bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance of a new furnace for high-resolution synchrotron powder diffraction up to 1900 K: application to determine electron density distribution of the cubic CaTiO3perovskite at 1674 K
Authors: Yashima Masatomo , Tanaka Masahiko
Published: September 2004

Accurate crystal structure analysis at high temperatures is an important challenge in science and technology. A new electric furnace for the measurement of high-resolution (δd/d= 0.03%) synchrotron radiation powder diffraction profiles from materials at high temperatures (up to 1900 K in air) has been designed and fabricated. This furnace consists of a ceramic refractory with MoSi2heaters, an aluminium body cooled by flowing water, and a sample stage with a spinner and a controller for sample-height adjustment.In situsynchrotron powder diffraction measurement for a calcium titanate perovskite specimen at 1674 K has been performed using the furnace at beamline 3A of the Photon Factory. The electron density distribution of the cubic perovskite at 1674 K was successfully obtained using a combination of Rietveld refinement, the maximum-entropy method (MEM) and MEM-based pattern-fitting techniques. The Ti atoms exhibit covalent bonding with the O atoms in the cubic CaTiO3perovskite at this temperature, while the Ca atoms are ionic. These results indicate that the new furnace yields high-quality data for accurate crystal structure analysis.
About the efficiency of the early FOMs inab initioprotein phasing
Authors: Burla Maria C. , Caliandro Rocco , Carrozzini Benedetta , Cascarano Giovanni L. , De Caro Liberato , Giacovazzo Carmelo , Polidori Giampiero
Published: September 2004

Allab initiotechniques for solving protein crystal structures use multisolution approaches. Several figures of merit that are found in the literature are efficient in the last steps of the phasing process, when some trials converge to the correct solution with a relatively small average phase error. Early figures of merit are much more critical; they should be able to recognize useful trials when the phase error is still large, and their efficiency determines the efficiency of the program. In the present work, a wide variety of known figures of merit at atomic and quasi-atomic (∼1.4 Å) resolution have been tested; new figures have also been devised and tested. Their application to a large set of test structures allows the study of their properties at different data resolutions and the selection of the most efficient figures within theSIR2003-Nframework.
Energetic materials: variable-temperature crystal structures of γ- and ∊-HNIW polymorphs
Authors: Bolotina Nadezhda B. , Hardie Michaele J. , Speer Jr Richard L. , Pinkerton A. Alan
Published: September 2004

Crystals of γ- and ∊-hexanitrohexaazaisowurtzitane (γ- and ∊-HNIW, space groupP21/nfor both crystals) have been investigated in the 100–298 K temperature range using single-crystal X-ray diffraction techniques. Temperature-dependent changes of their crystal lattices have been evaluated from the second-rank thermal expansion tensors. Both lattices undergo anisotropic thermal expansion, that of γ-HNIW being more anisotropic than that of the ∊ phase. Comparison with previously reported predictions from molecular dynamics calculations indicates significant differences. Although there are many short (less than van der Waals) intermolecular interactions in both polymorphs, there is no obvious relationship between the short distances and the difference in thermal expansion behavior. Non-linear temperature dependence of the atomic displacement parameters is indicative of anharmonicity of the crystal mean field potential.
Interpretation of small-angle scattering data of inhomogeneous ellipsoids
Authors: Fritz Gerhard , Bergmann Alexander
Published: September 2004

Small-angle scattering data of inhomogeneous ellipsoidal particles are discussed in terms of their pair distance distribution functionsp(r). Special attention is given to the determination of core and shell thicknesses and axis ratios as well as to large distances within the particles, since cross terms between parts of positive and negative contrast within the particle can produce misleading results, similar to homogeneous particles or Janus particles. Cross-section pair distance distribution functionspc(r) of cylinders with elliptical cross sections show similar behaviour. Theoretical calculations are compared with small-angle X-ray and neutron scattering (SAXS and SANS) data of cetyltrimethylammonium bromide in aqueous KCl solutions.
Transplanting cityscapes: the use of imagined globalization in housing commodification in Beijing
Authors: Wu Fulong
Published: September 2004

How does globalization unfold in the process of urban development? Rather than examine the impact of globalization on the city as if the former were independent of and superimposed on the latter, this paper aims to address how globalization can be imagined, pursued and exploited in the process of local growth. Through examining the emergence of Western architectural motifs in a late socialist capital, Beijing, it is shown that transplanting cityscapes is a conscious action by developers to exploit globalization and thereby overcome the constraints of local markets. By associating themselves with globalization, the development elite hope to sell the vision of the good life in the era of globalization.
London and Frankfurt in Europe's evolving financial centre network
Authors: Faulconbridge James R
Published: September 2004

The launch of the Euro and the location of the European Central Bank in Frankfurt initially was seen as a threat to London's pre‐eminent position in European financial geographies. This paper explains why in fact this was not the case. To do this, the paper is divided in two. Firstly, it reviews the literatures that help to explain financial geographies. It is argued that we need to move away from investigating attribute properties such as financial turnover and instead examine the role of networks and interdependencies in producing financial geographies. Secondly, it identifies London's dominance and Frankfurt's growth as a complementary centre through quantitative analysis and then explains how European networks and interdependencies produce this, based on insights from interviews with investment bankers and insurance institution workers in the two cities.
‘Muddy glee’: rounding out the picture of women and physical geography fieldwork
Authors: Bracken (née Bull) Louise , Mawdsley Emma
Published: September 2004

