bluuebunny/crossref_metadata_2025 huggingface dataset:
THE OZI RULE AND NUCLEONS
Authors: LIPKIN HARRY J.
Published: November 2004

The title of this lecture series raises two questions: (1) what is the OZI rule? (2) what is a nucleon. In the lectures both questions were addressed in parallel and the material moved back and forth between them. In a written version it seems more appropriate to treat the two questions separately, beginning with trying to understand the structure of the nucleon.

Experimental evidence for the symmetry and quark structure of hadrons is reviewed with a historical introduction and updated by presenting constituent quark model relations for hadron masses and magnetic moments. Three definitions of the OZI rule are presented, all of which forbid decays like ϕ → ρπ but making different selection rules for more complicated reactions. All suffer from the higher order paradox that a forbidden process can take place via a two-step transition in which each step is allowed; e.g. [Formula: see text]. No prescription is given for estimating the strength of forbidden processes. The role of cancellations between different higher order diagrams is discussed.
ENTREPRENEURIAL COMPETENCIES OF SME OWNER/MANAGERS IN THE HONG KONG SERVICES SECTOR: A QUALITATIVE ANALYSIS
Authors: MAN THOMAS W. Y. , LAU THERESA
Published: November 2004

Based on a theoretical framework linking entrepreneurial competencies and SME performance, we carried out an empirical study to investigate the entrepreneurial competencies of SME owner/managers in the Hong Kong services sector. Thirty-five clusters of behavioural competencies were identified under six competency areas, which are applied to three entrepreneurial tasks, together with seven supporting competencies which play supporting roles to these competency areas or focus personally on the entrepreneur rather than on the entrepreneurial tasks. Distinguishing supporting competencies from major competency areas allows us to be more focused on further investigation into the functions of different competencies. The results are also discussed with reference to the research context and the entrepreneurship in Hong Kong.
BUSINESS RISK, POLITICAL AFFILIATION AND FUTURE DEVELOPMENT PLANS OF SMALL BUSINESS OWNERS IN CHINA
Authors: KONG CLEMENT WING CHOW , KA MICHAEL YIU FUNG
Published: November 2004

This paper studies the future development choices of small business owners, getihu which literally means an individual family household in the People's Republic of China (P.R.C.). We attempt to find out what the major factors are that determine these getihu's choices of expanding, contracting or even closing down their businesses. By using a data set which includes 4,649 getihu collected from a nation-wide survey in 1991, we conduct an ordered probit analysis to obtain the following results: (1) About three quarters of sampled getihu would like to maintain the status quo and do not plan for any change. (2) Being a member of the Chinese Communist Party does not exert any statistically significant effect on their choices. (3) The level of financial risk has no significant effect while the level of failure risk is negatively related to the likelihood of business expansion. However, diversifying into different lines of business has a positive effect on the likelihood of business expansion. (4) The annual wage income of households has a positive and significant effect on the business development plan while company profit does not have any statisccally significant effect at all. (5) Female, aged getihu are less interested in expanding their business.
INTERNATIONAL GROWTH OF YOUNG TECHNOLOGY-BASED FIRMS: A RESOURCE-BASED NETWORK MODEL
Authors: AUTIO ERKKO , YLI-RENKO HELENA , SALONEN ARI
Published: November 2004

This paper analyzes the international growth of 82 young technology-based firms in Finland from a resource-based perspective. These firms manufacture electro-mechanical instruments or devices, are independent, technology-based, and internationally active. The analysis focuses on resource leveraging as a mechanism for facilitating international growth. It is suggested that resource leveraging leads to an interesting paradox: the more growth - oriented the firm is, the more embedded it becomes; that is, the higher the number of network relationships the firm has to set up.
FOUNDATIONS OF THE REVOLUTIONARY RATING METHOD FOR INNOVATIVE SMES
Authors: LAHTI ARTO
Published: November 2004

In a modern computerized financial market, the increasing professionalism of markets has created knowledge based barriers between innovative entrepreneurs and financial experts. Rating agency having pragmatic business orientation is able to build a bridge between the financial markets with scientific, computerized instruments and innovative entrepreneurs.

This paper demonstrates the foundation of a valid rating method. The method is called revolutionary since it combines process management based measurement with formal rating statement. In addition to the methodology used, the philosophy of organizing rating process is revolutionary since the rating agency is supposed to be a financial or even business consultant besides having its official status as rating agency.
POLICY'S CONSEQUENCES: THE COMMERCIALISATION OF AUSTRALIAN TERTIARY EDUCATION AND IMPLICATIONS FOR ITS ASIAN MARKET
Authors: CHENG SOO-MAY
Published: November 2004

Higher education has in the recent decade become in itself a major business. In some economies, it is an important contributor to the gross national product. This fact is true in the case of Australia. This paper discusses the commercialisation of Australian higher education in Asia and how Australian government policy has contributed to this internationalisation. In addition to addressing the policy consequences, it also examines issues surrounding the content, curricula and teaching in the programmes that are exported. Whilst the internationalisation of higher education may have led to the presence of an enterprising culture in the exporting institutions, the higher ideals of education need to be balanced.
THE PROFESSIONALIZATION OF CHINESE FAMILY BUSINESSES IN SINGAPORE
Authors: TAN WEE-LIANG , ALLAMPALLI D. G.
Published: November 2004

