bluuebunny/crossref_metadata_2025 huggingface dataset:
Traffic Lights in Trichodesmium. Regulation of Photosynthesis for Nitrogen Fixation Studied by Chlorophyll Fluorescence Kinetic Microscopy
Authors: Küpper Hendrik , Ferimazova Naila , Šetlík Ivan , Berman-Frank Ilana
Published: August 2004

We investigated interactions between photosynthesis and nitrogen fixation in the non-heterocystous marine cyanobacterium Trichodesmium IMS101 at the single-cell level by two-dimensional (imaging) microscopic measurements of chlorophyll fluorescence kinetics. Nitrogen fixation was closely associated with the appearance of cells with high basic fluorescence yield (F  0), termed bright cells. In cultures aerated with normal air, both nitrogen fixation and bright cells appeared in the middle of the light phase. In cultures aerated with 5% oxygen, both processes occurred at a low level throughout most of the day. Under 50% oxygen, nitrogen fixation commenced at the beginning of the light phase but declined soon afterwards. Rapid reversible switches between fluorescence levels were observed, which indicated that the elevated F  0 of the bright cells originates from reversible uncoupling of the photosystem II (PSII) antenna from the PSII reaction center. Two physiologically distinct types of bright cells were observed. Type I had about double F  0 compared to the normal F  0 in the dark phase and a PSII activity, measured as variable fluorescence (F  v = F  m − F  0), similar to normal non-diazotrophic cells. Correlation of type I cells with nitrogen fixation, oxygen concentration, and light suggests that this physiological state is connected to an up-regulation of the Mehler reaction, resulting in oxygen consumption despite functional PSII. Type II cells had more than three times the normal F  0 and hardly any PSII activity measurable by variable fluorescence. They did not occur under low-oxygen concentrations, but appeared under high-oxygen levels outside the diazotrophic period, suggesting that this state represents a reaction to oxidative stress not necessarily connected to nitrogen fixation. In addition to the two high-fluorescence states, cells were observed to reversibly enter a low-fluorescence state. This occurred mainly after a cell went through its bright phase and may represent a fluorescence-quenching recovery phase.
Identification of Syn-Pimara-7,15-Diene Synthase Reveals Functional Clustering of Terpene Synthases Involved in Rice Phytoalexin/Allelochemical Biosynthesis
Authors: Wilderman P. Ross , Xu Meimei , Jin Yinghua , Coates Robert M. , Peters Reuben J.
Published: August 2004

Rice (Oryza sativa) produces momilactone diterpenoids as both phytoalexins and allelochemicals. Accordingly, the committed step in biosynthesis of these natural products is catalyzed by the class I terpene synthase that converts syn-copalyl diphosphate to the corresponding polycyclic hydrocarbon intermediate syn-pimara-7,15-diene. Here, a functional genomics approach was utilized to identify a syn-copalyl diphosphate specific 9β-pimara-7,15-diene synthase (OsDTS2). To our knowledge, this is the first identified terpene synthase with this particular substrate stereoselectivity and, by comparison with the previously described and closely related ent-copalyl diphosphate specific cassa-12,15-diene synthase (OsDTC1), provides a model system for investigating the enzymatic determinants underlying the observed difference in substrate specificity. Further, OsDTS2 mRNA in leaves is up-regulated by conditions that stimulate phytoalexin biosynthesis but is constitutively expressed in roots, where momilactones are constantly synthesized as allelochemicals. Therefore, transcription of OsDTS2 seems to be an important regulatory point for controlling production of these defensive compounds. Finally, the gene identified here as OsDTS2 has previously been mapped at 14.3 cM on chromosome 4. The class II terpene synthase producing syn-copalyl diphosphate from the universal diterpenoid precursor geranylgeranyl diphosphate was also mapped to this same region. These genes catalyze sequential cyclization steps in momilactone biosynthesis and seem to have been evolutionarily coupled by physical linkage and resulting cosegregation. Further, the observed correlation between physical proximity and common metabolic function indicates that other such class I and class II terpene synthase gene clusters may similarly catalyze consecutive reactions in shared biosynthetic pathways.
Phycobilisome Diffusion Is Required for Light-State Transitions in Cyanobacteria
Authors: Joshua Sarah , Mullineaux Conrad W.
Published: August 2004

