bluuebunny/crossref_metadata_2025 huggingface dataset:
Selection and Characterization of Cyclic Peptides that Bind to a Monoclonal Antibody Against Meningococcal L3,7,9 lipopolysaccharides
Authors: Lauvrak V. , Berntzen G. , Heggelund U. , Herstad T. K. , Sandin R. H. , Dalseg R. , Rosenqvist E. , Sandlie I. , Michaelsen T. E.
Published: March 2004

There is still no general vaccine for prevention of disease caused by group‐B meningococcal strains. Meningococcal lipopolysaccharides (LPSs) have received attention as potential vaccine candidates, but concerns regarding their safety have been raised. Peptide mimics of LPS epitopes may represent safe alternatives to immunization with LPS. The monoclonal antibody (MoAb) 9‐2‐L3,7,9 [1] specific for Neisseria meningitidis LPS immunotype L3,7,9 is bactericidal and does not cross‐react with human tissue. To explore the possibility of isolating peptide mimics of the epitope recognized by MoAb 9‐2‐L3,7,9, we have constructed two phage display libraries of six and nine random amino acids flanked by cysteines. Furthermore, we developed a system for the easy exchange of peptide‐encoding sequences from the phage‐display system to a hepatitis B core (HBc) expression system. Cyclic peptides that specifically bound MoAb 9‐2‐L3,7,9 at a site overlapping with the LPS‐binding site were selected from both libraries. Three out of four tested peptides which reacted with MoAb 9‐2‐L3,7,9 were successfully presented as fusions to the immunodominant loop of HBc particles expressed in Escherichia coli. However, both peptide conjugates to keyhole limpet haemocyanin and HBc particle fusions failed to give an anti‐LPS response in mice.
EFFECTS OF MORPHINE ON METHOTREXATE DISPOSITION IN MICE
Authors: Li Yuai , Looney Greg A , Hurwitz Aryeh
Published: March 2004

1. Morphine has been shown to slow the renal excretion of other drugs. The present study in mice evaluated the effects of morphine on the disposition of methotrexate (MTX), an antimetabolite eliminated by the kidneys.

2. Mice were injected with morphine (20 mg/kg) or saline s.c. After 30 min, 20–80 mg/kg MTX was injected i.v. Blood and urine samples were assayed for MTX by HPLC.

3. Morphine reduced plasma clearance (CL) of MTX from 0.147 ± 0.015 to 0.061 ± 0.009 mL/min per g bodyweight (P < 0.01). The area under the plasma concentration–time curve (AUC0–∞) was raised by morphine from 151 ± 18 to 369 ± 36 µg·mL per min (P < 0.01). Without morphine administration, 22–27% of an MTX dose was excreted into the urine in 30 min. The corresponding fractions excreted into the urine after morphine were reduced to 15–18% (P < 0.01).

4. Plasma levels of MTX administered intravenously to mice are elevated by the concomitant administration of morphine, which reduces renal elimination of MTX.
NITRIC OXIDE DOES NOT MEDIATE PROMOTION OF CELLULAR POTASSIUM RELEASE BY PHENOLPHTHALEIN IN COS‐7 CELLS
Authors: Mason Robert W , Hopp Laszlo , Lloyd John B
Published: March 2004

1. It has been proposed that phenolphthalein exerts its laxative effect via an intracellular cascade that begins with the activation of nitric oxide synthase (NOS) and ends with an inhibition of NaCl and water reabsorption from the colon. Phenolphthalein also promotes the release of potassium from cells, but it is not known how this is related to its effect on sodium and water uptake.

2. An established in vitro system was used to examine the role of nitric oxide (NO) in phenolphthalein‐induced release of 86Rb+ from COS‐7 cells.

3. Sodium nitroprusside, an NOS‐independent NO source, was unable to mimic the effects of phenolphthalein and NG‐nitro‐l‐arginine methyl ester, an NOS inhibitor, was unable to block the effect of phenolphthalein.

4. It is concluded that NO generation is not required for phenolphthalein‐stimulated potassium release. It is proposed that the effect of phenolphthalein on cellular potassium release is mechanistically distinct from the effect on NaCl and water uptake by colonocytes.
Successive replacement of tending ant species at aggregations of scale insects (Hemiptera: Margarodidae and Eriococcidae) onEucalyptusin south‐east Queensland
Authors: Eastwood Rod
Published: March 2004

Abstract Scale insects generally display enhanced survival rates in the presence of tending ants, but studies of ant and scale–insect interactions typically examine a single tending ant species. This study investigated the successive changes in tending ant species during the lifespan of two species of scale aggregations, a monophlebuline margarodid and anEriococcussp. (Eriococcidae) on the Plunkett mallee,Eucalyptus curtisii. Scale aggregations were also subject to an ant‐exclusion experiment to quantify the degree to which ants increased the survival rates of both scale insect species. Tending ants assorted to two categories, dominant and secondary, with a significant bias according to the chronological age of the scale aggregation. Secondary ant species (opportunists and subordinates) tended juvenile‐scale aggregations. These were replaced by a dominant species ofIridomyrmex(Dolichoderinae), which almost exclusively tended larger (mature) aggregations until the senescent stages of the infestation when secondary ant species returned. Exclusion of the primary tendingIridomyrmexant increased mortality of both species of scale insects by 96% relative to controls.
Comparative nesting biology of two species of Australian lithocolous ants: Polyrhachis (Hedomyrma) turneri Forel and P. (Hagiomyrma) thusnelda Forel (Hymenoptera: Formicidae: Formicinae)
Authors: Robson Simon KA
Published: March 2004

