bluuebunny/crossref_metadata_2025 huggingface dataset:
A role for the exosome in the in vivo degradation of unstable mRNAs
Authors: HAILE SIMON , ESTÉVEZ ANTONIO M. , CLAYTON CHRISTINE
Published: November 2003

In mammals, the mRNAs encoding many proteins involved in inflammation bear destabilizing AU-rich elements (AREs) in the 3′-untranslated region. The exosome, a complex of 3′ → 5′ exonucleases, is rate limiting in the destruction of such mRNAs in a mammalian in vitro system, but a role in vivo has not been demonstrated. The phenomenon of ARE-mediated degradation also occurs in the protist parasite Trypanosoma brucei. Messenger RNAs with 3′-untranslated region U-rich elements, which strongly resemble AREs, are extremely unstable in the trypanosome form that parasitizes mammals. The first step in degradation of these mRNAs in vivo is rapid destruction of the 3′-untranslated region; subsequently the mRNA is destroyed by exonucleases acting in both 5′ → 3′ and 3′ → 5′ directions. We here investigated the roles of three subunits of the trypanosome exosome complex, RRP45, RRP4, and CSL4, in this process, depleting the individual subunits in vivo by inducible RNA interference. RRP45 depletion, which probably disrupts exosome integrity, caused a delay in the onset of degradation of the very unstable RNAs, but did not affect degradation of more stable species. Depletion of RRP4 or CSL4 does not affect the stability of the residual exosome and did not change mRNA degradation kinetics. We conclude that the exosome is required for the initiation of rapid degradation of unstable mRNAs in trypanosomes.
Proteoglycan and collagen sensitive MRI evaluation of normal and degenerated articular cartilage
Authors: Nissi M. J. , Töyräs J. , Laasanen M. S. , Rieppo J. , Saarakkala S. , Lappalainen R. , Jurvelin J. S. , Nieminen M. T.
Published: November 2003

Quantitative magnetic resonance imaging (MRI) techniques have earlier been developed to characterize the structure and composition of articular cartilage. Particularly, Gd‐DTPA2− ‐enhanced T1 imaging is sensitive to cartilage proteoglycan content, while T2 relaxation time mapping is indicative of the integrity and arrangement of the collagen network. However, the ability of these techniques to detect early osteoarthrotic changes in cartilage has not been demonstrated. In this study, normal and spontaneously degenerated bovine patellar cartilage samples (n = 32) were investigated in vitro using the aforementioned techniques. For reference, mechanical, histological and biochemical properties of the adjacent tissue were determined, and a grading system, the cartilage quality index (CQI), was used to score the structural and functional integrity of each sample. As cartilage degeneration progressed, a statistically significant increase in the superficial T2 (r = 0.494, p < 0.05) and a decrease in superficial and bulk T1 in the presence of Gd‐DTPA2− (r = −0.681 and −0.688 (p < 0.05), respectively) were observed. Gd‐DTPA2− ‐enhanced T1 imaging served as the best predictor of tissue integrity and accounted for about 50% of the variation in CQI. The present results reveal that changes in the quantitative MRI parameters studied are indicative of structural and compositional alterations as well as the mechanical impairment of spontaneously degenerated articular cartilage. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.
Acceleration of surgical angiogenesis in necrotic bone with a single injection of fibroblast growth factor‐2 (FGF‐2)
Authors: Nakamae Atsuo , Sunagawa Toru , Ishida Osamu , Suzuki Osami , Yasunaga Yuji , Hachisuka Hiroki , Ochi Mitsuo
Published: November 2003

The aim of this study was to accelerate angiogenesis in necrotic bone by combining vascular bundle implantation and fibroblast growth factor‐2 (FGF‐2) administration.

Twenty‐four Japanese white rabbits were evaluated in this study. A portion of a rabbit iliac crest bone was removed as a free bone graft and frozen in liquid nitrogen to ensure complete cellular necrosis. A narrow hole was created in the bone and the graft was placed in the proximal thigh. In group 1, FGF‐2 was injected into the hole at a single dose of 100 μg, and the saphenous artery and its venae comitantes were passed through the hole of the bone. In group 2, injection of saline into the hole and the vascular bundle implantation was used as a control. Neovascularization around the vessel was evaluated at weeks 1 and 2 after surgery.

Neovascularization was observed along the implanted vascular bundle in both groups. At both 1 and 2 weeks after surgery, the vessel density of group 1 was significantly higher than that of group 2. The average length of newly formed vessels of group 1 was also significantly longer than that of group 2 at both 1 and 2 weeks after surgery. Both the vessel density and length were greater in week 2 animals than week 1.

A local single injection of FGF‐2 improved surgical angiogenesis in necrotic bone in this study. As FGF‐2 is recognized as a potent mitogen for a variety of mesenchymal cells, the combination of vascular bundle implantation and FGF‐2 administration may contribute to the treatment of ischemic osteonecrosis. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.
Interaction between text structure representation and situation model in hypertext reading
Authors: Waniek Jacqueline , Brunstein Angela , Naumann Anja , Krems Josef F.
Published: November 2003

