bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of fault relay and clay smearing on groundwater flow patterns in the Lower Rhine Embayment
Authors: Bense Victor F. , Van Balen Ronald 
Published: August 2004

AbstractFaults strongly impact groundwater flow in the unconsolidated sediments of the Lower Rhine Embayment. Hydraulic head maps show that many individual faults form a barrier to fluid flow whereas relay structures in these faults are sites of hydraulic contact between otherwise separated aquifers. The fluid flow patterns around the Rurrand Fault close to the largest open‐pit mine in the Lower Rhine Embayment is one of the first well‐documented examples of fluid flow around a fault relay zone. The effect of clay smearing could be quantified using the Shale Gouge Ratio (SGR) method that is common in hydrocarbon‐related studies but has not been applied to groundwater flow data so far. The effect of fault relay zones on groundwater flow is analysed using numerical simulations. It is concluded that fault relay needs special consideration in the evaluation of the sealing capacities of faults in sedimentary basins. Moreover, it is demonstrated that the SGR methodology is a promising tool for the estimation of fault zone hydraulic properties in hydrogeological modelling.
Evidence for focused hot fluid flow within the Britannia Field, offshore Scotland, UK
Authors: Archer S. G. , Wycherley H. L. , Watt G. R. , Baron M. L. , Parnell J. , Chen H. 
Published: August 2004

AbstractFluid inclusion and scanning electron microscope‐cathodoluminescence evidence indicates focused hot, saline, diagenetic fluid flow within the Eastern Flank of the Britannia Field, offshore Scotland, UK. The fluid was sourced from the Andrew Salt Dome, 10 km to the east. The fluids, which promoted quartz cementation of the upper zones within the field, were up to ∼30°C hotter and had salinities up to ∼10 wt% NaCl equivalent higher than fluids from lower in the reservoir section. During diagenesis hot saline fluids migrated westwards as part of a radiating ‘diagenetic front’ from the Andrew Salt Dome. Structural dip associated with the Eastern Flank of the Fladen Ground Spur impeded the westward movement of the diagenetic fluid.The quartz cements from the upper and lower reservoir zones can be distinguished by morphology. In the upper zones the quartz cements have well‐developed macro‐crystalline zoning and heterogeneous luminescence across the grain. In the lower zones, the cements are much less developed, unzoned and very weakly luminescent. The diagenetic fluids were primarily focused into Zone 45 within the upper reservoir. Furthermore, within the Main Platform Area the most prolific producing zone is Zone 45, indicating the importance of this interval as a permeable flow unit during both diagenetic and production timescales.Within the Eastern Flank, the quartz overgrowths have a major impact on reservoir permeability and thus well productivity. The overgrowths are most extensive in the originally clean sandstones with low clay content. Clay in optimum volumes (5–10%) can inhibit nucleation of the damaging quartz overgrowths without having a detrimental effect on pore connectivity. These observations provide a predictive concept for use in the search for relative reservoir sweetspots within the degraded Eastern Flank.
Is decreased libido associated with the use of HMG‐CoA‐reductase inhibitors?
Authors: De Graaf L. , Brouwers A. H. P. M. , Diemont W. L. 
Published: August 2004

Aims and methodsTo describe patients with decreased libido during use of a HMG‐CoA‐reductase‐inhibitor, and to discuss causality and pharmacological hypotheses for this association by analysis of the adverse drug reactions (ADR) database of the Netherlands Pharmacovigilance Centre Lareb.ResultsEight patients were identified as having decreased libido during use of statins. In two of these cases testosterone levels were determined and appeared to be decreased.ConclusionDecreased libido is a probable adverse drug reaction of HMG‐CoA‐reductase‐inhibitors and is reversible. The ADR may be caused by low serum testosterone levels, mainly due to intracellular cholesterol depletion.
Statins and newly diagnosed diabetes
Authors: Jick Susan S. , Bradbury Brian D. 
Published: August 2004