Abstract  The nests of both Polyrhachis (Hagiomyrma) thusnelda and P. (Hedomyrma) turneri are restricted to the sides of rock walls (lithocoly), but, despite the similar nesting localities, the nests differ in the types of construction material used. The walls of nests of P. thusnelda are constructed of carton material without any silk, while those of P. turneri are comprised of a thick and diffuse mass of fluffy silk with very little carton. However, unlike other species of Polyrhachis that live in silk nests, the silk material in nests of P. turneri is produced entirely by spiders and not their own larvae. Scanning electron microscopy indicated that the silk strands found in natural P. turneri nests resembled those of nearby spider egg sacs rather than the strands found in the cocoons of their own larvae, and captive brood‐right colonies of P. turneri failed to produce silk nests in the absence of an external silk source. These results: confirm the existence of an additional nesting habit within the genus, lithocoly; suggest there are at least two ways by which lithocolous nesting habits can evolve, carton vs. silk; and indicate that the presence of silk within a nest need not imply that ant larvae are the source. Studies of the distribution and evolution of nest‐weaving within the genus Polyrhachis may need to be reassessed, now that the presence of silk nests could actually represent the origin of two independent behavioural traits (silk from larvae vs. silk from external sources such as spiders).
Impact of low release rates of the assassin bug Pristhesancus plagipennis (Walker) (Hemiptera: Reduviidae) on Helicoverpa spp. (Lepidoptera: Noctuidae) and Creontiades spp. (Hemiptera: Miridae) in cotton
Authors: Grundy Paul R
Published: March 2004

Abstract  A challenge with the inundative release of beneficial insects in pest management programs is to achieve a viable balance between predator release rates and biological control efficacy. This paper examines postrelease survival and biological control efficacy of the assassin bug, Pristhesancus plagipennis (Walker) released in cotton at rates of 1.0, 0.75, 0.5 and 0.25 nymphs per metre crop row. These releases resulted in >72% survival of nymphs with respective field populations of 0.75, 0.54, 0.41 and 0.25 nymphs m−1 4 weeks postrelease. Each of the P. plagipennis nymph release treatments gave significant reductions in Helicoverpa spp. larval densities, whilst only the higher nymph release rates of 1.0 and 0.75 m−1 decreased densities of mirids, Creontiades spp. The data suggest that release rates of P. plagipennis at or below 1.0 nymph m−1 aid postrelease survival and provide significant reductions in numbers of some cotton pest insects.
Mass rearing of two larval parasitoids of Helicoverpa spp. (Lepidoptera: Noctuidae): Netelia producta (Brullé) and Heteropelma scaposum (Morley) (Hymenoptera: Ichneumonidae) for field release
Authors: Johns Caitlin V , Whitehouse Mary E A
Published: March 2004

Abstract  Parasitoids are becoming an increasingly important part of our biological arsenal in Integrated Pest Management strategies against major insect pests like Helicoverpa armigera (Hübner). Inundative or supplementary releases of parasitoids have been successfully used in the past to help manage insect pests in the field. This paper reports attempts to mass rear two larval parasitoids of Helicoverpa spp., Heteropelma scaposum and Netelia producta. The results suggest that N. producta is the easier species to culture, although the parasitism rates for either wasp species were not high (29% for N. producta and 19% for H. scaposum). The authors suggest ways in which the parasitism rates could be increased and culturing made easier. It was found that culturing H. scaposum resulted in a male‐biased sex ratio that was less suitable for mass release. Possible reasons for the bias are discussed, including single‐locus complementary sex determination (CSD) that can result in a high proportion of homozygotic diploid males occurring in inbred populations. Although single‐locus CSD is a plausible explanation for the male biased sex ratio, the authors caution that more work is needed to confirm that it can occur in H. scaposum.
Hemielissum evansi, a new genus and species of Breddiniolini (Hemiptera: Fulgoromorpha), being the first Australian record of the tribe, with a discussion of the taxonomic position of the Breddiniolini
Authors: Emeljanov Alexandr F , Fletcher Murray J
Published: March 2004

Abstract  The first Australian record of the planthopper tribe Breddiniolini is established with the description of Hemielissum evansi gen. et sp. n. Examination of the male genitalia shows that the Breddiniolini belongs in the subfamily Cedusinae of the family Derbidae and the tribe is therefore transferred from the Achilidae.
Spatial and temporal definition of Ochlerotatus camptorhynchus (Thomson) (Diptera: Culicidae) in the Gippsland Lakes system of eastern Victoria
Authors: Barton Philip S , Aberton John G , Kay Brian H
Published: March 2004