Phycobilisomes are the major accessory light-harvesting complexes of cyanobacteria and red algae. Studies using fluorescence recovery after photobleaching on cyanobacteria in vivo have shown that the phycobilisomes are mobile complexes that rapidly diffuse on the thylakoid membrane surface. By contrast, the PSII core complexes are completely immobile. This indicates that the association of phycobilisomes with reaction centers must be transient and unstable. Here, we show that when cells of the cyanobacterium Synechococcus sp. PCC7942 are immersed in buffers of high osmotic strength, the diffusion coefficient for the phycobilisomes is greatly decreased. This suggests that the interaction between phycobilisomes and reaction centers becomes much less transient under these conditions. We discuss the possible reasons for this. State transitions are a rapid physiological adaptation mechanism that regulates the way in which absorbed light energy is distributed between PSI and PSII. Immersing cells in high osmotic strength buffers inhibits state transitions by locking cells into whichever state they were in prior to addition of the buffer. The effect on state transitions is induced at the same buffer concentrations as the effect on phycobilisome diffusion. This implies that phycobilisome diffusion is required for state transitions. The main physiological role for phycobilisome mobility may be to allow such flexibility in light harvesting.
Emission of Plutella xylostella-Induced Compounds from Cabbages Grown at Elevated CO2 and Orientation Behavior of the Natural Enemies
Authors: Vuorinen Terhi , Nerg Anne-Marja , Ibrahim M.A. , Reddy G.V.P. , Holopainen Jarmo K.
Published: August 2004

Several plant species defend themselves indirectly from herbivores by producing herbivore-induced volatile compounds that attract the natural enemies of herbivores. Here we tested the effects of elevated atmospheric CO2 (720 μmol mol−1) concentration on this indirect defense, physiological properties, and constitutive and induced emissions of white cabbage (Brassica oleracea ssp. capitata, cvs Lennox and Rinda). We monitored the orientation behavior of the generalist predator Podisus maculiventris (Heteroptera: Pentatomidae) and the specialist parasitoid Cotesia plutellae (Hymenoptera: Braconidae) to plants damaged by Plutella xylostella (Lepidoptera: Plutellidae) in the Y-tube olfactometer. Elevated CO2 levels did not affect stomatal densities but reduced specific leaf area and increased leaf thickness in cv Lennox. In addition to enhanced constitutive monoterpene emission, P. xylostella-damaged cabbages emitted homoterpene (E)-4,8-dimethyl-1,3,7-nonatriene, sesquiterpene (E,E)-α-farnesene, and (Z)-3-hexenyl acetate. Growth at elevated CO2 had no significant effect on the emissions expressed per leaf area, while minor reduction in the emission of homoterpene (E)-4,8-dimethyl-1,3,7-nonatriene and (E,E)-α-farnesene was observed at elevated CO2 in one of two experiments. The generalist predator P. maculiventris discriminated only between the odors of intact and P. xylostella-damaged cv Rinda plants grown at ambient CO2 concentration, preferring the odor of the damaged plants. The specialist parasitoid C. plutellae preferred the odor of damaged plants of both cultivars grown at ambient CO2 but did not detect damaged cv Lennox plants grown at elevated CO2. The results suggest that elevated atmospheric CO2 concentration could weaken the plant response induced by insect herbivore feeding and thereby lead to a disturbance of signaling to the third trophic level.
Combined Transcript and Metabolite Analysis Reveals Genes Involved in Spider Mite Induced Volatile Formation in Cucumber Plants
Authors: Mercke Per , Kappers Iris F. , Verstappen Francel W.A. , Vorst Oscar , Dicke Marcel , Bouwmeester Harro J.
Published: August 2004

