bluuebunny/crossref_metadata_2025 huggingface dataset:
Research and the RIBA. Lea's Pottery: The call to arms answered
Authors: Pringle Jack
Published: May 2003

Our profession suffers from a poor research base and what research we do is undervalued.
We need to do something about this. We also need to address prejudices that have become
established in the construction industry as exemplified by the outrageous references to
architecture in the Fairclough Report. The good news with regard to both issues is that,
for once, practice and the schools have a coincidence of interest.
Three views on the RAE Design and the computer. RAE 2: an official enquiry?
Authors: Pringle Jack
Published: May 2003

I am deeply concerned by the issues raised by Bill Hillier and Philip Steadman's article in arq 6/3 (pp203–207).
Three views on the RAE Design and the computer. RAE 3: let's all look ahead
Authors: Davidson Ian
Published: May 2003

Architectural education is under pressure: economic pressure to enrol more students, political pressure to award more degrees and more recently pressure from the Architects Registration Board (ARB) and RIBA to maintain and, in some cases, to improve standards. If this was not in itself enough, the schools must also undertake increasing amounts of research to obtain essential, additional HEFCE funding.
OPTIMAL INFLATION TAX AND STRUCTURAL REFORM
Authors: de V. Cavalcanti Tiago V. , Villamil Anne P.
Published: May 2003

This paper analyzes the optimal inflation tax in economies with structural imperfections in labor, commodity, and currency markets. The Friedman rule is a classic result in economics that claims that the optimal monetary policy is to set a zero nominal interest rate. This Ramsey equilibrium is robust in a wide range of environments without imperfections in input, output, or financial markets. In many developing countries, however, a large fraction of activity takes place in the “informal” sector. Roughly speaking, the informal sector is the untaxed and unregulated market sometimes referred to as the underground economy. We obtain three results. First, we show that when structural imperfections such as an informal sector exist, the optimal inflation tax is positive. Second, we show that structural imperfections introduce an important asymmetry in the welfare cost function. Third, we provide quantitative results.
Ambiguity and transfer in bilingual first language acquisition?
Authors: TREFFERS-DALLER JEANINE
Published: May 2003

Natascha Müller presents a very interesting analysis of the structure of the German subordinate clause in bilingual first language acquisition. The main issue in this paper is to explain the fact that some bilingual children – but not all of them – display non-target language structures in German subordinate clauses. That is, the finite verb does not appear in the final position of the subordinate clause. These non-target structures can in part be explained by transfer, but this cannot be the whole story, because some monolingual children produce these structures as well. Bilingual children, though, appear to have problems with the German subordinate clause more frequently than monolingual children. Interestingly, acquiring the target structures is a slow process for children who produce non-target structures. Ivar, the French-German child Müller discusses in most detail, for example, needs two years to acquire the correct position of the finite verb in German subordinate clauses. Müller argues that the problems arise because the input children receive is ambiguous: the finite verb does not always appear in the finite position in German subordinate clauses in adult speech. The ambiguity of this situation opens the way to transfer. In their uncertainty, the children turn to their other language as a relief strategy.
Frauen- und Männerbilder in Witzen. Eine qualitative Inhaltsanalyse
Authors: Hinz Arnold
Published: May 2003

Zusammenfassung: Zur Analyse und zum Vergleich der in Witzen vermittelten Bilder der Geschlechter wurden 453 Frauenwitze, 586 Blondinenwitze und 858 Männerwitze nach den Prinzipien der qualitativen Inhaltsanalyse interpretiert und kategorisiert. Das Witzmaterial wurde neueren Buchveröffentlichungen sowie Witzsammlungen aus dem Internet entnommen, wobei nur Witze berücksichtigt wurden, in denen jemand ausschließlich aufgrund seiner Geschlechtszugehörigkeit zum Witzobjekt wird. Als auffälligster Befund konnte erhoben werden, dass in den Witzen über Frauen (insbesondere in den Blondinenwitzen) das Männerwunschbild einer attraktiven, sexuell potenten und willigen Frau entworfen wird, während in den Witzen über Männer der Mann als überflüssiges und sexuell impotentes Wesen mit kümmerlichen Sexualorganen erscheint. Diskutiert wird der Bezug zur Geschlechtsstereotypforschung.
Schwarze Kassen, weiße Westen?
Authors: Jonas Eva , Graupmann Verena , Fischer Peter , Greitemeyer Tobias , Frey Dieter
Published: May 2003

Zusammenfassung: Die Parteispendenaffäre der christlich-demokratischen Union (CDU) Ende des Jahres 1999 wurde zur Untersuchung selektiver Informationssuche und -bewertungsprozesse im Feld herangezogen. Auf Grundlage der Dissonanztheorie wurde vorhergesagt, dass die Parteispendenaffäre insbesondere bei Wähler/innen der CDU/CSU zu kognitiver Dissonanz führte, welche durch einen verzerrten Umgang mit Informationen abgebaut werden konnte. In Übereinstimmung mit dieser Hypothese zeigten die Ergebnisse, dass CDU/CSU-Wähler/innen im Vergleich zu SPD-Wähler/innen eine stärkere Suche nach konsonanten und eine Vernachlässigung dissonanter Informationen aufwiesen und zugleich konsonante Informationen als wichtiger und interessanter bewerteten. Weiterhin zeigte sich, dass Personen, denen vor der Informationssuche ihre Parteipräferenz bewusst vor Augen geführt wurde, indem sie diese schriftlich darlegen und begründen sollten, im Vergleich zu solchen Personen, die hierzu nicht aufgefordert wurden, nach mehr dissonanten Informationen suchten, - obwohl sie diese bei der Informationsbewertung weiterhin als weniger wichtig bewerteten als die konsonanten Informationen. Dieses Ergebnis wird dahingehend interpretiert, dass Personen, denen Verzerrungen beim Umgang mit Informationen bewusst werden, versuchen gegen zu steuern, um auf diese Weise eine “Illusion der Objektivität” aufrechtzuerhalten. Theoretische und praktische Implikationen der Ergebnisse werden diskutiert.
Präferenzkonsistenz und Geteiltheit von Information
Authors: Greitemeyer Tobias , Schulz-Hardt Stefan , Frey Dieter
Published: May 2003