Hypertext research results suggest that building a correct representation of the hypertext structure enables users to navigate effectively within the text. Therefore, text comprehension processes involved in hypertext reading should be investigated. In an experimental study, we differentiated the text structure from the dimensions of a postulated coherent situation model in order to compare them. Three electronic text versions, varying in navigational facility, and text structure visualization were compared with respect to orientation, navigation, eye movements, mental representation of text structure and content (situation model). Results demonstrate that when text structure visualization was unavailable, a reorganization of readers’ representations of the text structure towards their situation model took place. Navigation within the text particularly affected mental representation of text structure and content.
Personality, cognitive style, demographic characteristics and Internet use - Findings from the HomeNetToo project
Authors: Jackson Linda A. , von Eye Alexander , Biocca Frank A. , Barbatsis Gretchen , Fitzgerald Hiram E. , Zhao Yong
Published: November 2003

Relationships between personality, cognitive style and Internet use were examined in a longitudinal field study. Participants were low-income African American and European American adults residing in a mid-size urban community in the United States whose Internet use was automatically and continuously recorded for 6 months. Results indicated that extraversion and neuroticism were related to Internet use, but only during the first 3 months of home Internet access. Preferences for global/relational and visual processing, and for abstract conceptualization were weakly related to Internet use at both time intervals. Strongest were relationships between race and Internet use and, to a lesser extent, between education, marital status, and Internet use. The importance of additional research to identify personal and cultural characteristics that may influence and sustain Internet use is discussed.
Controls on strain localization in a two‐dimensional elastoplastic layer: Insights into size‐frequency scaling of extensional fault populations
Authors: Hardacre Kathryn M. , Cowie Patience A.
Published: November 2003

We use a two‐dimensional (2‐D) finite element code to investigate how mechanical properties and boundary conditions influence progressive strain localization during extension of a 2‐D elastoplastic layer. The deforming medium is modeled using a strain softening Von Mises rheology, with a Gaussian heterogeneity in yield strength distributed randomly in space. Specifically, we examine the effects of changing (1) the thickness of the deforming layer, (2) the basal boundary condition, (3) the range of strengths in the deforming layer, (4) the strength loss on failure, and (5) the total accommodated strain. Discrete zones of plastic shear strain are observed to nucleate and grow progressively during each experiment. In order to quantify and thus discriminate between the deformation patterns produced under differing conditions, we calculate the size‐frequency distributions of the shear band populations. Size is defined as the total plastic strain represented by each discrete structure. A wide range of size‐frequency distributions is observed, including both power law and exponential as well as distributions that show breaks in scaling with a transition from power law (at small sizes) to exponential (at large sizes). We show that these variations in population statistics are directly reflecting a change in strain localization in space and time caused by changing model parameters. Furthermore, by making an analogy between the model shear bands and tectonic faults, we provide insights into key features of fault size‐frequency distributions that have been measured in continental and oceanic extensional settings and also observed in analogue experiments.
Slope water intrusions onto Georges Bank
Authors: Churchill James H. , Manning James P. , Beardsley Robert C.
Published: November 2003

Data from moored instruments and hydrographic cruises of the U.S. GLOBEC NW Atlantic/Georges Bank program reveal a series of intrusions of high‐salinity water extending onto the southern flank of Georges Bank during the spring and summer of 1995. On the basis of the layer of maximum salinity, these intrusions may be divided into three different types: near surface, near bottom, and pycnocline. The water mass and flow structure of all intrusions are highly variable, owing partly to wind‐driven motions and partly to meanders and eddies formed along the front of the intruding water. The mooring data of May clearly show the passage of two cyclonic features, each with a core of intruding water. While the intrusions are shown to dominate the flux of high‐salinity water onto the southern flank, the data examined offer no evidence that intrusions enhance nutrient concentrations over the southern flank.
Tropospheric distributions of sulfuric acid‐water vapor aerosol nucleation rates from dimethylsulfide oxidation
Authors: Lucas Donald D. , Prinn Ronald G.
Published: November 2003

Tropospheric distributions of H2SO4‐H2O binary nucleation rates are calculated from a 3D model with DMS chemistry. Two mechanisms are used that include and exclude an SO2‐independent H2SO4 production path. In the lower troposphere, the SO2‐independent path generates extra H2SO4 and, consequently, much higher aerosol nucleation rates. However, these rates are less than 10−5 particles cm−3 s−1 in most of the lower troposphere, which indicates that DMS oxidation does not lead to appreciable aerosol formation there. In the upper troposphere, binary nucleation is fairly insensitive to the mechanism differences, with both yielding rates that exceed 1 particle cm−3 s−1 in the upper tropics. These large upper tropospheric nucleation rates imply that the DMS cycle may have served as an important source of aerosols to the troposphere and stratosphere during preindustrial and volcanically‐quiescent periods, or during modern periods in clean marine regions where anthropogenic SO2 and H2SO4 are relatively low.
Ion‐ion kink instability in the magnetotail: 1. Linear theory
Authors: Karimabadi H. , Daughton W. , Pritchett P. L. , Krauss‐Varban D.
Published: November 2003

A number of different ion species are known to exist in the magnetotail. In particular, cold lobe ions and current‐carrying hot plasma sheet ions are a permanent feature of the magnetotail and result in various types of instabilities. One such instability is the ion‐ion kink mode. Detailed properties of this mode in the magnetotail are investigated in a two series paper using a combination of linear Vlasov theory, three‐dimensional (3‐D) full particle and hybrid (fluid electron, kinetic ions) simulations. Here we consider the linear properties of the mode in detail. Although the mode shows similarities to a velocity driven instability, its linear mode properties do exhibit dependencies on the kinetic details of the secondary ion population.
Ion‐ion kink instability in the magnetotail: 2. Three‐dimensional full particle and hybrid simulations and comparison with observations
Authors: Karimabadi H. , Pritchett P. L. , Daughton W. , Krauss‐Varban D.
Published: November 2003