Fieldwork in geography has come under close scrutiny from feminist and postcolonial scholars in recent years. In relation to physical geography, commentators have pointed to a range of practices and images (notably the ‘heroic’, masculinist ‘ideal’) that have acted to deter and exclude women, from undergraduates to senior academics. For some, fieldwork is one of the key sites of gender discrimination for women in physical geography. This paper starts from a position of agreement with many of these critiques, but also seeks to ‘reclaim’ some more positive accounts and perspectives on the subject. In doing so, it aims to critique and disrupt the dominant image of physical geography fieldwork as essentially a masculinist endeavour, and encourage a wider view of the challenges and pleasures of fieldwork for women in physical geography.
Geography, law and the centralizing state: wages arrestment in nineteenth‐ and twentieth‐century Scotland
Authors: Young Craig
Published: September 2004

This paper analyses reform of the law of wages arrestment in nineteenth‐ and twentieth‐century Scotland to examine the spatial nature of the ‘regulatory dilemmas’ faced by the state in legal interventions in a spatially heterogeneous context. Though this reform was an example of how the nineteenth‐century British state sought to regulate the spaces of everyday life, the analysis shows that law‐making processes are the outcome of complex tensions between and within the state and legal systems. In these processes, local legal cultures, tensions between systems of common and statute law and the complex geographies of social life play important roles in shaping the conjunction of space, place and law.
Social geographies of learning disability: narratives of exclusion and inclusion
Authors: Hall Edward
Published: September 2004

The social geographies of people with learning disabilities, one of the most marginalized groups in society, have largely been ignored. The paper explores these hidden geographies through the interpretation of narratives of people with learning disabilities in Scotland, within a social policy framework of social exclusion and inclusion. The paper interprets the experiences of being excluded from and included within mainstream socio‐spaces, and the safe spaces that many people with learning disabilities have formed for themselves in between the positions of social exclusion and inclusion.
(Re)thinking the dynamics between healthcare and place: therapeutic geographies in treatment and care practices
Authors: Andrews Gavin J
Published: September 2004

Although the concept of therapeutic landscapes has assisted health geographers to explore the intimate connections between well‐being and place, arguably, after a decade of applications, the common interpretations and assumptions of commentators should be reviewed. Based on theoretical insights from psychoanalytic geographies and geographies of nursing, this paper makes two observations. First, that landscape has been almost exclusively interpreted in a physical sense with co‐presence being a necessary condition. In turn, this assumption has led to the neglect of non‐physical (imagined) places. Second, that therapeutic effects have been interpreted as experiences attained outside of clinical practices. Hence, healthcare workers and their direct treatments and care have also been neglected. To explore these omissions together, an interview survey of complementary therapists investigates the many ways in which imagined places are constructed and manipulated in therapy sessions. Arguably, beyond this example, extending the therapeutic landscape concept to both physical and non‐physical features of treatments could provide fresh insights into the dynamics between healthcare and place. In disciplinary terms, the benefits are twofold. Whilst it could help develop a critical tradition in health geography, perhaps ironically, it could also provide a stronger disciplinary connection between qualitative health geography, various forms of medicine and their research traditions.
Transfer of Taiwanese ideas and technology to The Gambia, West Africa: a viable approach to rural development?
Authors: Baker Kathleen M , Edmonds Richard Louis
Published: September 2004

The development of Taiwan's agricultural sector contributed significantly to the country's transformation from virtual poverty after World War II to a modern industrial nation. Success resulted from the use of appropriate technologies, developed through an exceptionally close working relationship between government, research and development institutions, extension services and farmers in Taiwan. As part of their overseas development aid programme, the Republic of China on Taiwan has established Technical Missions in those developing countries where it receives political recognition. Among these is The Gambia, West Africa, where one focus of Taiwan's current Technical Mission is the development of women's market gardens. Although the gardens have proved successful, there is doubt as to whether their achievements will be sustained once Taiwan's Technical Mission in The Gambia has ended. Field research in Taiwan and in The Gambia, based largely on participatory techniques, has revealed that the low‐tech methods introduced from Taiwan are appropriate for the Gambian environment. However, much depends on whether women participating in the schemes can commit sufficient time and energy to the gardens, as at present this is a limiting factor. The potential of the gardens may also be constrained by a lack of appropriate institutional infrastructure, particularly the scope for profitable disposal of garden produce. A major conclusion of the article is that successful transfer of appropriate technology to The Gambia is likely to be impeded by poorly developed coordination between groups that proved to be key ‘players’ in the development of agriculture in Taiwan: government, research and development institutions, extension services and producers.
Cannabinoid receptor, CB1, expression follows neuronal differentiation in the early chick embryo
Authors: Begbie Jo , Doherty Patrick , Graham Anthony
Published: September 2004