Many plants have an indirect defense against herbivores by emitting volatiles that attract carnivorous enemies of the herbivores. In cucumber (Cucumis sativus) the production of carnivore attractants can be induced by herbivory or jasmonic acid spraying. From the leaves of cucumber plants with and without spider mite infestation, two subtractive cDNA libraries were made that were enriched in cDNA fragments up- or down-regulated by spider mite infestation. A total of 713 randomly selected clones from these libraries were used to make a cDNA microarray. Subsequently, cucumber plants were sprayed with jasmonic acid, mechanically damaged, infested with spider mites, or left untreated (control). Leaf samples were taken at a range of different time points, and induced volatile compounds and mRNA (from the same leaves) were collected. cDNAs prepared from the mRNA were hybridized to the clones on the microarray. The resulting gene expression profiles were analyzed in combination with volatile production data in order to gain insight in the possible involvement of the studied genes in the synthesis of those volatiles. The clones on the microarray and the induced cucumber volatiles could be grouped into a number of clusters in which specific biosynthetic genes clustered with the product of that pathway. For example, lipoxygenase cDNA clones clustered with the volatile (Z)-3-hexenyl acetate and the volatile sesquiterpene (E,E)- α-farnesene clustered with an up-regulated sesquiterpene synthase fragment. This fragment was used to screen a cDNA library which resulted in the cloning of the cucumber (E,E)-α-farnesene and (E)-β-caryophyllene synthases. The use of combined global gene expression analysis and metabolite analysis for the discovery of genes involved in specific biosynthetic processes is discussed.
Jasmonic Acid Is a Key Regulator of Spider Mite-Induced Volatile Terpenoid and Methyl Salicylate Emission in Tomato
Authors: Ament Kai , Kant Merijn R. , Sabelis Maurice W. , Haring Michel A. , Schuurink Robert C.
Published: August 2004

The tomato (Lycopersicon esculentum) mutant def-1, which is deficient in induced jasmonic acid (JA) accumulation upon wounding or herbivory, was used to study the role of JA in the direct and indirect defense responses to phytophagous mites (Tetranychus urticae). In contrast to earlier reports, spider mites laid as many eggs and caused as much damage on def-1 as on wild-type plants, even though def-1 lacked induction of proteinase inhibitor activity. However, the hatching-rate of eggs on def-1 was significantly higher, suggesting that JA-dependent direct defenses enhanced egg mortality or increased the time needed for embryonic development. As to gene expression, def-1 had lower levels of JA-related transcripts but higher levels of salicylic acid (SA) related transcripts after 1 d of spider mite infestation. Furthermore, the indirect defense response was absent in def-1, since the five typical spider mite-induced tomato-volatiles (methyl salicylate [MeSA], 4,8,12-trimethyltrideca-1,3,7,11-tetraene [TMTT], linalool, trans-nerolidol, and trans-β-ocimene) were not induced and the predatory mite Phytoseiulus persimilis did not discriminate between infested and uninfested def-1 tomatoes as it did with wild-type tomatoes. Similarly, the expression of the MeSA biosynthetic gene salicylic acid methyltransferase (SAMT) was induced by spider mites in wild type but not in def-1. Exogenous application of JA to def-1 induced the accumulation of SAMT and putative geranylgeranyl diphosphate synthase transcripts and restored MeSA- and TMTT-emission upon herbivory. JA is therefore necessary to induce the enzymatic conversion of SA into MeSA. We conclude that JA is essential for establishing the spider mite-induced indirect defense response in tomato.
Effects of Uncinula necator on the yield and quality of grapes (Vitis vinifera) and wine
Authors: Calonnec A. , Cartolaro P. , Poupot C. , Dubourdieu D. , Darriet P.
Published: August 2004

The effects of powdery mildew (Uncinula necator) on grape yield, juice and wine quality were quantified for cultivar Cabernet Sauvignon (CSa) in 1997 and 1999, and for Sauvignon blanc (Sa) in 1999. Analyses were carried out on batches of healthy berries to which known percentages (0–50%) of diseased berries were added, and on natural clusters that were classified into four visual classes from low (C1) to high (C4) disease severity. CSa diseased berries showed an average weight reduction of 12% (1997) and 20% (1999). The direct consequence of a higher percentage of smaller, diseased berries was a reduction in yield. The accompanying loss of weight in must from C1 to C4 clusters increased from 10 to 45%. Sugar content in diseased berries was not significantly different from disease‐free berries in 1997, but was 20–21% (CSa) and 14% (Sa) higher in 1999. Severely infected batches also showed a higher total acidity than healthy ones. The total anthocyanin content of CSa was decreased by 0·91% (1997) and 0·66% (1999) per percentage mildewed berries added by weight. In Sa wines the concentration of 3‐mercaptohexanol, a component of varietal aroma, was decreased by powdery mildew. Multidimensional analyses, based on all the variables studied, successfully grouped batches of CSa according to disease severity. Using directional triangular tests wine experts were able to recognize CSa wines produced from berries with ≈25% of powdery mildew; the threshold for nonexperts was 50%. CSa wines obtained from samples with more than 30% of diseased berries by weight were significantly classified as the worst according to preference order criteria, but below this value the preference was not significant. Sa wines with <50% mildewed berries could not be differentiated significantly by organoleptic tests performed by nonprofessionals.
Productivity Versus Welfare; Or GDP Versus Weitzman's NDP
Authors: Oulton Nicholas
Published: August 2004

