bluuebunny/crossref_metadata_2025 huggingface dataset:
Insularity and the evolution of melanism, sexual dichromatism and body size in the worldwide‐distributed barn owl
Authors: ROULIN A. , SALAMIN N.
Published: March 2010

Island biogeography has provided fundamental hypotheses in population genetics, ecology and evolutionary biology. Insular populations usually face different feeding conditions, predation pressure, intraspecific and interspecific competition than continental populations. This so‐called island syndrome can promote the evolution of specific phenotypes like a small (or large) body size and a light (or dark) colouration as well as influence the evolution of sexual dimorphism. To examine whether insularity leads to phenotypic differentiation in a consistent way in a worldwide‐distributed nonmigratory species, we compared body size, body shape and colouration between insular and continental barn owl (Tyto alba) populations by controlling indirectly for phylogeny. This species is suitable because it varies in pheomelanin‐based colouration from reddish‐brown to white, and it displays eumelanic black spots for which the number and size vary between individuals, populations and species. Females are on average darker pheomelanic and display more and larger eumelanic spots than males. Our results show that on islands barn owls exhibited smaller and fewer eumelanic spots and lighter pheomelanic colouration, and shorter wings than on continents. Sexual dimorphism in pheomelanin‐based colouration was less pronounced on islands than continents (i.e. on islands males tended to be as pheomelanic as females), and on small islands owls were redder pheomelanic and smaller in size than owls living on larger islands. Sexual dimorphism in the size of eumelanic spots was more pronounced (i.e. females displayed much larger spots than males) in barn owls living on islands located further away from a continent. Our study indicates that insular conditions drive the evolution towards a lower degree of eumelanism, smaller body size and affects the evolution of sexual dichromatism in melanin‐based colour traits. The effect of insularity was more pronounced on body size and shape than on melanic traits.
Sex chromosome evolution in the clam shrimp, Eulimnadia texana
Authors: WEEKS S. C. , BENVENUTO C. , SANDERSON T. F. , DUFF R. J.
Published: March 2010

Chromosomes that determine sex are predicted to evolve differently than autosomes: a lack of recombination on one of the two sex chromosomes is predicted to allow an accumulation of deleterious alleles that eventually leads to reduced functionality and potential physical degradation of the nonrecombining chromosome. Because these changes should occur at an elevated evolutionary rate, it is difficult to find appropriate species in which to test these evolutionary predictions. The unique genetic sex‐determining mechanism of the crustacean Eulimnadia texana prevents major chromosome degeneration because of expression of both ‘proto‐sex’ (i.e. early stage of development) chromosomes in homozygous form (ZZ and WW). Herein, we exploit this unique genetic system to examine the predicted accumulation of deleterious alleles by comparing both homogametic sexual types to their heterogametic counterpart. We report differences in crossing over in a sex‐linked region in the ZW hermaphrodites (∼ 3%) relative to the ZZ males (∼ 21%), indicative of cross‐over suppression in the ZW hermaphrodites. Additionally, we report that both ZZ and WW genotypes have reduced fitness relative to ZW hermaphrodites, which is consistent with the prediction of harboured recessive mutations embedded on both the Z and the W chromosomes. These results suggest that the proto‐sex chromosomes in E. texana accumulate recessive deleterious alleles. We hypothesize that recessive deleterious alleles of large effect cannot accumulate because of expression in both ZZ and WW individuals, keeping both chromosomes from losing significant function.
Developmental acclimation affects clinal variation in stress resistance traits in Drosophila buzzatii
Authors: SARUP P. , LOESCHCKE V.
Published: March 2010

Patterns of clinal genetic variation in Drosophila are often characterized after rearing at constant temperatures. However, clinal patterns might change after acclimation if populations differ in their plastic response to fluctuating environments. We studied longevity, starvation and heat knock‐down resistance after development at either constant or fluctuating temperatures in nine Drosophila buzzatii populations collected along an altitudinal gradient in Tenerife, Spain. Flies that developed at fluctuating temperatures had higher stress resistance despite experiencing a slightly lower average temperature than those at constant temperatures. Genetic variation along the gradient was found in both stress‐resistance traits. Because QST values greatly exceeded FST values, genetic drift could not explain this diversification. In general, differences among populations were larger after rearing at fluctuating temperatures, especially in heat knock‐down, for which clinal patterns disappeared when flies were reared at constant temperatures. This result emphasizes the importance of determining whether populations originating from different environments differ in their plastic responses to stress.
Heritability of anti‐predatory traits: vigilance and locomotor performance in marmots
Authors: BLUMSTEIN D. T. , LEA A. J. , OLSON L. E. , MARTIN J. G. A.
Published: March 2010