It has become common advice furnished to family businesses that in order for them grow and further develop, they need to professionalise their management. The literature suggests that firms that follow this advice will perform better and show higher survival and growth. This paper presents the findings of a study on the professionalisation of family businesses in Singapore. It examined whether family businesses that have professionalised their management differ from these that have not. It is anticipated that the professionalised Chinese family businesses would benefit from the introduction of professional managers. It was anticipated that they would be older in age (since succesion is not confined to family member), report better business performance, and adopt aggressive growth strategies. Firm differences were studies using three dimensions: firm characteristics like age and size when professionalised; performance differences using growth and business volume measures developed by Chandler and Hanks (1993) and growth strategies using the Miles and Stones typology (1978) of growth oriented firms. The study found that the professionalised family businesses did not differ in age but showed significant difference in size, better performance and aggressive growth strategies from those that were not.
INFORMATION NETWORKS OF SMALL AND MEDIUM-SIZED ENTERPRISES
Authors: WITT PETER
Published: November 2004

Information networks are established by communication links between firms, their business partners, personal friends, authorities, universities etc. The value of the information exchanges, especially for small and medium-sized enterprises, depends on the individual position in the information network. The paper discusses existing measures to evaluate network positions and proposes a new one. Extensive case study evidence indicates that the network position of startups and small enterprises is subject to constant changes which the individual firm cannot control completely. The paper develops a dynamic model for the development of network positions over time and indicates what firms can do to improve them. Information management in small and medium-sized enterprises can best be described as the management of dynamic information networks. Calculating position measures and development paths helps start-ups and small businesses to assess their current network position and to increase the efficiency of their information management.
Monocrotaline pyrrole-induced endothelial cell megalocytosis involves a Golgi blockade mechanism
Authors: Shah Mehul , Patel Kirit , Sehgal Pravin B.
Published: November 2004

Pyrrolizidine alkaloids initiate disease in the lung (pulmonary hypertension), liver (veno-occlusive disease and cirrhosis), and kidneys (afferent arteriolar block and mesangiolysis) by inducing a megalocytotic phenotype in target endothelial and parenchymal cells. A “hit-and-run” type of exposure to the bioactive pyrrolizidine results, within 2–3 days, in enlarged cells with large nuclei and enlarged Golgi and endoplasmic reticulum, while the cells remain in G2/M block. In the present study, we recapitulated monocrotaline pyrrole (MCTP)-induced megalocytosis in cultures of bovine pulmonary arterial endothelial cells (PAEC), human Hep3B hepatocytes, human type II-like alveolar epithelial cells (A549), and human pulmonary arterial smooth muscle cells (PASMC) and investigated the subcellular mechanism involved. There was an inverse relationship between reduction in caveolin (Cav)-1 levels and stimulation of promitogenic STAT3 and ERK1/2 cell signaling. In megalocytotic PAEC, the Golgi scaffolding protein GM130 was shifted from membranes with heavy density to those with a lighter density. This lighter Golgi fraction was enriched for hypo-oligomeric Cav-1, indicating dysfunctional trafficking of cargo. Immunofluorescence imaging studies confirmed the trapping of Cav-1 in a GM130-positive Golgi compartment. There was an increase in Ser25 phosphorylation of GM130 (typically a prelude to Golgi fragmentation and mitosis) and increased association between pGM130, cdc2 kinase, and Cav-1. Nevertheless, megalocytotic MCTP-treated cells showed reduced entry into mitosis upon stimulation with 2-methoxyestradiol (2-ME), reduced 2-ME-induced Golgi fragmentation, and a slowing of Golgi reassembly after nocodazole-induced fragmentation. These data suggest that a disruption of the trafficking and mitosis sensor functions of the Golgi may represent the subcellular mechanism leading to MCTP-induced megalocytosis (“the Golgi blockade hypothesis”).
Plasticity of TRPC expression in arterial smooth muscle: correlation with store-operated Ca2+ entry
Authors: Bergdahl Andreas , Gomez Maria F. , Wihlborg Anna-Karin , Erlinge David , Eyjolfson Atli , Xu Shang-Zhong , Beech David J. , Dreja Karl , Hellstrand Per
Published: November 2004

Loss of the smooth muscle contractile phenotype is critical in atherosclerosis and in restenosis after angioplasty, but its early signals are incompletely understood. In this study, we have explored the role of transient receptor potential canonical (TRPC) proteins, which have been suggested to mediate store-operated Ca2+ entry (SOCE). Contractility of rat cerebral arteries in organ culture is preserved for several days, whereas SOCE is increased. In correlation with this increase is that nifedipine-insensitive whole cell current, activated by depletion of intracellular Ca2+ stores, was increased by 50% in cells isolated from arteries cultured for 3 days. TRPC1 and TRPC6 mRNA were more than fivefold increased in cells isolated after organ culture, whereas TRPC3 was decreased. Immunofluorescent staining and/or Western blotting of arteries and isolated cells showed upregulation of TRPC1 and TRPC6 proteins during organ culture. In intact arteries, TRPC4 expression correlated with the amount of endothelium present. Ca2+ addition after store depletion caused a contraction in cultured, but not in freshly dissected, arteries. A polyclonal TRPC1 antibody directed against an extracellular epitope inhibited this contraction by ∼50%. To investigate the basis of the TRPC upregulation and assess its possible clinical significance, segments of human internal mammary artery were organ cultured for 24 h and then exposed to balloon dilatation in vitro, followed by further culturing for up to 48 h. After dilatation, TRPC1 and TRPC6 mRNA were progressively increased compared with undilated control segments. The results of this study indicate that vascular injury enhances plasticity in TRPC expression, that TRPC expression correlates with cellular Ca2+ handling, and that TRPC1 is a subunit of upregulated store-operated Ca2+ channels.
Combined ingestion of protein and free leucine with carbohydrate increases postexercise muscle protein synthesis in vivo in male subjects
Authors: Koopman René , Wagenmakers Anton J. M. , Manders Ralph J. F. , Zorenc Antoine H. G. , Senden Joan M. G. , Gorselink Marchel , Keizer Hans A. , van Loon Luc J. C.
Published: November 2004