AimsIn order to evaluate a hypothesized protective effect of the use of HMG Co‐A reductase inhibitors (statins) on the development of Type 2 diabetes, we conducted a nested case–control study based on data from the UK‐based General Practice Research Database (GPRD).MethodsWe identified a population of adults 30–79 years of age between 1 January 1991 and 31 March 2002, who were being treated with a statin or who were diagnosed with hyperlipidaemia but were not being treated with a lipid‐lowering drug. From this population we identified all incident cases of Type 2 diabetes. We conducted a nested case–control study encompassing 588 cases and 2063 matched controls.FindingsWe observed an adjusted odds ratio (OR) of 1.1 [95% confidence interval (CI) 0.8, 1.4] for current statin users compared with non‐exposed subjects and adjusted ORs for pravastatin use alone and simvastatin use alone compared with non‐exposed of 0.7 (95% CI 0.4, 1.2) and 1.0 (95% CI 0.7, 1.3), respectively. There was little evidence for a duration effect for simvastatin in these data, though there is a slight suggestion of a long‐term protective effect with pravastatin.ConclusionThe current study results are most consistent with the conclusion that there is little if any protective effect of statins on the development of Type 2 diabetes.
Vancomycin pharmacokinetics in critically ill patients receiving continuous venovenous haemodiafiltration
Authors: DelDot Megan E. , Lipman Jeffrey , Tett Susan E. 
Published: August 2004

AimsTo investigate the pharmacokinetics of vancomycin in critically ill patients on continuous venovenous haemodiafiltration (CVVHDF), a continuous renal replacement therapy (CRRT) and to see if routine measures approximate vancomycin clearance.MethodsPharmacokinetic profiles (15) of initial and steady‐state doses of 750 mg twice daily intravenous vancomycin were obtained from blood and ultrafiltrate samples from 10 critically ill patients in the intensive care unit, with acute renal failure on CVVHDF (1 l h−1 dialysate plus 2 l h−1 filtration solution; 3 l h−1 effluent; extracorporeal blood flow 200 ml min−1).ResultsCVVHDF clearance of vancomycin was 1.8 ± 0.4 l h−1 (30 ± 6.7 ml min−1). This was 1.3–7.2 times that reported previously for vancomycin using other forms of CRRT. Total vancomycin body clearance was 2.5 ± 0.7 l h−1 (41.7 ± 11.7 ml min−1). The clearance of vancomycin by CVVHDF was 76 ± 16.5% of the total body clearance. CVVHDF removed approximately half the vancomycin dose during the 12‐h period (ACVVHDF = 413 mg). The fraction eliminated by all routes was 60%. The sieving coefficient for vancomycin was 0.7 ± 0.1 and for urea was 0.8 ± 0.06.ConclusionsVancomycin is cleared effectively by CVVHDF. Clearance was faster than other forms of CRRT, therefore doses need to be relatively high. Urea clearance slightly overestimates vancomycin clearance. The administered doses of 750 mg every 12 h were too high and accumulation occurred, as only approximately 60% of a dose was cleared over this period. The maintenance dose required to achieve a target average steady‐state plasma concentration of 15 mg l−1 can be calculated as 450 mg every 12 h.
Genetic polymorphism of cytochrome P450 2C19 in healthy Malaysian subjects
Authors: Yang Y. S. , Wong L. P. , Lee T. C. , Mustafa A. M. , Mohamed Z. , Lang Chim C. 
Published: August 2004