Animals must allocate some proportion of their time to detecting predators. In birds and mammals, such anti‐predator vigilance has been well studied, and we know that it may be influenced by a variety of intrinsic and extrinsic factors. Despite hundreds of studies focusing on vigilance and suggestions that there are individual differences in vigilance, there have been no prior studies examining its heritability in the field. Here, we present one of the first reports of (additive) genetic variation in vigilance. Using a restricted maximum likelihood procedure, we found that, in yellow‐bellied marmots (Marmota flaviventris), the heritability of locomotor ability (h2 = 0.21), and especially vigilance (h2 = 0.08), is low. These modest heritability estimates suggest great environmental variation or a history of directional selection eliminating genetic variation in these traits. We also found a significant phenotypic (rP = −0.09 ± 0.04, P = 0.024) and a substantial, but not significant, genetic correlation (rA = −0.57 ± 0.28, P = 0.082) between the two traits (slower animals are less vigilant while foraging). We found no evidence of differential survival or longevity associated with particular phenotypes of either trait. The genetic correlation may persist because of environmental heterogeneity and genotype‐by‐environment interactions maintaining the correlation, or because there are two ways to solve the problem of foraging in exposed areas: be very vigilant and rely on early detection coupled with speed to escape, or reduce vigilance to minimize time spent in an exposed location. Both strategies seem to be equally successful, and this ‘locomotor ability‐wariness’ syndrome may therefore allow slow animals to compensate behaviourally for their impaired locomotor ability.
Spatial distribution ofHevea brasiliensistrunk phloem necrosis within a plot: aggregation but no evidence of constraint on cumulated growth
Authors: Do F. C. , Pierret A. , Couteron P. , Lesturgez G. , Boithias L. , Isarangkool Na Ayutthaya S. , Junjittakarn J. , Gonkhamdee S. , Maeght J. L. , Hartmann C. , Nandris D.
Published: March 2010

Trunk phloem necrosis (TPN) is a major constraint in rubber (Hevea brasiliensis) plantations. Current knowledge supports a scenario of a multi‐factor physiological ‘disease’ caused by an accumulation of endogenous and exogenous stresses. Without evidence of a pathogen, the apparent spread of the syndrome from tree to tree along the planting line, strongly suggested the implication of a major local soil constraint. The objectives of the study were to address, within a plot, three points of the above scenario: the short‐distance aggregation of affected trees; their correspondence with local micro‐areas facing the highest environmental constraints; and the relative weakness of TPN trees that had accumulated several stresses since planting. The study was conducted in a young rubber tree stand (clone RRIM 600) of Northeast Thailand, where the number of TPN affected individuals was 8% after 3 years of tapping. Trunk girth and trunk basal area were used as indicators of local environmental constraints. Spatial patterns were analysed using the framework of marked point processes andKfunctions. The results confirmed the short‐distance aggregation of TPN affected trees. But, TPN trees were not located within micro‐areas where trees had a lower trunk basal area than average. Hence, the clusters of TPN do not occur in the most constraining environmental micro‐areas of the plot in terms of growth since planting. Moreover, from comparison of girth, current girth increment and height of bark consumption, we infer that TPN trees were not smaller and less vigorous than other trees before the syndrome outbreak. Finally, our conclusions mean the previous scenario driven by major soil constraints becomes a ‘more complex scenario’ in which specific soil conditions (not the most constraining in term of cumulated growth), possibly in interaction with inter‐individual competition, induce a late and subtle stress favouring a necrotic reaction against tapping stress.
Ecology and distribution of Armillaria species in Norway
Authors: Keča N. , Solheim H.
Published: March 2010

The occurence of Armillaria species was assessed in Norway, enabling the northern‐most distribution of this genus to be determined in Europe. Four Armillaria species were found in Norway. Armillaria borealis was the most common species occurring on woody vegetation to the permafrost zone (ca. 69°N). Armillaria cepistipes was present in southern and central Norway, but was not found further than 66°N. Armillaria solidipes and Armillaria gallica were rare, found at only one locality each; 59°40′ and 59°32′, respectively. Armillaria species were found on 14 hosts, but there was no significant difference between occurrence of A. borealis and A. cepistipes on declining and dead trees. Phylogenetic analyses separated each species into separate clades. All isolates of A. borealis, except one, and most isolates of A. solidipes were in separate clades. However, a subclade within the A. borealis clade was formed of two A. ostoyae and one A. borealis isolates. Two small A. cepistipes genets were found in a declining oak stand.
Organotypic culture of human bone marrow adipose tissue
Authors: Uchihashi Kazuyoshi , Aoki Shigehisa , Shigematsu Masamori , Kamochi Noriyuki , Sonoda Emiko , Soejima Hidenobu , Fukudome Kenji , Sugihara Hajime , Hotokebuchi Takao , Toda Shuji
Published: March 2010

The precise role of bone marrow adipose tissue (BMAT) in the marrow remains unknown. The purpose of the present study was therefore to describe a novel method for studying BMAT using 3‐D collagen gel culture of BMAT fragments, immunohistochemistry, ELISA and real‐time reverse transcription–polymerase chain reaction. Mature adipocytes and CD45+ leukocytes were retained for >3 weeks. Bone marrow stromal cells (BMSC) including a small number of lipid‐laden preadipocytes and CD44+/CD105+ mesenchymal stem cell (MSC)‐like cells, developed from BMAT. Dexamethasone (10 µmol/L), but not insulin (20 mU/mL), significantly increased the number of preadipocytes. Dexamethasone and insulin also promoted leptin production and gene expression in BMAT. Adiponectin production by BMAT was <0.8 ng/mL under all culture conditions. Dexamethasone promoted adiponectin gene expression, while insulin inhibited it. This finding suggests that dexamethasone, but not insulin, may serve as a powerful adipogenic factor for BMAT, in which adiponectin protein secretion is normally very low, and that BMAT may exhibit a different phenotype from that of the visceral and subcutaneous adipose tissues. BMAT–osteoblast interactions were also examined, and it was found that osteoblasts inhibited the development of BMSC and reduced leptin production, while BMAT inhibited the growth and differentiation of osteoblasts. The present novel method proved to be useful for the study of BMAT biology.
Immunostaining of gastric cancer with neuroendocrine differentiation: Reg IV‐positive neuroendocrine cells are associated with gastrin, serotonin, pancreatic polypeptide and somatostatin
Authors: Sentani Kazuhiro , Oue Naohide , Noguchi Tsuyoshi , Sakamoto Naoya , Matsusaki Keisuke , Yasui Wataru
Published: March 2010