Zusammenfassung: In Gruppendiskussionen werden mehr Informationen genannt, die allen Gruppenmitgliedern bereits vor der Gruppendiskussion zugänglich sind (geteilte Informationen) als Informationen, die nur einzelnen Gruppenmitgliedern zuvor bekannt sind (ungeteilte Informationen). Weiterhin fließen geteilte Informationen stärker in Gruppenentscheidungen ein als ungeteilte Informationen. Da in vielen der hierzu durchgeführten Experimente die Geteiltheit von Informationen mit der Präferenzkonsistenz von Informationen konfundiert war, wurden im vorliegenden Experiment beide Merkmale im Rahmen einer simulierten Gruppendiskussion “entkonfundiert”. Es zeigte sich, dass geteilte bzw. präferenzkonsistente Informationen unabhängig vom jeweils anderen Merkmal als glaubwürdiger und entscheidungsrelevanter bewertet wurden als ungeteilte bzw. präferenzinkonsistente Informationen. Zudem intendierten die Probanden, geteilte und präferenzkonsistente Informationen bewusst häufiger in der Diskussion zu wiederholen. Weiterhin gaben die Probanden an, gezielt mehr präferenzkonsistente als -inkonsistente Informationen in die Diskussion einbringen und in der Diskussion erfragen zu wollen. Die Befunde legen nahe, dass individualpsychologische Prozesse der Informationsbewertung und Informationsbevorzugung stärker in die Erklärung der Dominanz geteilter Informationen bei Gruppendiskussionen und Gruppenentscheidungen einbezogen werden sollten.
Loss of mismatch repair proteins in sebaceous gland tumors
Authors: Popnikolov Nikolay K. , Gatalica Zoran , Colome‐Grimmer Maria I. , Sánchez Ramón L.
Published: May 2003

Background: Sebaceous gland neoplasms are rare tumors that are associated with visceral malignancies in patients with Muir–Torre syndrome (MTS). The majority of the MTS‐associated tumors reveal mutations in DNA mismatch repair (MMR) genes (most often hMSH‐2 and hMLH‐1) and microsatellite instability. The sebaceous gland lesions in patients with MTS can often precede or occur concurrently with the visceral neoplasms. The early recognition of those lesions and their differentiation from sporadic sebaceous gland tumors are critical for proper patient management. Here we investigate the MMR gene expression in a variety of sebaceous gland tumors, with or without associated visceral malignancy.

Methods: We studied the expressions of hMLH‐1 and hMSH‐2 in 10 consecutive sebaceous hyperplasias, 10 sebaceus nevi, 12 sebaceous adenomas, seven sebaceous carcinomas and the adjacent normal sebaceous glands using immunohistochemistry and paraffin‐embedded sections.

Results: The normal sebaceous glands and the glands of all the sebaceus nevi were positive for hMLH‐1 and hMSH‐2. Loss of hMSH‐2 expression was found in 1/10 (10%) sebaceous hyperplasias, 3/12 (25.0%) sebaceous adenomas, and 2/7 (28.6%) sebaceous carcinomas. Loss of hMLH‐1 expression was seen in 1/10 (10%) hyperplasias, 3/12 (25.0%) adenomas, and 1/7 (14.3%) carcinomas. No concurrent loss of both hMLH‐1 and hMSH‐2 was observed. Loss of MMR (either hMLH‐1 or hMSH‐2) was detected in 80% of the benign sebaceous lesions associated with malignancy. In comparison, only 23% of sebaceous lesions not associated with malignancy showed loss of MMR proteins. No loss of hMSH‐2 protein was found in the visceral cancer in one patient with hMSH‐2‐negative sebaceous adenoma.

Conclusions: Our results confirm the previous reports of alterations of mismatch repair genes in the sebaceous neoplasms of patients with MTS. However, we showed that those changes also occur early at the stage of sebaceous hyperplasia, even in the absence of a visceral malignancy. This indicates the importance of the abnormal DNA mismatch repair in the progression of this disease.
Loss of expression of tuberin and hamartin in tuberous sclerosis complex‐associated but not in sporadic angiofibromas
Authors: Fackler Ingrid , DeClue Jeffrey E. , Rust Heidi , Vu Phuong‐Anh , Kutzner Heinz , Rütten Arno , Kaddu Steven , Sander Christian A. , Volkenandt Matthias , Johnson Michael W. , Vinters Harry V. , Wienecke Ralf
Published: May 2003

Background:  Angiofibromas occur sporadically, and they develop in most patients with tuberous sclerosis complex (TSC), which is associated with alterations of the tumor suppressor genes TSC1 or TSC2. Loss of tuberin, the protein product of TSC2, has been shown in the interstitial fibroblast compartment of TSC‐associated angiofibromas. It is unclear whether there is also a loss of hamartin, the product of TSC1 in TSC‐associated and sporadic angiofibromas.

Methods:  The expression of hamartin and tuberin was analyzed by immunohistochemistry in 59 TSC‐associated and 12 sporadic angiofibromas using affinity‐purified antibodies.

Results:  Loss of expression of both tuberin and hamartin was detected in 14 angiofibromas, loss of only tuberin in three, and loss of only hamartin in four TSC‐associated angiofibromas; but there was no loss in the sporadic angiofibromas. Only the interstitial cells, but not the vascular cells, showed a loss of expression of tuberin or hamartin.

