bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of MgO Doping on the Phase Transformations of BaTiO3
Authors: Nagai Toru , Iijima Kenji , Hwang Hae Jin , Sando Mutsuo , Sekino Tohru , Niihara Koichi
Published: July 2008

The successive phase transformations in MgO‐doped BaTiO3 were studied. Upon MgO doping, dielectric anomalies corresponding to lower phase transformations were broadened and depressed, while an anomaly for a cubic–tetragonal transformation remained and shifted to a lower temperature. XRD peak splitting upon tetragonality of BaTiO3 was decreased, and the peaks exhibited abnormally broadened profiles which are different from the one for cubic BaTiO3 above Tc. Raman spectroscopy revealed the existence of orthorhombic phase at room temperature for the solid solution with 0.5 mol% or more MgO. The temperature dependence of the Raman spectrum showed that orthorhombic and rhombohedral phases in MgO‐doped BaTiO3 were stabilized at higher temperatures than pure BaTiO3.
Thermally Induced Coarsening of the Chemically Ordered Domains in Pb(Mg1/3Nb2/3)O3 (PMN)‐Based Relaxor Ferroelectrics
Authors: Akbas Mehmet A. , Davies Peter K.
Published: July 2008

The effect of different tetravalent octahedral‐site substitutions (M4+= Zr, Tb, and Ce) on the stability of the 1:1 chemically ordered phase in Pb(Mg1/3Nb2/3)O3 (PMN) relaxor ferroelectrics were investigated using X‐ray diffractometry and transmission electron microscopy. In their as‐sintered form, all the samples adopted a phase‐separated microstructure that consisted of nanosized 1:1 ordered domains dispersed in a disordered matrix. However, after annealing at 1250°C for 24 h, a fully 1:1 ordered microstructure with large domains (>100 nm) was stabilized in 10 mol%‐terbium‐doped PMN. No ordered‐domain coarsening was observed in pure or zirconium‐doped PMN, which indicated that the size of the solid‐solution additives was critical to stimulating the growth and stability of the 1:1 order. The observation of complete 1:1 order in the terbium‐doped system supports the “random‐site” model description of the Pb(β′1/2β″1/2)O3 structure. This model also can be used to explain the insensitivity of the diffuse frequency‐dependent dielectric properties to the size of the chemically ordered domains.
Influence of Processing Parameters on the Sintering and Electrical Properties of Pb(Zn1/3Nb2/3)O3‐Based Ceramics
Authors: Villegas Marina , Caballero Amador C. , Moure Carlos , Durán Pedro , Fernández José F. , Newnham Robert E.
Published: July 2008

Pb(Zn1/3Nb2/3)O3‐based ceramics have been prepared by two different processing methods: conventional (PZN‐C) and reaction‐sintering (PZN‐RS). The conventionally prepared PZN‐based ceramics densified at lower temperatures (950°C) than the reaction‐sintered samples (1100°C), but the perovskite/pyrochlore ratio was always higher in PZN‐RS. The presence of a substantial amount of pyrochlore phase in PZN‐C ceramics caused a decrease in the electrical properties. The maximum dielectric constant values in PZN‐C ceramics were 10%–15% lower than those of PZN‐RS, despite a similar average grain size, 7 ± 0.2 μm. The temperature of the maximum of the dielectric constant (Tmax) was lower than that expected from the mixing rule because of the possible formation of Ba–Nb clusters. The higher chemical homogeneity in PZN‐RS ceramics is the main reason for the higher dielectric constant, Tmax and electromechanical response, as well as for the lower difference between Tmax and the depolarization temperature (Td) and the lower diffusiveness parameter (δ).
Improved Oxidation Resistance of Silicon Nitride by Aluminum Implantation: I, Kinetics and Oxide Characteristics
Authors: Cheong Yong S. , Mukundhan Priya , Du Henry H. , Withrow Stephen P.
Published: July 2008

Hot‐isostatically‐pressed, additive‐free Si3N4 ceramics were implanted with aluminum at multi‐energies and multidoses to achieve uniform implant concentrations at 1, 5, and 10 at.% to a depth of about 200 nm. The oxidation behavior of unimplanted and aluminum‐implanted Si3N4 samples was investigated in 1 atm flowing oxygen entrained with 100 and 220 ppm NaNO3 vapor at 900–1100°C. Unimplanted Si3N4 exhibits a rapid, linear oxidation rate with an apparent activation energy of about 70 kJ/mol, independent of the sodium content in the gas phase. Oxides formed on the unimplanted samples are rough and are populated with cracks and pores. In contrast, aluminum‐implanted Si3N4 shows a significantly reduced, parabolic oxidation rate with apparent activation energies in the range of 90–140 kJ/mol, depending on the sodium content as well as the implant concentration. The oxides formed on the implanted samples are glassy and mostly free from surface flaws. The alteration of the oxidation kinetics and mechanism of Si3N4 in a sodium‐containing environment by aluminum implantation is a consequence of the effective modification of the properties of the sodium silicates through aluminum incorporation.
Improved Oxidation Resistance of Silicon Nitride by Aluminum Implantation: II, Analysis and Optimization
Authors: Cheong Yong S. , Mukundhan Priya , Du Henry H. , Withrow Stephen P.
Published: July 2008