We previously reported that Reg IV is associated with neuroendocrine (NE) differentiation in gastric cancers. The aim was to examine which NE hormone products are related to Reg IV‐positive NE cells and their roles in gastric cancers. In the present study, we performed immunohistochemical analysis in a tissue microarray (TMA) of a consecutive series of 630 cases with ten different antibodies, including chromogranin A, synaptophysin and neural cell adhesion molecule (NCAM) as NE differentiation markers, and gastrin, serotonin, calcitonin, gastrin‐releasing peptide (GRP), pancreatic polypeptide (PP), somatostatin and glucagon as NE hormones. In 630 cases, we identified 205 (33%) with NE differentiation and 147 (23%) positive for Reg IV. Reg IV‐positive cases showed NE differentiation more frequently than Reg IV‐negative cases (P < 0.0001). In 205 cases with NE differentiation, Reg IV‐positive cases expressed serotonin (P= 0.0032) and somatostatin (P= 0.036) more frequently than Reg IV‐negative cases. Double immunofluorescence staining revealed co‐expression of Reg IV with gastrin, serotonin and PP. These results indicate that Reg IV might be a mediating factor of several NE hormones.
A comparison of severely injured trauma patients admitted to level 1 trauma centres in Queensland and Germany
Authors: Nijboer Johanna M. M. , Wullschleger Martin E. , Nielsen Susan E. , McNamee Anitia M. , Lefering Rolf , Ten Duis Hendrik‐Jan , Schuetz Michael A.
Published: March 2010

Background:  The allocation of a trauma network in Queensland is still in the developmental phase. In a search for indicators to improve trauma care both locally as state‐wide, a study was carried out comparing trauma patients in Queensland to trauma patients in Germany, a country with 82.4 million inhabitants and a well‐established trauma system.

Methods:  Trauma patients ≥15 years of age, with an Injury Severity Score (ISS) ≥ 16 admitted to the Princess Alexandra Hospital (PAH) and to the 59 German hospitals participating in the Trauma Registry of the German Society for Trauma Surgery (DGU‐G) during the year 2005 were retrospectively identified and analysed.

Results:  Both cohorts are comparable when it comes to demographics and injury mechanism, but differ significantly in other important aspects. Striking is the low number of primary admitted patients in the PAH cohort: 58% versus 83% in the DGU‐G cohort. PAH patients were less physiologically deranged and less severely injured: ISS 25.2 ± 9.9 versus 29.9 ± 13.1 (P < 0.001). Subsequently, they less often needed surgery (61% versus 79%), ICU admission (49% versus 92%) and had a lower mortality: 9.8% versus 17.9% of the DGU‐G cohort.

Conclusions:  Relevant differences were the low number of primary admissions, the lesser severity of injuries, and the low mortality of the patients treated at the PAH. These differences are likely to be interrelated and Queensland's size and suboptimal organization of trauma care may have played an important role.
Comparison of open and closed staff‐assisted glove donning on the nature of surgical glove cuff contamination
Authors: Jones Christopher , Brooker Ben , Genon Michel
Published: March 2010

Background:  We have observed that surgical glove cuffs commonly fold over during an operation, exposing the inside of the glove cuff to the sterile field and wound, a potential source of contamination if the inside of the glove cuff has been in contact with the fingers during glove donning. We hypothesize that open staff‐assisted gloving results in more inside‐glove cuff contamination than a closed staff‐assisted technique.

Method:  We performed a blinded, randomized study comparing open and closed staff‐assisted glove donning. Two surgeons were gloved 20 times after covering their fingers and hands with GlitterBug(TM) powder. The gloves were turned inside out and the distance of GlitterBug(TM) powder from the free edge of the cuff was measured.

Results:  Staff‐assisted open glove donning was associated with significantly more glove cuff contamination than closed staff‐assisted glove donning (P= 0.001).

Conclusion:  Given glove cuff ‘turn down’ intra‐operatively, we strongly recommend closed staff‐assisted gloving.
Phaeochromocytoma‐associated critical peripheral ischaemia
Authors: Lutchman D. , Buchholz S. , Keightley C.
Published: March 2010

Limb Ischaemia is an exceptional complication of catecholamine toxicity caused by a phaeochromocytoma. We present a middle‐aged female patient with severe subacute peripheral ishaemia, gangrene and eventual amputation of all four distal limbs due to a large non‐metastatic left adrenal gland phaeochromocytoma and summarise the available literature concerning previously reported cases.
Practical guidelines for treating inflammatory bowel disease safely with anti‐tumour necrosis factor therapy in Australia
Authors: Connell W. , Andrews J. M. , Brown S. , Sparrow M.
Published: March 2010