The role of the CB1 cannabinoid receptor and endocannabinoid signalling has been widely studied in the adult nervous system. However, an emerging body of evidence suggests that the CB1 receptor may also play a role during development. Here we have scrutinized the expression profile of the CB1 receptor from the onset of neurogenesis in the chick embryo. We find that this gene exhibits a dynamic expression pattern that spatially and temporally follows neuronal differentiation in the early embryo.
Formation of cartilaginous foci in the central fibrous body of the heart in Syrian hamsters (Mesocricetus auratus)
Authors: Durán A. C. , López D. , Guerrero A. , Mendoza A. , Arqué J. M. , Sans‐Coma V.
Published: September 2004

The formation of cartilage in the mammalian heart has been studied in the aortic and pulmonary valves. The chondrogenetic process that takes place in the cardiac skeleton is still unknown. The present study was designed to illustrate the ontogeny of cartilaginous foci occurring in the central fibrous body of the Syrian hamster (Mesocricetus auratus) heart. Hearts from 472 animals aged 0–708 days were examined using histological, histochemical and immunohistochemical techniques. Cartilage was present in the central fibrous body of 118 (25%) specimens. A further 104 hamsters were used for the detection of calcific deposits in the central fibrous body. Six (5.8%) showed calcified cartilage. The first sign related to chondrogenesis was the presence of small groups of cells embedded in a type II collagen‐positive extracellular matrix. These cellular groups, which can appear as early as 2 days after birth, differentiate into hyaline cartilage or, less frequently, into fibrocartilage. The highest production of cartilaginous foci takes place between days 40 and 80. Thereafter, formation of new foci is uncommon. This indicates that appearance of cartilage in the central fibrous body of the heart is not a consequence of cardiac aging. The cartilaginous foci seem to act as pivots resisting mechanical tensions generated during the cardiac cycle. Deposition of calcium in the extracellular matrix of the foci can be regarded as a reinforcement of the cartilaginous tissue.
Smooth muscle actin and vimentin as markers of testis development in the harbour porpoise (Phocoena phocoena)
Authors: Holt W. V. , Waller J. , Moore A. , Jepson P. D. , Deaville R. , Bennett P. M.
Published: September 2004

Testicular development in the harbour porpoise Phocoena phocoena was examined using animals (n = 192) stranded or by‐caught off the coast of England, Wales and Scotland. Classification of animals according to their stage of sexual development was undertaken using gonadal morphology and the distribution of cytoskeletal proteins. Smooth muscle actin (SMA) and vimentin proved particularly useful in this respect; SMA was prominent in the myoid peritubular cells of the adult testis, and two stages of peritubular cell SMA expression could be recognized (‘absent’ or ‘incomplete’). The initial appearance of SMA in peritubular cells was associated with significant increases in body length and body weight (P < 0.001), and occurred during the second year of life. Vimentin, which was prominent in prespermatogonia and spermatogonia, sometimes showed a polarized cytoplasmic distribution. This correlated with a developmental stage at which the seminiferous tubule epithelium becomes populated by germ cells (mean age 1.8 years). Several antibodies were tested for their utility as Sertoli cell markers, but none was found to be specific or useful. Nevertheless, immunohistochemical localization of desmin, GATA‐4, Ki67 and androgen receptor was possible despite the poor quality of tissue preservation. This study showed that immunohistochemical classification of these individuals provides a robust basis for the recognition of key physiological stages of sexual development in the male harbour porpoise. This may provide an alternative to the estimation of age, body weight and body length in future analyses aimed at detecting possible adverse effects of environmental pollutants on the reproductive potential of wild marine mammals.
Biostratigraphic and palaeoecological implications of new fossil felid material from the Plio‐Pleistocene site of Tegelen, the Netherlands
Authors: O'Regan Hannah J. , Turner Alan
Published: September 2004

The Plio‐Pleistocene site of Tegelen in the Netherlands contains some of the oldest evidence for the presence of the medium‐sized pantherine felid of the European Pleistocene, Panthera gombaszoegensis, based on published fragmentary dental specimens. Measurements of these specimens, together with those from other localities, suggest that earlier representatives of the species are small, but one of a small number of previously unstudied specimens from the site now indicates the presence of a larger pantherine individual. Such a size difference could point to the presence of a second species, or suggest that the Tegelen deposits encompass a longer time span than has been supposed. Either of these would have serious implications; the first would increase the complexity of the early Pleistocene carnivore guild, and the second would threaten the status of Tegelen as a type site in the European Pleistocene biostratigraphic scheme. However, consideration of the size range in sexed samples of extant pantherines in conjunction with a re‐examination of the size distributions in the hypodigm of P. gombaszoegensis suggests that sexual dimorphism offers a more plausible interpretation.
Cooperative extension initiatives in marriage and couples education
Authors: Wallace Goddard H. , Shoup Olsen Charlotte
Published: September 2004

Cooperative extension has a long‐term history of delivering family life education. Further, the organization has developed numerous research‐based resources and undertaken statewide initiatives in marriage and couples education. Most promising of all is the work of a group of extension specialists to create a practical, research‐based curriculum that may reach communities in the United States through the established network of extension educators and their collaborators. We review various family relationship models and describe how the design of the new couples' curriculum is based on those models.
Rebinding the ties that bind: Government efforts to preserve and promote marriage*
Authors: Brotherson Sean E. , Duncan William C.
Published: September 2004

