bluuebunny/crossref_metadata_2025 huggingface dataset:
Water molecules insert into N—H...Cl—M hydrogen bonds while M—Cl...X—C halogen bonds remain intact in dihydrates of halopyridinium hexachloroplatinates
Authors: Zordan Fiorenzo , Brammer Lee
Published: September 2004

The crystal structures of the 3-halopyridinium hexachloroplatinate(IV) dihydrates (HPyX-3)2[PtCl6]·2H2O [(1), X = Br; (2a), (2b), X = I] comprise networks in which the molecular components are linked via N—H...O and O—H...Cl—Pt hydrogen bonds and Pt—Cl...X—C halogen bonds (X = Br, I). The iodo derivative has been isolated in two polymorphic forms. Of particular interest to the understanding of the utility of the hydrogen bonds and M—X...X′—C halogen bonds that propagate the networks in anhydrous salts of this type is that the water molecules insert exclusively into the putative N—H...Cl—Pt hydrogen bonds, while the Pt—Cl...X′—C halogen bonds remain undisrupted by the presence of water molecules.
Conformational change of N-benzylideneanilines in crystals
Authors: Harada Jun , Harakawa Mayuko , Ogawa Keiichiro
Published: September 2004

The crystal structures of N-(4-nitrobenzylidene)aniline (1), N-(4-chlorobenzylidene)-4-methylaniline (2) and N-(4-methylbenzylidene)-4-methylaniline (3) were determined by X-ray diffraction analyses at various temperatures. A dynamic disorder was observed in the crystal structures of all compounds. The dynamic disorder is accounted for in terms of a conformational change involving a pedal motion in the crystals.
Geikielite–ecandrewsite solid solutions: synthesis and crystal structures of the Mg1−x
Zn
x
TiO3 (0 ≤ x ≤ 0.8) series
Authors: Liferovich Ruslan P. , Mitchell Roger H.
Published: September 2004

The crystal structures of members of the geikielite–ecandrewsite solid solution series, Mg1 − x
Zn
x
TiO3 (0 ≤ x ≤ 0.8 a.p.f.u. Zn; a.p.f.u. = atoms per formula unit), synthesized by ceramic methods in air at ambient pressure, have been characterized by Rietveld analysis of X-ray powder diffraction patterns. These synthetic titanates adopt an ordered R\overline 3 structure similar to that of ilmenite. The maximum solubility of Zn in MgTiO3 is considered to be ∼ 0.8 a.p.f.u. Zn, as compounds with greater Zn content could not be synthesized at ambient conditions. Data are given for the cell dimensions and atomic coordinates, together with bond lengths, volumes and distortion indices for all the coordination polyhedra. Within the solid-solution series unit-cell parameters and unit-cell volumes increase with Zn content. All compounds consist of distorted (Mg,Zn)O6 and TiO6 polyhedra and, in common with geikielite and ilmenite (sensu lato), TiO6 polyhedra are distorted to a greater extent than (Mg,Zn)O6. The displacements of (Mg,Zn) and Ti from the centers of their coordination polyhedra vary insignificantly with increasing Zn content. The interlayer distance across the vacant octahedral site in the TiO6 layer decreases slightly with the entry of the larger Zn2+ cation into the vi
A site. The empirically obtained upper limit of the Goldschmidt tolerance factor (t) for A
2+
BO3 compounds adopting an ordered R\overline 3 structure is 0.755. The absence of natural solid solutions between geikielite and ecandrewsite seems to be due to the contrasting geochemistry of Mg and Zn rather than for crystallochemical reasons.
Encountering God: personal reflections on ‘geographer as pilgrim’
Authors: Slater Terry R
Published: September 2004

The geography of religion can be explored from a number of different perspectives. This paper takes an autobiographical approach to explore the numinous experience of God from the point of view of a practising Christian geographer. Such geographical aspects of faith experience remain an under‐researched area. The context for the exploration is an academic conference in the city of Bologna, which became, in turn, an experience of religious tourism, a pilgrimage and an unexpected encounter with God. It is contextualized in terms of debates on identity, the nature of pilgrimage, memorials of death, and time–space continuums and fractures.
Talking whilst walking: a geographical archaeology of knowledge
Authors: Anderson Jon
Published: September 2004

This paper explores how understandings of the knowledge and lives of individuals can be gained through making geographical context more explicit within qualitative research methods. The paper will focus on ‘conversations in place’. More particularly, it will suggest that conversations held whilst walking through a place have the potential to generate a collage of collaborative knowledge. Drawing on the work of Casey, the paper builds upon the notion of the ‘constitutive co‐ingredience’ of place and human identity, and, through using documentary and empirical examples, will argue that ‘talking whilst walking’ can harness place as an active trigger to prompt knowledge recollection and production.
Methodological challenges posed in studying an elite in the field
Authors: Desmond Margaret
Published: September 2004

This paper engages with recent debates in geography and associated disciplines that are concerned with the wider analytic issues to be confronted in researching an elite. Drawing on a case study of the construction of a policy position on GMOs and the Environment in Ireland, the methodological challenges encountered researching up the hybrid elite central to this development are interrogated. In particular, emphasis is placed on the politics of time, which becomes central when a new sector is emerging, and meanings and definitions are being constructed.
What is local about local environmental governance? Observations from the local biodiversity action planning process
Authors: Evans James
Published: September 2004