Anti‐tumour necrosis factor (TNF) therapy is an effective but expensive option for treating inflammatory bowel disease (IBD). Its use is generally reserved for patients with severe refractory disease, often involving long‐term administration. Anti‐TNF therapy has the potential to be associated with various adverse effects, such as infection, malignancy and immunogenicity. Clinicians and patients should be familiar with these possibilities and adopt appropriate precautions prior to and during treatment to minimize risk. Guidelines have been developed for Australian prescribers intending to use anti‐TNF therapy in IBD by a Working Party commissioned by IBD‐Australia, a Special Interest Group affiliated with the Gastroenterology Society of Australia.
Fracture and fatigue study of unidirectional glass/epoxy laminate under different mode of loading
Authors: KENANE M. , BENMEDAKHENE S. , AZARI Z.
Published: March 2010

Interlaminar fracture is the dominant failure mechanism in most advanced composite materials. The delaminating behaviour of materials is quantified in terms of the strain energy release rate G. In this paper, the experimental measurements of the fatigue delaminating growth for some combinations of energy release rate mode ratio have been carried out on unidirectional glass/epoxy laminates. On this base the constants in the Paris equation have been determined for each GII/GT considered modal ratio. The fatigue threshold strain energy release rate Δ GTth, below which delaminating doesn't occur, were measured. Three type specimens were tested, namely: double cantilever beam (DCB), end‐loaded split (ELS) and mixed‐mode bending (MMB) under mode I, mode II and mixed‐mode (I + II) loading, respectively. Scanning electron microscopy techniques were used to identify the fatigue delamination growth mechanisms and to define the differences between the various modes of fracture.
Regional Cultural Differences and Ethical Perspectives within the United States: Avoiding Pseudo‐emic Ethics Research
Authors: MACNAB BRENT , WORTHLEY REGINALD , JENNER STEVE
Published: March 2010

National cultures are often described as if they were homogeneous in spite of notable regional differences. As one example, there are significant differences between two distinct regions of the United States, Hawaii and Florida. This study provides a platform to exemplify a more regionally aware position for cultural and ethics research. Using select Hofstede cultural dimensions, regional differences were found in relation to both collectivism/individualism and uncertainty avoidance. The Hawaii sample had higher levels of collectivism and uncertainty avoidance, demonstrating unique regional‐cultural patterns within the United States. Regional samples were examined for potential differences in their general perception of what constitutes ethical business practice. While honesty appeared as a key trait across samples, significant differences emerged in the magnitude of importance between samples for integrity (which was more significant for the Hawaii sample) and loyalty (which was more significant for the Florida sample).
Rap and the Recording Industry
Authors: BEAVER WILLIAM
Published: March 2010

Nothing in the music industry has been more controversial than so‐called gangsta rap. This article examines the behavior of the major recording labels involved with rap music, and how they have responded to calls from the minority community and various politicians to clean up the offensive lyrics associated with the genre. In large part, the companies have basically ignored their critics and continued to market gangsta rap because for years it had been so highly profitable. Their basic tactic has been to diffuse responsibility and distance themselves from rap by allowing subsidiaries to handle that part of the business. The industry's behavior is certainly troubling. I argue that, at the very least, the companies should have met the “moral minimum” to avoid harm and correct social injuries by censoring certain lyrics. Unfortunately this never occurred, and, in the end, only declining sales appear to have had any mitigating effects on gangsta rap.
WAGE POLICY IN AN OPEN‐ECONOMY KALECKI–KALDOR MODEL: A SIMULATION STUDY
Authors: von Arnim Rudiger
Published: March 2010

This paper discusses a Post‐Keynesian model of income, production and trade. The one‐country, one‐sector model features Kaleckian investment demand, Kaldorian productivity and a labor market module based on a wage–price spiral. The model is first presented for a closed economy with exogenous real wages; second, for a closed economy with endogenous real wages; third, for an economy open to trade with endogenous real wages. Simulations with different calibrations show key characteristics of the model. Monte Carlo simulations over reasonable parameter ranges shed some light on the effectiveness of wage policies in open economies.
Risk‐Adjusted Measures of Value Creation in Financial Institutions
Authors: Milne Alistair , Onorato Mario
Published: March 2010

Abstract  Many financial institutions assess portfolio decisions using RAROC, the ratio of expected return to risk (or ‘economic’) capital. We use asset pricing theory to determine the appropriate hurdle rate, finding that this varies with the skewness of asset returns. We quantify this discrepancy under a range of assumptions showing that the RAROC hurdle rate differs substantially, being higher by a factor of five or more for equity which has a right skew compared to debt which has a pronounced left skew, and also between different qualities of debt exposure. We discuss implications for both financial institution risk management and supervision.
Shylock and Othello under the Nazis
Authors: Bonnell Andrew G.
Published: March 2010

While the long‐standing historical importance of Shakespeare's plays in the repertoire of German theatres is well‐documented, including even under the ‘Third Reich’, there are misconceptions in some of the literature about the stage history of two plays that one would expect to touch on Nazi racial sensitivities in very different ways: The Merchant of Venice and Othello. It would be natural to expect, as some authors have written, that The Merchant of Venice would lend itself to Nazi antisemitism and that the play would enjoy a particular currency on German stages after 1933, while one would expect Othello, with its theme of inter‐racial sex, to disappear from the stage under the Nazi régime. These assumptions were not borne out by the reality, however, and the stage histories of the two plays under the Nazi régime were more complex. The way in which the Jew Shylock and the Moor Othello were portrayed on the German stage after 1933 was nonetheless tightly constrained by the prescriptions of Nazi racial ideology.