While GDP is the appropriate measure of output, I argue that Weitzman's NDP (WNDP)—nominal net domestic product deflated by the price of consumption—is the appropriate measure of welfare. Total factor productivity (TFP) growth measures the shift in the GDP frontier, and there is an analogous concept for WNDP, which I call total factor welfare (TFW) growth. I calculate and compare WNDP and GDP, and TFP and TFW, for the United States in the 1990s. I find that the acceleration of WNDP post 1995 was as great as that of GDP, even though the aggregate depreciation rate was rising.
China's Statistical System in Transition: Challenges, Data Problems, and Institutional Innovations
Authors: Holz Carsten A.
Published: August 2004

While China's official statistics are often regarded as of questionable quality, critics are rarely aware of just how difficult it is to compile accurate statistics in a developing and transition economy. This paper traces the challenges economic reforms pose for the development of China's statistical system, establishes a typology of the resulting data problems in official Chinese statistics today, and examines how these challenges and data problems are being addressed through institutional innovations in data compilation. Analysis of China's data compilation methods allows broad judgments on data quality. Special attention is given to GDP data as the aggregate measure of productive activities in China.
CPI Quality Adjustment and Productivity Growth: Railway Services in Japan
Authors: Utsunomiya Kiyohito
Published: August 2004

In recent years quality adjustment of price indices has been vigorously explored and the hedonic regression method has become popular in official statistics. In service sectors, however, the current CPI seems not to have been successfully adjusted to accommodate quality changes. In this paper I focus on the railway industry in Japan, where quality change is a vital factor in the measurement of price indices and productivity. Using hedonic regressions to adjust CPI railway fares, the paper suggests that there may be a significant degree of upward bias in the current CPI railway fares. Also, this leads to the results that the total factor productivity (TFP) of the Japanese railway industry, which is calculated by using the newly adjusted CPI as a deflator, has been improved contrary to previous research on this issue.
Social Security Strategies and Redistributive Effects in European Social Transfer Systems
Authors: Kraus Margit
Published: August 2004

This paper evaluates the linkage between social security strategies and redistributive effects in EU social transfer systems. It is argued that the various European systems produce different patterns of redistribution that may be explained by the adoption of different mixes of social security strategies. In support of this argument, several ideal‐typical strategies are characterized and a classification of European social transfer systems is introduced. Subsequently, the redistributive effects of the systems are assessed and the relationship to their class assignment is investigated. We conclude that the redistributive effects differ markedly between systems of different classes, indicating that redistributive patterns are heavily influenced by the adopted strategy mix.
Oil outlook to 2025
Authors: Shihab‐Eldin Adnan , Hamel Mohamed , Brennand Garry
Published: August 2004

This paper presents the OPEC Secretariat's latest outlook to 2025 for oil supply and demand. The results have been developed using the OPEC World Energy Model, OWEM.

The next two decades are expected to see increases in energy demand met predominantly by fossil fuels, with oil set to continue to maintain its major role. There is also a clear expectation that the oil resource base is sufficiently abundant to satisfy this demand growth. Global oil demand rises in the reference case by 12 million barrels per day to 89 mb/d from 2002 to 2010, an average annual growth rate of 1.5 mb/d, or 1.8 per cent per annum, over the period. In the following decade, demand grows by a further 17 mb/d to 106 mb/d by 2020, and then by another 9 mb/d to 115 mb/d by 2025. Almost three‐quarters of the increase in demand over the period 2002–25 comes from developing countries.