Conclusions:  Loss of tuberin or hamartin occurred in a minority of the TSC‐linked angiofibromas, but not in the sporadic angiofibromas. The absence of both tuberin and hamartin in some of the tumors suggests that the stability of tuberin and hamartin, which are believed to form an active complex in vivo, is negatively affected by the absence of either of the partners.
Stream meanders increase insectivorous bird abundance in riparian deciduous forests
Authors: Iwata Tomoya , Nakano Shigeru , Murakami Masashi
Published: May 2003

Adult aquatic insects emerging from streams are a fundamental resource sustaining riparian bird communities in broad‐leaved deciduous forests. We investigated how stream geomorphology affects the aquatic insect flux and insectivorous bird abundance in 26 riparian‐forest plots during spring season in northern Japan. Lateral dispersal of emergent aquatic insects into the riparian forest exponentially decreased with distance from the stream. Similar to aquatic insect distribution, flycatchers and gleaners concentrated their foraging attacks around the stream channel, preying intensively upon emergent aquatic insects. In contrast, bark probers consumed fewer emergent aquatic insects. The abundance of flycatchers and gleaners was closely related to stream geomorphology, whereas that of bark probers was associated with snag density in the study plots. A path analysis showed that the study plots with longer stream channels had greater aquatic insect abundance. This can be interpreted as a consequence of the increased amount of both stream edge and stream surface, where emergent aquatic insects readily penetrate. The increased flux of aquatic insects by stream meanders elevated gleaner abundance in the study plots. In addition, their abundance was directly affected by stream length per se. On the other hand, flycatcher abundance was only directly affected by stream length. Flycatchers, which mainly consumed emergent aquatic insects in the air, may have increased in response to the increase in suitable foraging sites (i.e., open spaces adjacent to perches) accompanying longer stream channels. Although the causal links affecting bird abundance differed among guilds, meandering streams apparently support abundant insectivorous birds in riparian forests. Therefore, to conserve riparian bird communities, it will be necessary to maintain the functions of stream geomorphology that affect the magnitude of energy transfer across the forest‐stream interface.
Species‐richness patterns of vascular plants along seven altitudinal transects in Norway
Authors: Grytnes John Arvid
Published: May 2003

Altitudinal richness patterns were investigated along altitudinal gradients located in northern Norway (two transects) and along a west–east gradient in southern Norway (five transects). The transects were sampled for vascular plant species richness using a uniform sampling method. Each transect consisted of 38–48 5×5 m sample plots regularly spaced from sea level or valley bottom to a local mountain top. In five transects species richness peaked at mid‐altitudes, whereas in the two northern transects species richness decreased with altitude. The observations were qualitatively evaluated in relation to the influence of the area of the species pool, hard boundaries, temperature and precipitation, and mass effect. The observed patterns cannot be fully accounted for by any of these factors. However, the altitude of the peak in species richness was above the forest‐limit for all the humped relationships, which may suggest that species richness above the forest‐limit might be enhanced by a mass effect from forest taxa. The two monotonic relationships found in the north may be caused by the relatively low number of alpine species at these sites. The monotonic pattern may result from a decrease in “forest species” towards the mountain tops.
Screening of Human Primary Melanocytes of Defined Melanocortin‐1 Receptor Genotype: Pigmentation Marker, Ultrastructural and UV‐Survival Studies
Authors: Leonard J. Helen , Marks Lisa H. , Chen Wei , Cook Anthony L. , Boyle Glen M. , Smit Darren J. , Brown Darren L. , Stow Jennifer L. , Parsons Peter G. , Sturm Richard A.
Published: May 2003

Recent population studies have demonstrated an association with the red‐hair and fair‐skin phenotype with variant alleles of the melanocortin‐1 receptor (MC1R) which result in amino acid substitutions within the coding region leading to an altered receptor activity. In particular, Arg151Cys, Arg160Trp and Asp294His were the most commonly associated variants seen in the south‐east Queensland population with at least one of these alleles found in 93% of those with red hair. In order to study the individual effects of these variants on melanocyte biology and melanocytic pigmentation, we established a series of human melanocyte strains genotyped for the MC1R receptor which included wild‐type consensus, variant heterozygotes, compound heterozygotes and homozygotes for Arg151Cys, Arg160Trp, Val60Leu and Val92Met alleles. These strains ranged from darkly pigmented to amelanotic, with all strains of consensus sequence having dark pigmentation. UV sensitivity was found not to be associated with either MC1R genotype or the level of pigmentation with a range of sensitivities seen across all genotypes. Ultrastructural analysis demonstrated that while consensus strains contained stage IV melanosomes in their terminal dendrites, Arg151Cys and Arg160Trp homozygote strains contained only stage II melanosomes. This was despite being able to show expression of tyrosinase and tyrosinase‐related protein‐1 markers, although at reduced levels and an ability to convert exogenous 3,4‐dihydroxyphenyl‐alanine (DOPA) to melanin in these strains.
The Melanosome: An Ideal Model to Study Cellular Differentiation
Authors: Kushimoto Tsuneto , Valencia Julio C. , Costin Gertrude‐E. , Toyofuku Kazutomo , Watabe Hidenori , Yasumoto Ken‐Ichi , Rouzaud Francois , Vieira Wilfred D. , Hearing Vincent J.
Published: May 2003

Melanosomes provide an intriguing model for study at many levels. In part this is due to their unique structure and function, but also in part to their involvement in pigmentary diseases and as a model to study basic cellular mechanisms of organelle biogenesis. Recent studies have elucidated the full proteome of the melanosome and the metabolic and molecular lesions involved in a number of pigmentary diseases have been resolved. This paper summarizes recent advances in the field in these areas.
Melanocyte‐Specific Immune Response in Melanoma and Vitiligo: Two Faces of the Same Coin?
Authors: Wankowicz‐Kalinska Anna , Le poole Caroline , Van Den Wijngaard Rene , Storkus Walter J. , Das Pranab K.
Published: May 2003