In the preceding paper, it was shown that aluminum ion implantation significantly improves the oxidation resistance of Si3N4 ceramics under the influence of sodium. Not only is the oxidation rate reduced by up to an order of magnitude, the phase and morphological characteristics of the oxides grown on aluminum‐implanted samples are improved as well. The role of aluminum in negating the detrimental effect of sodium on the oxidation resistance of Si3N4 ceramics can be interpreted on the basis of network modification of the oxide layers by sodium and aluminum cations. The degree of improvement in the oxidation resistance does not, however, necessarily increase with the aluminum concentration. A simple quantitative analysis is presented which correlates the optimum aluminum implant concentration and the sodium content in the gas phase for the optimization of the oxidation resistance of Si3N4 ceramics.
Modeling the Ultimate Tensile Strength of Unidirectional Glass‐Matrix Composites
Authors: Dutton R. E. , Pagano N. J. , Kim R. Y. , Parthasarathy T. A.
Published: July 2008

The ultimate tensile strengths of a unidirectional glass‐matrix composite were measured as a function of fiber volume fraction. The results were compared with predictions, using a refined solution of the stress field generated by an axisymmetric damage model, which incorporated the effect of stress concentration in the fiber caused by the presence of a matrix crack both before and after deflection at the fiber/matrix interface. Two possible locations for the fiber failure were considered: (1) at a transverse matrix crack, near a bonded fiber/coating interface and (2) at the tip of a debond, at the fiber/coating interface. At low fiber volume fractions, the measured ultimate tensile strength matched the prediction calculated, assuming no crack deflection. For higher volume fractions, the predictions calculated for a debonded crack matched the observed values. The model results were relatively insensitive to debond length and interfacial shear stress for the range of values in this study. In comparison, the global load‐sharing model, which does not account for the stress singularity at the fiber/matrix interface, was found to overpredict the values of the ultimate tensile strength for all fiber volume fractions. An important contribution of the present work was to introduce the use of fiber volume fraction as a parameter for testing theoretical predictions of the mode of fiber failure.
Electrochemical Determination of the Gibbs Energy of Formation of Na2Fe2O4 and Na3Fe5O9 Employing Na‐β‐Al2O3 Solid Electrolyte
Authors: Kale Girish Madhav , Srikanth Srinivasan
Published: July 2008

The results of isothermal equilibration and X‐ray diffraction studies in Fe2O3‐rich compositions of the Na2Fe2O4–Fe2O3 pseudo‐binary system suggests the coexistence of an equilibrium between α‐Na2Fe2O4 and Fe2O3 at low temperatures (923–1023 K) and Na3Fe5O9 and α‐Fe2O3 at higher temperatures (>1023 K). The Gibbs energy of formation for the interoxide compounds Na2Fe2O4 and Na3Fe5O9 has been measured using solid‐state electrochemical cells that use Na‐β‐Al2O3 as the solid electrolyte. The electromotive force (emf) measurements are performed on cell I, which can be described as
image

and cell II, which can be described as
image

The temperature dependence of the steady‐state emf of cells I and II can be represented as
image

with a standard error of ±5 mV for each emf measurement. By combining the measured emf values of cells I and II with the activity of Na 2 O in α‐Al 2 O 3+ Na‐β‐Al 2 O 3 from the literature, the computed Gibbs energy of formation of Na 2 Fe 2 O 4 and Na 3 Fe 5 O 9 from solid Na 2 O and α‐Fe 2 O 3 can be expressed as
image
where the standard error is ±5500 J/mol for each ΔG° measurement. These uncertainty limits are due to the combined errors in the emf measurement and the thermodynamic data of the reference electrode material that have been used in the present study.
Modified Pressure‐Decay Technique for Evaluating the Permeability of Highly Dense Refractories
Authors: Innocentini Murilo D. M. , Pardo Arturo R. F. , Pandolfelli Victor C.
Published: July 2008

The experimental evaluation of permeability parameters encounters different difficulties, depending on the features of the materials. Traditional steady‐state techniques for refractory castables and other highly dense ceramics demand arduous work and require reliable measurements at high pressure and for extremely low flow rates. In this paper, a recent and promising technique known as vacuum‐decay permeametry is modified to consider the effect of gas compressibility and fluid inertia. Darcy's law is replaced by Forchheimer's equation, which has been proved to better represent the interactions between fluid and a castable porous medium. The modified method is modeled and applied experimentally to refractory samples with different permeability levels. Results that have been compared to a well‐established steady‐state permeametry method confirm the validity of the model.
Three‐Dimensional Analysis of Decorated Ceramic Fracture Surfaces by Automatic Stereophotogrammetry
Authors: Marschall Hans Ulrich , Danzer Robert , Pippan Reinhard
Published: July 2008

An improvement for the application of computer‐assisted stereophotogrammetry to ceramics is presented. To compensate for the lack of contrast in the fracture facets in scanning electron microscopy fractographs, a special decoration technique has been developed. The structure of the fracture facets is enhanced via heat treatment of a sputtered gold layer. This procedure enables the measurement of the three‐dimensional location of more than 10 000 points on the fracture surface by means of automatic stereophotogrammetry.
Nanosized Barium Titanate Powder by Mechanical Activation
Authors: Xue Junmin , Wang John , Wan Dongmei
Published: July 2008

Mechanical activation, without any additional heat treatment, is used to trigger the formation of a perovskite BaTiO3 phase in an oxide matrix that consists of BaO and TiO2 in a nitrogen atmosphere. The resulting BaTiO3 powder exhibits a well‐established nanocrystalline structure, as indicated by phase analysis using X‐ray diffractometry. A crystallite size of ∼14 nm is calculated, based on the half‐width of the BaTiO3 (110) peak, using the Scherrer equation, and an average particle size of 20–30 nm is observed using transmission electron microscopy for the activation‐derived BaTiO3 powder.
The Dentino‐enamel Junction is a Broad Transitional Zone Uniting Dissimilar Bioceramic Composites
Authors: White Shane N. , Paine Michael L. , Luo Wen , Sarikaya Mehmet , Fong Hanson , Yu Zhaokun , Li Zhen C. , Snead Malcolm L.
Published: July 2008