The present study was designed to determine postexercise muscle protein synthesis and whole body protein balance following the combined ingestion of carbohydrate with or without protein and/or free leucine. Eight male subjects were randomly assigned to three trials in which they consumed drinks containing either carbohydrate (CHO), carbohydrate and protein (CHO+PRO), or carbohydrate, protein, and free leucine (CHO+PRO+Leu) following 45 min of resistance exercise. A primed, continuous infusion of l-[ ring-13C6]phenylalanine was applied, with blood samples and muscle biopsies collected to assess fractional synthetic rate (FSR) in the vastus lateralis muscle as well as whole body protein turnover during 6 h of postexercise recovery. Plasma insulin response was higher in the CHO+PRO+Leu compared with the CHO and CHO+PRO trials (+240 ± 19% and +77 ± 11%, respectively, P < 0.05). Whole body protein breakdown rates were lower, and whole body protein synthesis rates were higher, in the CHO+PRO and CHO+PRO+Leu trials compared with the CHO trial ( P < 0.05). Addition of leucine in the CHO+PRO+Leu trial resulted in a lower protein oxidation rate compared with the CHO+PRO trial. Protein balance was negative during recovery in the CHO trial but positive in the CHO+PRO and CHO+PRO+Leu trials. In the CHO+PRO+Leu trial, whole body net protein balance was significantly greater compared with values observed in the CHO+PRO and CHO trials ( P < 0.05). Mixed muscle FSR, measured over a 6-h period of postexercise recovery, was significantly greater in the CHO+PRO+Leu trial compared with the CHO trial (0.095 ± 0.006 vs. 0.061 ± 0.008%/h, respectively, P < 0.05), with intermediate values observed in the CHO+PRO trial (0.0820 ± 0.0104%/h). We conclude that coingestion of protein and leucine stimulates muscle protein synthesis and optimizes whole body protein balance compared with the intake of carbohydrate only.
Stearoyl-CoA desaturase-1 deficiency reduces ceramide synthesis by downregulating serine palmitoyltransferase and increasing β-oxidation in skeletal muscle
Authors: Dobrzyn Agnieszka , Dobrzyn Pawel , Lee Seong-Ho , Miyazaki Makoto , Cohen Paul , Asilmaz Esra , Hardie D. Grahame , Friedman Jeffrey M. , Ntambi James M.
Published: November 2004

Stearoyl-CoA desaturase (SCD) has recently been shown to be a critical control point of lipid partitioning and body weight regulation. Lack of SCD1 function significantly increases insulin sensitivity in skeletal muscles and corrects the hypometabolic phenotype of leptin-deficient ob/ ob mice, indicating the direct antilipotoxic action of SCD1 deficiency. The mechanism underlying the metabolic effects of SCD1 mutation is currently unknown. Here we show that SCD1 deficiency reduced the total ceramide content in oxidative skeletal muscles (soleus and red gastrocnemius) by ∼40%. The mRNA levels and activity of serine palmitoyltransferase (SPT), a key enzyme in ceramide synthesis, as well as the incorporation of [14C]palmitate into ceramide were decreased by ∼50% in red muscles of SCD1−/−mice. The content of fatty acyl-CoAs, which contribute to de novo ceramide synthesis, was also reduced. The activity and mRNA levels of carnitine palmitoyltransferase I (CPT I) and the rate of β-oxidation were increased in oxidative muscles of SCD1−/−mice. Furthermore, SCD1 deficiency increased phosphorylation of AMP-activated protein kinase (AMPK), suggesting that AMPK activation may be partially responsible for the increased fatty acid oxidation and decreased ceramide synthesis in red muscles of SCD1−/−mice. SCD1 deficiency also reduced SPT activity and ceramide content and increased AMPK phosphorylation and CPT I activity in muscles of ob/ ob mice. Taken together, these results indicate that SCD1 deficiency reduces ceramide synthesis by decreasing SPT expression and increasing the rate of β-oxidation in oxidative muscles.
Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-α
Authors: Wang Bohan , Jenkins John R. , Trayhurn Paul
Published: November 2004