Dass die Werke Shakespeares einen bedeutenden Platz in der Geschichte des deutschen Theaters, auch in der Zeit des ‘Dritten Reichs’, eingenommen haben, darf als allgemein bekannt gelten. Jedoch sind in der theatergeschichtlichen Literatur immer noch irrige Annahmen anzutreffen, was die Bühnengeschichte zweier Shakespeareschen Stücke angeht, die auf verschiedene Weise von besonderer Relevanz für die Rassenideologie des Nationalsozialismus waren: Der Kaufmann von Venedig und Othello. Es läge nahe anzunehmen, wie manche Autoren auch vermutet haben, dass Der Kaufmann von Venedig dem Antisemitismus des NS‐Regimes besonders entgegenkommen würde, wogegen Othello, mit der Thematik der sexuellen Beziehung zwischen den ‘Rassen’ während der NS‐Zeit von der Bühne verschwinden würde. Die eigentliche Bühnengeschichte der jeweiligen Stücke im ‘Dritten Reich’ verlief aber anders, und war in der Wirklichkeit komplizierter als man oft angenommen hat. Nichtsdestoweniger waren Darstellungen des Juden Shylock und des Mohren Othello auf der deutschen Bühne nach 1933 von der NS‐Ideologie zunehmend stark geprägt und mussten innerhalb der durch sie eng gezogenen Grenzen bleiben.
Contralateral versus ipsilateral rTMS of temporoparietal cortex for the treatment of chronic unilateral tinnitus: comparative study
Authors: Khedr E. M. , Abo‐Elfetoh N. , Rothwell J. C. , El‐Atar A. , Sayed E. , Khalifa H.
Published: March 2010

Background:  Repetitive transcranial magnetic stimulation (rTMS) applied over left temporoparietal cortex has been reported to have a long‐term therapeutic effect on tinnitus. We compare the impact of 1 and 25 Hz rTMS delivered either contralateral or ipsilateral to symptoms in 62 patients with unilateral chronic tinnitus.

Material and methods:  Patients were randomly assigned to one of four treatment groups: with stimulation at 1 or 25 Hz applied either ipsilateral or contralateral to symptoms. Two thousand pulses per session were given daily for 2 weeks. Changes in tinnitus handicap inventory (THI), self‐rating scores of loudness, awareness, and annoyance were measured monthly for 10 months. Duration of residual inhibition (RI) and psychiatric morbidity were evaluated monthly for 3 months.

Results:  There was a significant main effect of time (P < 0.0001) and a significant time × side interaction (P = 0.032) between groups. This was because of the fact that contralateral stimulation had a greater effect on THI than ipsilateral stimulation; it was also superior to left side stimulation (P = 0.027). Ratings of loudness improved more after contralateral rTMS (P = 0.037). Twenty patients had no remaining tinnitus after 3 months; the remainder had a significant increase in RI. Patients with the shortest history of tinnitus tended to respond better to rTMS. There was a significant correlation between changes in THI score and changes in Hamilton anxiety and depression scores.

Conclusion:  Ten daily treatments of 1 and 25 Hz rTMS contralateral to the side of tinnitus have a greater beneficial effect on symptoms than either ipsilateral or left side stimulation.
Rising trends in incidence of cutaneous malignant melanoma and their future projections in Catalonia, Spain: increasing impact or future epidemic?
Authors: Marcos‐Gragera R , Vilar‐Coromina N , Galceran J , Borràs J , Clèries R , Ribes J , Gispert R , Izquierdo A , Borràs JM
Published: March 2010

Background  During the past decades, there has been a substantial increase in the incidence of cutaneous malignant melanoma (CMM) among all Caucasian populations. Spain presents one of Europe’s lowest incidence and mortality rates.

Objective  The aim of this study was to analyse the recent trends of CMM incidence and mortality in a region with lower incidence as well as to project their future trends.

Methods  Cutaneous malignant melanoma incidence data were provided by the Tarragona and Girona population‐based cancer registries and mortality data were provided by the Mortality Registry of Catalonia. Time trends of incidence and mortality rates by CMM were assessed through the estimated annual percentages of change of the incidence and mortality age‐standardized rates to the World Standard Population. Projections were based on a Bayesian age–period–cohort model using second order autoregressive effects on age.

Results  During the last 20 years CMM incidence has increased substantially at a faster rate than any other neoplasms in Catalonia, particularly among women and this trend will probably continue for the next several years. Nevertheless, CMM mortality trends have been and probably will remain stable during this period.

Conclusion  Improvements in preventive activities should be implemented to decrease incidence and mortality from this cancer. Monitoring stage‐specific trends in CMM incidence can assess the impact of preventive strategies; for this reason more complete information on diagnostic features of CMM patients in the Spanish population‐based cancer registries are necessary.
Adjuvant triamcinolone acetonide injections in oro‐pharyngeal pemphigus vulgaris
Authors: Mignogna MD , Fortuna G , Leuci S , Adamo D , Dell’Aversana Orabona G , Ruoppo E
Published: March 2010

Background  High‐potency topical and perilesional/intralesional corticosteroids are becoming increasingly useful as adjuvant to treat autoimmune blistering diseases.