The appearance of depigmentation during the course of malignant melanoma has been considered a good prognostic sign. Is it only a side‐effect, informative of the immune system's response to the treatment, or does it act as a necessary amplifier of these clinically important anti‐tumor responses? The current review will attempt to tackle this question by reviewing the current literature, as well as by posing some novel hypotheses. Understanding the nature of humoral and cellular immune responses directed against normal melanocytes and their malignant counterparts may lead to the design of improved therapeutic strategies relevant to both vitiligo and melanoma.
Melanosome Degradation: Fact or Fiction
Authors: Borovanský Jan , Elleder Milan
Published: May 2003

Our mini review summarizes what is known about the (bio)degradation of melanosomes. Unlike melanosome biogenesis where our knowledge enables us to explain it in molecular terms posing many interesting questions on the relation between lysosomes and melanosomes, melanosome degradation has remained ‘terra incognita’. Observations at optical and ultrastructural levels describe the disintegration of melanosomes in the lysosomal compartment (in auto‐ and heterophagosomes). Histochemical studies suggest the participation of acid hydrolases in the process of melanosome degradation. Biochemical data confirm the ability of lysosomal hydrolases to degrade melanosome constituents except the melanin moiety. The similarity of melanin structure to that of polycyclic aromatic hydrocarbons suggests that melanin should be sensitive mainly, if not exclusively, to oxidative breakdown. In vitro melanin can indeed be decomposed by an oxidative attack and the degradation is accompanied by fluorescence and decreasing absorbance. From enzymes engaged in the biotransformation of polycyclic hydrocarbons only phagosomal NADPH oxidase meets the criteria (particularly as for compartmental and catalytic properties) to be involved in melanin biodegradation. The in vivo biodegradation of melanin has so far been clearly demonstrated in Aspergillus and fungi melanins.
Oculocutaneous Albinism Type 1: The Last 100 Years
Authors: Oetting William S. , Fryer James P. , Shriram Sabitha , King Richard A.
Published: May 2003

Research on human albinism has been central to many of the major discoveries in human genetics. These include the first evidence that Mendel's rules of genetic segregation apply to humans, first published in 1903. Contrary to initial thought that albinism is caused by mutations in a single gene, we now know that the genetics of albinism are complex. The complexity of albinism was hinted at, in early publications, but has only recently been fully appreciated with the advent of molecular techniques. Currently, 12 different genes have been identified, that when mutated, result in a different type of albinism. Oculocutaneous albinism type 1 (OCA1), resulting from mutations of the tyrosinase gene, is genetically and biochemically the best understood type of albinism. Though much of the research in albinism has involved OCA1, there are many unanswered questions about OCA1 and albinism, in general. The next 100 yr should still provide many surprises as did the first 100 yr.
Acquired Melanocytic Nevi as Risk Factor for Melanoma Development. A Comprehensive Review of Epidemiological Data
Authors: Bauer Jürgen , Garbe Claus
Published: May 2003

Acquired melanocytic nevi (MN) in Caucasian populations are important markers for the risk of melanoma development. The total number of MN on the whole body is the most important independent risk factor for melanoma and the risk of melanoma development increases almost linearly with rising numbers of MN. Additionally, the presence of atypical MN and of actinic lentigines are likewise independent risk factors for melanoma. Atypical mole syndrome should be defined by the presence of many acquired MN and a threshold number of atypical MN. Acquired MN develops mainly during childhood and adolescence in the first two decades of life. The number of acquired nevi seems to be related to hereditary factors and nevus‐prone families exist. The amount of sun exposure is the most important environmental risk factor for nevus development, particularly in early childhood. Interestingly, sunburns may play a role in nevus development, but seem not to be required, and even moderate sun exposure promotes the process. Therefore, preventive measures for nevus and melanoma development should target young children and adolescents.
Regulation of Melanosome Movement by MAP Kinase
Authors: Andersson Tony P. M. , Svensson Samuel P. S. , Karlsson Annika M.
Published: May 2003

Our objectives were to further characterize the signaling pathways in melatonin‐induced aggregation in Xenopus melanophores, specifically to investigate a possible role of mitogen‐activated protein kinase (MAPK). By Western blotting we found that melatonin activates MAPK, which precedes melanosome aggregation measured in a microplate reader. Activation of MAPK, tyrosine phosphorylation of a previously described 280‐kDa protein, and melanosome aggregation are sensitive to PD98059, a selective inhibitor of MAPK kinase. The MAPK activation is also decreased by the adenylate cyclase stimulant forskolin. In summary, we found that MAPK is activated during melatonin‐induced melanosome aggregation. Activation was decreased by an inhibitor of MAPK kinase, and by forskolin. In addition to inhibition of cyclic adenosine 3′,5′‐monophosphate (cAMP), reduction in protein kinase A activity (PKA), and activation of protein phosphatase 2A, we suggest that melatonin receptors activate the MAPK cascade and tyrosine phosphorylation of the 280‐kDa protein. Although the cAMP/PKA signaling pathway is the most prominent, our data suggest that simultaneous activation of the MAPK cascade is of importance to obtain a completely aggregated state. This new regulatory mechanism of organelle transport by the MAPK cascade might be important in other eukaryotic cells.
β‐Catenin in the Melanocyte Lineage
Authors: Larue Lionel , Kumasaka Mayuko , Goding Colin R.
Published: May 2003

β‐Catenin is a multifunctional protein involved in cell–cell adhesion, intracellular signalling and gene transcription. It has been implicated in the development of various lineages, including neural crest derivatives. Melanocytes are derived from neural crest cells and β‐catenin is expressed throughout the development of this cell lineage. The multifunctional activity of β‐catenin is directly associated with its participation in multi protein–protein interactions. The cell–cell adhesion function of β‐catenin is mediated by the large cadherin cell adhesion molecule family, the intracellular signalling function by its interaction with GSK3β, and the gene transcription activity by the four known LEF/TCF DNA binding‐proteins. Here, we review the known β‐catenin interacting factors and targets involved in the development and transformation of melanocytes and in particular its role in the expression of the crucial gene of melanocyte development, Mitf.
Role of the bradykinin B2 receptor for the local and systemic inflammatory response that follows severe reperfusion injury
Authors: Souza Danielle G , Pinho Vanessa , Pesquero Jorge L , Lomez Eliane S , Poole Steve , Juliano Luiz , Correa Ary , de A Castro M Salete , Teixeira Mauro M
Published: May 2003

Bradykinin (BK) appears to play an important role in the development and maintenance of inflammation. Here, we assessed the role of the BK B2 receptor for the injuries that occur after ischemia and reperfusion (I/R) of the territory irrigated by the superior mesenteric artery.