AimsImpaired S‐mephenytoin 4′‐hydroxylation is a well‐described genetic polymorphism affecting drug metabolism in humans. Although ethnic differences in its distribution of polymorphism has been described, it is not known whether there is an ethnic heterogeneity of the structure and expression of the CYP2C19 enzyme in the Malaysian population.MethodsStudy subjects were 142 healthy, unrelated Malaysians aged 18–29 years. Baseline omeprazole and 2‐h postingestion omeprazole and 5′‐hydroxyomeprazole concentrations were measured for CYP2C19 phenotype determination. Identification of CYP2C19 genotypes was performed with the use of polymerase chain reaction.ResultsPhenotyping of CYP2C19 revealed that the prevalence of poor metabolizers (PMs) in the Malaysian population was 14.1%, whereas prevalence of PMs in genotyping was 12.6%. The PM genotypic prevalence rate was 5.6% in Malays, 19.1% in Chinese and 10.0% in Indian subjects. There were significant differences in PM genotypic prevalence rates among the three primary ethnic groups (P ≤ 0.05).ConclusionsPhenotyping and genotyping revealed significant differences in the prevalence rates among the three ethnic groups in Malaysia, with Chinese recording highest prevalence.
Alpha‐lipoic acid does not acutely affect resistance and conduit artery function or oxidative stress in healthy men
Authors: Sharman James E. , Gunaruwan Prasad , Knez Wade L. , Schmitt Matthias , Marsh Susan A. , Wilson Gary R. , Cockcroft John R. , Coombes Jeff S. 
Published: August 2004

AimsAlpha‐lipoic acid (ALA) is a thiol compound with antioxidant properties used in the treatment of diabetic polyneuropathy. ALA may also improve arterial function, but there have been scant human trials examining this notion. This project aimed to investigate the effects of oral and intra‐arterial ALA on changes in systemic and regional haemodynamics, respectively.MethodsIn study 1, 16 healthy older men aged 58 ± 7 years (mean ± SD) received 600 mg of ALA or placebo, on two occasions 1 week apart, in a randomized cross‐over design. Repeated measures of peripheral and central haemodynamics were then obtained for 90 min. Central blood pressure and indices of arterial stiffness [augmentation index (AIx) and estimated aortic pulse wave velocity] were recorded non‐invasively using pulse wave analysis. Blood samples obtained pre‐ and post‐treatments were analysed for erythrocyte antioxidant enzyme activity, plasma nitrite and malondialdehyde. In study 2 the effects of incremental cumulative doses (0.5, 1.0, 1.5 and 2.0 mg ml−1 min−1) of intra‐arterial ALA on forearm blood flow (FBF) were assessed in eight healthy subjects (aged 31 ± 5 years) by conventional venous occlusion plethysmography.ResultsThere were no significant changes on any of the central or peripheral haemodynamic measures after either oral or direct arterial administration of ALA. Plasma ALA was detected after oral supplementation (95% confidence intervals 463, 761 ng ml−1), but did not alter cellular or plasma measures of oxidative stress.ConclusionsNeither oral nor intra‐arterial ALA had any effect on regional and systemic haemodynamics or measures of oxidative stress in healthy men.
A comparison of the bioequivalence of two formulations of epoetin alfa after subcutaneous injection
Authors: Togawa Akashi , Tanaka Takanori , Nagashima Satoru , Keta Hiroyuki , Kobayashi Yasue , Nishikawa Yasuhiro , Yanai Masanobu , Tanaka Hideji 
Published: August 2004