Governmental efforts to strengthen marriage through a variety of approaches have become increasingly common in the last decade. Societal trends related to family formation, marriage, and divorce have shaped interest in marriage and its stability as a social institution. The public sector has targeted efforts at key stages in the life history of the family system, including preparation for marriage, formation of marriage, rights and responsibilities within marriage, and dissolution of marriage. Particular governmental approaches to preserving and promoting marriage in these contexts are reviewed and discussed, and implications for practitioners and policymakers are outlined.
Benefits of flexible delivery relationship education: An evaluation of the couple CARE program*
Authors: Kim Halford W. , Moore Elizabeth , Wilson Keithia L. , Farrugia Charles , Dyer Carmel
Published: September 2004

The current study evaluated Couple CARE, a flexible delivery relationship education program. Fifty‐nine couples were randomly assigned to either Couple CARE or a control condition and assessed on relationship self‐regulation, satisfaction and stability, and communication. Retention, engagement, and satisfaction with the program were all high. As predicted, Couple CARE increased relationship satisfaction and stability and increased report of relationship self‐regulation, but did not have the predicted effect on communication.
Marriage 101: An integrated academic and experiential undergraduate marriage education course*
Authors: Nielsen Arthur , Pinsof William , Rampage Cheryl , Solomon Alexandra H. , Goldstein Shayna
Published: September 2004

We describe “Marriage 101: Building Loving and Lasting Partnerships,” an innovative, for‐credit undergraduate course at a large, religiously unaffiliated research university. Marriage 101 engages students in the scientific literature and discourse in the psychology and sociology of marriage and marital success. The course has the additional explicitly practical goals of preparing students to choose compatible partners, to face inevitable challenges, and to experience greater marital and relationship satisfaction. To achieve these goals, Marriage 101 integrates traditional academic methods with experiential and self‐discovery assignments. Four years of experience with 150 students has found students eager to learn and able to do so, gaining considerable insight about themselves and the challenges of intimate relationships.
Use of an empirically based marriage education program by religious organizations: Results of a dissemination trial*
Authors: Markman Howard J. , Whitton Sarah W. , Kline Galena H. , Stanley Scott M. , Thompson Huette , St. Peters Michelle , Leber Douglas B. , Antonio Olmos‐Gallo P. , Prado Lydia , Williams Tamara , Gilbert Katy , Tonelli Laurie , Bobulinski Michelle , Cordova Allen
Published: September 2004

We present an evaluation of the extent to which an empirically based couples' intervention program was successfully disseminated in the community. Clergy and lay leaders from 27 religious organizations who were trained to deliver the Prevention and Relationship Enhancement Program (PREP) were contacted approximately yearly for 5 years following training to determine whether they still used PREP and which aspects were used. Results indicated that 82% continued to use at least parts of the program, especially parts dealing with communication and conflict management. Results also showed that clergy and lay leaders extended the use of the curriculum from premarital couples to married couples. We discuss implications for future efforts toward disseminating empirically based programs into community settings.
Adolescents' perceptions of marriage and premarital couples education
Authors: Silliman Benjamin , Schumm Walter R.
Published: September 2004

Adolescents in rural and small city high schools in the western United States (N= 159) reported their perceptions of marriage and marriage education. They considered preparation for marriage important, but expressed lower familiarity with and lower intentions to attend programs than college students assessed previously. Youth valued parents, peers, volunteer couples, and personal experience as sources of information on marriage and were most interested in a brief, low‐cost program led by a volunteer couple that focused on communication and conflict‐resolution skills and issues. Youth attitudes toward and expectations of marriage reflected some realistic but many unrealistic expectations, consistent with their developmental stage. Implications for programming, research, and policy are discussed.
Evaluation of the connections: Relationships and marriage curriculum*
Authors: Gardner Scott P. , Giese Kelly , Parrott Suzanne M.
Published: September 2004

Connections: Relationships and Marriage is a high school marriage education curriculum designed to teach students how to develop healthy relationships and marriages. This study evaluated the effectiveness of this curriculum with 410 high school students who were in Connections or a control group. Although the effects were relatively small, findings suggest that the curriculum increases knowledge of relationship concepts, decreases violence in dating relationships, decreases risk factors for adolescent pregnancy, and positively impacts attitudes related to future successful marriage. Implications for further development of the curriculum and other implications for practitioners are discussed.
Putting empirical knowledge to work: Linking research and programming on marital quality
Authors: Adler‐Baeder Francesca , Higginbotham Brian , Lamke Leanne
Published: September 2004

When selecting a marriage education curriculum, educators can turn to programs that have been evaluated for effectiveness; however, few curricula have undergone such study. An alternative approach, consistent with best practices, is to ensure a research base for program content. A translation process model is offered as an initial attempt to explicate the often advocated yet seldom described research–practice linkage. This process is used to examine recent research on marital quality and provide examples of research‐based content in existing marriage education programs.
The future of couple relationship education: Suggestions on how it can make a difference*
Authors: Kim Halford W.
Published: September 2004

Relationship education holds much promise for reducing the individual, family, and community costs of relationship distress and breakdown. To realize this, potential educators need to offer evidence‐based education that tailors content to the risk and resiliency profiles of the couples. Education needs to be offered at crucial developmental points in couple relationships, in an integrated manner with community development initiatives, to couples at high risk of future relationship problems and in a variety of delivery modes.
Comparison of the pharmacokinetics of miconazole after administration via a bioadhesive slow release tablet and an oral gel to healthy male and female subjects
Authors: Cardot J.‐M. , Chaumont C. , Dubray C. , Costantini D. , Aiache J.‐M.
Published: September 2004

Aims

The aim of this study was to compare salivary miconazole pharmacokinetics following once daily application of bioadhesive tablets (50 or 100 mg), vs the current treatment with a gel (3 times a day, 375 mg day−1).