In line with the tenets of sustainable development, environmental policy has privileged action at the local level. This paper explores how the local has been manifested in practice, drawing upon an extensive qualitative study of biodiversity action planning in Birmingham, UK, undertaken between 1999 and 2002. Analysis highlights the embedded and geographically uneven character of the process, and a number of local path dependencies are identified that act to both constrain and enable the process. It is concluded that environmental policy tends to accept the positive rhetoric of local action rather uncritically. In practice, the local is manifested in a number of different ways, with highly heterogeneous effects.
Comparative aspects of the inner root sheath in adult and developing hairs of mammals in relation to the evolution of hairs
Authors: Alibardi Lorenzo
Published: September 2004

The inner root sheath (IRS) allows the exit of hairs through the epidermal surface. The fine structure of monotreme and marsupial IRS and trichohyalin is not known. Using electron microscopy and immunocytochemistry, the localization of trichohyalin and transglutaminase have been studied in monotreme and marsupial hairs, and compared with trichohyalin localization in placental hairs. Trichohyalin in all mammalian species studied here is recognized by a polyclonal antibody against sheep trichohyalin. This generalized immunoreactivity suggests that common epitopes are present in trichohyalin across mammals. In differentiating IRS cells, trichohyalin granules of variable dimensions are composed of an immunolabelled amorphous matrix associated with a network of 10–12‐nm‐thick keratin filaments. Transglutaminase labelling is present among keratin bundles and trichohyalin granules, and in condensed nuclei of terminally differentiating cells of the inner root sheath. The IRS in monotreme hairs is multistratified but lacks a distinguishable Henle layer. Cornification of IRS determines the sculpturing of the fibre cuticle and later shedding from the follicle for the exit of the hair fibre on the epidermal surface. It is hypothesized that the stratification of IRS in Henle, Huxley and IRS cuticle layers is derived from a simpler organization, like that present in the IRS of monotremes. The IRS is regarded as a localized shedding/sloughing layer needed for the exit of hairs without injury to the epidermis. The formation of the IRS during the evolution of mammalian epidermis allowed the physiological exit of hairs produced inside the skin. The peculiar morphogenesis of hairs in possible primitive skins, such as those of the monotremes (mammals with some reptilian characteristics) or the tails of some rodents (a scaled skin), may elucidate the evolution of hairs. In monotreme and rodent tail skin, the dermal papilla remains localized on the proximal side of the hair peg and forms a hair placode with bilateral symmetry. The papilla is progressively surrounded by the down‐growing hair peg until a dermal papilla with radial symmetry is formed. It is speculated that the progressive reduction of the extended dermal papilla of reptilian scales into small and deep papillae of therapsid reptiles produced hairs in mammals.
Hyaline cartilage engineered by chondrocytes in pellet culture: histological, immunohistochemical and ultrastructural analysis in comparison with cartilage explants
Authors: Zhang Zijun , McCaffery J. Michael , Spencer Richard G. S. , Francomano Clair A.
Published: September 2004

Cartilage engineering is a strategic experimental goal for the treatment of multiple joint diseases. Based on the process of embryonic chondrogenesis, we hypothesized that cartilage could be engineered by condensing chondrocytes in pellet culture and, in the present study, examined the quality of regenerated cartilage in direct comparison with native cartilage. Chondrocytes isolated from the sterna of chick embryos were cultured in pellets (4 × 106 cells per pellet) for 2 weeks. Cartilage explants from the same source were cultured as controls. After 2 weeks, the regenerated cartilage from pellet culture had a disc shape and was on average 9 mm at the longest diameter. The chondrocyte phenotype was stabilized in pellet culture as shown by the synthesis of type II collagen and aggrecan, which was the same intensity as in the explant after 7 days in culture. During culture, chondrocytes also continuously synthesized type IX collagen. Type X collagen was negatively stained in both pellets and explants. Except for fibril orientation, collagen fibril diameter and density in the engineered cartilage were comparable with the native cartilage. In conclusion, hyaline cartilage engineered by chondrocytes in pellet culture, without the transformation of cell phenotypes and scaffold materials, shares similarities with native cartilage in cellular distribution, matrix composition and density, and ultrastructure.
Cardiac anatomy revisited
Authors: Anderson Robert H. , Razavi Reza , Taylor Andrew M.
Published: September 2004

In tomorrow's world of clinical medicine, students will increasingly be confronted by anatomic displays reconstructed from tomographically derived images. These images all display the structure of the various organs in anatomical orientation, this being determined in time‐honoured fashion by describing the individual in the ‘anatomical position’, standing upright and facing the observer. It follows from this approach that all adjectives used to describe the organs should be related to the three orthogonal planes of the body. Unfortunately, at present this convention is not followed for the heart, even though most students are taught that the so‐called ‘right chambers’ are, in reality, in front of their ‘left’ counterparts. Rigorous analysis of the tomographic images already available, along with comparison with dissected hearts displayed in attitudinally correct orientation, calls into question this continuing tendency to describe the heart in terms of its own orthogonal axes, but with the organ positioned on its apex, so that the chambers can artefactually be visualized with the right atrium and right ventricle in right‐sided position. Although adequate for describing functional aspects, such as ‘right‐to‐left’ shunting across intracardiac communications, this convention falls short when used to describe the position of the artery that supplies the diaphragmatic surface of the heart. Currently known as the ‘posterior descending artery’, in reality it is positioned inferiorly, and its blockage produces inferior myocardial infarction. In this review, we extend the concept of describing cardiac structure in attitudinally correct orientation, showing also how access to tomographic images clarifies many aspects of cardiac structure previously considered mysterious and arcane. We use images prepared using new techniques such as magnetic resonance imaging and computerized tomography, and compare them with dissection of the heart made in time‐honoured fashion, along with cartoons to illustrate contentious topics. We argue that there is much to gain by describing the components of the heart as seen in the anatomical position, along with all other organs and structures in the body. We recognize, nonetheless, that such changes will take many years to be put into practice, if at all.
Characterization and species differences in gastric ghrelin cells from mice, rats and hamsters
Authors: Yabuki Akira , Ojima Toshimichi , Kojima Masayasu , Nishi Yoshihiro , Mifune Hiroharu , Matsumoto Mitsuharu , Kamimura Ryozo , Masuyama Taku , Suzuki Syusaku
Published: September 2004