BackgroundThe previous formulation of epoetin alfa in Japan was a citrate‐buffered protein solution containing gelatin hydrolysate as the protein protective agent. To eliminate pain at injection sites, and the risks of anaphylactic shock and unknown infections by gelatin we have developed a new formulation of phosphate‐buffered epoetin alfa, which does not contain gelatin hydrolysate.AimTo compare the bioequivalence of two formulations of epoetin alfa administered by the subcutaneous route.MethodsFour separate studies were performed to assess the bioequivalence of two epoetin alfa formulations using different strength and doses, i.e. 750 IU per 0.5 ml × 0.5 ml (= 750 IU per subject), 750 IU per 0.5 ml × 4 ml (= 6000 IU per subject), 6000 IU per 0.5 ml × 0.5 ml (= 6000 IU per subject) and 24 000 IU per 0.5 ml × 0.125 ml (= 6000 IU per subject). Each study was a single‐centre, open‐label, randomized, two‐treatment, two‐period, crossover study for which healthy volunteers were enrolled. Bioequivalence was assessed using the confidence interval (CI) of the ratios for the log‐transformed, baseline‐corrected Cmax and AUC(0,t). Baseline‐corrected AUC(0,t) was calculated using the following equation: AUC(0,t) = AUC(0,t), uncorrected − predose level × observation period.ResultsThe ratios (gelatin‐free/gelatin‐containing) for the log‐transformed Cmax and AUC(0,t) after 6000 IU per subject injection of three different concentrations of epoetin alfa were well within the usual range for bioequivalence (90% CI 0.8, 1.25). The 90% CI of the ratio for Cmax after 750 IU per subject injection was 0.906, 1.24, which was within the bioequivalence range. However, the ratio for AUC(0,t) was not determined in this lowest dose because of negative AUC(0,t) values obtained in 12/60 cases. The overall safety data were consistent with those expected for a healthy study population, and did not present any concerns suggestive of adverse effects due to either formulation.ConclusionsThe point estimates and 90% CIs of the ratios of Cmax and AUC(0,t) for the gelatin‐free/gelatin‐containing formulations indicated that the two formulations are bioequivalent.
Recent trends in (under)treatment of hypercholesterolaemia in the Netherlands
Authors: Mantel‐Teeuwisse Aukje K. , Verschuren W. M. Monique , Klungel Olaf H. , De Boer Anthonius , Kromhout Daan 
Published: August 2004

AimTo assess recent trends in undertreatment of hypercholesterolaemia (1998–2002).MethodsData were obtained from the third cross‐sectional examination of the Monitoring Project on Risk Factors for Chronic Diseases (n = 4878; age 31–70 years), conducted in the Netherlands. Treatment eligibility was established according to Dutch guidelines. Data from the second examination (1993–1997) were used to assess time trends. The association between demographic variables, cardiovascular disease risk factors, drug use and lipid‐lowering medication was assessed using multivariable logistic regression.ResultsOverall, 45.9%[95% confidence interval (CI) 41.4, 50.4] of respondents eligible for treatment were treated, and 17.4% (95% CI 13.9, 20.9) were both treated and controlled (1998–2002). Treatment increased significantly after 1995, showed a slight decrease in subsequent years until 2000, when treatment increased again. Subgroups less frequently treated for primary prevention included among others males [odds ratio (OR) = 0.08; 95% CI 0.03, 0.21], younger patients (OR = 0.93 per year; 95% CI 0.88, 0.98), diabetics (OR = 0.19; 95% CI 0.07, 0.56), untreated hypertensives (OR = 0.21; 95% CI 0.09, 0.49) and current smokers (OR = 0.09; 95% CI 0.03, 0.25). In secondary prevention, patients with a history of stroke were less likely to receive treatment (OR = 0.41; 95% CI 0.18, 0.94) compared with patients with a history of ischaemic heart disease.ConclusionsTreatment of hypercholesterolaemia has steadily increased over the past 10 years in the Netherlands. However, at present still less than one out of two eligible for treatment is treated, and only about one out of six is both treated and controlled.
A convenient five‐drug cocktail for the assessment of major drug metabolizing enzymes: a pilot study
Authors: Sharma Ashish , Pilote Sylvie , Bélanger Pierre M. , Arsenault Marie , Hamelin Bettina A. 
Published: August 2004