Tissue (lung and duodenum) kallikrein activity increased after ischemia with greater enhancement after reperfusion. A selective inhibitor of tissue kallikrein, Phenylacetyl‐Phe‐Ser‐Arg‐N‐(2,3‐dinitrophenyl)‐ethylenediamine (TKI, 0.001–10 mg ml−1), inhibited kallikrein activity in a concentration‐dependent manner in vitro. In vivo, pretreatment with TKI (30 mg kg−1) prevented the extravasation of plasma and the recruitment of neutrophils.

Similarly, the bradykinin B2 receptor antagonists, HOE 140 (0.01–1.0 mg kg−1) or FR173657 (10.0 mg kg−1), inhibited reperfusion‐induced increases in vascular permeability and the recruitment of neutrophils in the intestine and lungs.

In a model of more severe I/R injury, HOE 140 (1.0 mg kg−1) inhibited the increase in vascular permeability, neutrophil recruitment, haemorrhage and tissue pathology. Furthermore, HOE 140 significantly inhibited the elevations of TNF‐α in tissue and serum and partially prevented lethality. This was associated with an increase in the concentrations of IL‐10 in tissue and serum.

Thus, our results demonstrate that, following intestinal I/R injury, there is an increase in tissue kallikrein activity and activation of BK B2 receptors. B2 receptor activation is essential for the development of inflammatory tissue injury and lethality. These results contrast with those of others showing that BK mostly exerts a protective role during I/R injury.

British Journal of Pharmacology (2003) 139, 129–139. doi:10.1038/sj.bjp.0705200
Downregulation of mdr1a expression in the brain and liver during CNS inflammation alters the in vivo disposition of digoxin
Authors: Goralski Kerry B , Hartmann Georgy , Piquette‐Miller Micheline , Renton Kenneth W
Published: May 2003

Inflammation is a pathophysiological event that has relevance for altered drug disposition in humans. Two functions of P‐glycoprotein (P‐gp) are hepatic drug elimination and prevention of drug entry into the central nervous system (CNS). Our objective was to investigate if localized CNS inflammation induced by Escherichia coli lipopolysaccharide (LPS) would modify mdr1a/P‐gp expression and function in the brain and liver.

Our major finding was that the CNS inflammation in male rats produced a loss in the expression of mdr1a mRNA in the brain and liver that was maximal 6 h after intracranial ventricle (i.c.v.) administration of LPS. When 3H‐digoxin was used at discrete time points, as a probe for P‐gp function in vivo, an increase in brain and liver 3H‐radioactivity and plasma level of parent digoxin was produced 6 and 24 h following LPS treatment compared to the saline controls. Digoxin disposition was similarly altered in mdr1a+/+ mice but not in mdr1a−/− mice 24 h after administering LPS i.c.v.

In male rats, the biliary elimination of parent digoxin was reduced at 24 h (60%) and 48 h (40%) after LPS treatment and was blocked by the P‐gp substrate cyclosporin A. An observed loss in CYP3A1/2 protein and organic anion transporting polypeptide 2 mRNA in the liver may make a minor contribution to digoxin elimination in male rats after LPS treatment.

Conditions which impose inflammation in the CNS produce dynamic changes in mdr1a/P‐gp expression/function that may alter hepatic drug elimination and the movement of drugs between the brain and the periphery. The use of experimental models of brain inflammation may provide novel insight into the regulation of P‐gp function in that organ.

British Journal of Pharmacology (2003) 139, 35–48. doi:10.1038/sj.bjp.0705227
YM‐53601, a novel squalene synthase inhibitor, suppresses lipogenic biosynthesis and lipid secretion in rodents
Authors: Ugawa Tohru , Kakuta Hirotoshi , Moritani Hiroshi , Inagaki Osamu , Shikama Hisataka
Published: May 2003

To better understand how it decreases plasma cholesterol and triglyceride levels, we evaluated the effect of (E)‐2‐[2‐fluoro‐2‐(quinuclidin‐3‐ylidene)ethoxy]‐9H‐carbazole monohydrochloride(YM‐53601) on lipogenic biosynthesis in the liver and lipid secretion from the liver in rats and hamsters.

Single administration of YM‐53601 in cholestyramine‐treated rats inhibited triglyceride and free fatty acid (FFA) biosynthesis at a similar dose range to that at which it inhibited cholesterol biosynthesis. YM‐53601 inhibited both triglyceride and FFA biosynthesis in hamsters treated with cholestyramine.

YM‐53601 by single oral administration decreased the enhanced plasma triglyceride levels in hamsters induced by an injection of protamine sulfate, which inhibits lipoprotein lipase (LPL) and consequently increases plasma very low‐density lipoprotein (VLDL) triglyceride levels. YM‐53601 also decreased the enhanced plasma triglyceride and cholesterol levels in hamsters treated with Triton WR1339, which also inhibits the degradation of VLDL. Plasma cholesterol was significantly decreased as soon as 1 h after single administration of YM‐53601 in hamsters fed a normal diet.