Ghrelin is a newly identified gastric peptide hormone that has various important functions, including growth‐hormone release and appetite stimulation. Ghrelin‐immunoreactive cells (ghrelin cells) are characterized by X‐type endocrine cells in the rat stomach. In the present study, we analysed ghrelin cells in fundi of stomach from ICR mice and Syrian hamsters immunohistochemically, immunoelectron microscopically and morphometrically, and compared the results with those from Wistar rats. Immunohistochemistry revealed that ghrelin cells were sparsely distributed in the proper gastric glands in all species. The number of ghrelin cells per unit area in hamsters was significantly lower than that in rats. Immunoelectron microscopy detected ghrelin immunolabelling in granules in the X‐type endocrine cells. However, the diameter of granules in the hamsters was significantly smaller than that in the mice and rats. Gastric ghrelin contents were determined by radioimmunoassay, and levels in the hamsters were significantly lower than those in mice and rats. The results from mice were identical to those from rats. In conclusion, gastric ghrelin cells in mice and hamsters are characterized by X‐type endocrine cells, as has been observed in rats. However, the data indicated that gastric ghrelin production was lower in hamster than in mouse or rat.
Investigation of the effects of partial coherence on exit wave reconstruction
Authors: ALLEN L. J. , MCBRIDE W. , O'LEARY N. L. , OXLEY M. P.
Published: September 2004

In a recent work we presented an iterative wave function reconstruction (IWFR) method that reconstructs a wave function from measurements of its amplitude taken as it propagates in free space (a focal series of images). Although the ideal environment for application of the IWFR method is in a coherent imaging system, it has been developed so that it can be applied in a partially coherent imaging system, in particular for a high‐resolution transmission electron microscope using a field‐emission gun. In this paper we investigate the effects of partial coherence on the accuracy of results obtained using the IWFR method. We then show how results obtained under such conditions can be improved by estimating and subtracting components from the amplitude measurements of the wave function that derive from incoherence in the electron beam.
Direct visualization of receptor arrays in frozen‐hydrated sections and plunge‐frozen specimens of E. coli engineered to overproduce the chemotaxis receptor Tsr
Authors: ZHANG P. , BOS E. , HEYMANN J. , GNAEGI H. , KESSEL M. , PETERS P. J. , SUBRAMANIAM S.
Published: September 2004

We have recently reported electron tomographic studies of sections obtained from chemically fixed E. coli cells overproducing the 60‐kDa chemotaxis receptor Tsr. Membrane extracts from these cells prepared in the presence of Tween‐80 display hexagonally close‐packed microcrystalline assemblies of Tsr, with a repeating unit large enough to accommodate six Tsr molecules arranged as trimers of receptor dimers. Here, we report the direct visualization of the Tsr receptor clusters in (i) vitrified cell suspensions of cells overproducing Tsr, prepared by rapid plunge‐freezing, and (ii) frozen‐hydrated sections obtained from cells frozen under high pressure. The frozen‐hydrated sections were generated by sectioning at −150 °C using a diamond knife with a 25° knife angle, with nominal thicknesses ranging from 20 to 60 nm. There is excellent correspondence between the spatial arrangement of receptors in thin frozen‐hydrated sections and the arrangements found in negatively stained membrane extracts and plunge‐frozen cells, highlighting the potential of using frozen‐hydrated sections for the study of macromolecular assemblies within cells under near‐native conditions.
Three‐dimensional analysis of porous BaTiO3 ceramics using FIB nanotomography
Authors: HOLZER L. , INDUTNYI F. , GASSER PH. , MÜNCH B. , WEGMANN M.
Published: September 2004

Three‐dimensional (3D) data represent the basis for reliable quantification of complex microstructures. Therefore, the development of high‐resolution tomography techniques is of major importance for many materials science disciplines. In this paper, we present a novel serial sectioning procedure for 3D analysis using a dual‐beam FIB (focused ion beam). A very narrow and reproducible spacing between the individual imaging planes is achieved by using drift correction algorithms in the automated slicing procedure. The spacing between the planes is nearly of the same magnitude as the pixel resolution on scanning electron microscopy images. Consequently, the acquired stack of images can be transformed directly into a 3D data volume with a voxel resolution of 6 × 7 × 17 nm. To demonstrate the capabilities of FIB nanotomography, a BaTiO3 ceramic with a high volume fraction of fine porosity was investigated using the method as a basis for computational microstructure analysis and the results compared with conventional physical measurements. Significant differences between the particle size distributions as measured by nanotomography and laser granulometry indicate that the latter analysis is skewed by particle agglomeration/aggregation in the raw powder and by uncertainties related to calculation assumptions. Significant differences are also observed between the results from mercury intrusion porosimetry (MIP) and 3D pore space analysis. There is strong evidence that the ink‐bottle effect leads to an overestimation of the frequency of small pores in MIP. FIB nanotomography thus reveals quantitative information of structural features smaller than 100 nm in size which cannot be acquired easily by other methods.
Community marriage initiatives
Authors: Doherty William J. , Anderson Jared R.
Published: September 2004

