplying environmental information that was otherwise unavailable.
Pharmacological characterization of rat amylin receptors: implications for the identification of amylin receptor subtypes
Authors: Bailey RJ , Walker CS , Ferner AH , Loomes KM , Prijic G , Halim A , Whiting L , Phillips ARJ , Hay DL
Published: October 2011

BACKGROUND AND PURPOSE Amylin (Amy) is an important glucoregulatory peptide and AMY receptors are clinical targets for diabetes and obesity. Human (h) AMY receptor subtypes are complexes of the calcitonin (CT) receptor with receptor activity‐modifying proteins (RAMPs); their rodent counterparts have not been characterized. To allow identification of the most clinically relevant receptor subtype, the elucidation of rat (r) AMY receptor pharmacology is necessary.

EXPERIMENTAL APPROACH Receptors were transiently transfected into COS‐7 cells and cAMP responses measured in response to different agonists, with or without antagonists. Competition binding experiments were performed to determine rAmy affinity.

KEY RESULTS rCT was the most potent agonist of rCT(a) receptors, whereas rAmy was most potent at rAMY1(a) and rAMY3(a) receptors. rAmy bound to these receptors with high affinity. Rat α‐calcitonin gene‐related peptide (CGRP) was equipotent to rAmy at both AMY receptors. Rat adrenomedullin (AM) and rAM2/intermedin activated all three receptors but were most effective at rAMY3(a). AC187, AC413 and sCT8‐32 were potent antagonists at all three receptors. rαCGRP8‐37 displayed selectivity for rAMY receptors over rCT(a) receptors. rAMY8‐37 was a weak antagonist but was more effective at rAMY1(a) than rAMY3(a).

CONCLUSIONS AND IMPLICATIONS AMY receptors were generated by co‐expression of rCT(a) with rRAMP1 or 3, forming rAMY1(a) and rAMY3(a) receptors, respectively. CGRP was more potent at rAMY than at hAMY receptors. No antagonist tested was able to differentiate the rAMY receptor subtypes. The data emphasize the need for and provide a useful resource for developing new CT or AMY receptor ligands as pharmacological tools or potential clinical candidates.

LINKED ARTICLES This article is part of a themed section on Secretin Family (Class B) G Protein‐Coupled Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue‐1
Using microdialysis to analyse the passage of monovalent nanobodies through the blood–brain barrier
Authors: Caljon G , Caveliers V , Lahoutte T , Stijlemans B , Ghassabeh GH , Van Den Abbeele J , Smolders I , De Baetselier P , Michotte Y , Muyldermans S , Magez S , Clinckers R
Published: October 2011

BACKGROUND AND PURPOSE Nanobodies are promising antigen‐binding moieties for molecular imaging and therapeutic purposes because of their favourable pharmacological and pharmacokinetic properties. However, the capability of monovalent nanobodies to reach targets in the CNS remains to be demonstrated.

EXPERIMENTAL APPROACH We have assessed the blood–brain barrier permeability of Nb_An33, a nanobody against the Trypanosoma brucei brucei variant‐specific surface glycoprotein (VSG). This analysis was performed in healthy rats and in rats that were in the encephalitic stage of African trypanosomiasis using intracerebral microdialysis, single photon emission computed tomography (SPECT) or a combination of both methodologies. This enabled the quantification of unlabelled and 99mTc‐labelled nanobodies using, respectively, a sensitive VSG‐based nanobody‐detection elisa, radioactivity measurement in collected microdialysates and SPECT image analysis.

KEY RESULTS The combined read‐out methodologies showed that Nb_An33 was detected in the brain of healthy rats following i.v. injection, inflammation‐induced damage to the blood–brain barrier, as in the late encephalitic stage of trypanosomiasis, significantly increased the efficiency of passage of the nanobody through this barrier. Complementing SPECT analyses with intracerebral microdialysis improved analysis of brain disposition. There is clear value in assessing penetration of the blood–brain barrier by monovalent nanobodies in models of CNS inflammation. Our data also suggest that rapid clearance from blood might hamper efficient targeting of specific nanobodies to the CNS.