In the short‐to‐medium term, overall non‐OPEC supply is expected to continue to increase—rising to a plateau of 55–57 mb/d in the post‐2010 period. The key sources for the increase in non‐OPEC supply will be Latin America, Africa, Russia and the Caspian. In the longer term, OPEC will increasingly be called upon to supply the incremental barrel.

Uncertainties over future economic growth, government policies and the rate of development and diffusion of newer technologies raise questions over the future scale of investment that will be required. These uncertainties, coupled with long lead times, inevitably complicate the task of maintaining market stability. Medium‐term prospects suggest that there is a need to ensure that spare capacity is not too high and that it is consistent with sustained market stability. There are genuine risks of downward pressure on oil prices, and this could sow the seeds of instability.
Oil price movements and production agreements
Authors: Mazraati M. , Jazayeri S.M. Tayyebi
Published: August 2004

The purpose of this technical exercise is to apply econometric modelling to study the relationship between movements in the oil price and compliance by the Organization of the Petroleum Exporting Countries (OPEC) with its self‐assigned production agreements, whose purpose is to bring order and stability to the international oil market.

After introducing various methods of measurement of compliance, the study applies these methods to monthly data for 1995–2002 for OPEC. It then identifies the method “over‐production as a percentage of ceiling” as the best‐fitting and most accurate criterion for measuring OPEC compliance. The paper then elaborates on intervention analysis, explains the various types of intervention in detail and introduces a number of econometric models to monitor oil price movements resulting from OPEC's intervention in the oil market, along with the extent of its compliance with its agreements.

On applying the models to a set of historical monthly data, the study finds that higher oil prices have been achieved when the effective level of compliance lies in the range of 94–99 per cent, and that lower oil prices have been experienced when there is less compliance and more volatility.

The paper notes that the achievement of order and stability is the responsibility of all parties in an international market that is inherently volatile.
Some risks related to the short‐term trading of natural gas
Authors: Mazighi Ahmed El Hachemi
Published: August 2004

Traditionally guided by long‐term contracts, the international natural gas trade is experiencing new methods of operating, based on the short term and more flexibility. Today, indeed, the existence of uncommitted quantities of natural gas, combined with gas price discrepancies among different regions of the world, gives room for the expansion of the spot‐trading of gas.

The main objective of this paper is to discuss three fundamental risks related to the short‐term trading of natural gas: volume risk, price risk and infrastructure risk. The defenders of globalisation argue that the transition from the long‐term to the short‐term trading of natural gas is mainly a question of access to gas reserves, decreasing costs of gas liquefaction, the building of liquefied natural gas (LNG) fleets and regasification facilities and third‐party access to the infrastructure. This process needs to be as short as possible, so that the risks related to the transition process will disappear rapidly. On the other hand, the detractors of globalisation put the emphasis on the complexity of the gas value chain and on the fact that eliminating long‐term contracts increases the risks inherent to the international natural gas business.

In this paper, we try to untangle and assess the risks related to the short‐term trading of natural gas. Our main conclusions are listed over the page:

the short‐term trading of gas is far from riskless;

volume risk requires stock‐building in both consuming and producing countries;

price risk, through the high volatility for gas, induces an increase in options prices; and

there is no evidence to suggest that money‐lenders' appetite for financing gas infrastructure projects will continue in a short‐term trading system, and this would be a threat to consumers' security of supply.
Nursing Interventions for a Chronically Ill, Nonadherent Teenager With a Psychiatric Diagnosis
Authors: Sieben Diane , Steinmiller Elizabeth A. , Bertolino Jennifer
Published: August 2004

ISSUES AND PURPOSE To describe the complex care of an adolescent with chronic psychiatric and medical problems.

CONCLUSIONS The nonadherent, self‐abusing, adolescent was empowered to progress developmentally, as well as medically.