The dentino‐enamel junction (DEJ) couples a hard, brittle, stiff layer of enamel to underlying flexible and resilient dentin. Prior microscopic images have shown an abrupt demarcation between enamel and dentin; however, new data on protein expression suggests a graded transition. In this study, Vickers microindentations reveal a gradation in hardness with a wide transitional zone across the DEJ region. Therefore, the DEJ must be regarded as a broad transitional region between two interacting tissues, not as a discrete interface. This zone may reduce stress concentrations and act as an important toughening mechanism between mechanically and structurally dissimilar tissues.
Nasal administration of Lactococcus lactis improves local and systemic immune responses against Streptococcus pneumoniae
Authors: Medina Marcela , Villena Julio , Salva Susana , Vintiñi Elisa , Langella Philippe , Alvarez Susana
Published: July 2008

Lactococcus lactis NZ9000 is a non‐pathogenic non‐invasive bacterium extensively used for the delivery of antigens and cytokines at the mucosal level. However, there are no reports concerning the per se immunomodulatory capacity of this strain. The aim of the present study was to investigate the intrinsic immunostimulating properties of the nasal administration of L. lactis NZ9000 in a pneumococcal infection model. Mice were preventively treated with L. lactis (2, 5 or 7 days with 108 cells/day per mouse) and then challenged with Streptococcus pneumoniae. The local and the systemic immune responses were evaluated. Our results showed that nasal administration of L. lactis for 5 days (LLN5d) increased the clearance rate of S. pneumoniae from lung and prevented the dissemination of pneumococci into blood. This effect coincided with an upregulation of the innate and specific immune responses in both local and systemic compartments. LLN5d increased phagocyte activation in lung, blood and bone marrow, determined by NBT and peroxidase tests. Anti‐pneumococcal immunoglobulin (Ig)A in bronchoalveolar lavages (BAL) and IgG in BAL and serum were increased in the LLN5d group. Lung tissue injury was reduced by LLN5d treatment as revealed by histopathological examination and albumin concentration and lactate dehydrogenase activity in BAL. The adjuvant effect of L. lactis in our infection model would be an important advantage for its use as a delivery vehicle of pneumococcal proteins and nasal immunization with recombinant L. lactis emerges as an effective route of vaccination for both systemic and mucosal immunity against pneumococcal infection.
Methamphetamine‐related fatalities in Australia: demographics, circumstances, toxicology and major organ pathology
Authors: Kaye Sharlene , Darke Shane , Duflou Johan , McKetin Rebecca
Published: July 2008

Aim  To examine the demographic characteristics, circumstances of death, toxicological results and major organ pathology of methamphetamine‐related deaths in Australia.

Design  Retrospective review of coronial files.

Setting  Australia.

Methods  Cases in which methamphetamine was listed as a cause of death were identified from the National Coronial Information System (NCIS).

Findings  A total of 371 cases were identified. The mean age of decedents was 32.7 years; 77% were male and 35% were employed. Route of administration was predominantly by injection (89%). Drugs other than methamphetamine were detected in 89% of cases, most commonly benzodiazepines (41%) and morphine (36%). The median blood methamphetamine concentration was 0.2 mg/l (range 0.02–15.0 mg/l). Deaths were overwhelmingly accidental, with 14% determined to be suicides, and occurred in a private home (71%). Cardiovascular pathology, typically coronary artery atherosclerosis, was detected in 54% of decedents. Cerebrovascular pathology, most commonly cerebral haemorrhage and hypoxia, was present in 20% of cases.

Conclusions  Methamphetamine has contributed to a substantial number of deaths in Australia. Users need to be informed of the potential harms of methamphetamine use, particularly those associated with the cardiotoxicity of methamphetamine and the use of methamphetamine in conjunction with other drugs.
Sleep architecture, cocaine and visual learning
Authors: Morgan Peter T. , Pace‐Schott Edward F. , Sahul Zakir H. , Coric Vladimir , Stickgold Robert , Malison Robert T.
Published: July 2008

Background  Disturbances in sleep associated with chronic cocaine use may underlie abstinence‐related cognitive dysfunction. We hypothesized that sleep‐related cognitive function would be impaired in chronic cocaine users, and that this impairment would be associated with abstinence‐related changes in sleep architecture.

Methods  Twelve chronic cocaine users completed a 23‐day in‐patient study that included randomized, placebo‐controlled, cocaine self‐administration sessions. We report polysomnographic measurement of rapid eye‐movement (REM) sleep and slow‐wave activity, and performance on a visual texture discrimination task.

Findings  Progressive abstinence from cocaine was associated with characteristic changes in REM sleep. REM sleep was shortest on nights following cocaine use and rebounded in the first week of abstinence before diminishing with progressive abstinence, following a pattern opposite that of slow‐wave activity. Overnight visual learning was observed over the first night following 3 consecutive days of laboratory cocaine use; however, learning was not observed at 3 days or 17 days of abstinence. Across all points of abstinence, early‐night slow‐wave activity was associated strongly with non‐deterioration of visual performance overnight. Furthermore, overnight enhancement of visual performance was predicted by the co‐occurrence of sufficient early‐night slow‐wave activity and late night REM sleep, similar to results from studies in healthy subjects.