CONCLUSIONS AND IMPLICATIONS Nanobodies can enter the brain parenchyma from the systemic circulation, especially in pathological conditions where the blood–brain barrier integrity is compromised.
OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies
Authors: Roth Megan , Obaidat Amanda , Hagenbuch Bruno
Published: October 2011

The human organic anion and cation transporters are classified within two SLC superfamilies. Superfamily SLCO (formerly SLC21A) consists of organic anion transporting polypeptides (OATPs), while the organic anion transporters (OATs) and the organic cation transporters (OCTs) are classified in the SLC22A superfamily. Individual members of each superfamily are expressed in essentially every epithelium throughout the body, where they play a significant role in drug absorption, distribution and elimination. Substrates of OATPs are mainly large hydrophobic organic anions, while OATs transport smaller and more hydrophilic organic anions and OCTs transport organic cations. In addition to endogenous substrates, such as steroids, hormones and neurotransmitters, numerous drugs and other xenobiotics are transported by these proteins, including statins, antivirals, antibiotics and anticancer drugs. Expression of OATPs, OATs and OCTs can be regulated at the protein or transcriptional level and appears to vary within each family by both protein and tissue type. All three superfamilies consist of 12 transmembrane domain proteins that have intracellular termini. Although no crystal structures have yet been determined, combinations of homology modelling and mutation experiments have been used to explore the mechanism of substrate recognition and transport. Several polymorphisms identified in members of these superfamilies have been shown to affect pharmacokinetics of their drug substrates, confirming the importance of these drug transporters for efficient pharmacological therapy. This review, unlike other reviews that focus on a single transporter family, briefly summarizes the current knowledge of all the functionally characterized human organic anion and cation drug uptake transporters of the SLCO and the SLC22A superfamilies.

LINKED ARTICLES BJP recently published a themed section on Transporters. To view the papers in this section visit http://dx.doi.org/10.1111/bph.2011.164.issue‐7
Bilobetin ameliorates insulin resistance by PKA‐mediated phosphorylation of PPARα in rats fed a high‐fat diet
Authors: Kou Xin‐Hui , Zhu Mei‐Feng , Chen Dai , Lu Yi , Song Hui‐Zhu , Ye Jian‐Lin , Yue Lin‐Feng
Published: October 2011

BACKGROUND AND PURPOSE The amelioration of insulin resistance by bilobetin is closely related to its hypolipidaemic effect. The aim of the present study was to determine the insulin‐sensitizing mechanism of bilobetin by elucidating its effect on lipid metabolism.

EXPERIMENTAL APPROACH Rats fed a high‐fat diet were treated with bilobetin for either 4 or 14 days before applying a hyperinsulinaemic–euglycaemic clamp. Triglyceride and fatty acids labelled with radioactive isotopes were used to track the transportation and the fate of lipids in tissues. The activity of lipid metabolism‐related enzymes and β‐oxidation rate were measured. Western blot was used to investigate the phosphorylation, translocation and expression of PPARα in several tissues and cultured cells. The location of amino acid residues subjected to phosphorylation in PPARα was also studied.

KEY RESULTS Bilobetin ameliorated insulin resistance, increased the hepatic uptake and oxidation of lipids, reduced very‐low‐density lipoprotein triglyceride secretion and blood triglyceride levels, enhanced the expression and activity of enzymes involved in β‐oxidation and attenuated the accumulation of triglycerides and their metabolites in tissues. Bilobetin also increased the phosphorylation, nuclear translocation and activity of PPARα accompanied by elevated cAMP level and PKA activity. Threonine‐129–alanine and/or serine‐163–alanine mutations on the PPARα genes and PKA inhibitors prevented the effects of bilobetin on PPARα. However, cells overexpressing PKA appeared to stimulate the phosphorylation, nuclear translocation and activity of PPARα.