The magnetotail current layer is thought to be subject to a variety of instabilities. One instability arising from the presence of two ion populations, the cold lobe ions and the current‐carrying hot plasma sheet ions, is the ion‐ion kink mode. Detailed linear properties of this mode in the magnetotail were investigated by Karimabadi et al. [2003], where it was shown that the mode differs from the standard Kelvin‐Helmholtz instability. In this paper the nonlinear properties of the ion‐ion kink mode are investigated using three‐dimensional (3‐D) full particle and hybrid (fluid electron, kinetic ions) simulations. It is shown that this mode is primarily driven by a velocity shear arising from the presence of multiple ion populations. The instability saturates as a result of broadening of the current layer and reduction of the velocity shear. The instability, however, differs in important aspects from the standard Kelvin‐Helmholtz instability (KHI). Its linear mode properties exhibit dependencies on the kinetic details of the secondary ion population and its nonlinear evolution is found to be significantly different from previous MHD and Hall MHD treatments of the instability as well as from the KHI. In particular, the usual formation of vortices and coalescence that occur for the Kelvin‐Helmholtz instability are absent for the ion‐ion kink mode. Although the lobe ions can form vortices, such vortices are localized and do not affect current‐carrying hot plasma sheet ions. Recent Cluster observations of modulated and bifurcated current sheets [Runov et al., 2003] are discussed within the context of the ion‐ion kink mode. Hybrid simulations with open boundary conditions and using the parameters for this event demonstrate a very good agreement between the wavelength, period, and amplitude of the ion‐ion kink mode and the observed wave‐like disturbance. It is shown that the “bifurcated” current sheet can be explained in terms of a traveling kink displacement in which the current has a single continuous displacement into both hemispheres.
Northeast Asian dust storms: Real‐time numerical prediction and validation
Authors: Shao Yaping , Yang Yan , Wang Jianjie , Song Zhenxin , Leslie Lance M. , Dong Chaohua , Zhang Zhihuang , Lin Zhaohui , Kanai Yutaka , Yabuki Sadayo , Chun Youngsin
Published: November 2003

This study is concerned with the quantitative prediction of dust storms in real time. An integrated wind erosion modeling system is used for 24‐, 48‐, and 72‐hour forecasts of northeast Asian dust events for March and April 2002. The predictions are validated with synoptic records from the meteorological network and dust concentration measurements at 12 stations in China, Japan, and Korea. The predicted spatial patterns and temporal evolutions of dust events and the predicted near‐surface dust concentrations are found to agree well with the observations. The validation confirms the capacity of the modeling system in quantitative forecasting of dust events in real time. On the basis of the predictions, dust activities in northeast Asia are examined using quantities such as dust emission, deposition, and load. During an individual dust episode, dust sources and intensities vary in space and time, but on average the Gobi Desert, the Hexi (Yellow River West) Corridor, the Chaidam Basin, the Tulufan Basin, and the fringes of the Talimu and Zhunge'er Basins are identified to be the main source regions. The Gobi Desert is the strongest dust source, where the maximum dust emission reaches 5000 μg m−2 s−1 and the net dust emission reaches 16 t km−2 d−1 in March and April 2002. Net dust deposition covers a large area, with the Loess Plateau receiving about 1.6 to 4.3 t km−2 d−1. A zone of high dust load exists along the northern boundary of the Tibet Plateau, with a maximum of around 2 t km−2 situated over the Gobi Desert. The total dust emission, total dust deposition, and total dust load for the domain of the simulation are estimated. The average (maximum) total dust emission is 11.5 × 106 (65.7 × 106) t d−1, the average (maximum) total dust deposition is 10.8 × 106 (51.4 × 106) t d−1, and the average (maximum) total dust load is 5.5 × 106 (15.9 × 106) t.
Effect of adsorption on the uptake of organic trace gas by cloud droplets
Authors: Djikaev Y. S. , Tabazadeh A.
Published: November 2003

Adsorption can greatly influence the partitioning of organic trace species between the gas and liquid phases. Here we investigate how adsorption of organic species at the air‐water interface in clouds can increase the amount of trace gas found in cloud water. For atmospherically relevant cloud surface areas and realistic ranges of adsorption parameters, we show that a significant amount of organic molecules can reside at the cloud droplet surface. Two different physical situations are considered corresponding to the cases where the surfactant is water‐soluble and where it is water‐insoluble. For both cases, numerical calculations were carried out for a wide range of adsorption parameters, effective Henry's law constants (the former case only), and cloud surface areas. For a soluble surfactant, our calculations show that the “overall” Henry's law constant, which takes into account for both adsorption at the droplet surface and partitioning into the droplet interior, can significantly differ from the standard Henry's law constant. For a moderately soluble species the overall uptake can strongly depend on the surface coverage if the species has a strong affinity for partitioning into the surface layer. Our results also suggest that even insoluble and/or scarcely soluble species can be scavenged by clouds if they are surface‐active.
Organizational Structure and Performance: Evidence From the Nonlife Insurance Industry in Japan
Authors: Lai Gene C. , Limpaphayom Piman
Published: November 2003