Methods

A three way cross over study was carried out in 18 healthy subjects (nine males, nine females) with a 1 week washout period between each treatment. Plasma and salivary pharmacokinetics of miconazole were assessed over a 24‐h period.

Results

In all subjects the tablets gave higher and more prolonged salivary miconazole concentrations than the gel. Thus salivary miconazole AUC(0,24 h) was 37.2 times greater for the 100 mg tablet (90% confidence interval [CI] 22.9, 60.5) and 18.9 times greater for the 50 mg tablet (CI 11.7, 30.6) compared with the gel. Similarly, Cmax was 17.2 times greater (CI 11.8, 25.2) and 7.8 times greater (CI 5.3, 11.4) for the 100 mg tablet and 50 mg tablet, respectively. Comparison of the 100 mg and 50 mg tablets gave ratios of 2.2 and 2.0 for Cmax and AUC(0,24 h), respectively (CI 1.5, 3.2 and 1.2, 3.2). The mean time that salivary miconazole concentrations were above 0.4 µg ml−1 (the concentration reached 3 h after application of the oral gel according to published data) or above 1.0 µg ml−1 (the MIC of some Candida species) was greater for both bioadhesive tablets than for the oral gel (10–14 h vs 1.5 h and 7 h vs 0.6 h). Only 19 plasma samples from eight subjects had concentrations of miconazole above 0.4 µg ml−1. Ten of these were taken from five subjects after administration of the gel and nine from three subjects after administration of the tablets.

Conclusions

These data strongly support the further development of miconazole bioadhesive tablets as a sustained release formulation leading to improved antifungal exposure in the buccal cavity. A single daily application should improve compliance, whereas the low systemic absorption of miconazole will alleviate concerns regarding drug interactions and adverse effects.
Lack of effect of bezafibrate and fenofibrate on the pharmacokinetics and pharmacodynamics of repaglinide
Authors: Kajosaari Lauri I. , Backman Janne T. , Neuvonen Mikko , Laitila Jouko , Neuvonen Pertti J.
Published: September 2004

Aims

Gemfibrozil markedly increases the plasma concentrations and blood glucose‐lowering effects of repaglinide, but the effects of other fibrates on repaglinide pharmacokinetics are not known. Our aim was to investigate the effects of bezafibrate and fenofibrate on the pharmacokinetics and pharmacodynamics of repaglinide.

Methods

In a randomized, three‐phase cross‐over study, 12 healthy subjects received 400 mg bezafibrate, 200 mg fenofibrate or placebo once daily for 5 days. On day 5, a single 0.25 mg dose of repaglinide was ingested 1 h after the last pretreatment dose. The concentrations of plasma repaglinide, bezafibrate and fenofibrate and blood glucose were measured up to 7 h postdose.

Results

During the bezafibrate and fenofibrate phases, the total area under the concentration‐time curve [AUC(0,∞)] of repaglinide was 99% (95% confidence interval of the ratio to the control phase 73, 143%) and 99% (85, 127%) of the corresponding value during the placebo (control) phase, respectively. Bezafibrate and fenofibrate had no significant effect on the peak concentration (Cmax) of repaglinide. The mean half‐life of repaglinide was 1.3 h in all phases. The blood glucose‐lowering effect of repaglinide was not affected by bezafibrate or fenofibrate. The AUC(0,8 h) values for bezafibrate and fenofibrate varied 3.0‐fold and 4.4‐fold between individual subjects, respectively. Neither bezafibrate nor fenofibrate affected the pharmacokinetic variables of repaglinide.

Conclusions

Bezafibrate and fenofibrate do not affect the pharmacokinetics or pharmacodynamics of repaglinide.
Effect of the oral renin inhibitor aliskiren on the pharmacokinetics and pharmacodynamics of a single dose of warfarin in healthy subjects
Authors: Dieterle Walter , Corynen Sophie , Mann Jessica
Published: September 2004

Aims

To investigate the effects of aliskiren, an oral renin inhibitor, on the pharmacokinetics and pharmacodynamics of warfarin.

Methods

In a single‐blind, placebo‐controlled, randomized, two‐period crossover study, 15 healthy male and female subjects received a single oral dose of 25 mg racemic warfarin twice, once in the morning of the 8th day of treatment with 150 mg aliskiren and once at the same time point during treatment with placebo. Blood samples were collected for the measurement of prothrombin time (PT) and activated thromboplastin time (aPTT) and for determination of plasma concentrations of (R)‐ and (S)‐warfarin.