This is the first report that a squalene synthase inhibitor suppresses lipogenic biosynthesis in the liver and cholesterol and triglyceride secretion from the liver in vivo. We therefore suggest that the mechanism by which YM‐53601 decreases plasma triglyceride might include these effects. The finding that YM‐53601 rapidly decreased plasma cholesterol suggests that this compound may be effective in decreasing plasma cholesterol levels early in the course of treatment of hypercholesterolemia in humans.

British Journal of Pharmacology (2003) 139, 140–146. doi:10.1038/sj.bjp.0705229
Pharmacological characterisation of native somatostatin receptors in AtT‐20 mouse tumour corticotrophs
Authors: Cervia Davide , Nunn Caroline , Fehlmann Dominique , Langenegger Daniel , Schuepbach Edi , Hoyer Daniel
Published: May 2003

The mouse corticotroph tumour cell line AtT‐20 is a useful model to investigate the physiological role of native somatostatin (SRIF, Somatotropin release inhibitory factor) receptor subtypes (sst1 – sst5). The objective of this study was to characterise the pharmacological features and the functional effects of SRIF receptors expressed by AtT‐20 cells using radioligand binding and cAMP accumulation.

[125I]LTT‐SRIF‐28, [125I]CGP 23996, [125I]Tyr10‐cortistatin‐14 and [125I]Tyr3‐octreotide labelled SRIF receptor binding sites with high affinity and in a saturable manner (Bmax=315, 274, 239 and 206 fmol mg−1, respectively). [125I]LTT‐SRIF‐28 labels significantly more sites than [125I]Tyr10 ‐cortistatin‐14 and [125I]Tyr3 ‐octreotide as seen previously in cells expressing pure populations of sst2 or sst5 receptors.

SRIF analogues displaced the binding of the four radioligands. sst2/5 receptor‐selective ligands showed much higher affinity than sst1/3/4 receptor‐selective ligands. The binding profile of [125I]Tyr3‐octreotide was different from that of [125I]LTT‐SRIF‐28, [125I]CGP 23996 and [125I]Tyr10‐cortistatin‐14. The sst5/1 receptor‐selective ligand L‐817,818 identified two binding sites, one with subnanomolar affinity (sst5 receptors) and one with micromolar affinity (sst2 receptors); however, the proportions were different: 70 – 80% high affinity with [125I]LTT‐SRIF‐28, [125I]CGP 23996, [125I]Tyr10‐cortistatin‐14, but only 20% with [125I]Tyr3‐octreotide.

SRIF analogues inhibited the forskolin‐stimulated cAMP levels depending on concentration. sst2/5 receptor‐selective ligands were highly potent, whereas sst1/3/4 receptor‐selective ligands had no significant effects. The sst2 receptor antagonist D‐Tyr8‐CYN 154806 competitively antagonised the effects of SRIF‐14 and sst2 receptor‐preferring agonists, but not those of L‐817,818.

The complex binding properties of SRIF receptor analogues indicate that sst2 and sst5 receptors are the predominant SRIF receptors expressed on AtT‐20 cell membranes with no or only negligible presence of sst1, sst3 and sst4 receptors. In the functional studies using cAMP accumulation, only sst2 and sst5 receptors appear to play a role. However, the ‘predominant’ receptor appears to be the sst2 receptor, although sst5 receptors can also mediate the effect, when the ligand is not able to activate sst2 receptors. This clearly adds flexibility to SRIF‐mediated functional effects and suggests that the physiological role of SRIF and its analogues may be mediated preferentially via one subtype over another.

British Journal of Pharmacology (2003) 139, 109–121. doi:10.1038/sj.bjp.0705235
Macrophages of patients with X‐linked thrombocytopenia display an attenuated Wiskott‐Aldrich syndrome phenotype
Authors: Linder Stefan , Wintergerst Uwe , Bender‐Götze Christine , Schwarz Klaus , Pannicke Ulrich , Aepfelbacher Martin
Published: May 2003

The immunodeficiency disorder Wiskott‐Aldrich syndrome and its milder form X‐linked thrombocytopenia are caused by mutations in the WASp gene. Wiskott‐Aldrich syndrome is characterized by a plethora of clinical symptoms which are due to functional defects of haematopoietic cells, including the inability of macrophages to form actin‐rich adhesion structures called podosomes. In contrast, X‐linked thrombocytopenia patients show reduced platelet size and counts but no cytoskeletal white blood cell defects have been detected so far. Here we use immunofluorescence technique to evaluate podosome formation in macrophages from X‐linked thrombocytopenia and Wiskott‐Aldrich syndrome patients and from healthy donors. We find that X‐linked thrombocytopenia macrophages, cells previously thought to be unaffected in this disorder, are compromised in the formation of podosomes. Western blot analysis shows that this phenotype is not due to lower levels of WASp expression. Interestingly, the bacterial chemoattractant formyl‐methionyl‐leucyl‐phenylalanine can rescue podosome formation in X‐linked thrombocytopenia cells. Our findings indicate that: 1. The spectrum of WASp‐dependent disorders contains defects more subtle than originally recognized and 2. in X‐linked thrombocytopenia, some of these defects may not be evident under conditions of bacterial stimulation. Further evaluation of this and other, as yet unrecognized, cellular defects may provide a more complete picture of the continuum of Wiskott‐Aldrich syndrome and X‐linked thrombocytopenia defects.
Skeletal muscle blood flow in humans and its regulation during exercise
Authors: SALTIN B. , RÅDEGRAN G. , KOSKOLOU M. D. , ROACH R. C.
Published: May 2003