Conclusions  These results suggest that abstinence‐associated sleep‐dependent learning deficits are related to characteristic changes in sleep architecture, and promote the idea that treatments directed at sleep (‘somno‐tropic’ treatments) could be helpful in offsetting physiological consequences of cocaine abstinence.
Stress, social support and problem drinking among women in poverty
Authors: Mulia Nina , Schmidt Laura , Bond Jason , Jacobs Laurie , Korcha Rachael
Published: July 2008

Aims Previous studies have found that stress contributes to problem drinking, while social support can buffer its effects. However, these studies are confined largely to middle‐class and general populations. We extend what is known by examining how the unique stressors and forms of social support experienced by women in poverty impact alcohol problems over a 4‐year time‐period.

Design, setting and participants This prospective study used generalized estimating equations (GEE) transition modeling and four annual waves of survey data from 392 American mothers receiving Temporary Assistance for Needy Families (TANF) in a large Northern California county.

Measurements We examined the effects of neighborhood disorder, stressful life events and economic hardship on psychological distress and problem drinking over time, and whether social support moderated these relationships for women in poverty.

Findings Neighborhood disorder and stressful life events increased significantly the risk for problem drinking, largely through their effect on psychological distress. We found little evidence, however, that social support buffers poor women from the effects of these stressors.

Conclusions Women in poverty are exposed to severe, chronic stressors within their communities and immediate social networks which increase vulnerability to psychological distress and problem drinking. The finding that social support does not buffer stress among these women may reflect their high level of exposure to stressors, as well as the hardships and scarce resources within their networks. If the ‘private safety net’ of the social network fails to provide a strong buffer, more effective environmental interventions that reduce exposure to stressors may be needed to prevent alcohol problems in poor women's lives.
Genetic and environmental contributions to nicotine, alcohol and cannabis dependence in male twins
Authors: Xian Hong , Scherrer Jeffrey F. , Grant Julia D. , Eisen Seth A. , True William R. , Jacob Theodore , Bucholz Kathleen K.
Published: July 2008

Aims  To compute the common and specific genetic and environmental contributions to nicotine dependence (ND) alcohol dependence (AD) and cannabis dependence (CD).

Design  Twin model.

Participants  Data from 1874 monozygotic and 1498 dizygotic twin pair members of the Vietnam Era Twin Registry were obtained via telephone administration of a structured psychiatric interview in 1992.

Measurements  Data to derive life‐time diagnoses of DSM‐III‐R ND, AD and CD were obtained via telephone administration of the Diagnostic Interview Schedule.

Findings  The best‐fitting model allowed for additive genetic contributions and unique environmental influences that were common to all three phenotypes. Risks for ND and AD were also due to genetic and unique environmental influences specific to each drug. A specific shared environmental factor contributed to CD.

Conclusions  These results suggest that the life‐time co‐occurrence of ND, AD and CD is due to common and specific genetic factors as well as unique environmental influences, and vulnerability for CD is also due to shared environmental factors that do not contribute to ND and AD. The majority of genetic variance is shared across drugs and the majority of unique environmental influences are drug‐specific in these middle‐aged men. Because differences between models allowing for specific genetic versus shared environment were small, we are most confident in concluding that there are specific familial contributions—either additive genetic or shared environment—to CD.
Precipitated withdrawal during maintenance opioid blockade with extended release naltrexone
Authors: Fishman Marc
Published: July 2008

Background There has been increasing interest in the use of extended release injectable naltrexone for the treatment of opioid dependence.

Case description We report a case of precipitated withdrawal in a 17‐year‐old adolescent female receiving extended release naltrexone (Vivitrol) for opioid dependence, following her third serial monthly dose of the medication, several days after using oxycodone with mild intoxication.

Conclusions This case suggests that, in some circumstances, the opioid blockade may be overcome when naltrexone levels drop towards the end of the dosing interval, producing vulnerability to subsequent naltrexone‐induced withdrawal. This may provide cautionary guidance for clinical management and dosing strategies.
Guidelines for research on drugged driving
Authors: Walsh J. Michael , Verstraete Alain G. , Huestis Marilyn A. , Mørland Jørg
Published: July 2008

Aim  A major problem in assessing the true public health impact of drug‐use on driving and overall traffic safety is that the variables being measured across studies vary significantly. In studies reported in a growing global literature, basic parameters assessed, analytical techniques and drugs tested are simply not comparable due to lack of standardization in the field. These shortcomings severely limit the value of this research to add knowledge to the field. A set of standards to harmonize research findings is sorely needed. This project was initiated by several international organizations to develop guidelines for research on drugged driving.

Methods  A September 2006 meeting of international experts discussed the harmonization of protocols for future research on drugged driving. The principal objective of the meeting was to develop a consensus report setting guidelines, standards, core data variables and other controls that would form the basis for future international research. A modified Delphi method was utilized to develop draft guidelines. Subsequently, these draft guidelines were posted on the internet for global review, and comments received were integrated into the final document.

Results  The Guidelines Document is divided into three major sections, each focusing upon different aspects of drugged driving research (e.g. roadside surveys, prevalence studies, hospital studies, fatality and crash investigations, etc.) within the critical issue areas of ‘behavior’, ‘epidemiology’ and ‘toxicology’. The behavioral section contains 32 specific recommendations; (2) epidemiology 40 recommendations; and (3) toxicology 64 recommendations.