Abstract  The confirmed vector of Ross River virus, Ochlerotatus camptorhynchus (Thomson), is the dominant mosquito species inhabiting saline marshes in coastal Victoria. This paper re‐examines previously published data on Oc. camptorhynchus, plus additional data collected since that time, and provides greater spatial and temporal definition of Oc. camptorhynchus numbers at seven sites across the Gippsland Lakes system of eastern Victoria. A total of 357 672 Oc. camptorhynchus was captured from 1188 trap‐nights across the seven trap sites during trapping seasons from 1990 to 2001. The dominance of Oc. camptorhynchus across the seven sites averaged 75%, with significant differences in mean abundance of Oc. camptorhynchus found between all trap sites. Significant differences in monthly abundance of Oc. camptorhynchus were observed for Wellington Shire. Increase in populations of Oc. camptorhynchus was associated with increases in rainfall at all trap sites, higher minimum temperatures at two of the seven trap sites, and wind speed at one trap site. Prioritisation of mosquito control may be applied based on spatial and temporal factors according to the findings of this study.
Seed‐feeding species of Bruchophagus Ashmead (Hymenoptera: Eurytomidae) associated with native Australian acacias that are invasive in South Africa, with the description of two new species
Authors: Neser Ottilie C , Prinsloo Gerhard L
Published: March 2004

Abstract  A search for phytophagous eurytomid wasps of the genus Bruchophagus Ashmead that develop in the seeds of certain native Australian acacias in Australia and New Zealand has yielded three species. Although these three species are probably restricted to members of the subgenus Phyllodineae, to which the vast majority of Australian Acacia species belong, they are not host specific at the species level. Interest in these phytophagous wasps stems from an ongoing search for suitable natural enemies to limit the invasiveness of certain Australian acacias in South Africa. The three species are B. acaciae (Cameron), B. orarius sp. n and B. interior sp. n. A key for their separation, and comments on their relationship with other eurytomids that are associated with the genus Acacia, are also provided.
The plot thickens: Land administration and policy in post‐New Order Indonesia
Authors: Thorburn Craig C.
Published: March 2004

Abstract:  The turbulent events in Indonesia during the closing years of the 20th century prompted the reopening of public discussion on many longstanding issues of social and economic reform. Land reform is one of many agendas that have preoccupied policy makers, scholars and activists as the nation attempts to reinvent itself in the wake of the collapse of the 32‐year New Order government of ex‐President Suharto. This article examines some of the main debates swirling around the issue of land management and policy during the post‐Suharto ‘reformasi’ period, and provides illustrations of current problems and emerging trends.
The article begins with a brief overview of land law and policy in Indonesia, followed by a discussion of its philosophical and ideological basis. This is followed by a discussion of government reform during the New Order period and beyond, and the social and environmental costs of Indonesia's development. The discussion then turns to efforts to decentralise government, and implications on land admin‐istration and policy. Case study examples are provided to illustrate the complex dynamic unfolding across the country.
Negotiating local livelihoods: Scales of conflict in the Se San River Basin
Authors: Hirsch Philip , Wyatt Andrew
Published: March 2004

Abstract:  The Se San is an important tributary river basin of the Mekong. In 1993, Vietnam began building the Yali
Falls Dam 80 kilometres upstream of the point at which this westward flowing river enters Cambodia. Ninety indigenous communities along the Se San River in two provinces of north‐eastern Cambodia have been impacted severely by flooding, and a dramatically altered hydrological regime that affects fisheries and all other aspects of livelihood, such as river bank agriculture. Since 2000, when the first turbines were commissioned, the affected communities have been increasingly vocal regarding the impacts of Yali and the plans for several more dams on upper reaches of the river. A complex set of actors including non‐governmental organisations, village, district and provincial authorities, national committees in Cambodia and Vietnam, the Mekong River Commission and a range of international players have become involved in a two‐track process, which has nevertheless allowed little space for negotiation over the Se San River on the part of those most directly affected. This case has fundamental implications for governance and conflict management in the Mekong and more widely. The Australian Mekong Resource Centre has been working with local actors to document the Se San case as part of an international project on River Basin Management: a negotiated approach, in support of six cases that involve up‐scaling of grassroots river basin initiatives in Africa, Latin America and Asia. In this article, we illustrate the significance of and problematise negotiation as a socially and politically embedded conflict management principle, with reference to the Se San case.
Changing positions and interests of stakeholders in environmental conflict: A New Zealand transport infrastructure case
Authors: Elias Arun A. , Jackson Laurie Skuba , Cavana Robert Y.
Published: March 2004

Abstract:  Stakeholders are an integral part of environmental conflict. Analysing the positions and interests of stakeholders is vital in effective environmental conflict management. This paper reviews the literature related to stakeholders and their dynamics in environmental conflict. It also presents the results of a study relating to a New Zealand transport infrastructure project where the positions and interests of stakeholders have kept on changing during the life of the project. This study plots the changing positions of some of the key stakeholders, towards this project. These stakeholders include a policy manager, a community stakeholder, an environmental stakeholder and a political stakeholder. The paper also analyses the changing positions by identifying and classifying the key drivers for these changes.
Old Questions for New Schools: What Are the Students Doing?
Authors: Wallace John , Wildy Helen
Published: March 2004

This study was conducted in a lighthouse school with a long and successful history of restructuring. In this article we describe our (surprising) impressions of shadowing Jake, one of the highest achieving students in the school. We present a researcher's account of Jake's classroom experience over the first four periods of a single day and an analysis of what happened in terms of the idea of studenting. We employ an actor-oriented view of studenting, comprising four aspects—pacing, attending, conforming, and selecting. We contrast this with a structure-oriented view of studenting and draw parallels with the notions of students-as-participants and students-as-benefciaries in school reform. Finally, we discuss the problems and possibilities of engaging and involving students in the process of reform.
Negotiating Power, Developing Trust: Transgressing Race and Status in the Academy
Authors: Gasman Marybeth , Gerstl-Pepin Cynthia , Anderson-Thompkins Sibby , Rasheed Lisa , Hathaway Karry
Published: March 2004