Objective  We sought to evaluate the role of perilesional/intralesional triamcinolone acetonide (PITA) injections in reducing the time for first complete clinical remission and the total amount of systemic corticosteroids in oro‐pharyngeal pemphigus vulgaris (OPV) patients, and also the compliance of PITA injections, in terms of satisfaction, pain and discomfort.

Methods  Thirty‐five OPV patients were treated with conventional immunosuppressive therapy (CIST) and received high potency topical corticosteroids (clobetasol and/or methylprednisolone) and/or PITA injections. Patients were grouped as follows: (i) a group of 16 patients was treated with PITA injections and (ii) a group of 19 patients without PITA injections.

Results  Sixteen patients treated with PITA injections and 19 without PITA injections reached complete clinical remission within 126.6 days (SD: 41; 95% CI: 104.7–148.8) and 153.2 days (SD: 97.4; 95% CI: 106.2–200.1) (P = 0.4) respectively. The total amount of corticosteroids in patients treated with PITA and without PITA was 4894 mg (SD: 2832; 95% CI: 3385–6403) and 5312 mg (SD: 4009; 95% CI: 3380–7245) (P = 0.4) respectively. Patients treated with PITA reported a satisfaction score significantly higher than pain (P = 0.0007) and discomfort score (P = 0.0006).

Conclusion  Perilesional/intralesional triamcinolone acetonide injections seems to represent a helpful clinical tool to successfully join CIST, in terms of shortening the time of complete clinical remission, reducing the total amount of corticosteroids and obtaining an acceptable compliance.
Function of the shoulder muscles during arm elevation: an assessment using positron emission tomography
Authors: Omi Rei , Sano Hirotaka , Ohnuma Masahiro , Kishimoto Koshi N. , Watanuki Shoichi , Tashiro Manabu , Itoi Eiji
Published: March 2010

Although 2‐deoxy‐2‐[18F]fluoro‐D‐glucose (FDG) positron emission tomography (PET) has been used for the assessment of skeletal muscle activities, its application to the shoulder muscles is only sparse. The purpose of this study was to investigate the activities of the shoulder muscles during arm elevation using PET. Six healthy volunteers performed an arm elevation exercise before and after FDG injection. The exercise consisted of 200 repetitions of arm elevation in the scapular plane with a 0.25‐kg weight fixed to the wrist on both arms. PET examination was performed 50 min after FDG injection. For control data, PET scan was repeated for each subject on a separate day without any exercise. The volume of interest was established for each shoulder muscle. The subscapularis was divided into three portions (superior, middle, and inferior). The standardized uptake value (SUV) was calculated in each muscle to quantify its activity. The SUVs increased significantly after exercise in the deltoid, supraspinatus, and the superior portion of subscapularis. Among three divided portions of the subscapularis, the SUV of the superior one‐third was significantly greater than the rest of the muscle after exercise. Our current study clearly indicated that there were two functionally different portions in the subscapularis muscle and the superior one‐third played an important role during arm elevation in the scapular plane.
Distinct functionalities of bone morphogenetic protein antagonists during fracture healing in mice
Authors: Dean Daniel B. , Watson John T. , Jin Wu , Peters Charlie , Enders J. T. , Chen Andrew , Moed Berton R. , Zhang Zijun
Published: March 2010

The bone morphogenetic protein (BMP) family of growth factors plays critical roles in bone formation. BMPs are regulated at multiple levels by various BMP antagonists. This study investigated how BMP antagonists are integrated into the cascade of events of bone formation during fracture healing. Forty mice underwent a controlled femur fracture; tissue samples at the fracture site were harvested at days 1, 3, 7, 14 and 21 after fracture, for quantification of the expression of BMPs and BMP antagonists. During fracture healing, BMP‐2, ‐4 and ‐7 were up‐regulated, but BMPR‐1A and BMPR‐2 showed reduced expression after day 14. Among BMP antagonists, the expressions of PRDC, SOST, Smad7, GREM1 and CERBERUS were generally down‐regulated during fracture healing. In contrast, Noggin was significantly up‐regulated in the first week after fracture; 7 days after fracture, other BMP antagonists, including DAN, CHRD, Smad6 and BAMBI, also showed significantly increased expression. In conclusion, this study indicates that BMP antagonists can be divided into two functional groups in relation to fracture healing: (1) those whose suppression may be essential for the initiation of osteogenesis; (2) those that are upregulated and may function in the remodeling of newly formed bone.
Effect of heat treatment on the antibacterial activity of bovine lactoferrin against three foodborne pathogens
Authors: CONESA CELIA , ROTA CARMEN , CASTILLO EDUARDO , PÉREZ MARÍA D , CALVO MIGUEL , SÁNCHEZ LOURDES
Published: March 2010

The effect of different heat treatments on the antimicrobial activity of bovine lactoferrin against Escherichia coli O157:H7, Salmonella enteritidis and Listeria monocytogenes has been studied. We have observed that the heat treatments lower than 85°C for 10 min did not affect the antibacterial activity of the protein. Hydrolysates of bovine lactoferrin were found to be more active than the native protein against the three pathogens. Moreover, the antibacterial effect of bovine lactoferrin was also assayed in milk and whey, and although we found a reduction in the number of viable cells, this reduction was lower than in culture media.
Activation of submucosal 5‐HT3receptors elicits a somatostatin‐dependent inhibition of ion secretion in rat colon
Authors: Yang N , Liu SM , Zheng LF , Ji T , Li Y , Mi XL , Xue H , Ren W , Xu JD , Zhang XH , Li LS , Zhang Y , Zhu JX
Published: March 2010

Background and purpose: 5‐Hydroxytryptamine (5‐HT) is a key regulator of the gastrointestinal system and we have shown that submucosal neuronal 5‐HT3receptors exerted a novel inhibitory effect on colonic ion transport. The aim of the present study was to investigate the precise mechanism(s) underlying this inhibitory effect.