Results

Aliskiren treatment had no effect on the blood coagulation parameters (PT, INR and aPTT). The ratios of least square means (90% CI) of pharmacokinetic parameters in the presence and absence of aliskiren for (R)‐ and (S)‐warfarin were Cmax 0.89 (0.82, 0.96) and 0.88 (0.80, 0.97), AUC(0,∞) 1.00 (0.94, 1.07) and 1.06 (0.96, 1.16) and t1/2 0.99 (0.92, 1.07) and 1.05 (0.96, 1.14).

Conclusions

Multiple doses of aliskiren had no detectable effect on the pharmacokinetics or pharmacodynamics of a single dose of warfarin in healthy subjects.
Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects
Authors: Park Ji‐Young , Kim Kyoung‐Ah , Shin Jae‐Gook , Lee Ki Young
Published: September 2004

Aims

Fungal infection is a significant comorbidity in patients with diabetes mellitus, and ketoconazole, an antifungal agent, causes a number of drug interactions with coadministered drugs. Rosiglitazone is a novel thiazolidinedione antidiabetic drug, mainly metabolized by CYP2C8 and to a lesser extent CYP2C9. We investigated the possible effect of ketoconazole on the pharmacokinetics of rosiglitazone in humans.

Methods

Ten healthy Korean male volunteers were treated twice daily for 5 days with 200 mg ketoconazole or with placebo, using a randomized, open‐label, two‐way crossover study. On day 5, a single dose of 8 mg rosiglitazone was administered orally, and plasma rosiglitazone concentrations were measured.

Results

Ketoconazole increased the mean area under the plasma concentration–time curve for rosiglitazone by 47%[P = 0.0003; 95% confidence interval (CI) 23, 70] and the mean elimination half‐life from 3.55 to 5.50 h (P = 0.0003; 95% CI in difference 1.1, 2.4). The peak plasma concentration of rosiglitazone was increased by ketoconazole treatment by 17% (P = 0.03; 95% CI 5, 29). The apparent oral clearance of rosiglitazone decreased by 28% after ketoconazole treatment (P = 0.0005; 95% CI 18, 38).

Conclusions

This study revealed that ketoconazole affected the disposition of rosiglitazone in humans, probably by the inhibition of CYP2C8 and CYP2C9, leading to increasing rosiglitazone concentrations that could increase the efficacy of rosiglitazone or its adverse events.
European Surveillance of Antimicrobial Consumption (ESAC): Data Collection Performance and Methodological Approach
Authors: Vander Stichele R. H. , Elseviers M. M. , Ferech M. , Blot S. , Goossens H. ,   the ESAC Project Group
Published: September 2004

Background

Europe is a continent with strong public healthcare systems, but diverging antibiotic policies and resistance patterns.

Aims

To describe the performance and methodological approach in a retrospective data collection effort (1997–2001), through an international network of surveillance systems, aiming to collect publicly available, comparable and reliable data on antibiotic use in Europe.

Methods

A central multidisciplinary management team co‐ordinated a network of national representatives, liasing with national data providers and bodies responsible for antibiotic policy. The data collected were screened for bias, using a checklist. We focused on detection bias in sample and census data; errors in assigning medicinal product packages to the Anatomical Therapeutic Chemical Classification (ATC); errors in calculations of defined daily doses (DDD) per package; bias by over‐the‐counter sales and parallel trade; and bias in ambulatory care (AC)/hospital care (HC) mix. Datasets were corrected after national feedback, and classified as valid; valid but with minor bias; not valid.

Results

Of the 31 participating countries, 21 countries delivered AC data suitable for cross‐national comparison (14 for all 5 years). Of these, 17 countries provided data on a quarterly basis for at least 1 year. For HC, 14 countries were able to deliver valid data (nine for all 5 years). A valid estimate of the total exposure of national populations to human antibiotic consumption could be made in 17 countries.

Conclusion

In cross‐national comparisons of antibiotic consumption in Europe, methodological rigour in correcting for various sources of bias and checking the validity of ATC/DDD assignment is needed.
Serial passage of MC3T3‐E1 cells down‐regulates proliferation during osteogenesis in vitro
Authors: Peterson W. J. , Tachiki K. H. , Yamaguchi D. T.
Published: September 2004

Abstract.  Generally, fibroblast‐like cells and other types of human cells have been used to demonstrate the principles of replicative senescence in vitro and in vivo. These cells go through three stages of proliferation, including vigorous proliferation, declining proliferation and quiescence or no proliferation. Any variation of this process occurring in osteoprogenitor cells may offer insight into the mechanism of age‐related osteopaenia that predisposes individuals to osteoporosis and bone fractures. We selected MC3T3‐E1 cells derived from mouse calvaria to study the mechanism of replicative senescence of pre‐osteogenic cells because: (i) these cells constitute a well‐known model for studying osteogenesis in vitro; (ii) they undergo a developmental sequence of proliferation and differentiation similar to primary cells in culture; and (iii) they show signs of replicative senescence. These cells were aged by multiple passaging before their use for studying growth kinetics and the effects of population density, effect of extracellular matrix (ECM), size and phases of the cell cycle. Our results show that (i) MC3T3‐E1 cells go through the first two stages of proliferation in a manner similar to human cells, but escape the quiescent phase; (ii) the rate of proliferation is similar for low passage (LP) and high passage (HP) cells, but is decreased in very high passage cells (VHP); (iii) growth inhibition is observed using HP cells seeded at high density; (iv) HP ECM stimulates proliferation of both LP and HP cells; (v) a small increase in cell size is observed in HP cells, but no change is seen in the distribution analysis of their cell cycle; (vi) distribution analysis of the cell cycle of VHP cells reveals a decreased and an increased frequency of cells in S and G2 + M phases of their cell cycle, respectively. These results suggest that the mouse MC3T3‐E1 cell line exhibits many of the cellular and molecular markers associated with replicative senescence in culture as defined by human cells, such as fibroblast‐like cells. Alteration in the sensitivity of MC3T3‐E1 cells to intercellular contact and increase in cell size are the primary factors contributing to decreased proliferation of HP cells.
Counteraction of pRb‐dependent protection after extreme hypoxia by elevated ribonucleotide reductase
Authors: Graff P. , Seim J. , Åmellem Ø. , Arakawa H. , Nakamura Y. , Andersson K. K. , Stokke T. , Pettersen E. O.
Published: September 2004