Exploring the experiences of African American students engaged in doctoral studies reveals disturbing realities. In this article, we use narrative inquiry to engage in a collaborative project between two White faculty members and three African American graduate students. Transgressive pedagogy provided a conceptual framework for both our initial study and our subsequent reflections on the need to create supportive networks for graduate students of color in the academy. In the project we conversed and reflected about how our understanding of race and status had an impact on our experiences in the academy. Our study contrasted student experiences in environments in which students expressed feeling like “casualties of war” with those in which they expressed feeling like valued colleagues. We found that unspoken assumptions about race and status often created a turbulent climate for the participating African American doctoral students and White faculty members who shared values of inclusivity.
(Re)Framing Classroom Contexts: How New Teachers and Mentors View Diverse Learners and Challenges of Practice
Authors: Achinstein Betty , Barrett Adele
Published: March 2004

Research on new teachers identifies two critical challenges in relation to how novices view their students: “practice shock” that results in an overfocus on controlling students and a cultural mismatch that causes novices to see diversity as a problem. This article explores how mentoring strategies intervene at this critical phase, influencing novices’ beliefs about students and teaching practices. This study examined 15 new teacher-mentor pairs over 2 years in northern California through mentoring conversations, classroom observations, and interviews with mentors and novices working with culturally and linguistically diverse elementary students. Drawing on sociological, organizational, and new teacher educational literature, the study explores how novices and mentors come to “frame” and negotiate student diversity in the classroom. The authors describe three ways of viewing classroom relations that the new teachers and mentors used—managerial, human relations, and political. This article challenges current thinking about novice development by revealing how mentors offer new teachers a repertoire of frames to diagnose challenges and develop alternative approaches to meet the needs of diverse students.
Negotiating a Teaching Identity: An African American Teacher's Struggle to Teach in Test-Driven Contexts
Authors: Agee Jane
Published: March 2004

This case study examines the experiences of a young African American English teacher over 3 years as she tried to teach multicultural literature. The study began in her senior year of college when she was enrolled in a progressive undergraduate preservice program in English education and continued through her first 2 years as a high school English teacher. In the university program, she expressed a desire to teach multicultural literature, to use constructivist approaches to teaching that built on students’ personal experiences, and to broaden students’ understanding of racial and cultural differences. Yet in her preservice teaching as well as in her first 2 years as a teacher, she found her goals difficult to implement. Her envisioned identity as a teacher who would help students to understand and celebrate racial diversity began to unravel as she struggled with the demands of school policies, mandated assessments, and racial bias. Teacher identity, as described here, is a discursive space where an imagined role is negotiated among possible roles. In this case, a young African American teacher found her imagined teacher identity thwarted by state mandates, mainstream constructions of a teacher role, and ideologies of curriculum and assessment. Her story speaks to the gap between progressive teacher education programs and the demands of mandated, high-stakes tests on schools and teachers. One result of mandated tests is their tendency to silence diverse points of view, a factor that may further contribute to the lack of teachers of color in American schools.
Mentor-Novice Conversations about Teaching: A Comparison of Two U.S. and Two Chinese Cases
Authors: Wang Jian , Strong Michael , Odell Sandra J.
Published: March 2004

Mentor-novice collaborative reflection about teaching is crucial to the development of novices’ professional knowledge. However, few studies examine content and forms of mentor-novice conversations and opportunities that such interactions create for developing professional knowledge. Drawing on observation data from two U.S. and two Chinese mentor-novice pairs in induction contexts, this study analyzed the content and forms of mentor-novice conversations about novices’ lessons. We found that the U.S. and Chinese mentor-novice interactions were different in focus and form, and these differences were likely related to the curriculum structures and organization of teaching and mentoring in each country. The interactions either offered or restricted novices’ opportunities for developing professional knowledge necessary for reform-minded teaching.
A fuzzy derivative approach to classification of outcomes from the ADRAC database
Authors: Mamedov M.A. , Saunders G.W. , Yearwood J.
Published: March 2004

The Australian Adverse Drug Reaction Advisory Committee (ADRAC) database has been collected and maintained by the Therapeutic Goods Administration. In this paper we study a part of his database (Card2) which contains records having just reactions from the Cardiovascular group. Drug‐reaction relationships are presented by a vector of degrees which shows the degree of association of a drug with each class of reactions. In this work we examine these relationships in the classification of reaction outcomes. A modified version of the fuzzy derivative method (FDM2) is used for classification.
An investigation of the mineralogical properties of chemical grade chromite minerals
Authors: Tathavadkar V. D. , Antony M. P. , Jha A.
Published: March 2004