Abstract

This study examines the impact of organizational structure on firm performance, incentive problems, and financial decisions in the Japanese nonlife (property‐casualty) insurance industry. Stock companies that belong to one of six horizontal keiretsu groups have lower expenses and lower levels of free cash flow than independent stock and mutual insurance companies. Keiretsu insurers also have higher profitability and higher loss ratios than independent insurers. With a limited sample size, there is some evidence that mutual insurers have higher levels of free cash flows, higher investment incomes, and lower financial leverage than their stock counterparts. Overall, empirical evidence suggests that each structure has its own comparative advantage.
“Cultivating Children as You Would Valuable Plants:” The Gardening Governmentality of Child Saving, Toronto, Canada, 1880s–1920s1
Authors: Chen Xiaobei
Published: November 2003

Abstract  Gardening metaphors with English middle‐class overtones were widely used in the late nineteenth‐century child saving writings in Toronto, Canada to explain and promote the ideal mode of parenting and the objective of child saving. An analysis of gardening metaphors contributes to understanding mechanisms of bio‐power on the site of child saving. This paper argues that the child saving movement attempted to install a mode of proper parental control that can be described as “the gardening governmentality”– it was primarily positive/productive (yet without excluding repressive elements), individualized, intelligent, and localized.
Pulmonary drug delivery. Part II: The role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications
Authors: Labiris N. R. , Dolovich M. B.
Published: November 2003

Research in the area of pulmonary drug delivery has gathered momentum in the last several years, with increased interest in using the lung as a means of delivering drugs systemically. Advances in device technology have led to the development of more efficient delivery systems capable of delivering larger doses and finer particles into the lung. As more efficient pulmonary delivery devices and sophisticated formulations become available, physicians and health professionals will have a choice of a wide variety of device and formulation combinations that will target specific cells or regions of the lung, avoid the lung's clearance mechanisms and be retained within the lung for longer periods. It is now recognized that it is not enough just to have inhalation therapy available for prescribing; physicians and other healthcare providers need a basic understanding of aerosol science, inhaled formulations, delivery devices, and bioequivalence of products to prescribe these therapies optimally.
Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route
Authors: Sharabi Amir , Cohen Eytan , Sulkes Jaqueline , Garty Moshe
Published: November 2003

Aims  To compare the efficacy of sublingual and oral administration of 500 µg of cobalamin in subjects with cobalamin deficiency.

Materials and results  Thirty subjects with low serum concentrations of cobalamin participated in the study. Subjects were randomly allocated to receive one tablet daily of 500 µg cobalamin sublingually or orally, or two tablets daily of a vitamin B complex. Serum cobalamin concentrations before treatment were 94 ± 30 pmol l−1,  108 ± 17 pmol l−1  and  98 ± 14 pmol l−1  in  the  sublingual  B12,  oral  B12  and oral B‐complex groups, respectively. After 4 weeks, concentrations rose to 288 ± 74 pmol l−1, 286 ± 87 pmol l−1 and 293 ± 78 pmol l−1, respectively. The increase in each group across time was statistically significant (P = 0.0001, differences [95% confidence intervals] 194.2 (114.5, 273.9), 178.3 (104.2, 252.4), and 195.1 (135.0, 255.2) pmol l−1, respectively). There was no significant difference in concentrations between the treatment groups.

Conclusion  A dose of 500 µg of cobalamin given either sublingually or orally is effective in correcting cobalamin deficiency.
Diltiazem co‐treatment in renal transplant patients receiving microemulsion cyclosporin
Authors: Kumana Cyrus R. , Tong Matthew K. L. , Li Chun‐Sang , Lauder Ian J. , Lee Joseph S. K. , Kou Maybelle , Walley Tom , Haycox Alan , Chan Tak Mao
Published: November 2003

Background Usage of cyclosporin (the Hong Kong Hospital Authority's single largest item of drug expenditure) continues to increase, mainly due to increasing numbers of renal allograft patients taking it as long‐term antirejection therapy. Diltiazem, an antihypertensive agent, interferes with the first pass extraction of oral cyclosporin, thus serving to conserve its dosage.

Aims In renal transplant patients, to assess whether diltiazem co‐treatment could achieve worthwhile dosage conservation of Neoral®(a relatively new microemulsified cyclosporin formulation), safely.

Methods A randomized, placebo‐controlled, double‐blind clinical trial was undertaken at three local hospitals. Renal transplant recipients receiving Neoral®as prophylactic immunosuppression were randomized to two treatment arms. Active treatment consisted of diltiazem tablets 30 or 60 mg twice daily for patients weighing < 60 or ≥ 60 kg, respectively. One hundred and ten eligible patients gave their informed consent, and were followed up for at least six months. The mean difference in the dollar cost in the sixth month was the primary outcome. Secondary/ancillary outcomes included changes in cyclosporin dosage and blood level, and untoward clinical events including rejection. Outcomes were evaluated by intention to treat analyses.

Results During weeks 23–26 (sixth month) post randomization, diltiazem co‐treatment yielded an estimated average cost saving per patient on drugs of 15%[the 95% confidence interval (CI) of the difference being HK$609 ± 517 or £50 ± 42], with no apparent excess of untoward or adverse events, complications, hospitalization, outpatient visits, or inferior quality of life.

Conclusions This diltiazem co‐treatment regime applied to the nearly 1800 surviving renal allograft patients followed up in Hospital Authority hospitals could have saved approximately HK$ 14.3 million (£1.17 million) annually, without adverse sequelae.
Differential binding of disopyramide and warfarin enantiomers to human α1‐acid glycoprotein variants
Authors: Nakagawa T. , Kishino S. , Itoh S. , Sugawara M. , Miyazaki K.
Published: November 2003

Aims  The F1S and A genetic variants of α1‐acid glycoprotein (AAG) change under various physiological and pathological conditions. They also vary in their drug binding abilities. We have studied the stereoselective binding ability of each of the AAG variants using enantiomers of disopyramide (DP) and warfarin (WR).