Conclusions  It is anticipated that these guidelines will improve significantly the overall quality of drugged driving research and facilitate future cross‐study comparisons nationally and globally.
Joint meeting with the British Pharmacological Society and the Pharmacological and Clinical Pharmacological Societies of Canada, University of Bath, Symposium on Pharmacogenetics, 12 July 1996
Authors: & ROBERT RANGNO , BENNETT PETER
Published: July 2008

The symposium was presented by speakers from both Canada and the United Kingdom. It was fitting that Werner Kalow, who has been so active in the field for nearly 40 years, should give a historical perspective and indicate future directions for the subject. Important among the latter is the growing contribution of pharmacogenetics to clarifying susceptibility to certain disease states. This was illustrated by Maria Arranz in respect of drug response to schizophrenia, Denise Tompkins in a discussion of drug dependence and Ann Daly in connection with lung cancer. Denis Grant reviewed the pharmacogenetics of N‐acetylation and indicated the susceptibility of certain allelic variants to cancer, notably of the urinary bladder. Nigel Baber described the implications that variation in drug metabolism has for selecting candidate compounds to develop into therapeutic drugs. Abstracts of the lectures follow.
Population pharmacokinetics of proguanil in patients with acute P. falciparum malaria after combined therapy with atovaquone
Authors: HUSSEIN Z. , EAVES C. J. , & D. B. HUTCHINSON , CANFIELD C. J.
Published: July 2008

1 The pharmacokinetics of proguanil were evaluated in patients with acute P. falciparum malaria receiving concomitantly proguanil hydrochloride and atovaquone. The population consisted of 203 Blacks, 112 Orientals and 55 Malays; 274 males and 96 females. Of the 370 patients, 114 and 256 patients were classified as‘poor’and‘extensive’metabolizers of proguanil, respectively. Body weight and age ranged between 11‐110 kg and 3‐65 years, respectively.

2 A one compartment model with first‐order absorption and elimination was fitted to proguanil plasma concentration‐time profiles, using non‐linear mixed effect modelling (NONMEM).

3 Oral clearance (CLo) showed a 0.785 power relationship with body weight and was 13% higher in Orientals than Blacks and Malays and 17% lower in‘poor’than‘extensive’metabolizers. According to the mean weight of each population, the final population estimates of CLo in Blacks, Orientals and Malays who are‘extensive’metabolizers were 54.0, 61.5 and 64.31 h‐1, respectively. Age, gender and dose had no significant effects on CLo.

4 Apparent volume of distribution (V/F) showed a 0.88 power relationship with body weight. The final population estimates were 562 and 16291 in children (± 15 years) and patients aged > 15 years, respectively, who had a mean body weight of 22.6 and 54.8 kg, respectively. The effect of other covariates on V/F was not examined.

5 The final magnitudes of interpatient variability in CLo and V/F were relatively low at 22.5 and 17.0%, respectively.

6 Population pharmacokinetic parameter estimates in Black, Oriental and Malay patients with acute P. falcipraum malaria are in good agreement with results of pharmacokinetic studies in healthy Caucasian volunteers. In view of the 30‐50% residual variability in proguanil plasma concentrations, the slight effects of Orientals and‘poor’metabolizers on CLo are unlikely to be clinically significant. Hence, dose recommendation will be solely based on body weight.
Comparative bioavailability of oral, rectal, and intramuscular artemether in healthy subjects: use of simultaneous measurement by high performance liquid chromatography and bioassay
Authors: TEJA‐ISAVADHARM P. , NOSTEN F. , KYLE D. E. , LUXEMBURGER C. , TER KUILE F. , PEGGINS J. O. , BREWER T. G. , WHITE N. J.
Published: July 2008

1 The pharmacokinetic and effect kinetic properties of oral (p.o.), intramuscular (i.m.), and intrarectal (i.r.) artemether (5 mg kg‐1) were compared in a crossover study in eight healthy adult volunteers. Plasma concentrations of artemether (AM) and its active metabolite dihydroartemisinin (DHA) were measured by high performance liquid chromatography with reductive mode electrochemical detection (h.p.l.c.‐ECD), and plasma antimalarial activity in vitro (effect) was assessed on the same samples by a sensitive bioassay (BA).

2 Artemether was absorbed rapidly after oral administration with a mean (95% CI) Cmax for the parent compound of 406 (249 to 561) nmol l‐1 and for DHA of 1009 (639 to 1379) nmol l‐1 with tmax values of 1.7 (1.2 to 2.2) and 1.8 (1.4 to 2.2) h respectively. The mean (95% CI) elimination half‐life of AM was 2.6 (1.8 to 3.4) h and for DHA was 1.9 (1.4 to 2.4) h. Plasma concentration and effect profiles with h.p.l.c.‐ECD and BA were similar suggesting that other unidentified bioactive metabolites contributed little to antimalarial activity in vivo.

3 Absorption was slower, more variable, and DHA concentrations were lower following the i.m. and i.r. routes of administration. The mean (95% CI) relative bioavailability compared with oral artemether in the 6 h following administration AUC(0,6h) was 25 (9 to 41)% following i.m. and 35 (10 to 60)% following i.r. artemether.