CONCLUSIONS AND IMPLICATIONS Bilobetin treatment ameliorates hyperlipidaemia, lipotoxicity and insulin resistance in rats by stimulating PPARα‐mediated lipid catabolism. PKA activation is crucial for this process.
Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments
Authors: Keravis Thérèse , Lugnier Claire
Published: October 2011

Cyclic nucleotide phosphodiesterases (PDEs) that specifically inactivate the intracellular messengers cAMP and cGMP in a compartmentalized manner represent an important enzyme class constituted by 11 gene‐related families of isozymes (PDE1 to PDE11). Downstream receptors, PDEs play a major role in controlling the signalosome at various levels of phosphorylations and protein/protein interactions. Due to the multiplicity of isozymes, their various intracellular regulations and their different cellular and subcellular distributions, PDEs represent interesting targets in intracellular pathways. Therefore, the investigation of PDE isozyme alterations related to various pathologies and the design of specific PDE inhibitors might lead to the development of new specific therapeutic strategies in numerous pathologies.

This manuscript (i) overviews the different PDEs including their endogenous regulations and their specific inhibitors; (ii) analyses the intracellular implications of PDEs in regulating signalling cascades in pathogenesis, exemplified by two diseases affecting cell cycle and proliferation; and (iii) discusses perspectives for future therapeutic developments.
So what do we call GPR18 now?
Authors: Alexander SPH
Published: October 2011

The further characterization of the orphan GPCR GPR18 conducted by McHugh et al. in this issue of the British Journal of Pharmacology has generated a pharmacological profile that raises some interesting questions about the nomenclature of this receptor and may also prompt some questions about the pharmacological definition of the classical cannabinoid receptors, CB1 and CB2.

LINKED ARTICLES This article is a commentary on McHugh et al., pp. 2414–2424 of this issue and is part of a themed section on Cannabinoids in Biology and Medicine. To view McHugh et al. visit http://dx.doi.org/10.1111/j.1476‐5381.2011.01497.x. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue‐8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue‐7
Role of neurosteroids in the anticonvulsant activity of midazolam
Authors: Dhir Ashish , Rogawski Michael A
Published: October 2011

BACKGROUND AND PURPOSE Midazolam is a short‐acting benzodiazepine that is widely used as an i.v. sedative and anticonvulsant. Besides interacting with the benzodiazepine site associated with GABAA receptors, some benzodiazepines act as agonists of translocator protein (18 kDa) (TSPO) to enhance the synthesis of steroids, including neurosteroids with positive modulatory actions on GABAA receptors. We sought to determine if neurosteroidogenesis induced by midazolam contributes to its anticonvulsant action.

EXPERIMENTAL APPROACH Mice were pretreated with neurosteroid synthesis inhibitors and potentiators followed by midazolam or clonazepam, a weak TSPO ligand. Anticonvulsant activity was assessed with the i.v. pentylenetetrazol (PTZ) threshold test.

KEY RESULTS Midazolam (500–5000 µg·kg−1, i.p.) caused a dose‐dependent increase in seizure threshold. Pretreatment with the neurosteroid synthesis inhibitors finasteride, a 5α‐reductase inhibitor, and a functional TSPO antagonist PK 11195, reduced the anticonvulsant action of midazolam. The anticonvulsant action of midazolam was enhanced by the neurosteroidogenic drug metyrapone, an 11β‐hydroxylase inhibitor. In contrast, the anticonvulsant action of clonazepam (100 µg·kg−1) was reduced by finasteride but not by PK 11195, indicating a possible contribution of neurosteroids unrelated to TSPO.

CONCLUSION AND IMPLICATIONS Enhanced endogenous neurosteroid synthesis, possibly mediated by an interaction with TSPO, contributed to the anticonvulsant action of midazolam. Enhanced neurosteroidogenesis may also be a factor in the actions of other benzodiazepines, even those that only weakly interact with TSPO.
‘But when are they going to produce some artwork?’ Against Pastiche: Issue‐Based Art and Authorship within the Key Stage 3 Curriculum
Authors: Kirlew Stefanie
Published: October 2011