Methods  The AAG variants were separated by hydroxyapatite chromatography. Binding of drug enantiomers to the AAG variants was studied by the Hummel–Dreyer method. The characteristics of the binding activities were examined by Scatchard plot analysis. The first five amino‐terminal amino acids (residues 112–116) of the cyanogen bromide (CNBr) fragment (residues 112–181) of each of the separated AAG fractions were elucidated by Edman degradation.

Results  Commercial AAG was separated into two main fractions. Residues 112–116 of fraction 2 were identical to the amino acid sequences predicted from the AAG A gene, LAFDV, and encode the F1S variant. In fraction 3, the deduced amino acid sequence of the AAG B gene, FGSYL, was established, and encodes the A variant. The binding affinities of both DP enantiomers in fraction 3 were significantly higher than those in fraction 2. The differences between dissociation constants (Kd) in fractions 2 and 3 were 5.2‐fold for (S)‐DP (P < 0.05) and 3.7‐fold for (R)‐DP (P < 0.001). The dissociation constant of (S)‐DP (0.39 ± 0.08 µm) was lower than that of (R)‐DP (0.53 ± 0.10 µm) in fraction 3 [95% confidence interval (CI) − 0.282, − 0.010; P < 0.05], although the binding activities of the DP enantiomers were almost the same in fraction 2. By contrast WR enantiomers had a higher binding affinity in fraction 2 than in fraction 3, the differences in dissociation constants between fractions 2 and 3 being 12.6‐fold for (S)‐WR (P < 0.001) and 8.3‐fold for (R)‐WR (P < 0.001). The dissociation constant of (S)‐WR (0.28 ± 0.10 µm) was significantly lower than that of (R)‐WR (0.48 ± 0.08 µm) in fraction 2 (95% CI − 0.369, − 0.028; P < 0.05), but there were no significant differences between the binding activities of WR enantiomers in fraction 3.

Conclusions  DP and WR enantiomers bind preferentially to fraction 3 and fraction 2, respectively. Fractions 2 and 3 are encoded by the AAG A and the AAG B genes, respectively.
The epidemiology of self‐poisoning in the UK
Authors: Camidge D. R. , Wood R. J. , Bateman D. N.
Published: November 2003

Self‐poisoning by ingestion or inhalation is common, and it is important to study its various epidemiological manifestations with clear definitions. Data on fatal self‐poisonings are recorded nationally within the UK and are codified according to the International Classification of Diseases (ICD) revision relevant at the time. Most fatal self‐poisonings are codified as suicides, accidental deaths or undetermined deaths (‘open verdicts’). Non‐fatal self‐poisoning data, whether accidental or as a manifestation of deliberate self‐harm, are recorded through hospital discharge information nationally but are not routinely published in the same way as mortality data. The bulk of the UK's published epidemiological information on nonfatal self‐poisoning episodes is largely based on individual hospitals’ admission or discharge records (‘special studies’). After establishing definitions for different self‐poisoning categories we discuss the published data on self‐poisoning as they relate to suicide, accidental self‐poisoning and deliberate self‐harm in the UK.
Population pharmacokinetics of ceftazidime in burn patients
Authors: Dailly Eric , Pannier Michel , Jolliet Pascale , Bourin Michel
Published: November 2003

Aim  The aim of this study was to characterize, via a population pharmacokinetic approach, the pharmacokinetics of ceftazidime in burn patients who were not in the acute post‐injury phase.

Methods  The development of the pharmacokinetic model was based on data from therapeutic drug monitoring (41 patients, 94 samples). The estimation of population pharmacokinetic parameters and the selection of covariates (age, gender, body weight, size of burn and creatinine plasma concentration) that could affect the pharmacokinetics were performed with a nonlinear mixed effect modelling method.

Results  No relationship between covariates and the pharmacokinetic parameters was established with the exception of an inverse‐linear relationship between creatinine plasma concentration and ceftazidime total clearance. The total clearance of ceftazidime was 2.72 l h−1[coefficient variation (CV) = 56.3%] and the distribution volume of the central compartment was 0.28 l kg−1 (CV = 13.2%) The transfer rate constants (k12, k 21) between the central and peripheral compartments were 0.06718 h−1 (CV = 87.2%) and 0.001823 h−1 (CV = 82.7%), respectively. From these parameters, the total ceftazidime volume of distribution (10.64 l kg−1) was calculated.

Conclusion  The population parameters were different from those obtained in a previous study performed in fewer patients and in the early period after burn injury. In our study, the lower ceftazidime clearance could be explained by the relative decrease in ceftazidime elimination in relation to the burn area, and the higher ceftazidime volume of distribution in the presence of interstitial oedema, which could act as a reservoir from which ceftazidime returns slowly to the circulation.
Voriconazole does not affect the steady‐state pharmacokinetics of digoxin
Authors: Purkins Lynn , Wood Nolan , Kleinermans Diane , Nichols Don
Published: November 2003

Aims  Voriconazole is a triazole antifungal agent with potent fungicidal activity against Aspergillus species. Digoxin is a commonly prescribed cardiac glycoside with a narrow therapeutic index. This aim of this study was to investigate the effect of multiple‐dose voriconazole on the steady‐state pharmacokinetics of digoxin in healthy male volunteers.