Regional limb blood flow has been measured with dilution techniques (cardio‐green or thermodilution) and ultrasound Doppler. When applied to the femoral artery and vein at rest and during dynamical exercise these methods give similar reproducible results. The blood flow in the femoral artery is ∼0.3 L min−1at rest and increases linearly with dynamical knee‐extensor exercise as a function of the power output to 6–10 L min−1(Q = 1.94 + 0.07 load). Considering the size of the knee‐extensor muscles, perfusion during peak effort may amount to 2–3 L kg−1 min−1, i.e. ∼100‐fold elevation from rest. The onset of hyperaemia is very fast at the start of exercise withT½of 2–10 s related to the power output with the muscle pump bringing about the very first increase in blood flow. A steady level is reached within ∼10–150 s of exercise. At all exercise intensities the blood flow fluctuates primarily due to the variation in intramuscular pressure, resulting in a phase shift with the pulse pressure as a superimposed minor influence. Among the many vasoactive compounds likely to contribute to the vasodilation after the first contraction adenosine is a primary candidate as it can be demonstrated to (1) cause a change in limb blood flow when infused i.a., that is similar in time and magnitude as observed in exercise, and (2) become elevated in the interstitial space (microdialysis technique) during exercise to levels inducing vasodilation. NO appears less likely since NOS blockade withL‐NMMA causing a reduced blood flow at rest and during recovery, it has no effect during exercise. Muscle contraction causes with some delay (60 s) an elevation in muscle sympathetic nerve activity (MSNA), related to the exercise intensity. The compounds produced in the contracting muscle activating the group III–IV sensory nerves (the muscle reflex) are unknown. In small muscle group exercise an elevation in MSNA may not cause vasoconstriction (functional sympatholysis). The mechanism for functional sympatholysis is still unknown. However, when engaging a large fraction of the muscle mass more intensely during exercise, the MSNA has an important functional role in maintaining blood pressure by limiting blood flow also to exercising muscles.
Cation pumps in skeletal muscle: potential role in muscle fatigue.
Authors: GREEN H. J.
Published: May 2003

Two membrane bound pumps in skeletal muscle, the sarcolemma Na+‐K+ adenosine triphosphatase (ATPase) and the sarcoplasmic reticulum Ca2+‐ATPase, provide for the maintenance of transmembrane ionic gradients necessary for excitation and activation of the myofibrillar apparatus. The rate at which the pumps are capable of establishing ionic homeostasis depends on the maximal activity of the enzyme and the potential of the metabolic pathways for supplying adenosine triphosphate (ATP). The activity of the Ca2+‐ATPase appears to be expressed in a fibre type specific manner with both the amount of the enzyme and the isoform type related to the speed of contraction. In contrast, only minimal differences exist between slow‐twitch and fast‐twitch fibres in Na+‐K+ ATPase activity. Evidence is accumulating that both active transport of Na+ and K+ across the sarcolemma and Ca2+‐uptake by the sarcoplasmic reticulum may be impaired in vivo in a task specific manner resulting in loss of contractile function. In contrast to the Ca2+‐ATPase, the Na+‐K+ ATPase can be rapidly upregulated soon after the onset of a sustained pattern of activity. Similar programmes of activity result in a downregulation of Ca2+‐ATPase but at a much later time point. The manner in which the metabolic pathways reorganize following chronic activity to meet the changes in ATP demand by the cation pumps and the degree to which these adaptations are compartmentalized is uncertain.
Regulation of skeletal muscle perfusion during exercise
Authors: DELP M. D. , LAUGHLIN M. H.
Published: May 2003

For exercise to be sustained, it is essential that adequate blood flow be provided to skeletal muscle. The local vascular control mechanisms involved in regulating muscle perfusion during exercise include metabolic control, endothelium‐mediated control, propagated responses, myogenic control, and the muscle pump. The primary determinant of muscle perfusion during sustained exercise is the metabolic rate of the muscle. Metabolites from contracting muscle diffuse to resistance arterioles and act directly to induce vasodilation, or indirectly to inhibit noradrenaline release from sympathetic nerve endings and oppose α‐adrenoreceptor‐mediated vasoconstriction. The vascular endothelium also releases vasodilator substances (e.g., prostacyclin and nitric oxide) that are prominent in establishing basal vascular tone, but these substances do not appear to contribute to the exercise hyperemia in muscle. Endothelial and smooth muscle cells may also be involved in propagating vasodilator signals along arterioles to parent and daughter vessels. Myogenic autoregulation does not appear to be involved in the exercise hyperemia in muscle, but the rhythmic propulsion of blood from skeletal muscle veins facilitates venous return to the heart and muscle perfusion. It appears that the primary determinants of sustained exercise hyperemia in skeletal muscle are metabolic vasodilation and increased vascular conductance via the muscle pump. Additionally, sympathetic neural control is important in regulating muscle blood flow during exercise.
Muscle mass and function in thyrotoxic patients before and during medical treatment
Authors: Nørrelund Helene , Hove Karen Yde , Brems‐Dalgaard Eva , Jurik Anne Grethe , Nielsen Lars Peter , Nielsen Søren , Nielsen Steen , Jørgensen Jens Otto Lunde , Weeke Jørgen , Møller Niels
Published: May 2003

OBJECTIVE

Development of muscle weakness and atrophy are well known complications of thyrotoxicosis, although little is known about its clinical course. The present longitudinal study was therefore undertaken to monitor muscle mass and strength before and during treatment of hyperthyroidism.

DESIGN AND PATIENTS

Five patients (2 male, 3 female; Age 41 ± 6 years; BMI 22.2 ± 1.1 kg/m2) with newly diagnosed hyperthyroidism were studied with respect to muscle area, muscle strength, body composition and substrate metabolism at baseline and after 1, 3, 6, 9 and 12 months of treatment.

MEASUREMENTS

Midthigh muscle areas were assessed by computed tomography (CT), while bioelectrical impedance analysis (BIA) was used for assessment of body composition. The isometric strength of the biceps brachialis and quadriceps muscles was assessed by means of a dynamometer and the maximal static ins‐ and ex‐piratory mouth pressures were measured with a respiratory pressure module.