Experimental approach: Mucosa/submucosa or mucosa‐only preparations from rat distal colon were mounted in Ussing chambers for measurement of short‐circuit current (Isc) as an indicator of ion secretion. Somatostatin release was determined with radioimmunoassay. Intracellular cAMP content was measured with enzyme‐linked immunoadsorbent assay (elisa). Immunohistochemical techniques were used to study the expression of 5‐HT3receptors, somatostatin and somatostatin receptors in colonic tissue.

Key results: In rat distal colonic mucosa/submucosa preparations, pretreatment with 5‐HT3receptor antagonists enhanced 5‐HT‐induced increases inIsc. However, in mucosa‐only preparations without retained neural elements, pretreatment with 5‐HT3receptor antagonists inhibited 5‐HT‐induced ΔIsc. Pretreatment with a somatostatin‐2 (sst2) receptor antagonist in mucosa/submucosa preparations augmented 5‐HT‐induced ΔIsc. Combination of sst2and 5‐HT3receptor antagonists did not cause further enhancement of 5‐HT‐induced ΔIsc. Moreover, both sst2and 5‐HT3receptor antagonists enhanced 5‐HT‐induced increase in intracellular cAMP concentration in the mucosa/submucosa preparations. 5‐HT released somatostatin from rat colonic mucosa/submucosa preparations, an effect prevented by pretreatment with 5‐HT3receptor antagonists. Immunohistochemical staining demonstrated the presence of 5‐HT3receptors on submucosal somatostatin neurons and of sst2receptors on colonic mucosa.

Conclusion and implications: Activation of neuronal 5‐HT3receptors in the submucosal plexus of rat colon suppressed 5‐HT‐induced ion secretion by releasing somatostatin from submucosal neurons.
Challenges for and current status of research into positive modulators of AMPA receptors
Authors: Ward Simon E , Bax Benjamin D , Harries Mark
Published: March 2010

AMPA receptors consist of a family of hetero‐oligomeric (tetrameric) receptors arising from four genes, each of which encodes a distinct receptor subunit (GluA1‐4). Recombinant homo‐tetrameric AMPA receptors, comprising four identical subunits, are functionally active and have been used inin vitroassays. However, the many different subunit permutations make possible the functional and anatomical diversity of AMPA receptors throughout the CNS. Furthermore, AMPA receptor subunit stoichiometry influences the biophysical and functional properties of the receptor. A number of chemically diverse positive modulators of AMPA receptor have been identified which potentiate AMPA receptor‐mediated activity in vitro as well as improving cognitive performance in rodents and non‐human primates with several being taken further in the clinic. This review article summarizes the current status in the research on positive allosteric modulation of AMPA receptors and outlines the challenges involved in identifying a chemically distinct series of AMPA receptor positive modulators, addressing the challenges created by the heterogeneity of the AMPA receptor populations and the development of structure‐activity relationships driven by homomeric, recombinant systems on high‐throughput platforms. We also review the role of X‐ray crystallography in the selection and prioritization of targets for lead optimization for AMPA receptor positive modulators.
CB2: a cannabinoid receptor with an identity crisis
Authors: Atwood Brady K , Mackie Ken
Published: March 2010

CB2was first considered to be the ‘peripheral cannabinoid receptor’. This title was bestowed based on its abundant expression in the immune system and presumed absence from the central nervous system. However, multiple recent reports question the absence of CB2from the central nervous system. For example, it is now well accepted that CB2is expressed in brain microglia during neuroinflammation. However, the extent of CB2expression in neurons has remained controversial. There have been studies claiming either extreme‐its complete absence to its widespread expression‐as well as everything in between. This review will discuss the reported tissue distribution of CB2with a focus on CB2in neurons, particularly those in the central nervous system as well as the implications of that presence. As CB2is an attractive therapeutic target for pain management and immune system modulation without overt psychoactivity, defining the extent of its presence in neurons will have a significant impact on drug discovery. Our recommendation is to encourage cautious interpretation of data that have been presented for and against CB2's presence in neurons and to encourage continued rigorous study.

This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visithttp://dx.doi.org/10.1111/j.1476‐5381.2010.00831.x
Pharmacological characterization of the first potent and selective antagonist at the cysteinyl leukotriene 2 (CysLT2) receptor
Authors: Wunder F , Tinel H , Kast R , Geerts A , Becker EM , Kolkhof P , Hütter J , Ergüden J , Härter M
Published: March 2010

Background and purpose: Cysteinyl leukotrienes (CysLTs) have been implicated in the pathophysiology of inflammatory and cardiovascular disorders. Their actions are mediated by CysLT1and CysLT2receptors. Here we report the discovery of 3‐({[(1S,3S)‐3‐carboxycyclohexyl]amino}carbonyl)‐4‐(3‐{4‐[4‐(cyclo‐hexyloxy)butoxy]phenyl}propoxy) benzoic acid (HAMI3379), the first potent and selective CysLT2receptor antagonist.