Abstract.  We have studied hypoxia‐induced cell cycle arrest in human cells where the retinoblastoma tumour suppressor protein (pRb) is either functional (T‐47D and T‐47DHU‐res cells) or abrogated by expression of the HPV18 E7 oncoprotein (NHIK 3025 cells). We have previously found that pRb is dephosphorylated and rebound in the nucleus in T‐47D cells arrested in S‐phase during hypoxia and that this binding is protracted even following re‐oxygenation. In the present study, however, we show that the long‐lasting arrest following re‐oxygenation induced by pRb‐binding in the cell nuclei may be overruled by an elevated level of ribonucleotide reductase (RNR). This seems to create a forced DNA‐synthesis, uncoordinated with cell division, which induces endoreduplication of the DNA. The data indicate that the cells initiating endoreduplication continue DNA‐synthesis until all DNA is replicated once and then may start cycling and cell division with a doubled DNA‐content. Corresponding data on the pRb‐incompetent NHIK 3025‐cells show similar endoreduplication in these. Thus, the data indicate that endoreduplication of DNA following re‐oxygenation may come, either as a result of hypoxic arrest of DNA‐synthesis when pRb‐function is absent in the cells, or if it is overruled by increased RNR. The present study further shows that pRb not only protects the culture by arresting most of the cells that are exposed to extreme hypoxia in S‐phase, but also increases cell survival by means of increased clonogenic ability of these cells. Interestingly, however, cells having an elevated level of RNR have equally high survival as wild‐type cells following 20 h extreme hypoxia. If RNR‐overruling of pRb‐mediated arrest following re‐oxygenation results in an unstable genome, this may therefore represent a danger of oncogenic selection as the protective effect of pRb on cell survival seems to be maintained.
Impact of tobacco smoke on interleukin-16 protein in human airways, lymphoid tissue and T lymphocytes
Authors: ANDERSSON A , QVARFORDT I , LAAN M , SJÖSTRAND M , MALMHÄLL C , RIISE G C , CARDELL L-O , LINDÉN A
Published: September 2004

CD4+ and CD8+ lymphocytes are mobilized in severe chronic obstructive pulmonary disease (COPD) and the CD8+ cytokine interleukin (IL)-16 is believed to be important in regulating the recruitment and activity of CD4+ lymphocytes. In the current study, we examined whether tobacco smoke exerts an impact not only on IL-16 in the lower airways but also in CD4+ or CD8+ lymphocytes or in lymphoid tissue. The concentration of IL-16 protein was measured by enzyme-linked immunosorbent assay (ELISA) in concentrated bronchoalveolar lavage fluid (BALF) collected from 33 smokers with chronic bronchitis (CB), eight asymptomatic smokers (AS) and seven healthy never-smokers (NS). The concentrations of IL-16 and soluble IL-2 receptor alpha (sIL-2Rα) protein were also measured in conditioned medium from human blood CD4+ and CD8+ lymphocytes stimulated with tobacco smoke extract (TSE) in vitro. IL-16 mRNA was assessed in vitro as well, using reverse transcription–polymerase chain reaction (RT-PCR). Finally, the intracellular immunoreactivity for IL-16 protein (IL-16IR) was assessed in six matched pairs of palatine tonsils from smokers and non-smokers. BALF IL-16 was higher in CB and AS than in NS. TSE substantially increased the concentration of IL-16 but not sIL-2Rα in conditioned medium from CD4+ and CD8+ lymphocytes. There was no corresponding effect on IL-16 mRNA. IL-16IR in tonsils was lower in smokers than in non-smokers. The current findings demonstrate that tobacco smoke exerts a wide impact on the CD8+ cytokine IL-16, in the airway lumen, in blood CD4+ and CD8+ lymphocytes and in lymphoid tissue. The effect on IL-16 release may be selective for preformed IL-16 in CD4+ lymphocytes. New clinical studies are required to evaluate whether tobacco smoke mobilizes T lymphocytes via IL-16 in the lower airways and whether this mechanism can be targeted in COPD.
Cryptococcal capsular glucuronoxylomannan reduces ischaemia‐related neutrophil influx
Authors: Ellerbroek P. M. , Schoemaker R. G. , Van Veghel R. , Hoepelman A. I. M. , Coenjaerts F. E. J.
Published: September 2004

Background  The capsular polysaccharide glucuronoxylomannan (GXM) of Cryptococcus neoformans interferes with the chemotaxis and transendothelial migration of neutrophils. Intravenous administration of purified GXM has been shown to reduce the influx of inflammatory cells in an animal model of bacterial infection. Here we show that isolated GXM can also interfere with neutrophil migration in a model of inflammation not related to infection. We assessed the effects of intravenous GXM on neutrophil infiltration in a rat model of myocardial ischaemia, where neutrophil infiltration has been shown to contribute to postischaemic reperfusion injury.