The expression profile of a series of adipokine genes linked to inflammation has been examined by quantitative PCR during the differentiation of human preadipocytes to adipocytes in primary culture, together with the integrated effects of TNF-α on the expression of these adipokines in the differentiated adipocytes. Expression of the genes encoding adiponectin, leptin, and haptoglobin was highly differentiation dependent, the mRNA being undetectable predifferentiation with the level peaking 9–15 days postdifferentiation. Although angiotensinogen (AGT) and monocyte chemoattractant protein-1 (MCP-1) were both expressed before differentiation, the mRNA level increased markedly on differentiation. The expression of nerve growth factor (NGF) and plasminogen activator inhibitor-1 (PAI-1) fell after differentiation, whereas that of TNF-α and IL-6 changed little. Measurement of adiponectin, leptin, MCP-1, and NGF in the medium by ELISA showed that the protein secretion pattern paralleled cellular mRNA levels. Treatment of differentiated human adipocytes with TNF-α (5 or 100 ng/ml for 24 h) significantly decreased the level of adiponectin, AGT, and haptoglobin mRNA (by 2- to 4-fold), whereas that of leptin and PAI-1 was unchanged. In contrast, TNF-α induced substantial increases in IL-6, TNF-α, metallothionein, MCP-1, and NGF mRNAs, the largest increase being with MCP-1 (14.5-fold). MCP-1 and NGF secretion increased 8- to 10-fold with TNF-α, whereas leptin and adiponectin did not change. These results demonstrate that there are major quantitative changes in adipokine gene expression during differentiation of human adipocytes and that TNF-α has a pleiotropic effect on inflammation-related adipokine production, the synthesis of MCP-1 and NGF being highly induced by the cytokine.
Stimulation of soluble guanylyl cyclase inhibits mesangial cell proliferation and matrix accumulation in experimental glomerulonephritis
Authors: Hohenstein Bernd , Daniel Christoph , Wagner Andrea , Stasch Johannes-Peter , Hugo Christian
Published: November 2004

To date, no specific treatment is established in mesangial proliferative glomerulonephritis in humans. Specific stimulation of soluble guanylyl cyclase (sGC), an enzyme catalyzing the synthesis of cGMP from GTP, can be achieved by the novel pyrazolopyridine derivative BAY 41–2272. The effect of sGC stimulation via BAY 41–2272 on mesangial proliferation was assessed in vivo using a mesangial proliferative glomerulonephritis model in rats (anti-Thy1 model). Renal biopsies, as well as glomerular isolates, urine samples, and blood samples were compared in BAY 41–2272- and placebo-treated groups during anti-Thy1 nephritis. The sGC β1-subunit is upregulated during anti-Thy1 nephritis and mainly confined to mesangial areas by immunohistochemistry. Specific therapeutic sGC stimulation during anti-Thy1 nephritis in vivo was achieved via BAY 41–2272 treatment as demonstrated by increased glomerular cGMP levels causing inhibition of mesangial proliferation, glomerular matrix accumulation, and proteinuria compared with placebo-treated animals. sGC is tightly regulated in glomeruli during experimental glomerulonephritis. Considering its beneficial antiproliferative, antifibrotic, and antiproteinuric effect in experimental glomerulonephritis, the therapeutic stimulation of sGC could become a promising future goal in mesangial proliferative glomerulonephritis in humans.
Biotin uptake by human proximal tubular epithelial cells: cellular and molecular aspects
Authors: Balamurugan Krishnaswamy , Vaziri Nosratola D. , Said Hamid M.
Published: November 2004

Cellular and molecular regulation of renal biotin uptake in humans is not well defined. The contribution of the human Na+-dependent multivitamin transporter (hSMVT) to carrier-mediated biotin uptake by human proximal tubular epithelial cells is not clear. The aim of this study was to address these issues, with the human-derived proximal tubular epithelial HK-2 cells used as a model. First, we characterized the mechanism of biotin uptake by these cells and obtained evidence for involvement of an Na+-, temperature-, and energy-dependent carrier-mediated uptake system. This system was inhibited by the biotin structural analog desthiobiotin, pantothenic acid, and lipoate. These findings suggest involvement of the hSMVT system in the uptake process. This was confirmed by demonstrating that the hSMVT system is expressed in HK-2 cells at the protein and mRNA levels and by selective silencing of the hSMVT gene with the use of gene-specific small interfering RNAs, which led to specific and significant inhibition of carrier-mediated biotin uptake. Of the two recently cloned promoters of the hSMVT gene, promoter 1 was more active than promoter 2 in these cells. Pretreatment of HK-2 cells with modulators of PKC- and Ca2+/calmodulin-mediated pathways (but not those that modulate PKA-, protein tyrosine kinase-, or nitric oxide-mediated pathways) led to significant alterations in biotin uptake. Maintaining the HK-2 cells in a biotin-deficient growth medium led to a marked upregulation in biotin transport, which was associated with an increase in hSMVT protein and RNA levels and an increase in activity of the hSMVT promoters. These results demonstrate that biotin uptake by human renal epithelial cells occurs via the hSMVT system and that the process is regulated by intracellular PKC- and Ca2+/calmodulin-mediated pathways. The uptake process appears to be adaptively regulated by extracellular biotin level, which involves transcriptional regulatory mechanism(s).
Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages
Authors: Day Yuan-Ji , Huang Liping , Ye Hong , Linden Joel , Okusa Mark D.
Published: November 2004