The chemical grade chromite ores are used extensively for the production of sodium chromate. The mineralogical properties, which pose a major limitation in utilising a wide variety of chemical grade chromite ores from different origins, determine the yield of sodium chromate in the soda‐ash roasting process. In this paper, the mineralogical properties of chemical grade chromite ores from 5 different countries, namely South Africa, India, Philippines, Indonesia and China are reported. The physical and chemical properties of the chromite ores were investigated using the atomic absorption spectroscopy (AAS), X‐ray fluorescence spectroscopy (XRF), X‐ray diffraction analysis (XRD), scanning electron microscopy (SEM) and electron probe microanalysis (EPMA) techniques. The results obtained from the X‐ray diffraction of phases and their scanning electron microscopic analyses were used for explaining the properties of chemical grade chromite ores. The research is aimed at improving the efficiency of extraction of chromium from chromite minerals from different origins, and thereby reducing the amount of chromium lost in the waste stream after the extraction process.
A study on the mechanism of desulphurisation and dephosphorisation of liquid steel by Na2CO3 flux treatment
Authors: Jana B. D. , Chakrabarti A. K.
Published: March 2004

An investigation was undertaken to examine the mechanism of refining liquid steel by Na2CO3 flux treatment. EDX and XRD analysis of a sample of the slag formed after Na2CO3 flux treatment of liquid steel in an induction furnace suggests that sulphur and phosphorus are removed mainly as sodium sulphides and sodium phosphides and partly as silicon sulphide and silicon phosphide. A part of the sodium vapour generated through reduction of Na2O burns over the bath. Iron and traces of other elements are also vaporised from the induction furnace bath. Oxides of these elements are co‐deposited with sodium oxide.
Wootz Damascus steel of ancient orient
Authors: Perttula Juha
Published: March 2004

The legendary Damascus blades of ancient Orient are forged from high carbon (ca. 1.5% C) crucible steel, i.e., wootz. The famous damascene surface pattern is formed from carbide particles arranged into parallel layers. The cutting quality and impact toughness of these blades were respectively studied with leather knives and Charpy specimens made from reproduced steel. The advantageous effect of carbides on edge‐holding quality may be less than is often believed. It was difficult or even impossible to detect when leather was cut. The steel with a uniform distribution of carbides was somewhat tougher than the steel with carbide‐rich layers. Oriental ore often contained a high amount of phosphorus, which presumably made the majority of the blades somewhat brittle, but in the cases when carbon and phosphorus contents are not excessive, wootz Damascus steel can be ductile.
A numerical study of an insulating end‐quench test for high hardenability steels
Authors: Yao Xin , Gu Jianfeng , Hu Mingjuan , Zhu Zuchang
Published: March 2004

A numerical model is presented to determine the heat transfer, phase transformation and hardness distribution of extension Jominy bars in an insulating end‐quenching test designed to evaluate the hardenablility of steels having middle or high hardenability. The end‐quenching test is conducted in a revised device with a refractory insulating liner to decrease the cooling rate of the specimen. Heat transfer coefficients varying not only with temperature of end surface but also with radius are adopted when examining the water jet on the end side. A modified model based on Avrami equation and Koistien–Marburger law is developed to determine the microstructure distribution, and an empirical based formula developed by Maynier is applied to calculate the Vickers hardness of each phase at different cooling rate. The microstructure and hardness predictions obtained in the present model are found to be in good agreement with experimental measurements.
Combustion performance and numerical simulation of a high‐temperature air–LPG flame on a regenerative burner
Authors: Weihong Yang , Blasiak Wlodzimierz
Published: March 2004

High‐temperature air combustion is attracting great interest in the metallurgical industry lately as its claimed benefits include large energy saving, low air emissions, increased product quality and increased productivity. This paper presents a numerical study of combustion performance in a semi‐industrial test furnace equipped with a regenerative burner and with a conventional turbulent jet burner. The numerical calculation is also validated by experiment. In this regard, flow field was calculated with k‐ɛ turbulence model, the model of combustion employed the eddy dissipation concept with a two‐step mechanism to describe chemical reactions; radiation was handled using the discrete transfer method. The results indicate that equipping a furnace with high‐cycle regenerative burner systems can provide more uniform gas temperature profiles, a higher energy utilizing efficiency, a low NOx emission, a larger flame, the low maximum local heat release and the possibility of low combustion noise.
Role of Purine Nucleoside Phosphorylase in Interactions between 2′,3′-Dideoxyinosine and Allopurinol, Ganciclovir, or Tenofovir
Authors: Ray Adrian S. , Olson Loren , Fridland Arnold
Published: March 2004

The level of systemic exposure to 2′,3′-dideoxyinosine (ddI) is increased 40 to 300% when it is coadministered with allopurinol (Allo), ganciclovir (GCV), or tenofovir. However, the mechanism for these drug interactions remains undefined. A metabolic route for ddI clearance is its breakdown by purine nucleoside phosphorylase (PNP). Consistent with previous reports, enzymatic inhibition assays showed that acyclic nucleotide analogs can inhibit the phosphorolysis of inosine. It was further established that the mono- and diphosphate forms of tenofovir were inhibitors of PNP-dependent degradation of ddI (

K
i

s, 38 nM and 1.3 μM, respectively). Allo and its metabolites were found to be relatively weak inhibitors of PNP (