Materials and methods  Rats were subjected to coronary artery ligation followed by a 3‐h reperfusion period. Myeloperoxidase‐activity was measured in the ischaemic tissues as a marker of neutrophil infiltration.

Results  Intravenous administration of GXM markedly reduced the influx of neutrophils in the ischaemic myocardium as measured by a 65% reduction of tissue MPO activity. This reduction of MPO activity was clearly correlated to the serum concentration of GXM. As complement activation by GXM was minimal at the doses applied in vivo, it is unlikely that generation of chemotactic C5a in the circulation by GXM caused the observed reduction in leucocyte migration.

Conclusion  Purified cryptococcal GXM has the ability to reduce neutrophil influx even outside the scope of infection.
Patterns of co‐occurrence of three single nucleotide polymorphisms of the 5,10‐methylenetetrahydrofolate reductase gene in kidney transplant recipients
Authors: Winkelmayer W. C. , Sunder‐Plassmann G. , Huber A. , Födinger M.
Published: September 2004

Background  Recently, a new mutation of the 5,10‐methylenetetrahydrofolate reductase (MTHFR) encoding gene was first described (1793G > A). Only few reports have studied the prevalence of this polymorphism, especially in combination with other MTHFR mutations (677C > T, 1298A > C).

Methods  We cross‐sectionally identified the novel MTHFR 1793G > A polymorphism in 730 kidney transplant recipients. MTHFR 677C > T and 1298A > C were also assessed and the frequency of each was described individually as well as in cross‐tabulation with the other MTHFR genotypes. The expected number of patients for each MTHFR genotype combination was calculated and contrasted with the observed numbers. Fisher's exact test was used for statistical inference.

Results  The allelic frequency of MTHFR 1793G > A was 0·052. Seventy‐two patients (9·9%) were heterozygous and two patients (0·3%) were homozygous. From the cross‐tabulations, we identified 53 patients (expected: 33·6) with the MTHFR 1298AC/1793GA genotype and 17 patients (expected: 6·7) with the MTHFR 1298CC/1793GA genotype. Furthermore, we found two patients with double homozygosity for MTHFR 1793G > A and MTHFR 1298A > C (MTHFR 1793AA/1298CC genotype). The frequencies of these genotype combinations were substantially larger than could be expected (P < 0·001).

Conclusions  These findings suggest a selection or survival advantage for individuals with combined MTHFR 1793G > A and MTHFR 1298A > C genotypes, possibly owing to a mutually stabilizing effect on MTHFR enzyme activity.
Mechanism of in vitro heme‐induced LDL oxidation: effects of antioxidants
Authors: Klouche K. , Morena M. , Canaud B. , Descomps B. , Beraud J. J. , Cristol J. P.
Published: September 2004

Background  Heme protein toxicity, owing to generation of reactive oxygen species most likely by direct interaction between heme iron and hydrogen peroxide (H2O2), may be involved in various pathologies, including atherogenesis and pigmentary acute renal failure. The aim of this study was to investigate the mechanism of heme cytotoxicity and the effects of antioxidant therapies in an in vitro model of heme‐induced low‐density lipoprotein (LDL) oxidation.

Materials and methods  Human LDLs were exposed to heme, iron (Fe), protoporphyrin (PPIX) and PPIX‐Zinc (Zn) with or without H2O2. Lipid peroxidation was monitored by measurement of conjugated diene formation (at the 234‐nm absorbance). The effect of various antioxidants, such as vitamin E and vitamin C, reduced glutathione (GSH), and oxidized glutathione (GSSG), mannitol and desferoxamine (DFO) was further investigated in the established in vitro model of LDL oxidation.

Results  Incubation of LDLs in the presence of heme/H2O2 induced lipid peroxidation with the optimal oxidation rate being at 5 µm heme/100 µm H2O2 doses. By contrast, incubation of LDL with H2O2, Fe, Fe/H2O2, PPIX, PPIX/H2O2, heme or PPIX‐Zn did not initiate any LDL oxidation. In vitro, the vitamin E load protected native LDLs against heme/H2O2 oxidative modifications. Incubation of LDLs with increasing doses of vitamin C, GSH and DFO conferred a dose‐dependent protection, while mannitol and GSSG had no effect.

Conclusions  Initiation and propagation of heme‐induced lipid peroxidation is not mediated by a Fenton reaction but depends on specific interactions between heme and H2O2. It may result from the generation of ferryl and perferryl radicals derived from hemic Fe and H2O2 interactions. A protective effect of vitamins E, C, GSH and DFO was demonstrated in this model.