bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preparation of Iron Oxide Nanoparticles via Successive Reduction–Oxidation in Reverse Micelles
Authors: Nakanishi Takuya , Iida Hironori , Osaka Tetsuya 
Published: November 2003

Abstract
Nanometer-size particles of iron oxide were prepared by a successive reduction–oxidation of ferric or ferrous ions within reverse micelles. Nanoparticles of iron oxide were collected from reverse micellar solution as precipitates by adding modifier molecules. The X-ray diffraction patterns and magnetic properties of thus-prepared samples suggested the formation of nanocrystalline phase of maghemite, γ-Fe2O3.
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

AbstractQuantitative 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

AbstractThe 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.
Organizational Structure and Performance: Evidence From the Nonlife Insurance Industry in Japan
Authors: Lai Gene C. , Limpaphayom Piman 
Published: November 2003

AbstractThis 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.
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.
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.
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.
Hypoxia‐induced irreversible S‐phase arrest involves down‐regulation of cyclin A
Authors: Seim J. , Graff P. , Åmellem Ø. , Landsverk K. S. , Stokke T. , Pettersen E. O. 
Published: November 2003

Abstract.  We have studied hypoxia‐induced cell cycle arrest in human cells where the retinoblastoma tumour suppressor protein (pRB) is either functional (T‐47D cells) or abrogated by expression of the HPV18 E7 oncoprotein (NHIK 3025 cells). All cells in S phase are immediately arrested upon exposure to extreme hypoxia. During an 18‐h extreme hypoxia regime, the cyclin A protein level is down‐regulated in cells of both types when in S‐phase, and, as we have previously shown, pRB re‐binds in the nuclei of all T‐47D cells (Åmellem et al. 1996). Hence, pRB is not necessary for the down‐regulation of cyclin A during hypoxia. However, our findings indicate that re‐oxygenation cannot release pRB from its nuclear binding following this prolonged exposure. The result is permanent S‐phase arrest even after re‐oxygenation, and this is correlated with a complete and permanent down‐regulation of cyclin A in the pRB functional T‐47D cells. In contrast, both cell cycle arrest and cyclin A down‐regulation in S phase are reversed upon re‐oxygenation in non‐pRB‐functional NHIK 3025 cells after prolonged exposure to extreme hypoxia. Our results indicate that pRB is involved in permanent S‐phase arrest and down‐regulation of cyclin A after extreme hypoxia.
Out of the Alps: colonization of Northern Europe by East Alpine populations of the Glacier Buttercup Ranunculus glacialis L. (Ranunculaceae)
Authors: Schönswetter P. , Paun O. , Tribsch A. , Niklfeld H. 
Published: November 2003

Abstract Ranunculus glacialis ssp. glacialis is an arctic‐alpine plant growing in central and southern European and Scandinavian mountain ranges and the European Arctic. In order to elucidate the taxon's migration history, we applied amplified fragment length polymorphism (AFLP) to populations from the Pyrenees, Tatra mountains and Northern Europe and included data from a previous study on Alpine accessions. Populations from the Alps and the Tatra mountains were genetically highly divergent and harboured many private AFLP fragments, indicating old vicariance. Whereas nearly all Alpine populations of R. glacialis were genetically highly variable, the Tatrean population showed only little variation. Our data suggest that the Pyrenees were colonized more recently than the separation of the Tatra from the Alps. Populations in Northern Europe, by contrast, were similar to those of the Eastern Alps but showed only little genetic variation. They harboured no private AFLP fragments and only a subset of East Alpine ones, and they exhibited no phylogeographical structure. It is very likely therefore that R. glacialis colonized Northern Europe in postglacial times from source populations in the Eastern Alps.