K
i

s, >100 μM). Coadministration of tenofovir, GCV, or Allo decreased the amounts of intracellular ddI breakdown products in CEM cells, while they increased the ddI concentrations (twofold increase with each drug at approximately 20 μM). While inhibition of the physiological function of PNP is unlikely due to the ubiquitous presence of high levels of enzymatic activity, phosphorylated metabolites of GCV and tenofovir may cause the increased level of exposure to ddI by direct inhibition of its phosphorolysis by PNP. The discrepancy between the cellular activity of Allo and the weak enzyme inhibition by Allo and its metabolites may be explained by an indirect mechanism of PNP inhibition. This mechanism may be facilitated by the unfavorable equilibrium of PNP and the buildup of one of its products (hypoxanthine) through the inhibition of xanthine oxidase by Allo. These findings support the inhibition of PNP-dependent ddI degradation as the molecular mechanism of these drug interactions.
In Vivo Detection and Quantification of Tetracycline by Use of a Whole-Cell Biosensor in the Rat Intestine
Authors: Bahl Martin Iain , Hansen Lars Hestbjerg , Licht Tine Rask , Sørensen Søren J.
Published: March 2004

An
Escherichia coli
biosensor strain, harboring the plasmid pTGFP2, was introduced into the gastrointestinal tract of gnotobiotic rats that continuously received drinking water containing tetracycline. Plasmid pTGFP2 contains a transcriptional fusion between a green fluorescent protein (GFP) gene and a tetracycline-regulated promoter and was shown to produce a proportional GFP signal in response to exposure to various tetracycline concentrations when harbored by an
E. coli
strain. The plasmid was highly unstable in the host bacteria colonizing the intestinal system of the animals, and rapid plasmid loss was observed. Reintroduction of the
E. coli
MC4100/pTGFP2 strain into animals already colonized by the plasmid-free
E. coli
strain the day before euthanasia made it possible to extract and analyze the biosensors from intestinal samples. The induction of GFP in the biosensor cells extracted from the animals was estimated on a single-cell basis by use of flow cytometry, and the mean induction of GFP in the samples was compared to a standard curve prepared from known tetracycline concentrations. The results showed that the bioavailable tetracycline concentration within the bacterial growth habitat of the intestine was proportional to the concentration of tetracycline in drinking water but represented only approximately 0.4% of the intake concentration. This is a significant finding which will help to clarify antimicrobial therapy in the intestinal environment.
Efficacy of Dalbavancin against Methicillin-Resistant
Staphylococcus aureus
in the Rat Granuloma Pouch Infection Model
Authors: Jabés Daniela , Candiani Gianpaolo , Romanó Gabriella , Brunati Cristina , Riva Simona , Cavaleri Marco
Published: March 2004

Infections due to methicillin-resistant
Staphylococcus aureus
(MRSA) are an important cause of morbidity and mortality in hospital patients. Moreover, increased incidences of outpatient MRSA have been recently reported. This study investigated the bactericidal activity of dalbavancin, a novel, semisynthetic glycopeptide antibiotic, against methicillin-sensitive
S. aureus
(MSSA) and MRSA in the rat granuloma pouch infection model. A single intravenous dose of 10 mg of dalbavancin/kg of body weight reduced the viable MRSA count in pouch exudates by more than 2 log CFU/ml, and regrowth was prevented for up to 120 h. Comparable results with vancomycin required four 100-mg/kg intramuscular doses. With one or two doses of vancomycin, the bacterial load declined over proportionately shorter periods of time, followed by regrowth. Reduction of the bacterial load obtained with 100- and 200-mg/kg oral doses of linezolid was relatively transient, with regrowth starting at 48 h. A single 10-mg/kg dose of dalbavancin reduced the MSSA count at 24 h to below the limit of detection, with no regrowth for at least 96 h. Dalbavancin demonstrated good exudate penetration; the ratio of the area under the curve (AUC) in plasma to the AUC in pouch exudate was 1.01. The in vivo activity of dalbavancin in this model is consistent with the antibiotic concentrations that are reached and maintained for extended periods of time after a single 10-mg/kg dose and with in vitro data showing that these concentrations are bactericidal for staphylococci. The pharmacokinetic and efficacy data seen in this relevant model of infection suggest that dalbavancin may be administered less frequently than vancomycin and linezolid.
In Vitro Activities of 28 Antimicrobial Agents against
Staphylococcus aureus
Isolates from Tertiary-Care Hospitals in Korea: a Nationwide Survey
Authors: Kim Hong Bin , Jang Hee-Chang , Nam Hee Jung , Lee Yeong Seon , Kim Bong Su , Park Wan Beom , Lee Ki Deok , Choi Young Joo , Park Sang Won , Oh Myoung-don , Kim Eui-Chong , Choe Kang Won
Published: March 2004

Staphylococcus aureus
, one of the most frequently isolated pathogens in both hospitals and the community, has been particularly efficient at developing resistance to antimicrobial agents. As methicillin-resistant
S. aureus
(MRSA) has prevailed and, furthermore, as
S. aureus
with reduced susceptibility to vancomycin has emerged, the therapeutic options for the treatment of
S. aureus
infections have become limited. To update the current status of antibiotic resistance, clinical
S. aureus
isolates were collected from eight university-affiliated hospitals from June 1999 to January 2001. Susceptibility tests with 28 antibiotics were performed by the disk diffusion method. Among a total of 682 isolates, the methicillin resistance rate was 64% (439 of 682), and most of the MRSA isolates were resistant to multiple classes of antibiotics. Although a constitutive macrolide-lincosamide-streptogramin B resistance phenotype was common, no isolates were resistant to quinupristin-dalfopristin or linezolid. Rifampin, fusidic acid, trimethoprim-sulfamethoxazole, and arbekacin showed superior in vitro activity compared with the other antibiotics against the MRSA isolates. No isolates showed reduced susceptibility to vancomycin.
BpeAB-OprB, a Multidrug Efflux Pump inBurkholderia pseudomallei
Authors: Chan Y. Y. , Tan T. M. C. , Ong Y. M. , Chua K. L.
Published: March 2004