Ideas and issues based contemporary art is often seen as something to be avoided in schools, as the controversial subjects that it broaches are often perceived as problematic and inappropriate. However, by censoring education, it can be seen that educators are missing vital opportunities to confront the relevant personal, social, political and cultural issues that shape young peoples' lives in our postmodern, contemporary society. This article reflects on the experiences of an artist/teacher gained through the Recreating Landscapes (Illuminate Project), which aimed to utilise LeWitt's concept of the ideas ‘machine’ to broaden the way that Key Stage 3 art is taught and explore student voice. The construct of the teacher as giver of knowledge was challenged, informed by Barthes' work on the deconstruction of the modernist concept of Authorship. Issues were derived from a pupil voice workshop and the ownership of response to this stimulus belonged to the students. The aim was to challenge mimetic, technical achievement often favoured in ‘traditional’ school art pedagogy, allowing ideas and discussion to be the lynchpin, shifting away from the emphasis commonly placed on outcomes. Through this practice it was hoped that the ‘landscape’ of the learning environment would be recreated: a discursive setting where issues perceived as ‘challenging’ could be broached in a supportive environment, enabled by a reconsidered, culturally relevant pedagogy.
The Artist‐Teacher in the Classroom and Changes in the Teacher–Student Relationship, with Reference to the Issue of Censorship
Authors: Stanhope Clare
Published: October 2011

This article examines a case study of an A‐Level student's work and how the inclusion and integration of my own practice as artist‐teacher into the classroom has changed the teacher‐student relationship, resulting in a more collaborative environment. It investigates how the mutual sharing of practice supports opportunities for pupils to discuss and investigate socially provocative issues and raises the issues of censorship. Through the case study the following questions will be addressed: how a collaborative classroom environment impacts on process and outcomes; the effect of discussing social/ political/ cultural issues within the art and design classroom; and the issues of censorship and ownership within the environment of a comprehensive secondary school context.
‘The falcon cannot hear the falconer …’. The Pedagogical Turn and the Negative Space of Irish Art Education
Authors: Granville Gary
Published: October 2011

Current education policy discourse in Ireland, as elsewhere, is replete with reference to innovation, creativity and enterprise. Meanwhile, the ‘pedagogical turn’ is a dominant motif in current discourse in art practice, curating and critique, in Ireland and internationally. This article firstly considers some of the implications of the ‘turn’ as a concept in art and education. In that context, it goes on to address changing patterns of curriculum design, development and reform in Ireland. Next, it describes the evolution of Irish education policy over the past decade in the context of global experiences. The particular experience of art education in Ireland is then considered in the light of the curriculum culture and the wider policy discourses already identified. Finally, some implications of the Irish experience are addressed, in terms of art practice at the edges of art education, and art education at the edges of education practice.
From the Saltmarsh and the Deershelter
Authors: Key Paul
Published: October 2011

When we think about approaches to teaching and learning in art and design education the diverse and complex role of the teacher soon becomes apparent. Teachers often find themselves working through situations which require them to shift between subject‐ and learner‐centred approaches, where they negotiate authority and freedom in their teaching relationships. On closer inspection the tensions found in these negotiations reveal contradictions for teachers, where they try to do one thing but cannot avoid doing another. The article explores these perplexing and contradictory experiences as possible encounters where we can speculate about ourselves as teachers and discover powerful opportunities for learning. It aims to do this through the critical lens of Tubbs's (2005) ‘Philosophy of the teacher’. Tubbs's analysis provides an opportunity to closely examine the tensions in teaching approaches, and proposes the possibility of their contradiction as educational. In addition, the article explores Henri Lefebvre's ‘moments of presence’, suggesting that encounters in our lives, which appear to exist at the intersection of one thing and another, where we find ourselves experiencing a contradiction, offer exciting possibilities for teaching and learning. The article builds its ideas around landscape encounters, from the saltmarsh and the deer‐shelter. It uses these encounters with landscapes to locate experiences of contradiction, and to work out how a teacher could respond.
In the Rat, Chronic Intermittent Ethanol Exposure During Adolescence Alters the Ethanol Sensitivity of Tonic Inhibition in Adulthood
Authors: Fleming Rebekah L. , Acheson Shawn K. , Moore Scott D. , Wilson Wilkie A. , Swartzwelder H. Scott
Published: October 2011