4 These data demonstrate that oral artemether undergoes extensive first pass metabolism to the more active metabolite DHA. Plasma antimalarial activity following oral administration is significantly greater than following i.m. administration. The i.r. route of administration provided similar bioavailability to i.m. injection but there was considerable variability in absorption following both routes. Further studies are needed to determine whether i.r. artemether would be an effective treatment of severe malaria in the rural tropics in situations where oral or parenteral administration is not possible.
Pharmacokinetics and haemodynamic effects of the angiotensin converting enzyme inhibitor cilazapril in hypertensive patients with normal and impaired renal function
Authors: KLOKE H. J. , AMBROS R. J. , VAN HAMERSVELT H. W. , WETZELS J. F. M. , & R. A. P. KOENE , HUYSMANS F. T. M.
Published: July 2008

1 The pharmacokinetic and pharmacodynamic properties of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 30 hypertensive patients with various degrees of renal function.

2 After a single oral dose, apparent cilazaprilat clearance was dependent on renal function being 16.0±3.0, 11.1 ± 3.0, 8.7 ± 3.7 and 6.7 ± 2.1 l h‐1 (means ± s.d.) in patients with creatinine clearances (CLcr) of > 100, 41‐100, 21‐40, and 8‐20 ml min‐1, respectively.

3 During 11 weeks of treatment with cilazapril, doses were adjusted to the CLcr and varied from 0.5 to 5.0 mg once daily. At 24 h after drug administration a clear antihypertensive response was seen only in the low clearance groups (CLcr < 40ml min‐1). In contrast, and despite higher once daily dosages, the decline of mean arterial pressure was small and cilazaprilat concentrations after 24 h were lower in the high clearance groups.

4 This study demonstrates that chronic once daily treatment with cilazapril is effective in patients with impaired renal function at dosages adjusted to creatinine clearance. No accumulation was seen. Since cilazaprilat clearance was high in the high creatinine clearance groups, a clear antihypertensive response in these groups was only seen at 3 h after drug administration.
A reply:
Authors: DRAKE J. , & C.E. HORTH , CRAWFORD F.E.
Published: July 2008

Oramorph SR (OSR) meets design specification criteria similar to those of MST Continus (MST); both are modified‐release tablets with similar in vitro dissolution rates. Our study [1] like that sponsored by Napp Laboratories (Houston & Yeang [2]) compared these two, essentially similar formulations in healthy subjects under fasting and fed conditions. In dispute is the interpretation of what are probably two similar data sets. Houston & Yeang made conclusions about the quality and reliability of OSR based selectively on the Cmax data. Their analysis made no direct statistical comparison between the two formulations and no plasma morphine vs time profile was published. Our study was carried out to provide data for what we consider to be a more in‐depth analysis.
Interobserver variation in the classification of thymic tumours – a multicentre study using the WHO classification system
Authors: Verghese E T , Den Bakker M A , Campbell A , Hussein A , Nicholson A G , Rice A , Corrin B , Rassl D , Langman G , Monaghan H , Gosney J , Seet J , Kerr K , Suvarna S K , Burke M , Bishop P , Pomplun S , Willemsen S , Addis B
Published: July 2008

Aims:  To test the reproducibility of the current World Health Organization (WHO) classification of thymic epithelial tumours and to determine the level of interobserver variation within a group of pathologists, all with experience and expertise in thoracic pathology.

Methods and results:  Ninety‐five thymic tumours were circulated to a group of 17 pathologists in the UK and The Netherlands over a 1‐year period. Participants were asked to classify them according to WHO criteria. The diagnoses were subjected to statistical analysis and κ values calculated. The overall level of agreement was moderate (κ 0.45). When the categories were reduced in number by creating two groups, (A + AB + B1 + B2 and B3 + C), the level of agreement increased to 0.62. An alternative grouping (A + AB + B1 and B2 + B3 + C) increased it slightly further. The best agreement was in tumour types A and AB. Difficulties arose in distinguishing B1 tumours from B2 tumours and B2 tumours from B3 tumours.

Conclusions:  Although the WHO system describes a number of well‐defined tumour types with clear diagnostic criteria, the overall level of agreement was moderate and improved if some groups were amalgamated.
Handling and reporting of radical prostatectomy specimens in Europe: a web‐based survey by the European Network of Uropathology (ENUP)
Authors: Egevad L , Algaba F , Berney D M , Boccon‐Gibod L , Griffiths D F , Lopez‐Beltran A , Mikuz G , Varma M , Montironi R
Published: July 2008

Aims:  To survey current European practices in handling and reporting of radical prostatectomy (RP) specimens.

Methods and results:  A European Network of Uropathology (ENUP) was organized for the dissemination of information, survey studies and research collaborations. Contact data of uropathologists were collected from 321 pathology laboratories in 15 West European countries. In the first ENUP survey, 67.6% (217/321) of the members replied to a web‐based questionnaire. Some practices were adopted by a large majority, e.g. inking of the specimen (96.6%), Gleason grading (99.5%), stratifying extraprostatic extension (EPE) according to extent (88.2%), reporting TNM stage (88.6%) and reporting location of positive margins (98%). As many as 71.6% of respondents always embedded the entire prostate and only 10.8% always practised partial embedding. Whole mounts were routinely used by 37.5% and standard blocks by 55.5%. Among areas with variable routines were methods to define focal versus extensive EPE and methods to quantify margin positivity, probably reflecting that the optimal method has yet to be determined.