This article reviews the development of community marriage initiatives and their relationship with family professionals, with particular emphasis on sociohistorical context. We describe five leading community marriage initiatives, discuss the state of the evaluation research, and propose new directions for this promising area of work.
The challenges of offering relationship and marriage education to low‐income populations
Authors: Ooms Theodora , Wilson Pamela
Published: September 2004

Relationship and marriage education has been primarily developed for and offered to middle‐class committed couples. Increasing government funding of these programs raises questions about the extent to which these curricula and programs need to be adapted for low‐income populations. We review the limited body of relevant research and program experience to identify the challenges and guiding principles that need to be addressed when offering these programs to more diverse populations.
Implications of remarriage and stepfamily formation for marriage education*
Authors: Adler‐Baeder Francesca , Higginbotham Brian
Published: September 2004

Couples in remarriages with stepchildren are a significant portion of the marriage population and have unique educational needs regarding aspects of couple functioning within the context of stepfamily development. From a review of the literature, we examine current curricula focused on these couples. Information is offered on implementation issues regarding recruitment, delivery context, facilitator and participant characteristics, and evaluation.
The Couples Coping Enhancement Training (CCET): A new approach to prevention of marital distress based upon stress and coping*
Authors: Bodenmann Guy , Shantinath S. D.
Published: September 2004

We describe a distress prevention training program for couples and three empirical studies that support its effectiveness. The program, Couples Coping Enhancement Training (CCET), is based both upon stress and coping theory and research on couples. In addition to traditional elements of couples programs (e.g., communication and problem‐solving skills), the CCET also addresses individual and dyadic coping in promoting marital satisfaction and reducing marital distress. The CCET enjoys good consumer acceptance. Outcome results indicate that, in addition to acquiring relationship skills, participants experienced reduced martial distress and increased marital satisfaction, even among couples who have been in long‐standing relationships where dissatisfaction exists.
Assessing the impact of community marriage policies® on county divorce rates*
Authors: James Birch Paul , Weed Stan E. , Olsen Joseph
Published: September 2004

Community marriage initiatives (CMIs) are designed to strengthen marriage and increase marital stability by addressing relevant laws, policies, and cultural factors. We examined a specific CMI designed to lower divorce rates by establishing a shared public commitment among clergy to strengthen marriage. A mixed‐effects general linear model was used to determine whether changes in divorce rates over time were different before than after in 122 sites. Results indicate that divorce rates declined more rapidly following adoption, and this decline was larger than that observed in comparison counties. This difference in declines translates into a 2% difference annually in favor of CMI counties. Implications for measuring the effectiveness of CMIs are addressed.
A review of empirically supported marital enrichment programs*
Authors: Jakubowski Scott F. , Milne Eric P. , Brunner Heidi , Miller Richard B.
Published: September 2004

Considering the popularity of marriage enrichment programs, it is important for clinicians and marriage educators to know which programs have received empirical support. Using criteria established for determining empirically supported treatments (ESTs), we provide a comprehensive review of the outcome research on 13 specific marital enrichment programs. Only four programs could be considered “efficacious,” three were found to be “possibly efficacious,” and six were considered “empirically untested.”
A comprehensive framework for marriage education*
Authors: Hawkins Alan J. , Carroll Jason S. , Doherty William J. , Willoughby Brian
Published: September 2004

We offer a framework to help marriage educators think more thoroughly, systematically, and creatively about intervention opportunities to strengthen marriage. We draw attention to the educational dimensions of content, intensity, methods, timing, setting, target, and delivery, and their implications for marriage education. Our discussion points out the potential value of developing marriage education with greater specificity in content, timing, and target. We call for intervention that embeds marriage education in diverse institutional settings and provides access to couples across the socioeconomic spectrum. In the end, we address the need to take marriage education beyond a valuable helping profession and an expanding educational service to a vibrant social movement.
Habitat‐specific life‐history variation in the Caribbean termiteNasutitermes acajutlae(Isoptera: Termitidae)
Authors: Jeyasingh Punidan D. , Fuller Claire A.
Published: September 2004

Abstract. 1. Population and individual colony characteristics ofNasutitermes acajutlaeon St John, U.S. Virgin Islands were studied over a 5‐year period.

2. Four habitat types (dry forests, moist forests, sparse vegetation, and woodlands) were sampled forN. acajutlae, using quadrat‐based methods. Lying dead wood was also quantified in the same sites.

3. Habitats differed significantly in the volume of lying dead wood, and total termite nest volume within quadrats was positively related to wood volume. It was hypothesised that the volume of dead wood affected growth, reproduction, and yearly survival of individual colonies.

4. In a sample of > 100 colonies assessed in 1998, 2000, 2001, and 2002, no significant differences in the growth rate of colonies (= increase in nest volume) could be found between habitat types; however, colonies in sparse vegetation were smaller, less likely to survive, and reproduced at a smaller size compared with those in the other three habitats.