Methods  This was a double‐blind, randomized, placebo‐controlled, parallel‐group study. All subjects received daily administration of oral digoxin for a total of 22 days (0.5 mg twice daily on day 1, 0.25 mg twice daily on day 2 and 0.25 mg once daily on days 3–22). In addition, on days 11–22 the subjects were randomized to receive either voriconazole (200 mg twice daily) or matching placebo.

Results  Concomitant administration with voriconazole did not significantly alter the Cmax, AUCτ, tmax or CLR of digoxin at steady state. The ratios between groups for Cmax and AUCτ at day 22, corrected for baseline (day 10) were 109.8%[90% confidence interval (CI) 97.1, 124.1] and 100.5% (90% CI 91.4, 110.5), respectively. In addition, group mean Cmin values were similar in both treatment groups throughout the study. There were no significant differences between treatments with respect to the incidence of adverse events, all of which were classified as mild and transient in nature.

Conclusions  The steady‐state pharmacokinetics of digoxin are not affected in a clinically relevant manner by the concomitant administration of voriconazole.
Histamine H2‐receptor antagonists have no clinically significant effect on the steady‐state pharmacokinetics of voriconazole
Authors: Purkins Lynn , Wood Nolan , Kleinermans Diane , Nichols Don
Published: November 2003

Aims  Voriconazole, a new triazole antifungal agent, is metabolized mainly by cytochrome P450s CYP2C19 and CYP2C9, and also by CYP3A4. The aim of this open‐label, placebo‐controlled, randomized, three‐way crossover study was to determine the effects of cimetidine and ranitidine on the steady‐state pharmacokinetics of voriconazole.

Methods  Twelve healthy male subjects received oral voriconazole 200 mg twice daily plus cimetidine 400 mg twice daily, voriconazole 200 mg twice daily plus ranitidine 150 mg twice daily, and voriconazole 200 mg twice daily plus placebo twice daily. Treatment periods were separated by at least 7 days.

Results  When cimetidine was administered with voriconazole, the maximum plasma voriconazole concentration (Cmax) and the area under the plasma concentration–time curve of voriconazole (AUCτ) was increased by 18.3%[90% confidence interval (CI) 6.0, 32.0] and 22.5% (90% CI 13.3, 32.5), respectively. Concomitant ranitidine had no significant effect on voriconazole Cmax or AUCτ. Time of Cmax (tmax) elimination half‐life (t 1/2) or terminal phase rate constant (kel) for voriconazole were similar in all three treatment groups. Most adverse events were mild and transitory; two subjects were withdrawn due to adverse events.

Conclusions  Coadministration of the histamine H2‐receptor antagonists cimetidine or ranitidine does not affect the steady‐state pharmacokinetics of voriconazole in a clinically relevant manner.
Interaction of St John's wort with low‐dose oral contraceptive therapy: a randomized controlled trial
Authors: Pfrunder Arabelle , Schiesser Monika , Gerber Simone , Haschke Manuel , Bitzer Johannes , Drewe Juergen
Published: November 2003

Aims  Breakthrough bleeding or even unwanted pregnancies have been reported in women during concomitant  therapy with oral contraceptives and St  John's wort extract. The aim of the present study was to investigate the effects of St John's wort extract on oral contraceptive therapy with respect to ovarian activity, breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3‐ketodesogestrel.

Methods  Eighteen healthy females were treated with a low‐dose oral contraceptive (0.02 mg ethinyloestradiol, 0.150 mg desogestrel) alone (control cycle) or combined with 300 mg St John's wort extract given twice daily (cycle A) or three times daily (cycle B). Ovarian activity was assessed by measuring follicle maturation and serum oestradiol and progesterone concentrations. The number of breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3‐ketodesogestrel were assessed under steady‐state conditions.

Results  During concomitant administration of low‐dose oral contraceptive and St John's wort, there was no significant change in follicle maturation, serum oestradiol or progesterone concentrations when compared with oral contraceptive treatment alone. However, significantly more subjects reported intracyclic bleeding during cycles A (13/17 (77%), P < 0.015) and cycle B (15/17 (88%), P < 0.001) than with oral contraceptives alone (6/17 (35%)). The AUC(0,24 h) and Cmax of ethinyloestradiol remained unchanged during all study cycles, whereas the AUC(0,24 h) and Cmax of 3‐ketodesogestrel decreased significantly from 31.2 ng ml−1 h to 17.7 ng ml−1 h (43.9%; 95% confidence interval (CI) −49.3, −38.5, P = 0.001) and from 3.6 ng ml −1 to 3.0 ng ml −1(17.8%; CI −29.9, −5.7, P = 0.005), respectively, during cycle A and by 41.7% (CI −47.9, −35.6; P = 0.001) and by 22.8% (CI −31.2, −13.3; P < 0.001) during cycle B respectively, compared with the control cycle.