AimsTo assess the feasibility of administering at the same time low doses of five probe drugs, metoprolol (25 mg), chlorzoxazone (250 mg), tolbutamide (250 mg), dapsone (100 mg) and caffeine (100 mg) to determine simultaneously the activities of CYP2D6, CYP2E1, CYP2C9, CYP3A4, CYP1A2, N‐acetyltransferase‐2 and xanthine oxidase.MethodsTen healthy young non‐smoking males received the following drugs or combinations of drugs over a 5‐week period: week 1) metoprolol; 2) tolbutamide; 3) caffeine, chlorzoxazone and dapsone; 4) caffeine, chlorzoxazone, dapsone and metoprolol; 5) caffeine, chlorzoxazone, dapsone, metoprolol and tolbutamide. The drugs were self‐administered at bedtime and urine was collected for the following 8 h.ResultsMean molar phenotypic ratios obtained after administering metoprolol (mean change of −11%) or tolbutamide (mean change of −0.3%) alone, were not significantly different from those obtained when other drugs were co‐administered (P > 0.05). The mean within‐subject coefficients of variation were 33%, 18%, 22%, 13%, 16%, 13% and 5% for CYP3A4, CYP2D6, CYP2C9, CYP2E1, CYP1A2, N‐acetyltransferase 2 and xanthine oxidase metabolic ratios, respectively. No significant interactions (P > 0.5) were observed during the simultaneous administration of various combinations of the five probe drugs.ConclusionsWe propose that this cocktail, composed of five widely available drugs, constitutes a promising means of simultaneously determining the activities of the major CYP enzymes in large populations.
Homozygosis for (12) CA repeats in the first intron of the human IFN‐γ gene is significantly associated with the risk of aplastic anaemia in Caucasian population
Authors: Dufour Carlo , Capasso Mario , Svahn Johanna , Marrone Agnese , Haupt Riccardo , Bacigalupo Andrea , Giordani Lucia , Longoni Daniela , Pillon Marta , Pistorio Angela , Michele Paola Di , Iori Anna Paola , Pongiglione Carola , Lanciotti Marina , Iolascon Achille ,   the Associazione Italiana di Emato‐Oncologia Pediatrica (AIEOP) and of the Department of Hematology, Ospedale S. Martino, Genova, Italy
Published: August 2004

SummaryInterferon‐γ (IFN‐γ) mediates the final damage of the stem cell compartment in Aplastic Anaemia (AA). Normal subjects homozygous for 12 (CA) repeats of polymorphism variable number of dinucleotide (CA) repeat (VNDR) in position 1349 of the IFN‐γ gene (IFNG) were shown to overproduce IFN‐γin vitro. We studied the distribution of polymorphism VNDR 1349 of IFNG in 67 Caucasian AA patients and in normal controls. Genotype (CA)12‐12, (homozygosis for allele 2) and the single allele 12 were significantly more frequent (P = 0·005 and 0·004 respectively) in patients versus controls. The polymorphism was equally distributed in AA patients regardless of their response to immunosuppression. Homozygosity for 12 (CA) repeats of polymorphism VNDR 1349 of IFNG is strongly associated with the risk of AA in Caucasian subjects.
Magnetic resonance imaging in the evaluation of iron overload in patients with beta thalassaemia and sickle cell disease
Authors: Voskaridou Ersi , Douskou Maroussa , Terpos Evangelos , Papassotiriou Ioannis , Stamoulakatou Alexandra , Ourailidis Akis , Loutradi Aphroditi , Loukopoulos Dimitris 
Published: August 2004

SummaryMagnetic resonance imaging (MRI) appears to be useful for monitoring iron overload in thalassaemia. We studied 106 patients with beta‐thalassaemia: 80 with thalassaemia major (TM) and 26 with thalassaemia intermedia (TI). Thirty‐five patients with sickle cell disease (SCD) were also evaluated. Serum ferritin, liver and myocardial T2‐relaxation time and liver iron concentration (LIC) were measured. LIC values, based on biopsies from 29 patients, showed a close inverse correlation with the respective liver T2‐values, along with a strong positive correlation with ferritin levels in all patients. Heart T2‐values correlated with left ventricular ejection fraction in TM and SCD, but not in TI patients. Both liver and heart T2‐values were significantly lower in TM patients than those of TI, and SCD patients. Ferritin levels showed a strong correlation with liver T2‐values in all three groups of patients. Similarly, a negative correlation was found between serum ferritin levels and heart T2‐values in TM, but not in TI and SCD patients. Heart and liver T2‐values showed a significant correlation only in TM patients. These results suggest that the MRI technique (T2 relaxation time) used in our study, is a reliable, safe and non‐invasive method for the assessment of the deposition of iron in the liver; results for the heart become reliable only when there is heavy iron deposition.
Aberrant methylation in the promoter region of the reduced folate carrier gene is a potential mechanism of resistance to methotrexate in primary central nervous system lymphomas
Authors: Ferreri Andrés J. M. , Dell'Oro Stefania , Capello Daniela , Ponzoni Maurilio , Iuzzolino Paolo , Rossi Davide , Pasini Felice , Ambrosetti Achille , Orvieto Enrico , Ferrarese Fabio , Arrigoni Gianluigi , Foppoli Marco , Reni Michele , Gaidano Gianluca 
Published: August 2004