5. Overall nest volume in sparse vegetation was high, compared with dry and moist forest, but colonies showed, on average, poorer survival (interpreted as lower fitness), and produced alates at an early stage of development. Optimum habitat characteristics forN. acajutlaemay include not only favourable microclimate but also the reliable acquisition of new dead wood after storms.
A review of relationships between interspecific competition and invasions in fruit flies (Diptera: Tephritidae)
Authors: Duyck Pierre‐Francois , David Patrice , Quilici Serge
Published: September 2004

Abstract.  1. A number of invasions in the family Tephritidae (fruit flies) have been observed worldwide despite quarantine procedures. In this review, the potential importance of interspecific competition and competitive displacement among different tephritid species is evaluated in the context of recent invasions.

2. Where polyphagous tephritid species have been introduced in areas already occupied by a polyphagous tephritid, interspecific competition has resulted in a decrease in number and niche shift of the pre‐established species. No reciprocal invasions have been observed.

3. The data on tephritid invasions seem to support a hierarchical mode of competition; however, complete exclusion usually did not occur. Indeed, tephritid distribution and abundance are markedly structured by various abiotic (mostly climatic) and biotic (host plants) factors.

4. The primary determinant of competitive interactions in near‐optimal conditions, such as lowlands with abundant fruit plantations, is probably the life‐history strategy. The r–K gradient could be used as a predictor of potential invaders, because K traits (such as large adult size) may favour both exploitation and interference competition.

5. For future research, a better understanding of competition mechanisms seems essential. Different species competing in the same area should be compared with respect to: (i) demographic parameters, (ii) the outcome of experimental co‐infestations on the same fruit, and (iii) behavioural and chemical interference mechanisms.
The interactive effects of climate, life history, and interspecific neighbours on mortality in a population of seed harvester ants
Authors: Sanders Nathan J. , Gordon Deborah M.
Published: September 2004

Abstract.  1. Fifteen years of census data from a population of the red harvester ant (Pogonomyrmex barbatus), 5 years of census data from populations of Aphaenogaster cockerelli and Myrmecocystus mimicus at the same site, and long‐term precipitation data from a nearby weather station were used to examine how nearest interspecific neighbours, climate, and life history influence P. barbatus colony mortality.

2. It was found that more P. barbatus colonies die following dry summers than following wet summers, but there is no relationship between the establishment of new colonies and rainfall.

3. Aphaenogaster cockerelli, but not M. mimicus, nearest neighbours influence P. barbatus colony mortality in some years and for some ages.

4. The effects of nearest A. cockerelli neighbours are usually most severe following dry summers, when resource availability is reduced.
Pharmacokinetics of oral fumarates in healthy subjects
Authors: Litjens Nicolle H. R. , Burggraaf Jacobus , Van Strijen Elisabeth , Van Gulpen Co , Mattie Herman , Schoemaker Rik C. , Van Dissel Jaap T. , Thio H. Bing , Nibbering Peter H.
Published: September 2004

Aims

To characterize the pharmacokinetics of fumarates in healthy subjects.

Methods

Ten subjects received a single fumarate tablet (containing 120 mg of dimethylfumarate and 95 mg of calcium‐monoethylfumarate) in the fasted state and after a standardized breakfast in randomized order. Prior to and at fixed intervals after the dose, blood samples were drawn and the concentrations of monomethylfumarate, the biologically active metabolite, as well as dimethylfumarate and fumaric acid were measured using high‐performance liquid chromatography.

Results

After a lag time, a transient increase in serum monomethylfumarate concentrations in the blood was observed, whereas dimethylfumarate and fumaric acid concentrations remained below the detection limit. The tlag was 240 min [range 60–603 min; 95% confidence interval (CI) 139, 471] shorter when the tablet was taken after an overnight fast (90 min; range 60–120 min; 95% CI 66, 107) than when taken with breakfast (300 min; range 180–723 min; 95% CI 0, 1002). The tmax was 241 min (range 60–1189 min, 95% CI 53, 781) shorter when the tablet was taken after an overnight fast (182 min; range 120–240 min; 95% CI 146, 211) than when taken with breakfast (361 min; range 240–1429 min; 95% CI 0, 1062). The mean Cmax for monomethylfumarate in the blood of fasting subjects was to 0.84 mg l−1 (range 0.37–1.29 mg l−1; 95% CI 0.52, 1.07) and did not differ from that in fed subjects (0.48 mg l−1; range 0–1.22 mg l−1; 95% CI 0, 5.55).

Conclusions

The pharmacokinetics of monomethylfumarate in healthy subjects after a single tablet of fumarate are highly variable, particularly after food intake. Further experiments exploring the pharmacokinetics of oral fumarates are warranted in order to elucidate the mechanisms underlying variability in reponse in patients.
Undeclared exposure to St. John's Wort in hospitalized patients
Authors: Martin‐Facklam Meret , Rieger Karin , Riedel Klaus‐Dieter , Burhenne Jürgen , Walter‐Sack Ingeborg , Haefeli Walter E.
Published: September 2004

Aim

The herbal medicine St. John's Wort (SJW) causes substantial decreases in the plasma concentrations of a range of co‐administered drugs. Therefore, we evaluated the extent of systemic exposure to hyperforin and hypericin, two of the main constituents of SJW, in patients on admission and during hospital stay, and compared the results with known use of SJW as documented in the drug chart and detected in additional interviews.