Experimental approach: Pharmacological characterization of HAMI3379 was performed using stably transfected CysLT1and CysLT2receptor cell lines, and isolated, Langendorff‐perfused, guinea pig hearts.

Key results: In a CysLT2receptor reporter cell line, HAMI3379 antagonized leukotriene D4‐ (LTD4‐) and leukotriene C4‐ (LTC4‐) induced intracellular calcium mobilization with IC50values of 3.8 nM and 4.4 nM respectively. In contrast, HAMI3379 exhibited very low potency on a recombinant CysLT1receptor cell line (IC50> 10 000 nM). In addition, HAMI3379 did not exhibit any agonistic activity on both CysLT receptor cell lines. In binding studies using membranes from the CysLT2and CysLT1receptor cell lines, HAMI3379 inhibited [3H]‐LTD4binding with IC50values of 38 nM and >10 000 nM respectively. In isolated Langendorff‐perfused guinea pig hearts HAMI3379 concentration‐dependently inhibited and reversed the LTC4‐induced perfusion pressure increase and contractility decrease. The selective CysLT1receptor antagonist zafirlukast was found to be inactive in this experimental setting.

Conclusions and implications: HAMI3379 was identified as a potent and selective CysLT2receptor antagonist, which was devoid of CysLT receptor agonism. Using this compound, we showed that the cardiac effects of CysLTs are predominantly mediated by the CysLT2receptor.
Simultaneous detection of intracellular target and off‐target binding of small molecule cancer drugs at nanomolar concentrations
Authors: Glauner Heike , Ruttekolk Ivo R , Hansen Kerrin , Steemers Ben , Chung Yi‐Da , Becker Frank , Hannus Stefan , Brock Roland
Published: March 2010

Background and purpose: In vitroassays that determine activities of drug candidates with isolated targets have only limited predictive value for activities in cellular assays. Poor membrane permeability and off‐target binding are major reasons for such discrepancies. However, it still difficult to directly analyse off‐target binding at the same time as target binding, on a subcellular level. Here, we present a combination of fluorescence correlation spectroscopy (FCS) and fluorescence cross‐correlation spectroscopy (FCCS) as a solution to this problem.

Experimental approach: The well‐established dihydrofolate reductase inhibitor methotrexate and the kinase inhibitors PD173956 and purvalanol B were conjugated via polyethylene glycol linkers with the fluorophore Cy5. The cellular uptake and subcellular distribution of these compounds in single human cancer‐derived cells were investigated by confocal laser scanning microscopy. In addition, molecular interactions inside the cell with the respective target proteins and off‐target binding were detected simultaneously in the nanomolar range by FCCS and FCS, respectively, using cells expressing green fluorescent protein fusion proteins of dihydrofolate reductase and Abelson kinase 1.

Key results: Large differences in the interaction patterns were found for these compounds. For methotrexate‐Cy5, drug–target interactions could be detected and dissociation constants determined. In contrast, PD173956‐Cy5 showed strong interactions with intracellular high‐molecular weight structures, other than its target.

Conclusions and implications: The combination of FCS and FCCS provides a powerful means to assess subcellular pharmacokinetics and dynamics of drug candidates at nanomolar concentrations.
Effects of ionotropic glutamate receptor antagonists on rat dural artery diameter in an intravital microscopy model
Authors: Chan KY , Gupta S , de Vries R , Danser AHJ , Villalón CM , Muñoz‐Islas E , MaassenVanDenBrink A
Published: March 2010

Background and purpose:  During migraine, trigeminal nerves may release calcitonin gene‐related peptide (CGRP), inducing cranial vasodilatation and central nociception; hence, trigeminal inhibition or blockade of craniovascular CGRP receptors may prevent this vasodilatation and abort migraine headache. Several preclinical studies have shown that glutamate receptor antagonists affect the pathophysiology of migraine. This study investigated whether antagonists of NMDA (ketamine and MK801), AMPA (GYKI52466) and kainate (LY466195) glutamate receptors affected dural vasodilatation induced by α‐CGRP, capsaicin and periarterial electrical stimulation in rats, using intravital microscopy.

Experimental approach:  Male Sprague‐Dawley rats were anaesthetized and the overlying bone was thinned to visualize the dural artery. Then, vasodilator responses to exogenous (i.v. α‐CGRP) and endogenous (released by i.v. capsaicin and periarterial electrical stimulation) CGRP were elicited in the absence or presence of the above antagonists.

Key results:  α‐CGRP, capsaicin and periarterial electrical stimulation increased dural artery diameter. Ketamine and MK801 inhibited the vasodilator responses to capsaicin and electrical stimulation, while only ketamine attenuated those to α‐CGRP. In contrast, GYKI52466 only attenuated the vasodilatation to exogenous α‐CGRP, while LY466195 did not affect the vasodilator responses to endogenous or exogenous CGRP.

Conclusions and implications:  Although GYKI52466 has not been tested clinically, our data suggest that it would not inhibit migraine via vascular mechanisms. Similarly, the antimigraine efficacy of LY466195 seems unrelated to vascular CGRP‐mediated pathways and/or receptors. In contrast, the cranial vascular effects of ketamine and MK801 may represent a therapeutic mechanism, although the same mechanism might contribute, peripherally, to cardiovascular side effects.