Conclusions:  Some practices are almost universally adopted in Europe, whereas others still need to be standardized. The results of the study may be helpful when judging what recommendations are reasonable to issue.
Phosphate‐rich deposits associated with the Mio‐Pliocene unconformity in south‐east Australia
Authors: DICKINSON JULIE A. , WALLACE MALCOLM W.
Published: July 2008

Phosphates are present on the surface of the Mio‐Pliocene unconformity in the Otway, Port Phillip and Gippsland basins of south‐east Australia. The phosphates occur as lenticular lag deposits and include reworked phosphatic intraclasts, vertebrate bone and teeth. In situ phosphatized burrows are also found in sediments of Late Miocene and Early Pliocene age. The phosphatic intraclasts on the unconformity are interpreted as reworked phosphatized burrows derived from latest Miocene sediments (6 to 5 Ma). The phosphatization of these intraclasts is temporally related to the unconformity. The timing of phosphogenesis coincides with a period of transgression across the south‐east Australian margin following Late Miocene uplift. This transgression is responsible for initial marine erosion of the underlying Miocene sequence, creation of a period of very slow sedimentation that was favourable to phosphate formation and subsequent deposition of the latest Miocene through to Pliocene sediments. The continental weathering of the uplifted highlands adjacent to the sedimentary basins, global phosphorus enrichment in the Late Miocene oceans and localized upwelling may all have contributed to phosphatization in south‐eastern Australia.
RING1 E3 ligase localizes to plasma membrane lipid rafts to trigger FB1‐induced programmed cell death in Arabidopsis
Authors: Lin Shih‐Shun , Martin Raquel , Mongrand Sebastien , Vandenabeele Steven , Chen Kuan‐Chun , Jang In‐Cheol , Chua Nam‐Hai
Published: July 2008

Ubiquitination plays important roles in plant development, including programmed cell death. Here, we characterize a novel membrane‐bound RING motif protein, encoded by RING1, that is expressed at a low level in all Arabidopsis tissues but can be upregulated by fumonisin B1 (FB1) treatment and pathogen infection. RING1 displays E3 ubiquitin ligase activity in vitro, which is dependent on the integrity of the RING motif. GFP fusion protein localization and cell fractionation experiments show that this E3 ligase is associated with the lipid rafts of plasma membranes. Knock‐down of RING1 transcripts using artificial microRNA (amiR‐R1159) leads to FB1 hyposensitivity, but overexpression of RING1 confers hypersensitivity. Additionally, expression of the pathogenesis‐related 1 (PR‐1) gene is lower and delayed in amiR‐R1159 plants compared with wild‐type and RING1‐overexpressing plants. The FB1 hyposensitivity of amiR‐R1159 plants can be rescued by expression of cleavage‐resistant RING1mut transcripts. Our results suggest that RING1 acts as a signal from the plasma membrane lipid rafts to trigger the FB1‐induced plant programmed cell death pathway.
High‐resolution chromosome mapping of BACs using multi‐colour FISH and pooled‐BAC FISH as a backbone for sequencing tomato chromosome 6
Authors: Szinay Dóra , Chang Song‐Bin , Khrustaleva Ludmila , Peters Sander , Schijlen Elio , Bai Yuling , Stiekema Willem J. , Van Ham Roeland C.H.J. , De Jong Hans , Klein Lankhorst René M.
Published: July 2008

Within the framework of the International Solanaceae Genome Project, the genome of tomato (Solanum lycopersicum) is currently being sequenced. We follow a ‘BAC‐by‐BAC’ approach that aims to deliver high‐quality sequences of the euchromatin part of the tomato genome. BACs are selected from various libraries of the tomato genome on the basis of markers from the F2.2000 linkage map. Prior to sequencing, we validated the precise physical location of the selected BACs on the chromosomes by five‐colour high‐resolution fluorescent in situ hybridization (FISH) mapping. This paper describes the strategies and results of cytogenetic mapping for chromosome 6 using 75 seed BACs for FISH on pachytene complements. The cytogenetic map obtained showed discrepancies between the actual chromosomal positions of these BACs and their markers on the linkage group. These discrepancies were most notable in the pericentromere heterochromatin, thus confirming previously described suppression of cross‐over recombination in that region. In a so called pooled‐BAC FISH, we hybridized all seed BACs simultaneously and found a few large gaps in the euchromatin parts of the long arm that are still devoid of seed BACs and are too large for coverage by expanding BAC contigs. Combining FISH with pooled BACs and newly recruited seed BACs will thus aid in efficient targeting of novel seed BACs into these areas. Finally, we established the occurrence of repetitive DNA in heterochromatin/euchromatin borders by combining BAC FISH with hybridization of a labelled repetitive DNA fraction (Cot‐100). This strategy provides an excellent means to establish the borders between euchromatin and heterochromatin in this chromosome.
Mechanism of plant eIF4E‐mediated resistance against a Carmovirus (Tombusviridae): cap‐independent translation of a viral RNA controlled in cis by an (a)virulence determinant
Authors: Truniger Verónica , Nieto Cristina , González‐Ibeas Daniel , Aranda Miguel
Published: July 2008