Methods

One hundred and fifty patients aged ≥ 18 years and admitted, between August 2000 and February 2002, to an internal medicine ward of a large German university hospital were included. Hyperforin and hypericin was determined in plasma by a sensitive liquid chromotography/mass spectometry (LC/MS/MS) method. To assess undeclared use of SJW the data were compared to information obtained from drug charts and from up to three interviews that had a particular focus on intake of herbal medicines and self‐medication during hospitalization.

Results

Hyperforin was detected in 12 patients (plasma concentration on the first day of hospitalization = 12–100 ng ml−1 in five patients and <3 ng ml−1 in seven), and hypericin in five patients (0.5–4.3 ng ml−1). Nine patients (6%) were taking/had taken SJW without the knowledge of the medical team and the pharmacist, who conducted the additional interviews, and 11 (7.3%) were taking/had taken SJW without the knowledge of the medical team alone. Seven of these patients were treated concurrently with drugs that can interact with SJW.

Conclusions

Unrecognized use of SJW is frequent and may have an important influence on the effectiveness and safety of drug therapy during hospital stay.
Models for time‐varying covariates in population pharmacokinetic‐pharmacodynamic analysis
Authors: Wählby Ulrika , Thomson Alison H. , Milligan Peter A. , Karlsson Mats O.
Published: September 2004

Aim

If appropriately accounted for in a pharmacokinetic (PK)–pharmacodynamic (PD) model, time‐varying covariates can provide additional information to that obtained from time‐constant covariates. The aim was to present and apply two models applicable to time‐varying covariates that capture such additional information.

Methods

The first model estimates different covariate–parameter relationships for within‐ and between‐individual variation in covariate values, by splitting the standard covariate model into a baseline covariate (BCOV) effect and a difference from baseline covariate (DCOV) effect. The second model allows the magnitude of the covariate effect to vary between individuals, by inclusion of interindividual variability in the covariate effect. The models were applied to four previously analysed data sets.

Results

The models were applied to 10 covariate–parameter relationships and for three of these the first extended model resulted in a significant improvement of the fit. Even when this model did not improve the fit significantly, it provided useful information because the standard covariate model, which assumes within‐ and between‐patient covariate relationships of the same magnitude, was only supported by the data in four cases. The inclusion of BCOV was not supported in two cases and DCOV was unnecessary in three cases. In one case, significantly different, nonzero, relationships were found for DCOV and BCOV. The second extended model was found to be significant for four of the 10 covariate–parameter relationships.

Conclusions

On the basis of the examples presented, traditionally made simplifications of covariate–parameter relationships are often inadequate. Extensions to the covariate–parameter relationships that include time‐varying covariates have been developed, and their appropriateness and benefits have been described.
Drug interaction between St John's Wort and quazepam
Authors: Kawaguchi Atsuhiro , Ohmori Masami , Tsuruoka Shu‐ichi , Nishiki Kenta , Harada Kenichi , Miyamori Isamu , Yano Ryo‐ichi , Nakamura Toshiaki , Masada Mikio , Fujimura Akio
Published: September 2004

Aim

St John's Wort (SJW) enhances CYP3A4 activity and decreases blood concentrations of CYP3A4 substrates. In this study, the effects of SJW on a benzodiazepine hypnotic, quazepam, which is metabolized by CYP3A4, were examined.

Methods

Thirteen healthy subjects took a single dose of quazepam 15 mg after treatment with SJW (900 mg day−1) or placebo for 14 days. The study was performed in a randomized, placebo‐controlled, cross‐over design with an interval of 4 weeks between the two treatments. Blood samples were obtained during a 48 h period and urine was collected for 24 h after each dose of quazepam. Pharmacodynamic effects were determined using visual analogue scales (VAS) and the digit symbol substitution test (DSST) on days 13 and 14.

Results

SJW decreased the plasma quazepam concentration. The Cmax and AUC0‐48 of quazepam after SJW were significantly lower than those after placebo [Cmax; −8.7 ng ml−1 (95% confidence interval (CI) −17.1 to −0.2), AUC0‐48; −55 ng h ml−1 (95% CI −96 to −15)]. The urinary ratio of 6β‐hydroxycortisol to cortisol, which reflects CYP3A4 activity, also increased after dosing with SJW (ratio; 2.1 (95%CI 0.85–3.4)). Quazepam, but not SJW, produced sedative‐like effects in the VAS test (drowsiness; P < 0.01, mental slowness; P < 0.01, calmness; P < 0.05, discontentment; P < 0.01). On the other hand, SJW, but not quazepam impaired psychomotor performance in the DSST test. SJW did not influence the pharmacodynamic profile of quazepam.

Conclusions

These results suggest that SJW decreases plasma quazepam concentrations, probably by enhancing CYP3A4 activity, but does not influence the pharmacodynamic effects of the drug.
Comparison of bronchoprotective and bronchodilator effects of a single dose of formoterol delivered by hydrofluoroalkane and chlorofluorocarbon aerosols and dry powder in a double blind, placebo‐controlled, crossover study
Authors: Houghton C. M. , Langley S. J. , Singh S. D. , Holden J. , Monici Preti A. P. , Acerbi D. , Poli G. , Woodcock A.
Published: September 2004

Background

In response to the phasing out of chlorofluorocarbon (CFC) inhalers, a metered dose hydrofluoroalkane (HFA) formulation, Modulite (Chiesi Farmaceutici S.p.A, Parma, Italy), to be delivered with a pressurized metered dose inhaler (pMDI), has been developed. Modulite is a HFA formulation technology that has been designed to provide stable and uniform dose delivery of HFA‐based formulations to enable an easy transition from CFC to HFA inhalers.