PRACTICE IMPLICATIONS A planned team approach helped the adolescent become more developmentally appropriate and independent in self‐care. The care plan designed by nursing staff included a change in nursing focus, creative problem solving, team nursing, and utilization of multidisciplinary resources.
Lack of Relationship Between Acceptance and Knowledge of Asthma in School‐Age Children and Early Adolescents
Authors: Kintner Eileen Kae
Published: August 2004

ISSUES AND PURPOSE Early adolescents diagnosed with asthma have difficulty accepting their condition. This study is part of an ongoing program of research designed to increase understanding of the adolescent process of coming to acceptance. The purpose was to explore relationships among variables in the Acceptance of Asthma Model.

DESIGN AND METHODS A cross‐sectional, theory‐testing design with a sample of 94 students ages 9 to 14 years.

RESULTS Acceptance was dependent on psychosocial influences and disease characteristics rather than knowledge of asthma.

PRACTICE IMPLICATIONS Psychosocial interventions are needed to facilitate acceptance.
How to Read a Research Article
Authors: Hudson‐Barr Diane , Hudson‐Barr Diane
Published: August 2004

Scientific Inquiry provides a forum to facilitate the ongoing process of questioning and evaluating practice, presents informed practice based on available data, and innovates new practices through research and experimental learning.
Origin of the in situ stress field in south‐eastern Australia
Authors: Sandiford Mike , Wallace Malcolm , Coblentz David
Published: August 2004

The in situ stress field of south‐eastern Australia inferred from earthquake focal mechanisms and bore‐hole breakouts is unusual in that it is characterised by large obliquity between the maximum horizontal compressive stress orientation (SHmax) and the absolute plate motion azimuth. The evolution of the neotectonic strain field deduced from historical seismicity and both onshore and offshore faulting records is used to address the origin of this unusual stress field. Strain rates derived from estimates of the seismic moment release rate (up to ∼10−16 s−1) are compatible with Quaternary fault–slip rates. The record of more or less continuous tectonic activity extends back to the terminal Miocene or early Pliocene (10–5 Ma). Terminal Miocene tectonic activity was characterised by regional‐scale tilting and local uplift and erosion, now best preserved by unconformities in offshore basins. Plate‐scale stress modelling suggests the in situ stress field reflects increased coupling of the Australian and Pacific Plate boundary in the late Miocene, associated with the formation of the Southern Alps in New Zealand.
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

Faults 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

Fluid 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 methods

To 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.

Results

Eight 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.

Conclusion

Decreased 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.
Severe overdosage with the antiepileptic drug oxcarbazepine
Authors: Van Opstal J. M. , Janknegt R. , Cilissen J. , L’Ortije W. H. V. M. , Nel J. E. , De Heer F.
Published: August 2004

Few published human data are available concerning the acute toxicity of the new antiepileptic drug oxcarbazepine of which the metabolite 10‐ monohydroxy derivate (MHD) is the pharmacologically effective compound. Two hours after a documented overdosage of more than 100 tablets oxcarbazepine, the serum level of the parent compound was 10‐fold higher than the therapeutic dosage (31.6 mg l−1). However, the concentration of MHD, which peaked 7 h after intake, was only twofold higher (59.0 mg l−1). No life‐threatening situations occurred and the patient fully recovered. The fact that oxcarbazepine is a prodrug and that the formation of the active MHD metabolite is a rate‐limiting process may contribute to the relative low toxicity of the drug in overdose.
Statins and newly diagnosed diabetes
Authors: Jick Susan S. , Bradbury Brian D.
Published: August 2004

Aims

In 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).

Methods

We 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.

Findings

We 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.

Conclusion

The 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

Aims

To 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.

Methods

Pharmacokinetic 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).

Results

CVVHDF 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.

Conclusions

Vancomycin 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

Aims

Impaired 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.

Methods

Study 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.

Results

Phenotyping 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).

Conclusions

Phenotyping 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

Aims

Alpha‐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.

Methods

In 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.

Results

There 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.

Conclusions

Neither 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

Background

The 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.

Aim

To compare the bioequivalence of two formulations of epoetin alfa administered by the subcutaneous route.

Methods

Four 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.

Results

The 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.

Conclusions

The 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

Aim

To assess recent trends in undertreatment of hypercholesterolaemia (1998–2002).

Methods

Data 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.

Results

Overall, 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.

Conclusions

Treatment 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

Aims

To 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.

Methods

Ten 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.

Results

Mean 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.

Conclusions

We 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

Interferon‐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

Magnetic 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.