Translation initiation factors are universal determinants of plant susceptibility to RNA viruses, but the underlying mechanisms are poorly understood. Here, we show that a sequence in the 3′ untranslated region (3′‐UTR) of a viral genome that is responsible for overcoming plant eIF4E‐mediated resistance (virulence determinant) functions as a 3′ cap‐independent translational enhancer (3′‐CITE). The virus/plant pair studied here is Melon necrotic spot virus (MNSV) and melon, for which a recessive resistance controlled by melon eIF4E was previously described. Chimeric viruses between virulent and avirulent isolates enabled us to map the virulence and avirulence determinants to 49 and 26 nucleotides, respectively. The translational efficiency of a luc reporter gene flanked by 5′‐ and 3′‐UTRs from virulent, avirulent and chimeric viruses was analysed in vitro, in wheatgerm extract, and in vivo, in melon protoplasts, showing that: (i) the virulence determinant mediates the efficient cap‐independent translation in vitro and in vivo; (ii) the avirulence determinant was able to promote efficient cap‐independent translation in vitro, but only when eIF4E from susceptible melon was added in trans, and, coherently, only in protoplasts of susceptible melon, but not in the protoplasts of resistant melon; (iii) these activities required the 5′‐UTR of MNSV in cis. Thus, the virulence and avirulence determinants function as 3′‐CITEs. The activity of these 3′‐CITEs was host specific, suggesting that an inefficient interaction between the viral 3′‐CITE of the avirulent isolate and eIF4E of resistant melon impedes the correct formation of the translation initiation complex at the viral RNA ends, thereby leading to resistance.
Possible donor–recipient bartonellosis transmission in a pediatric liver transplant
Authors: Scolfaro C. , Mignone F. , Gennari F. , Alfarano A. , Veltri A. , Romagnoli R. , Salizzoni M.
Published: July 2008

Abstract: Bartonella henselae is the causative agent of cat‐scratch disease and other disorders, including hepatosplenic granulomatosis. This infection has only rarely been reported after solid organ transplantation, where it can mimic the more common post‐transplant lymphoproliferative disease. Here we present a case of asymptomatic B. henselae hepatic and lymph nodal granulomatosis in a pediatric patient who had received orthotopic liver transplant 2 months before; we hypothesize that the causative agent was transmitted from the donor. This infection developed early in the post‐transplant period; the disease involved only the graft liver and the regional lymph nodes, and the patient did not have a cat or any history of contact, scratches, or bites by a cat. In our patient this infection resolved successfully with a combination of 2 associated antibiotics and reduction of immunosuppressive therapy.
The characterization and impact of microparticles on haemostasis within fresh‐frozen plasma
Authors: Lawrie A. S. , Harrison P. , Cardigan R. A. , Mackie I. J.
Published: July 2008

Background  We have previously demonstrated that clot formation in fresh‐frozen plasma (FFP) is influenced by the presence of microparticles (MP). In this study, the cellular source(s), properties and influence of MPs on clot formation within FFP were further characterized.

Methods  Fresh‐frozen plasma was prepared after an overnight hold of whole blood at 4°C. We examined the effect of a 0·2 µm filtration device designed to remove cellular MPs on thrombin generation test (TGT) and Thrombelastography (TEG®) as well as clotting factors and physiological inhibitors: prothrombin time (PT); activated partial thromboplastin time (APTT), fibrinogen (Fg), factor VIII (FVIII), von Willebrand factor antigen (VWF:Ag), antithrombin III (AT‐III) and protein C (PC). MPs were measured using a functional assay and also by flow cytometry.

Results  Microparticle levels by functional assay were reduced by filtration (pre‐ 5·11 vs. post‐ 4·43 nmol/l phosphatidylserine equivalent, P < 0·0001). Flow cytometry showed that the most numerous MPs were derived from red blood cells, with ~87% binding annexin V, most of which (94%) were removed by filtration. MP removal had minimal effect on the PT, APTT, Fg, VWF:Ag, AT‐III or PC or FVIII, but a major effect on TGT (endogenous thrombin potential: pre‐ 1722 vs. post‐ 990 nM thrombin, P < 0·0001; peak thrombin: pre‐ 91 vs. post‐ 44 nM thrombin, P < 0·0001), which in turn reflected the changes seen in TEG®, where post‐filtration clots started forming more slowly and the rate of clot formation was reduced.

Conclusion  These data suggest that MPs contribute towards clot formation in FFP.
Pharmacological approaches to preventing vascular access failure
Authors: Polkinghorne Kevan
Published: July 2008

Date written: December 2006

Final submission: March 2008
Diversification of unicellular eukaryotes: cryptomonad colonizations of marine and fresh waters inferred from revised 18S rRNA phylogeny
Authors: Shalchian‐Tabrizi Kamran , Bråte Jon , Logares Ramiro , Klaveness Dag , Berney Cédric , Jakobsen Kjetill S.
Published: July 2008

The cryptomonads is a well‐defined lineage of unicellular eukaryotes, composed of several marine and freshwater groups. However, the evolutionary relationships among these groups are unclear due to conflicting inferences between morphological and molecular phylogenies. Here, we have inferred the evolutionary relationships among marine and freshwater species in order to better understand the importance of the marine–freshwater boundary on the historical diversification patterns of cryptomonads. We have constructed improved molecular phylogenies by taking into account rate variation both across sites and across sequences (covarion substitutions), and by analysing the vast majority of publicly available cryptomonad 18S rRNA sequences and related environmental phylotypes. The resulting phylogenies included 55 sequences, and revealed two novel freshwater cryptomonad clades (CRY1 and CRY2) and a large hidden diversity of cryptomonads. CRY1 was placed deeply within the cryptomonad phylogeny together with all the major freshwater lineages (i.e.GoniomonasandCryptomonas), while CRY2 was placed within a lineage of marine species identified asPlagioselmis‐like with the aid of a new sequence generated from a cultured species. The inferred phylogenies suggest only few successful marine–freshwater transitions over the history of cryptomonads. Most of the transitions seem to have occurred from marine to fresh waters, but re‐colonizations of marine habitats have also taken place. This implies that the differences in the biogeophysical conditions between marine and fresh waters constitute a substantial barrier for the cross‐colonization of these environments by cryptomonads.