Objectives

The aim of this study was to compare the bronchoprotective and bronchodilator effects of a single dose of 12 µg of formoterol from the HFA Modulite inhaler with the Foradil Aerolizer (dry powder inhaler, DPI) and the Foradil CFC inhalers (Novartis Health Consumer, Basel, Switzerland).

Methods

This was a double blind, double dummy, randomized, placebo‐controlled, crossover study conducted in 38 subjects with mild to moderate asthma (mean forced expiratory volume in 1 s [FEV1] 87.5% predicted). The primary endpoint was methacholine challenge provocative dose required for 20% fall in the FEV1 (PD20) 90 min post dose. Bronchodilation was assessed with spirometry (FEV1, FVC, FEF25–75) and impulse oscillometry (resistance at 5 and 20 Hz, reactance at 5 Hz and resonant frequency) over the 90 min post dose. In a subset of 12 subjects formoterol plasma levels, serum potassium and glucose were determined up to 480 min post dose.

Results

The three formoterol formulations demonstrated significant (P ≤ 0.05) improvements in bronchoprotection compared to placebo and non‐inferiority of the HFA preparation compared to the CFC and DPI preparations was demonstrated. Geometric mean PD20 values were 0.51 mg with HFA, 0.62 mg with DPI, 0.62 mg with CFC and 0.2 mg with placebo. The log transformed mean differences in PD20 doubling dose between HFA and (a) DPI was −0.28 (95% CI −0.84–0.29, P = 0.57) (b) CFC was −0.28 (95% CI −0.84–0.28, P = 0.57) and (c) placebo was 1.38 (95% CI 0.82–1.94, P < 0.001). Serum potassium, glucose and formoterol plasma profiles were comparable for the CFC, HFA and DPI devices.

Conclusion

Our findings of similar efficacy, pharmacokinetics and systemic effects of the HFA formoterol inhaler compared to the CFC and DPI preparations supports the potential use of this novel formulation in the treatment of asthma.
Pharmacokinetics and renal excretion of desmopressin after intravenous administration to healthy subjects and renally impaired patients
Authors: Agersø Henrik , Seiding Larsen Lotte , Riis Anders , Lövgren Ulf , Karlsson Mats O. , Senderovitz Thomas
Published: September 2004

Objective

To evaluate the influence of renal impairment on the pharmacokinetics of desmopressin.

Methods

Twenty‐four subjects were enrolled in the study, 18 with varying degrees of renal impairment and six healthy volunteers. Each subject received a single intravenous dose of 2 µg desmopressin. Blood and urine samples were collected for 24 h and assayed for desmopressin by radioimmunoassay. Plasma concentrations and the amounts of desmopressin excreted in the urine were analysed simultaneously by use of mixed effects modelling.

Results

Only mild adverse events were observed. Both the renal and the nonrenal clearance of desmopressin were found to vary with the creatinine clearance (CrCL). A decrease of 1.67% in the CrCL (corresponding to 1 ml min−1 from 60 ml min−1) was found to cause a 1.74% decrease in the renal clearance and a 0.93% decrease in the nonrenal clearance. The fall in renal clearance caused the amount of desmopressin excreted in urine to decrease from 47% in healthy subjects to 21% in the patients with severe renal impairment. The mean systemic clearance of desmopressin was 10 litres h−1 in healthy subjects and 2.9 litres h−1 in patients with severe renal impairment (difference −7.5 litres h−1, 95% CI [−11; −4.3] litres h−1). Correspondingly, the mean terminal half‐life, was 3.7 h in healthy subjects and 10 h in patients with severe renal impairment (difference 6.7 h, 95% CI [4.0; 9.4] h).

Conclusion

Although desmopressin appears to be safe and well‐tolerated by patients with impaired renal function, great caution should be exercised when titrating towards an efficient dosage regimen if patients with moderately or severely impaired renal function are to be treated with desmopressin at all.
Pharmacokinetic/pharmacodynamic models for the depletion of Vβ5.2/5.3 T cells by the monoclonal antibody ATM‐027 in patients with multiple sclerosis, as measured by FACS
Authors: Zingmark Per‐Henrik , Edenius Charlotte , Karlsson Mats O.
Published: September 2004

Aims

(i) To model the effects of the monoclonal antibody ATM‐027 on the number of target cells and on the receptor density on the cell surface as measured by Fluorescence Activated Cell Sorter analysis, (ii) to investigate the effects of categorizing a continuous scale, and (iii) to simulate a phase II trial from phase I data in order to evaluate the predictive performance of the model by comparison with the actual trial results.

Methods

Based on the data from one phase I and one phase II study in multiple sclerosis (MS) patients, models were developed to characterize the pharmacokinetics and pharmacodynamics of the monoclonal antibody ATM‐027 and its effects on Vβ5.2/5.3+ T cells. The pharmacodynamic variables were the number of target T cells and the expression of its receptor. The latter was modelled in both a categorical and continuous way. The modelling was performed with a nonlinear mixed effects approach using the software NONMEM. The joint continuous models were used to simulate the phase II trial from the phase I data.