SummaryWe investigated the prevalence and prognostic role of CpG island methylation of the reduced folate carrier (RFC) gene promoter region in primary central nervous system lymphoma (PCNSL) in immunocompetent patients. Genomic DNA from 40 PCNSL was used for methylation‐specific polymerase chain reaction and bisulphite genomic sequencing of the RFC promoter region. Human immunodeficiency virus‐negative systemic diffuse large B‐cell lymphomas (DLBCL) were used as controls (n = 50). The impact on outcome of RFC promoter methylation was assessed in 37 PCNSL patients treated with high‐dose methotrexate (HD‐MTX)‐based chemotherapy ± radiotherapy. RFC promoter methylation occurred in 12 of 40 (30%) PCNSL and in four of 50 (8%) DLBCL (P = 0·01). Of 37 PCNSL treated with HD‐MTX‐based chemotherapy, methylation occurred in nine cases (24%, M‐PCNSL), while 28 cases (76%, U‐PCNSL) were negative. Three M‐PCNSL (33%) and 15 U‐PCNSL (54%) achieved complete remission (CR) after primary chemotherapy. Logistic regression confirmed the independent association between CR rate and International Extranodal Lymphoma Study Group score (P = 0·03), RFC promoter methylation (P = 0·07) and use of cytarabine (P = 0·08). The 3‐year failure‐free survival (FFS) and overall survival for M‐PCNSL and U‐PCNSL was 0% vs. 31 ± 9% (P = 0·34) and 0% vs. 31 ± 9% (P = 0·35) respectively. This is the first study to assess the methylation status of the RFC promoter in human tumour samples. RFC methylation is more common in PCNSL compared with systemic DLBCL, and is associated with a lower CR rate to HD‐MTX‐based chemotherapy. If confirmed in prospective trials on PCNSL treated with HD‐MTX alone, these data may suggest the necessity for alternative strategies in M‐PCNSL considering the increased risk of MTX resistance by tumour cells.
Post‐transplantation tumour load in bone marrow, as assessed by quantitative ASO‐PCR, is a prognostic parameter in multiple myeloma
Authors: Bakkus Marleen H. C. , Bouko Yasmina , Samson Diana , Apperley Jane F. , Thielemans Kris , Camp Benjamin Van , Benner Axel , Goldschmidt Hartmut , Moos Marion , Cremer Friedrich W. 
Published: August 2004

SummaryHigh‐dose therapy (HDT) and autologous transplantation prolongs remission duration and survival in multiple myeloma (MM), but relapse still occurs at a median of 2 years post‐HDT. In order to investigate whether the number of residual tumour cells in the bone marrow (BM) after transplantation can predict the duration of response, a quantitative allele‐specific oligonucleotide polymerase chain reaction (qASO‐PCR) assay was used to measure tumour load in BM at 3–6 months post‐HDT in 67 patients. The method of maximally selected log‐rank statistics was used to test for the existence of a cut‐off value in the BM tumour load data set. A cut‐off value with respect to progression‐free survival (PFS) was identified (P = 0·001). The estimated threshold for placing patients into a ‘good’ or ‘bad’ prognostic group was 0·015% (n = 22 and 38 respectively) with a median PFS of 64 months vs. 16. Multivariate analysis showed grouping by PCR result to be an independent prognostic factor for PFS (estimated hazard ratio after shrinkage, 3·91). This study identifies for the first time a threshold of the post‐HDT tumour load with prognostic significance for PFS in MM. Quantitative molecular assessment thus may help to identify those patients who are in need of further treatment early after autologous transplantation.