The role of monocytes/macrophages in the pathogenesis of ischemia-reperfusion injury (IRI) is unknown. We sought to determine whether activation of macrophage adenosine 2A (A2A) receptors (A2ARs) mediates tissue protection. We subjected C57Bl/6 mice infused with clodronate [dichloromethylene bisphosphonate (Cl2MBP)] to IRI (32 min of ischemia followed by 24 h of reperfusion) to deplete them of macrophages. IRI induced an elevation of plasma creatinine that was reduced with Cl2MBP (26% of control). Adoptive transfer of murine RAW 264.7 cells reconstituted injury, an effect blocked significantly by A2Aagonists (27% of plasma creatinine from mice reconstituted with macrophages). Macrophages subjected to A2Aknockout by small interfering RNA were adoptively transferred to macrophage-depleted mice and reconstituted injury (110% of control mice); however, the increase in plasma creatinine was blocked by A2Aagonists (20% of vehicle treatment). Finally, the A2Aagonist effect on IRI was blocked in macrophage-depleted A2A-knockout mice reconstituted with wild-type RAW 264.7 cells. RNase protection assays 24 h after IRI demonstrated that macrophages are required for IL-6 and TGF-β mRNA induction. However, A2Aagonist-mediated tissue protection is independent of IL-6 and TGF-β mRNA. We conclude that the full extent of IRI requires macrophages and that A2Aagonist-mediated tissue protection is independent of activation of macrophage A2ARs.
Serum Estradiol Concentration as Measured by HPLC-RIA and Bone Mineral Density in Postmenopausal Women during Hormone Replacement Therapy
Authors: Yasui Toshiyuki , Uemura Hirokazu , Umino Yuka , Takikawa Masaya , Kuwahara Akira , Saito Seiichiro , Matsuzaki Toshiya , Maegawa Masahiko , Furumoto Hiroyuki , Miura Masakazu , Irahara Minoru
Published: November 2004

Objective: To determine the relationship between the serum estradiol concentration and bone mineral density (BMD) of the lumbar spine in postmenopausal women treated with conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) every other day and every day. Methods: Eighty-four postmenopausal women were randomly treated with hormone replacement therapy (HRT) every other day and every day. Forty-seven women received oral administration of 0.625 mg CEE and 2.5 mg MPA every other day, and 37 women received oral administration of 0.625 mg CEE and 2.5 mg MPA every day. BMD of the lumbar spine at 12 months and serum concentrations of estradiol and estrone at 6 and 12 months after treatment were examined. Results: The estradiol concentration in subjects treated every other day showed a significant (p < 0.001) positive correlation with the percentage change in lumbar BMD, while that in subjects treated every day was not correlated with the percentage change in BMD. The differences between serum estradiol concentrations after 12 months of treatment and initial serum estradiol values in women treated every other day and every day also showed a significant (p < 0.01 and 0.05, respectively) positive correlation with percentage changes in BMD. In women treated every other day, body mass index (BMI) in the subjects in whom BMD did not increase was significantly (p < 0.01) lower than that in the subjects in whom BMD did increase. Conclusions: The serum estradiol concentration in women treated every other day has a strong positive correlation with the percentage change in lumbar BMD, but a higher estradiol concentration may be needed for women in whom BMD did not increase with HRT every other day after due consideration of individual characteristics such as BMI.
Endothelium-Dependent Relaxant Responses to Selective 5-HT1B/1D Receptor Agonists in the Isolated Middle Cerebral Artery of the Rat
Authors: Hansen-Schwartz Jacob , Løvland Hoel Natalie , Nilsson Elisabeth , Tfelt-Hansen Peer , Edvinsson Lars
Published: November 2004

The vasomotor effects of triptans in the middle cerebral artery (MCA) of rats were studied using the pressurised arteriography method and in vitro vessel baths. Using the arteriograph, MCAs from Sprague-Dawley rats were mounted on two glass micropipettes, pressurised to 85 mm Hg and luminally perfused. Luminally added 5- hydroxytryptamine (5-HT), sumatriptan and rizatriptan induced maximal dilatations of 22 ± 4, 10 ± 2 and 13 ± 5%, respectively, compared to the resting diameter. The relaxant effect of sumatriptan was blocked by the 5- HT1B/1D receptor selective antagonist GR 55562 (10–6M). The use of Nω-nitro-L-arginine and charybdotoxin revealed that the dilatation involved both nitric oxide and endothelially derived hyperpolarising factor. Thus, the earlier demonstrated expression of 5-HT1B/1D immunoreactivity in the endothelium may well translate into a relaxant response to 5-HT and triptans. Using the vessel bath technique, MCA segments were mounted on two metal wires. The relaxant responses to sumatriptan could not be reproduced using this model; instead, weak contractile responses (6 ± 3% of submaximal contractile capacity) were observed. The difference in observations between the experimental models may be related to the maintenance of shear stress in the arteriograph.
Regulation of Vascular Calcification by Osteoclast Regulatory Factors RANKL and Osteoprotegerin
Authors: Collin-Osdoby Patricia
Published: November 2004

Vascular calcification often occurs with advancing age, atherosclerosis, various metabolic disorders such as diabetes mellitus and end-stage renal disease, or in rare genetic diseases, leading to serious clinical consequences. Such mineralization can occur at various sites (cardiac valves, arterial intima or media, capillaries), involve localized or diffuse widespread calcification, and result from numerous causes that provoke active inflammatory and osteogenic processes or disordered mineral homeostasis. Although valuable research has defined many key factors and cell types involved, surprising new insights continue to arise that deepen our understanding and suggest novel research directions or strategies for clinical intervention in calcific vasculopathies. One emerging area in vascular biology involves the RANKL/RANK/OPG system, molecules of the tumor necrosis factor-related family recently discovered to be critical regulators of immune and skeletal biology. Evidence is accumulating that such signals may be expressed, regulated, and function in vascular physiology and pathology in unique ways to promote endothelial cell survival, angiogenesis, monocyte or endothelial cell recruitment, and smooth muscle cell osteogenesis and calcification. Concerted research efforts are greatly needed to understand these potential roles, clarify whether RANKL (
r
eceptor
a
ctivator of
n
uclear factor
κ
B ligand) promotes and osteoprotegerin (OPG) protects against vascular calcification, define how OPG genetic polymorphisms relate to cardiovascular disease, and learn whether elevated serum OPG levels reflect endothelial dysfunction in patients. Overall, the RANKL/RANK/OPG system may mediate important and complex links between the vascular, skeletal, and immune systems. Thus, these molecules may play a central role in regulating the development of vascular calcification coincident with declines in skeletal mineralization with age, osteoporosis, or disease.
Forging the European Cartel Offence: The Supranational Regulation of Business Conspiracy
Authors: Harding Christopher
Published: November 2004