Results

The pharmacokinetics of ATM‐027 were characterized by a two‐compartment model with a total volume of distribution of 5.9 litres and a terminal half‐life of 22.3 days (phase II parameter estimates) in the typical patient. Continuous receptor expression was modelled using an inhibitory sigmoidal Emax‐model. Similar results from the phase I and phase II data were obtained, and EC50 was estimated to be 138 and 148 µg litre−1, respectively. Categorical receptor expression was modelled using a proportional odds model, and the EC50 values obtained were highly correlated with those from the continuous model. The numbers of target T cells were also modelled and treatment with ATM‐027 decreased the number of cells to 25.7% and 28.9% of their baseline values in the phase I and II trials, respectively. EC50s for the decrease in the number of T cells were 83 µg litre−1 and 307 µg litre−1, respectively. Simulations of the phase II trial from the phase I models gave good predictions of the dosing regimens administered in the phase II study.

Conclusion

All aspects of effects of the monoclonal antibody ATM‐027 on Vβ5.2/5.3+ T cells were modelled and the phase II trial was simulated from phase I data. The effects of categorizing a continuous scale were also evaluated.
Cumulative high doses of inhaled formoterol have less systemic effects in asthmatic children 6–11 years‐old than cumulative high doses of inhaled terbutaline
Authors: Kaae Rikke , Agertoft Lone , Pedersen Sören , Nordvall S Lennart , Pedroletti Christophe , Bengtsson Thomas , Johannes‐Hellberg Ingegerd , Rosenborg Johan
Published: September 2004

Objectives

To evaluate high dose tolerability and relative systemic dose potency between inhaled clinically equipotent dose increments of formoterol and terbutaline in children.

Methods

Twenty boys and girls (6–11 years‐old) with asthma and normal ECGs were studied. Ten doses of formoterol (Oxis®) 4.5 µg (F4.5) or terbutaline (Bricanyl®) 500 µg (T500) were inhaled cumulatively via a dry powder inhaler (Turbuhaler®) over 1 h (three patients) or 2.5 h (17 patients) and compared to a day of no treatment, in a randomised, double‐blind (active treatments only), crossover trial. Blood pressure (BP), ECG, plasma potassium, glucose, lactate, and adverse events were monitored up to 10 h to assess tolerability and relative systemic dose potency.

Results

Formoterol and terbutaline had significant β2‐adrenergic effects on most outcomes. Apart from the effect on systolic BP, QRS duration and PR interval, the systemic effects were significantly more pronounced with terbutaline than with formoterol. Thus, mean minimum plasma potassium, was suppressed from 3.56 (95% confidence interval, CI: 3.48–3.65) mmol l−1 on the day of no treatment to 2.98 (CI: 2.90–3.08) after 10 × F4.5 and 2.70 (CI: 2.61–2.78) mmol l−1 after 10 × T500, and maximum Q‐Tc (heart rate corrected Q‐T interval [Bazett's formula]) was prolonged from 429 (CI: 422–435) ms on the day of no treatment, to 455 (CI: 448–462) ms after 10 × F4.5 and 470 (CI: 463–476) ms after 10 × T500. Estimates of relative dose potency indicated that F4.5 µg had the same systemic activity as the clinically less effective dose of 250 µg terbutaline. The duration of systemic effects differed marginally between treatments. Spontaneously reported adverse events (most frequently tremor) were fewer with formoterol (78% of the children) than with terbutaline (95%). A serious adverse event occurred after inhalation of 45 µg formoterol over the 1 h dosing time, that prompted the extension of dosing time to 2.5 h.

Conclusions

Multiple inhalations over 2.5 h of formoterol (4.5 µg) via Turbuhaler® are at least as safe as and associated with less systemic effects than multiple inhalations of the clinically equipotent dose of terbutaline (500 µg) in children with asthma.
Modifications in cell cycle kinetics and in expression of G1 phase‐regulating proteins in human amniotic cells after exposure to electromagnetic fields and ionizing radiation
Authors: Lange S. , Viergutz T. , Simkó M.
Published: September 2004

Abstract.  Low‐frequency electromagnetic fields are suspected of being involved in carcinogenesis, particularly in processes that could be related to cancer promotion. Because development of cancer is associated with deregulated cell growth and we previously observed a magnetic field‐induced decrease in DNA synthesis [Lange et al. (2002) Alterations in the cell cycle and in the protein level of cyclin D1p, 21CIP1, and p16INK4a after exposure to 50 HZ. MF in human cells. Radiat. Environ. Biophys.41, 131], this study aims to document the influence of 50 Hz, 1 mT magnetic fields (MF), with or without initial γ‐ionizing radiation (IR), on the following cell proliferation‐relevant parameters in human amniotic fluid cells (AFC): cell cycle distribution, expression of the G1 phase‐regulating proteins Cdk4, cyclin D1, p21CIP1 and p16INK4a, and Cdk4 activity. While IR induced a G1 delay and a dose‐dependent G2 arrest, no discernible changes in cell cycle kinetics were observed due to MF exposure. However, a significant decrease in the protein expression of cyclin D1 and an increase in p21CIP1‐ and p16INK4a‐expression could be detected after exposure to MF alone. IR‐exposure caused an augmentation of p21CIP1‐ and p16INK4a‐ levels as well, but did not alter cyclin D1 expression. A slight diminution of Cdk4 activity was noticed after MF exposure only, indicating that Cdk4 appears not to act as a mediator of MF‐ or IR‐induced changes in the cell cycle of AFC cells. Co‐exposure to MF/IR affected neither cell cycle distribution nor protein expression or kinase activity additionally or synergistically, and therefore MF seems not to modify the mutagenic potency of IR.