Background:  Alcohol drinking by adolescents is a major public health concern. Adolescents tend to drink in a chronic, intermittent, that is, “binge,” pattern, and such patterns of ethanol exposure are associated with increased risk of neurotoxicity and the development of alcohol use disorders (Crews et al., 2000; Hunt, 1993). Both adolescent humans and rats are more sensitive to acute ethanol‐induced memory impairment than adults (Acheson et al., 1998; Markwiese et al., 1998). Furthermore, in rats, chronic intermittent ethanol (CIE) exposure during adolescence produces a long‐lasting, perhaps permanent, maintenance of the adolescent high sensitivity to ethanol’s amnestic effects (White et al., 2000a). We have previously shown that acute ethanol increases tonic inhibitory current mediated by extrasynaptic GABAA receptors more efficaciously in dentate granule cells (DGCs) from adolescent than adult rats (Fleming et al., 2007). In this study, we determined if CIE during adolescence produced long‐lasting changes in this tonic current.

Methods:  Adolescent rats were subjected to a CIE exposure regimen and allowed to mature to full adulthood. Whole‐cell voltage‐clamp measurements of tonic inhibitory current and mean phasic current were made in vitro in hippocampal brain slices.

Results:  CIE exposure during adolescence increased the ethanol sensitivity of tonic inhibitory current mediated by extrasynaptic GABAA receptors and decreased the ethanol sensitivity of phasic, synaptic GABAA receptor‐mediated current in adult DGCs.

Conclusions:  CIE exposure during adolescence produces long‐lasting changes in the function and ethanol sensitivity of extrasynaptic GABAA receptors in DGCs. These changes appear to “lock‐in” and maintain the high adolescent sensitivity to ethanol in these cells. Furthermore, greater ethanol enhancement of tonic inhibition in the hippocampal formation after CIE is consistent with the greater sensitivity to ethanol‐induced memory impairment after adolescent CIE. This finding represents the first demonstration of a long‐term, memory‐related cellular effect of CIE during adolescence, and the “lock‐in” of adolescent ethanol sensitivity that these results suggest could represent a conceptual step forward in understanding the vulnerability of the adolescent brain to alcohol.
The Impact of Alcohol on BCG‐Induced Immunity Against Mycobacterium tuberculosis
Authors: Porretta Elizabeth , Happel Kyle I. , Teng Xu S. , Ramsay Alistair , Mason Carol M.
Published: October 2011

Background:  Alcoholics are at heightened risk for developing active tuberculosis. This study evaluates chronic alcohol consumption in a murine model of vaccination with Mycobacterium bovis Bacille Calmette–Guèrin (BCG) and subsequent pulmonary infection with virulent Mycobacterium tuberculosis.

Methods:  BALB/c mice were administered the Lieber–DeCarli liquid ethanol diet or pair‐fed the liquid control diet for 3 weeks either before or after subcutaneous vaccination with M. bovis BCG. At least 3 weeks after BCG vaccination, groups of mice on the aforesaid diets were challenged with intratracheal infection with M. tuberculosis H37Rv. Lung mycobacterial burden, and lung and lung‐associated lymph node CD4+ lymphocyte production of tuberculosis‐specific interferon (IFN)‐γ were assayed. Popliteal lymph node lymphocytes from both dietary regimens undergoing BCG vaccination (in the absence of M. tuberculosis infection) were also evaluated for purified protein derivative–induced IFN‐γ production by ELISpot assay.

Results:  Mice begun on alcohol prior to vaccination with M. bovis BCG demonstrated impaired control of pulmonary challenge with virulent M. tuberculosis, as well as impaired lung CD4+ and popliteal lymph node T‐cell IFN‐γ responses. If BCG vaccination was delivered prior to initiation of alcohol feeding, the mice remained protected against a subsequent challenge with M. tuberculosis, and BCG‐induced immunity was not impaired in either the lung or the popliteal lymph nodes.

Conclusions:  Alcohol consumption blunts the development of the adaptive immune response to M. bovis BCG vaccination, which impairs the control of a secondary challenge with M. tuberculosis, but only if the alcohol exposure is begun prior to BCG vaccination. These results provide insight into mechanisms by which alcohol consumption impairs antimycobacterial immunity, including in response to vaccination and subsequent pathogenic challenge.