RESULTS

Prior to treatment thyrotoxic patients all displayed elevated levels of total and free T3 and T4 together with suppressed TSH. BMI, fat mass and lean body mass increased significantly during the treatment period, while energy expenditure (EE) decreased. Thigh muscle areas increased by 24% (101.5 ± 11.5 vs. 125.3 ± 13.1 cm2, P < 0.05) from entry to peak. Peak time was 9 ± 0.9 months. During treatment a significant (P < 0.01) increase in muscle strength was observed; arm capacity increased by 48%, while leg capacity increased by 51%. Peak time (months) was: Right arm: 8 ± 3, left arm: 7 ± 2, right leg: 5 ± 3, left leg: 9 ± 2. Respiratory muscle strength, expressed as maximal ins‐ or ex‐piratory mouth pressure, was significantly impaired among patients at entry. A significant increase in inspiratory and expiratory strength was found from entry to peak (P < 0.05), as inspiratory strength increased by 35% and expiratory by 19%. Inspiratory strength peaked after 7 ± 1 months, expiratory muscle strength after 6 ± 1 months.

CONCLUSIONS

In conclusion we find that in patients with thyrotoxicosis muscle mass is reduced by approximately 20% and muscle strength by approximately 40% and that between 5 and 9 months elapse before normal muscle mass and function are reestablished.
Initial characterization of the GH–IGF axis and nutritional status of the Ati Negritos of the Philippines
Authors: Clavano‐Harding Amabel B. , Ambler Geoffrey R. , Cowell Christopher T. , Garnett Sarah P. , Al‐Toumah Ban , Coakley John C. , Ho Ken K.Y. , Baxter Robert C.
Published: May 2003

BACKGROUND AND OBJECTIVE

The Ati Negritos are a Pygmy‐like aboriginal population from the Philippines with physical characteristics of short stature, dark skin and woolly, kinked hair. Their final height, components of their GH–IGF axis and various nutritional markers are described.

SUBJECTS, DESIGN AND MEASUREMENTS

Auxological data and sera for the components of the GH–IGF axis and nutritional parameters were collected from 9 adult Ati Negritos in their native environment and 10 Filipinos in Sydney.

RESULTS

The height SDS (− 3.66 ± 1.1 vs. ‐ 1.01 ± 1.2), weight SDS (− 2.30 ± 1.6 vs. 0.10 ± 0.7), and BMI SDS (− 1.4 ± 1.8 vs. − 0.2 ± 0.5) between the two groups were significantly different (P < 0.01). The mean height of the 6 male Ati Negritos was 149 ± 7 and 144 ± 3 cm for the females and are comparable with the African Pygmies and the Mountain Ok people of Papua New Guinea. The Ati Negritos showed lower growth hormone binding protein (GHBP), insulin‐like growth factor I (IGF‐I), insulin‐like growth factor binding protein 3 (IGFBP‐3), acid labile subunit (ALS), zinc, albumin, ferritin, iron, iron saturation and much higher insulin‐like growth factor binding protein 2 (IGFBP‐2) and plasma transferrin concentrations. No differences were noted in random growth hormone (GH), plasma insulin‐like growth factor II (IGF‐II), nor in their plasma concentrations of prealbumin, thyroid stimulating hormone (TSH) and free thyroxine (T4).

CONCLUSION

Perturbations of both the GH–IGF‐I axis and nutritional markers exist in the Ati Negritos. These findings may be determinants of their stature; however, the aetiology of these changes remains to be fully elucidated.
Reversibility of endurance training‐induced changes on glucocorticoid sensitivity of monocytes by an acute exercise
Authors: Duclos M. , Minkhar M. , Sarrieau A. , Bonnemaison D. , Manier G. , Mormede P.
Published: May 2003

OBJECTIVE

The aim of this study was to address the effect of endurance training on monocyte glucocorticoid sensitivity in vitro.

METHODS

For this purpose, in vitro dexamethasone inhibition of lipopolysaccharide (LPS)‐induced interleukin‐6 (IL‐6) secretion in cultures of peripheral monocytes was compared in 6 untrained subjects (UT) and in 6 endurance‐trained (ET) men at 0800 h, 24 h after the end of the last session of exercise (ET men). Moreover, to test the plasticity of these monocytes glucocorticoid sensitivity in ET men, the effect of an acute bout of exercise was further studied 2 h after the end of a 2‐h run at 65–75% VO2max (1200 h) and compared to the results of UT after 4 h of rest.

RESULTS

At 0800 h, monocytes from ET were more sensitive to LPS: lower LPS concentration in ET compared to UT men (0.003 vs. 0.03 μg/ml) induced similar IL‐6 concentrations in both ET and UT men (168.4 ± 29.9 pg/ml with 0.003 μg/ml LPS vs. 160.1 ± 34.4 pg/ml with 0.03 μg/ml LPS, ET vs. UT, respectively, P > 0.05 for IL‐6). No effect of sampling time was observed in UT subjects (0800 h vs. 1200 h). This was not the case for ET as at 1200 h, compared to pre‐exercise values, the LPS‐induced IL‐6 production was not significantly different from that obtained in UT. Moreover, when sensitivity to dexamethasone (Dex) was studied and expressed as the percent inhibition of stimulated IL‐6 production with 0.3 μg/ml LPS, at 0800 h the percent inhibition was lower in ET subjects compared to UT (P < 0.01 ET vs. UT men) for each Dex concentration used [10−11–10−8 M]. After exercise, the inhibitory effect of Dex on LPS‐induced IL‐6 production was restored in ET and was no longer significantly different from that obtained in UT.

CONCLUSION

We demonstrate in vitro plasticity of monocyte glucocorticoid sensitivity of endurance trained men, with training‐induced decreased glucocorticoid sensitivity and acute exercise‐induced return to the levels of the control untrained men.