Conclusions  There was no evidence of ovulation during low‐dose oral contraceptive and St John's wort extract combination therapy, but intracyclic bleeding episodes increased. Bleeding irregularities may adversely effect compliance to oral contraceptives and together with St John's wort‐induced decreases in serum 3‐ketodesogestrel concentrations, enhance the risk of unintended pregnancies.
Polymerase chain reaction on cerebrospinal fluid cells in the detection of leptomeningeal involvement by B‐cell lymphoma and leukaemia: a novel strategy and its implications
Authors: Galoin Sandrine , Daste Ghislaine , Apoil Paul‐André , Chollet François , Roda Daniel , Blancher Antoine , Delsol Georges , Chittal Shashikant , Al Saati Talal
Published: November 2003

In the search of B‐cell lymphoma/leukaemia dissemination to cerebrospinal fluid (CSF), we used the highly sensitive semi‐nested PCR (snPCR) for the analysis of IgH gene rearrangements. This method detects a rearranged IgH gene from a single B lymphocyte which may or may not represent the neoplastic B‐cell population. We therefore performed multiple snPCR (three to five) experiments on the same CSF sample, postulating that the detection of a band of the same size and sequence in different PCR runs was highly indicative of a clonal population. 17 consecutive cases with a differential diagnosis of primary (PcnsL) (n=10) or secondary (ScnsL) (n=7) CNS lymphoma or leukaemia were investigated by the new strategy. The clonal nature of the B‐cell population was confirmed in 3/10 of suspected PcnsL, and in six other cases the PCR study was indicative of reactive lymphocytosis. One case revealed a clonal B‐cell population in the clinical context of an autoimmune disorder. Evidence of clonal B‐cell population was found in 4/7 of suspected ScnsL. In one of these cases the detected band and its sequence proved identical to that of the primary nodal lymphoma. We believe that the evaluation of B‐cell clonality in CSF requires multiple snPCR amplification on the same sample to compare the size of the products and, if necessary, the DNA sequences to ascertain the diagnosis of malignancy in equivocal cytologic and clinical findings.
Initiation of contact system activation in plasma is dependent on factor XII autoactivation and not on enhanced susceptibility of factor XII for kallikrein cleavage
Authors: Citarella Franca , Wuillemin Walter A. , Lubbers Yvonne T. P. , Hack C. Erik
Published: November 2003

Various mechanisms have been hypothesized to explain the initiation of contact system activation in plasma. We investigated the capability of dextran sulphate (DS) of different molecular weights to initiate contact system activation in normal human plasma, and compared this with their capability to support factor XII autoactivation and to enhance factor XII susceptibility for cleavage by kallikrein.

Dextran sulphate of Mr 500 000 (DS500) and 50 000 (DS50) was able to initiate contact system activation in plasma (determined by measuring the amount of factor XIIa–C1‐inhibitor, kallikrein–C1‐inhibitor and factor XIa–C1‐inhibitor complexes generated) as well as to support factor XII autoactivation and to enhance factor XII susceptibility for cleavage by kallikrein (as measured with amidolytic assays using purified proteins). In contrast, dextran sulphate of Mr 15 000 (DS15) and 5000 (DS5) neither induced contact system activation in plasma, nor supported autoactivation of factor XII, although both of these DS species enhanced the rate of activation of factor XII by kallikrein in the purified system. Based on these properties (i.e. binding of factor XII without inducing autoactivation), DS15 and DS5 were predicted to be inhibitors of contact system activation induced in plasma by DS500, which indeed was observed.

We conclude that enhanced factor XII susceptibility for kallikrein activation and factor XII autoactivation are distinct phenomena, the latter being necessary to support activation of the contact system in plasma.
Primary familial polycythaemia associated with a novel point mutation in the erythropoietin receptor
Authors: Furukawa Tatsuo , Narita Miwako , Sakaue Minori , Otsuka Tomio , Kuroha Takashi , Masuko Masayoshi , Azegami Takuaki , Kishi Kenji , Takahashi Masuhiro , Utsumi Jirou , Koike Tadashi , Aizawa Yoshifusa
Published: November 2003

Primary familial and congenital polycythaemia (PFCP) is a rare disease characterized by congenital erythrocytosis inherited in an autosomal dominant fashion. Recently, mutations in the erythropoietin receptor (EpoR) have been identified in PFCP families. We describe a Japanese family with an autosomal dominant inheritance of PFCP. An in vitro colony assay demonstrated hypersensitivity of erythroid progenitors to erythropoietin (Epo) in affected family members. Sequence analysis of RT‐PCR products amplified from the C‐terminal region of EpoR transcripts in affected family members revealed that they were all heterozygous for C and T bases at position 5986, which suggested a genetic mutation (C to T) on one allele of EpoR. This mutation gave rise to a translation termination codon TAG at amino acid 435. Thus, the resulting EpoR is a truncated protein product lacking all 74 amino acids downstream of the mutation. To date, all genetic mutations affecting a family with PFCP, including this one, have been located in the cytoplasmic negative regulatory region of the EpoR. All mutations gave rise to truncated Epo receptors between Tyrosine 427 and Tyrosine 455. The phosphotyrosines in this region of EpoR have been demonstrated to be binding sites for SHP‐1 phosphatase. Therefore PFCP is presumably brought about as a result of genetic mutations which cause the loss of the SHP‐1 binding site in the cytoplasmic region of EpoR.
Unrelated donor bone marrow transplantation in children and young adults with acute myeloid leukaemia in remission
Authors: Chown Sally R. , Marks David I. , Cornish Jacqueline M. , Pamphilon Derwood H. , Potter Michael N. , Steward Colin G. , Oakhill Anthony
Published: November 2003