The discussion in this paper examines the emergence of what may now be fairly described as the ‘European cartel offence’: that species of infringement of Article 81 of the EC Treaty, increasingly referred to as ‘hard core cartel’ activity, connoting real delinquency which justifies the imposition of severe penal sanctions. This development is significant not just as a matter of more explicit regulation within the field of competition law, but also as part of a wider context of vilification and criminalisation of certain well-established forms of cartel behaviour. As national systems (such as that in Britain) have introduced new criminal offences in relation to cartels, it is illuminating to consider and compare the evolution of the supranational ‘European cartel offence’. Having its basis in the infringement of Article 81 of the EC Treaty, the offence is necessarily one of collusion, being an agreement or concertation for anti-competitive purposes. As such, the more specific nature of the ‘offence’ has been established incrementally, very much as the product of argument presented in appeals relating to issues of evidence and penalties. It has been necessary to consider whether the offence resides in the planning or the implementation of anti-competitive activity, or both, and whether it comprises specific acts or a continuing pattern of behaviour. The mature version of the ‘offence’, worked out in the jurisprudence of the European Commission and the Community Courts, is based on the organising concept of ‘the cartel as a whole’. This process of forging a ‘European cartel offence’ provides an instructive lesson in the legal construction of criminality and the resort to a form of organisational responsibility. It also points to the emergence of a bifurcated system of both individual and corporate liability in this context.
WTO Negotiations with Respect to Geographical Indications and Russia's Position on the Protection of Appellations of Origin
Authors: Vergano Paolo , Kireeva Irina
Published: November 2004

The present article examines the current stage of the WTO negotiations with respect to the protection of geographical indications (GIs). GIs are distinctive signs that associate products of quality and reputation with their place or area of production and, thereby, help identify and distinguish such products on the market. Well-known examples of geographical indications include Irish Whiskey, Gorgonzola, Tequila, Bordeaux, Roquefort, Antigua Coffee, and Parma Ham. This article examines the manner in which geographical indications are protected in the Russian Federation. Russia considers protection of this type of intellectual property to be one of the key TRIPs issues and is seen to fully support the position of those countries that are demanding enhanced protection of geographical indications around the world. One of the major problems in respect to the protection of intellectual property in Russia is the fact that enforcement of intellectual property laws has—thus far—been rather limited. In conclusion, the authors suggest that Russia's entry into the WTO will prove benefi cial to both Russia itself and to other WTO Members with respect to intellectual property protection.
Functions of heparan sulfate proteoglycans in cell signaling during development
Authors: Lin Xinhua
Published: November 2004

Heparan sulfate proteoglycans (HSPGs) are cell-surface and extracellular matrix macromolecules that are composed of a core protein decorated with covalently linked glycosaminoglycan (GAG) chains. In vitro studies have demonstrated the roles of these molecules in many cellular functions, and recent in vivo studies have begun to clarify their essential functions in development. In particular, HSPGs play crucial roles in regulating key developmental signaling pathways, such as the Wnt, Hedgehog, transforming growth factor-β, and fibroblast growth factor pathways. This review highlights recent findings regarding the functions of HSPGs in these signaling pathways during development.
Nuclear import of the BTB/POZ transcriptional regulator Kaiso
Authors: Kelly Kevin F. , Otchere Abena A. , Graham Monica , Daniel Juliet M.
Published: November 2004

Kaiso is a BTB/POZ transcription factor that functions in vitro as a transcriptional repressor of the matrix metalloproteinase gene matrilysin and the non-canonical Wnt signaling gene Wnt-11, and as an activator of the acetylcholine-receptor-clustering gene rapsyn. Similar to other BTB/POZ proteins (e.g. Bcl-6, PLZF, HIC-1), endogenous Kaiso localizes predominantly to the nuclei of mammalian cells. To date, however, the mechanism of nuclear import for most POZ transcription factors, including Kaiso, remain unknown. Here, we report the identification and characterization of a highly basic nuclear localization signal (NLS) in Kaiso. The functionality of this NLS was verified by its ability to target a heterologous β-galactosidase/green-fluorescent-protein fusion protein to nuclei. The mutation of one positively charged lysine to alanine in the NLS of full-length Kaiso significantly inhibited its nuclear localization in various cell types. In addition, wild-type Kaiso, but not NLS-defective Kaiso, interacted directly with the nuclear import receptor Importin-α2 both in vitro and in vivo. Finally, minimal promoter assays using a sequence-specific Kaiso-binding-site fusion with luciferase as reporter demonstrated that the identified NLS was crucial for Kaiso-mediated transcriptional repression. The identification of a Kaiso NLS thus clarifies the mechanism by which Kaiso translocates to the nucleus to regulate transcription of genes with diverse roles in cell growth and development.
Multiple regions contribute to membrane targeting of Rab GTPases
Authors: Ali Bassam R. , Wasmeier Christina , Lamoreux Lynn , Strom Molly , Seabra Miguel C.
Published: November 2004