Burkholderia pseudomallei, the causative agent of melioidosis, is intrinsically resistant to a wide range of antimicrobial agents, including β-lactams, aminoglycosides, macrolides, and polymyxins. An operon,bpeR-bpeA-bpeB-oprB, which encodes a putative repressor, a membrane fusion protein, an inner membrane protein, and an outer membrane protein, respectively, of a multidrug efflux pump of the resistance-nodulation-division family was identified inB. pseudomallei. The divergently transcribedbpeRgene encodes a putative repressor protein of the TetR family which probably regulates the expression of thebpeAB-oprBgene cluster. Comparison of the MICs and minimal bactericidal concentrations of antimicrobials forbpeABdeletion mutant KHWΔbpeABand its isogenic wild-type parent, KHW, showed that theB. pseudomalleiBpeAB-OprB pump is responsible for the efflux of the aminoglycosides gentamicin and streptomycin, the macrolide erythromycin, and the dye acriflavine. Antibiotic efflux by the BpeAB-OprB pump was dependent on a proton gradient and differs from that by the AmrAB-OprA pump in that it did not efflux the aminoglycoside spectinomycin or the macrolide clarithromycin. The broad-spectrum efflux pump inhibitor MC-207,110 did not potentiate the effectiveness of the antimicrobials erythromycin and streptomycin inB. pseudomallei.
Expression ofacrB,acrF,acrD,marA, andsoxSinSalmonella entericaSerovar Typhimurium: Role in Multiple Antibiotic Resistance
Authors: Eaves Deborah J. , Ricci Vito , Piddock Laura J. V.
Published: March 2004

Comparative reverse transcription-PCR in combination with denaturing high-pressure liquid chromatography analysis was used to determine the levels of expression ofsoxS,marA,acrF,acrB, andacrDin multiple-antibiotic-resistant (MAR)Salmonella entericaserovar Typhimurium isolates and mutants ofS. entericaserovar Typhimurium SL1344 with defined deletions. Posttherapy MAR clinical isolates had increased levels of expression of all genes exceptsoxS. S. entericaserovar Typhimurium SL1344 ΔacrBexpressed 7.9-fold moreacrFthan the parent strain. A strain with anacrFdeletion expressed 4.6-fold moreacrB. Deletion ofacrBand/oracrFresulted in 2.7- to 4.3-fold moremarAmRNA and 3.6- to 4.9-fold increases in the levels of expression ofacrDbut had a variable effect on the expression ofsoxS. All mutants were hypersusceptible to antibiotics, dyes, and detergents; but the MIC changes were more noticeable for SL1344 with theacrBdeletion than for the mutant with theacrFdisruption. These mutants had different but overlapping phenotypes, and the concentrations of ciprofloxacin accumulated by the mutants were different. These data suggest thatacrB,acrF, andacrDare coordinately regulated and that their expression influences the expression of the transcriptional activatorsmarAandsoxS.
CFE-1, a Novel Plasmid-Encoded AmpC β-Lactamase with anampRGene Originating fromCitrobacter freundii
Authors: Nakano Ryuichi , Okamoto Ryoichi , Nakano Yumiko , Kaneko Kenichi , Okitsu Naohiro , Hosaka Yoshio , Inoue Matsuhisa
Published: March 2004

A clinical isolate ofEscherichia colifrom a patient in Japan, isolate KU6400, was found to produce a plasmid-encoded β-lactamase that conferred resistance to extended-spectrum cephalosporins and cephamycins. Resistance arising from production of a β-lactamase could be transferred by either conjugation or transformation with plasmid pKU601 intoE. coliML4947. The substrate and inhibition profiles of this enzyme resembled those of the AmpC β-lactamase. The resistance gene of pKU601, which was cloned and expressed inE. coli, proved to contain an open reading frame showing 99.8% DNA sequence identity with theampCgene ofCitrobacter freundiiGC3. DNA sequence analysis also identified a gene upstream ofampCwhose sequence was 99.0% identical to theampRgene fromC. freundiiGC3. In addition, a fumarate operon (frdABCD) and an outer membrane lipoprotein (blc) surrounding theampR-ampCgenes inC. freundiiwere identified, and insertion sequence (IS26) elements were observed on both sides of the sequences identified (forming an IS26composite transposon); these results confirm the evidence of the translocation of a β-lactamase-associated gene region from the chromosome to a plasmid. Finally, we describe a novel plasmid-encoded AmpC β-lactamase, CFE-1, with anampRgene derived fromC. freundii.
Population Pharmacokinetics of Arbekacin, Vancomycin, and Panipenem in Neonates
Authors: Kimura Toshimi , Sunakawa Keisuke , Matsuura Nobuo , Kubo Hiroaki , Shimada Shigehiko , Yago Kazuo
Published: March 2004

Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem. Eighty-three neonates received arbekacin (
n
= 41), vancomycin (
n
= 19), or panipenem (
n
= 23). The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g. A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis. In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution (
V
) was BW. The final formulas for the population pharmacokinetic parameters are as follows: CL
arbekacin
= 0.0238 × BW/serum creatinine level for PCAs of <33 weeks and CL
arbekacin
= 0.0367 × BW/serum creatinine level for PCAs of ≥33 weeks,
V
arbekacin
= 0.54 liters/kg, CL
vancomycin
= 0.0250 × BW/serum creatinine level for PCAs of <34 weeks and CL
vancomycin
= 0.0323 × BW/serum creatinine level for PCAs of ≥34 weeks,
V
vancomycin
= 0.66 liters/kg, CL
panipenem
= 0.0832 for PCAs of <33 weeks and CL
panipenem
= 0.179 × BW for PCAs of ≥33 weeks, and
V
panipenem
= 0.53 liters/kg. When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of <33 to 34 weeks was significantly smaller than those with PCAs of ≥33 to 34 weeks, and CL showed an exponential increase with PCA. Many antibiotics are excreted by glomerular filtration, and maturation of glomerular filtration is the most important factor for estimation of antibiotic clearance. Clinicians should consider PCA, serum creatinine level, BW, and chemical features when determining the initial antibiotic dosing regimen for neonates.
Pseudomonas aeruginosa
Biofilms Exposed to Imipenem Exhibit Changes in Global Gene Expression and β-Lactamase and Alginate Production
Authors: Bagge Niels , Schuster Martin , Hentzer Morten , Ciofu Oana , Givskov Michael , Greenberg Everett Peter , Høiby Niels
Published: March 2004

The lungs of cystic fibrosis (CF) patients are commonly colonized with
Pseudomonas aeruginosa
biofilms. Chronic endobronchial
P. aeruginosa
infections are impossible to eradicate with antibiotics, but intensive suppressive antibiotic therapy is essential to maintain the lung function of CF patients. The treatment often includes β-lactam antibiotics. How these antibiotics influence gene expression in the surviving biofilm population of
P. aeruginosa
is not clear. Thus, we used the microarray technology to study the effects of subinhibitory concentrations of a β-lactam antibiotic, imipenem, on gene expression in biofilm populations. Many genes showed small but statistically significant differential expression in response to imipenem. We identified 34 genes that were induced or repressed in biofilms exposed to imipenem more than fivefold compared to the levels of induction or repression for the controls. As expected, the most strongly induced gene was
ampC
, which codes for chromosomal β-lactamase. We also found that genes coding for alginate biosynthesis were induced by exposure to imipenem. Alginate production is correlated to the development of impaired lung function, and
P. aeruginosa
strains isolated from chronically colonized lungs of CF patients are nearly always mucoid due to the overproduction of alginate. Exposure to subinhibitory concentrations of imipenem caused structural changes in the biofilm, e.g., an increased biofilm volume. Increased levels of alginate production may be an unintended adverse consequence of imipenem treatment in CF patients.
Efficacy, Safety, and Plasma Pharmacokinetics of Escalating Dosages of Intravenously Administered Ravuconazole Lysine Phosphoester for Treatment of Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits
Authors: Petraitiene Ruta , Petraitis Vidmantas , Lyman Caron A. , Groll Andreas H. , Mickiene Diana , Peter Joanne , Bacher John , Roussillon Kristin , Hemmings Melissa , Armstrong Derrek , Avila Nilo A. , Walsh Thomas J.
Published: March 2004

Ravuconazole is a new antifungal triazole with broad-spectrum activity and a long half-life in plasma. We studied the antifungal efficacy, safety, and pharmacokinetics of ravuconazole lysine phosphoester in escalating dosages for the treatment of invasive pulmonary aspergillosis due to
Aspergillus fumigatus
in persistently neutropenic rabbits. Treatment groups consisted of rabbits treated with ravuconazole at 2.5 (RVC2.5), 5 (RVC5), and 10 (RVC10) mg/kg of body weight/day, rabbits treated with amphotericin B (AMB) at 1 mg/kg/day, or untreated controls. There was a dose-dependent reduction of pulmonary residual fungal burden (CFU per gram) in RVC5-, RVC10-, and AMB-treated rabbits in comparison to untreated controls (
P
< 0.01,
P
< 0.001, and
P
< 0.01, respectively). These findings correlated with progressive galactomannan antigenemia in untreated controls and the RVC2.5-treated rabbits, a lower galactomannan index (GMI) in RVC5- and RVC10-treated rabbits, and a similarly low GMI in AMB-treated rabbits (
P
< 0.01). Rabbits treated with RVC5, RVC10, and AMB also showed a reduction of organism-mediated pulmonary injury, as measured by infarct scores and lung weights, in comparison to untreated controls (
P
< 0.001). These results were supported by decreased pulmonary infiltrates detected by computed tomography in RVC5- and RVC10-treated rabbits in comparison to untreated controls (
P
< 0.05). Survival throughout the entire study was achieved in 95% of RVC5-treated rabbits (
P
< 0.001), 85% of RVC10-treated rabbits (
P
< 0.001), and 50% of AMB-treated rabbits (
P
< 0.05) in comparison to none of the untreated controls. Ravuconazole showed linear plasma pharmacokinetics and a large volume of distribution while maintaining concentrations in plasma above the MIC throughout the dosing interval. There was no evidence of hepatotoxicity or nephrotoxicity among ravuconazole-treated animals. Intravenously administered ravuconazole lysine phosphoester showed dose-dependent efficacy and an excellent safety profile for the treatment of invasive pulmonary aspergillosis in persistently neutropenic rabbits.