The role of unrelated donor bone marrow transplantation (UD‐BMT) in the management of patients with acute myeloid leukaemia (AML) is uncertain. We describe 18 patients with a median age of 13 years (range 4–31) who received an ex vivo T‐cell‐depleted UD‐BMT for AML (13 in second complete remission (CR2) and five in first complete remission (CR1) with high‐risk features). Nine donor recipient pairs were fully matched; eight of these donor–recipient pairs had a single class I HLA mismatch; one patient had both single class I and class II HLA mismatches. Grade II GVHD of the skin occurred in four patients (22%) and limited chronic GVHD in two patients (11%). There have been four deaths: one from relapse and three from infection. With a median follow‐up of 27 months, 14 patients survive and the actuarial event‐free survival at 2 years is 70 ± 20% (95% confidence interval). We conclude that unrelated donor BMT can result in prolonged disease‐free survival in children and young adults with AML.
The majority of myeloid‐antigen‐positive (My+) childhood B‐cell precursor acute lymphoblastic leukaemias express TEL‐AML1 fusion transcripts
Authors: BARUCHEL A. , CAYUELA J. M. , BALLERINI P. , LANDMAN‐PARKER J. , CEZARD V. , FIRAT H. , HADDAD E. , AUCLERC M. F. , VALENSI F. , CAYRE Y. E. , MACINTYRE E. A. , SIGAUX F.
Published: November 2003

The t(12;21) translocation fuses the TEL and AML1 genes and has been found in up to 28% of paediatric B‐cell precursor acute lymphoblastic leukaemias (BCP‐ALL). The AML1 gene is a transcription factor which regulates expression of several myeloid differentiation associated genes. A molecular analysis of TEL‐AML1, E2A‐PBX1, MLL‐AF4, BCR‐ABL expression and an immunophenotypic study of CD13/CD33 myeloid antigen expression have been performed prospectively on tumour cells from 96 paediatric BCP‐ALL patients. Percentages of CD13 or CD33 expressing leukaemic cells were found to be higher in TEL‐AML1 positive cases (n = 22) than in TEL‐AML1 negative (n = 74) cases (P < 0.001). In 22/96 cases (23%) >10% of neoplastic cells were found to express at least one of the two markers. In 14 of these cases (63%), TEL‐AML1 expression was detected, whereas t(4;11), t(11;19) and t(9;22) translocations were found by molecular methods in only three cases (14%). In four cases (18%) no molecular marker was found. These data show that TEL‐AML1 expression is significantly associated with myeloid antigen expression by leukaemic cells and suggests that the prognostic significance of myeloid antigen expression in paediatric ALLs should be re‐evaluated in the light of molecular cytogenetic markers.
Intensification of treatment for adults with acute lymphoblastic leukaemia: results of U.K. Medical Research Council randomized trial UKALL XA
Authors: Durrant I. J. , Grant Prentice H , Richards S. M.
Published: November 2003

The MRC UKALL XA trial for patients aged 15 years and over with acute lymphoblastic leukaemia was designed to evaluate short blocks of intensive ‘AML‐style’ treatment. Between 1985 and 1992, 618 eligible patients were entered into the trial. 450 patients were randomized to receive early intensification at 5 weeks, late intensification at 20 weeks, both, or neither. Unlike the concurrent children's trial, UKALL X, which was of similar design, UKALL XA does not demonstrate a clear benefit for intensification, although there was a significant reduction in the relapse risk due to the early block. The estimated increase in disease‐free survival at 5 years was 2% with 95% confidence interval from 1% reduction to 5% increase. There may be a real difference between the effect of these treatments in adults and in children, but this result may be somewhat weakened by poorer compliance, with a greater proportion of adults not receiving the treatment arm to which they were randomized.
Complications experienced with central venous catheters in children with congenital bleeding disorders
Authors: Collins P. W. , Khair K. S. , Liesner R. , Hann I. M.
Published: November 2003

The use of central venous catheters (CVC) in children with coagulation disorders allows home treatment, the use of prophylactic blood product replacement and induction of immune tolerance. Previous reports have suggested an almost complete lack of infective complications in this patient group. We reviewed 23 patients with bleeding disorders who have had 32 CVC inserted at this institution with a median follow‐up of 27 months (range 1–92 months). There were 25 documented line‐associated infections, including two subcutaneous infections at the port site, and 23 bacteraemias (one episode per 26 patient months at risk). There were 15 Gram‐positive, nine Gram‐negative and one mixed infection. Infections occurred in 48% of the patients. 15 CVCs were removed: one for erosion through the skin, two for line blockage and 12 for infection. Five patients with inhibitors to factor VIII suffered 14 infections in 12 lines (one per 8.3 months) whereas the 18 without inhibitors suffered 11 infections in 20 lines (one per 50 months) (P < 0.03). The use of CVCs is favoured by families of children with bleeding disorders in spite of these complications, but close liaison between families and experienced staff at a Haemophilia Centre is essential to ensure that patients gain the benefits of a CVC as safely as possible.
Adult onset of acute myeloid leukaemia (M6) in patients with Shwachman‐Diamond syndrome
Authors: Dokal Inderjeet , Rule Simon , Chen Fred , Potter Mike , Goldman John
Published: November 2003

Three male patients (two of whom were brothers) with Shwachman‐Diamond (SDS) syndrome presented with acute myeloid leukaemia in adulthood. In all three cases there was trilineage myelodysplasia and the morphology was consistent with FAB subtype M6. SDS is an inherited bone marrow failure syndrome with a high propensity to leukaemic transformation. Since this may not occur until adulthood, SDS should be considered in the differential diagnosis of adults presenting with acute myeloid leukaemia, particularly where features of myelodysplasia are prominent.