Small GTPases of the Rab family are key regulators of membrane trafficking. Each Rab shows a characteristic subcellular distribution, and may serve as an important determinant of organelle identity. The molecular mechanisms responsible for targeting Rabs to specific intracellular compartments, however, remain poorly understood. The divergent C-terminal hypervariable region was postulated to contain Rab targeting information. We generated a series of hybrid Rab proteins by exchanging the hypervariable domains of Rab1a, Rab2a, Rab5a, Rab7 and Rab27a, and analysed their subcellular localisations. We found that the various hybrid proteins retained their targeting to the parent organelle and were functionally active. We conclude that the hypervariable region does not contain a general Rab targeting signal. Furthermore, we identified other regions within the RabF and RabSF motifs that are required for specific targeting of Rab27a to secretory granules or melanosomes, and Rab5a to endosomes. We observed only partial overlap between targeting-determining regions in the Rab proteins examined, suggesting that Rab recruitment may be complex and at least partially Rab-specific. Mutations in these targeting-determining regions induced localisation to the ER, an observation that further strengthens our previous finding that ER/Golgi membranes serve as the default location for Rabs that have lost targeting information.
A role for the small GTPase Rab21 in the early endocytic pathway
Authors: Simpson Jeremy C. , Griffiths Gareth , Wessling-Resnick Marianne , Fransen Jack A. M. , Bennett Holly , Jones Arwyn T.
Published: November 2004

Rab proteins comprise a family of monomeric GTPases that control cellular membrane traffic. Rab21 is a poorly characterised member with no known function. Human Rab21 cDNA from K562 cells was subcloned into GFP expression vectors to generate Rab21 and Rab21 mutants defective in either GTP hydrolysis (Rab21 Q78L) or binding (Rab21 T33N) for transfection studies in HeLa cells. Confocal fluorescence microscopy and ultrastructural studies revealed Rab21 to be predominantly localised to the early endocytic pathway, on vesicles containing earlyendosomal antigen 1 EEA1, transferrin receptor and internalised ligands. EEA1 was localised to enlarged endosomes in Rab21 wild-type expressing cells but the GTP hydrolysis and GDP binding mutants had unique phenotypes labelling tubular reticular structures and the trans-Golgi network, respectively. Early endosome localisation for Rab21 was confirmed in a hepatoma cell line that allowed analysis of the subcellular distribution of the endogenous protein. Comparison of the localisation of Rab21 with other Rabs revealed extensive colocalisation with early endocytic variants Rab4, Rab5, Rab17 and Rab22 but much less overlap with those associated with late endosomes, recycling endosomes and the early secretory pathway. Cells expressing Rab21 T33N had defects in endocytosis of transferrin and epidermal growth factor and failed to effectively deliver the latter ligand to late endosomes and lysosomes for degradation. Collectively, our data provide the first characterisation of Rab21 function in early endosome dynamics.
AtRabF2b (Ara7) acts on the vacuolar trafficking pathway in tobacco leaf epidermal cells
Authors: Kotzer Amanda M. , Brandizzi Federica , Neumann Ulla , Paris Nadine , Moore Ian , Hawes Chris
Published: November 2004

Rab GTPases are universal key regulators of intracellular secretory trafficking events. In particular, Rab 5 homologues have been implicated in endocytic events and in the vacuolar pathway. In this study, we investigate the location and function of a member of this family, AtRabF2b (Ara7) in tobacco (Nicotiana tabacum) leaf epidermal cells using a live cell imaging approach. Fluorescent-tagged AtRabF2b[wt] localized to the prevacuolar compartment and Golgi apparatus, as determined by coexpression studies with fluorescent markers for these compartments. Mutations that impair AtRabF2b function also alter the subcellular location of the GTPase. In addition, coexpression studies of the protein with the vacuole-targeted aleurain-green fluorescent protein (GFP) and rescue experiments with wild-type AtRabF2b indicate that the dominant-negative mutant of AtRabF2b causes the vacuolar marker to be secreted to the apoplast. Our results indicate a clear role of AtRabF2b in the vacuolar trafficking pathway.
Analysis of the LKB1-STRAD-MO25 complex
Authors: Boudeau Jérôme , Scott John W. , Resta Nicoletta , Deak Maria , Kieloch Agnieszka , Komander David , Hardie D. Grahame , Prescott Alan R. , van Aalten Daan M. F. , Alessi Dario R.
Published: November 2004

Mutations in the LKB1 tumour suppressor threonine kinase cause the inherited Peutz-Jeghers cancer syndrome and are also observed in some sporadic cancers. Recent work indicates that LKB1 exerts effects on metabolism, polarity and proliferation by phosphorylating and activating protein kinases belonging to the AMPK subfamily. In vivo, LKB1 forms a complex with STRAD, an inactive pseudokinase, and MO25, an armadillo repeat scaffolding-like protein. Binding of LKB1 to STRAD-MO25 activates LKB1 and re-localises it from the nucleus to the cytoplasm. To learn more about the inherent properties of the LKB1-STRAD-MO25 complex, we first investigated the activity of 34 point mutants of LKB1 found in human cancers and their ability to interact with STRAD and MO25. Interestingly, 12 of these mutants failed to interact with STRAD-MO25. Performing mutagenesis analysis, we defined two binding sites located on opposite surfaces of MO25α, which are required for the assembly of MO25α into a complex with STRADα and LKB1. In addition, we demonstrate that LKB1 does not require phosphorylation of its own T-loop to be activated by STRADα-MO25α, and discuss the possibility that this unusual mechanism of regulation arises from LKB1 functioning as an upstream kinase. Finally, we establish that STRADα, despite being catalytically inactive, is still capable of binding ATP with high affinity, but that this is not required for activation of LKB1. Taken together, our findings reinforce the functional importance of the binding of LKB1 to STRAD, and provide a greater understanding of the mechanism by which LKB1 is regulated and activated through its interaction with STRAD and MO25.
Inhaled Tobramycin in Non—Cystic Fibrosis Patients with Bronchiectasis and Chronic Bronchial Infection with Pseudomonas Aeruginosa
Authors: Drobnic M Estrella , Suñé Pilar , Montoro J Bruno , Ferrer Adelaida , Orriols Ramon
Published: November 2004

BACKGROUND:

Non—cystic fibrosis (CF) patients with bronchiectasis usually develop chronic bronchial infection with Pseudomonas aeruginosa (PA) that is related to worsening lung function and increased morbidity and mortality.

OBJECTIVE:

To determine whether direct aerosol delivery of tobramycin to the lower airways may control infection and produce only low systemic toxicity.

METHODS:

A double-blind, placebo-controlled crossover trial involving 30 patients was conducted to determine the clinical effectiveness and safety of 6-month tobramycin inhalation therapy. Patients received 300 mg of aerosolized tobramycin or placebo twice daily in 2 cycles, each for 6 months, with a one-month washout period. The number of exacerbations, number of hospital admissions, number of hospital admission days, antibiotic use, pulmonary function, quality of life, tobramycin toxicity, density of PA in sputum, emergence of bacterial resistance, and emergence of other opportunistic bacteria were recorded.

RESULTS:

The number of admissions and days of admission (mean ± SD) during the tobramycin period (0.15 ± 0.37 and 2.05 ± 5.03) were lower than those during the placebo period (0.75 ± 1.16 and 12.65 ± 21.8) (p < 0.047). A decrease in PA density in sputum was associated with tobramycin administration in the analysis of the first 6-month cycle (p = 0.038). No significant differences were observed in the number of exacerbations, antibiotic use, pulmonary function, and quality of life. The emergence of bacterial resistance and other bacteria did not differ between the 2 periods of study. Inhaled tobramycin was associated with bronchospasm in 3 patients, but not with detectable ototoxicity or nephrotoxicity.

CONCLUSIONS:

Aerosol administration of high-dose tobramycin in non-CF bronchiectatic patients for endobronchial infection with PA appears to be safe and decreases the risk of hospitalization and PA density in sputum. Nevertheless, pulmonary function and quality of life are not improved, and the risk of bronchospasm is appreciable.
Use of Selective Serotonin-Reuptake Inhibitors in the Treatment of Depression in Adults with HIV
Authors: Caballero Joshua , Nahata Milap C
Published: November 2004

OBJECTIVE:

To review the safety and efficacy of selective serotonin-reuptake inhibitors (SSRIs) for the treatment of depression in adults with HIV.

DATA SOURCES:

We searched Pre-MEDLINE and MEDLINE (1966-May 2004) using terms including generic names of antidepressants and antiretrovirals, depression, HIV, and acquired immunodeficiency syndrome. All English-language articles were included in this review.

DATA SYNTHESIS:

SSRIs may be effective and better tolerated than tricyclic antidepressants in HIV-positive adults. SSRIs did not appear to affect CD4+ cell counts.

CONCLUSIONS:

Controlled trials comparing SSRIs are lacking; thus, it is difficult to determine whether one SSRI is more efficacious than another. It appears that most SSRIs may be used in HIV-positive adults. If drug-drug interactions are a concern, sertraline, citalopram, and possibly escitalopram may be considered.
Use of Macrolides and Tetracyclines for Chronic Inflammatory Diseases
Authors: Voils Stacy A , Evans Martin E , Lane Matthew T , Schosser Robert H , Rapp Robert P
Published: November 2004

OBJECTIVE:

To review the efficacy of macrolides and tetracyclines in several chronic inflammatory conditions.

DATA SOURCES:

Searches of MEDLINE (1966–March 2004) and an extensive bibliography search were undertaken. Key terms included acne, blepharitis, cardiovascular disease, cystic fibrosis, periodontitis, rosacea, and rheumatoid arthritis.

STUDY SELECTION AND DATA EXTRACTION:

Data were obtained primarily from randomized placebo-controlled trials upon which key recommendations are based.

DATA SYNTHESIS:

Antibiotics are often prescribed for months or even years for treatment of chronic inflammatory conditions such as acne, blepharitis, cardiovascular disease, cystic fibrosis, periodontitis, rosacea, and rheumatoid arthritis. Randomized controlled trials have shown that azithromycin is useful in the management of cystic fibrosis and the tetracyclines are beneficial in the management of rheumatoid arthritis, acne, blepharitis, and periodontitis. Several large, randomized controlled trials have failed to show any benefit of macrolides in the secondary prevention of cardiovascular disease. No randomized placebo-controlled clinical trials have been performed to assess the efficacy of macrolides or tetracyclines in patients with rosacea.

CONCLUSIONS:

The use of tetracyclines and macrolides for rosacea is based primarily on anecdotal reports or open-label trials. Limited clinical trials support the use of tetracyclines or macrolides in acne, blepharitis, periodontitis, rheumatoid arthritis, and cystic fibrosis. Trials to date do not support the use of antibiotics for secondary prevention of cardiovascular disease.