bluuebunny/crossref_metadata_2025 huggingface dataset:
Time-domain measurement of picosecond light-pulse propagation in a two-dimensional photonic crystal-slab waveguide
Authors: Asano Takashi , Kiyota Kazuaki , Kumamoto Daisuke , Song Bong-Shik , Noda Susumu
Published: May 2004

The optical properties of line-defect waveguides in two-dimensional photonic crystal slabs are investigated using picosecond light pulses. Time-domain waveforms of the light pulse propagating through the waveguide are successfully observed using an autocorrelation method. The group velocity of the waveguide is directly determined from the group delay time for light pulses reflected back and forth along the waveguide. A small group velocity of one-twentieth the speed of light in vacuum is observed at a frequency near the edge of the waveguide mode. The frequency dependence of the group velocity is also measured, and the group-velocity dispersion is found to be larger than that of normal single-mode optical fibers by a factor of 104–105.
Light coupling with multimode photonic crystal waveguides
Authors: Li Zhi-Yuan , Lin Lan-Lan , Ho Kai-Ming
Published: May 2004

We use a transfer-matrix method (TMM) to investigate light coupling into and out of single-end multimode photonic crystal waveguides. Without multiple-reflection complexity, this approach allows for unambiguous quantitative determination of the coupling efficiency of external light into each guided mode and transition among various guided modes. The TMM can provide a powerful analytical tool to understand and design complex multimode photonic crystal waveguides.
Strong magnetic-field effects in weak manganite-based heterojunction
Authors: Sun J. R. , Li C. M. , Wong H. K.
Published: May 2004

Oxide heterojunctions were fabricated by growing a La0.67Ca0.33MnO3−δ (LCMO) film on a 0.5 wt % Nb-doped SrTiO3 single crystal (STON). By removing the oxygen of LCMO, a junction with a rather small diffusion/breakdown voltage and junction resistance has been obtained. The most striking observation of the present work is the extremely strong magnetic-field effects in this weak junction. A field of H≈1.7 T can cause an increase of ∼1130% of the diffusion/breakdown voltage and a magnetoresistance as high as R(H)/R(0)−1≈1100%. It is interesting to note that the magnetoresistance is positive, which indicates a basically different mechanism from the manganite, for which a negative magnetoresistance is observed, and could be a result of the change of magnetic and electronic structures of LCMO with respect to STON under magnetic field.
The Reaction of 8-Amino-p-menthene Derivatives with Electrophiles
Authors: Bernhardt Paul V. , Carman Raymond M. , Derbyshire Roger P. C.
Published: May 2004

Attempts to ring-close the nitrogen atom of 8-amino-p-menth-1-ene and of N-substituted 8-amino-p-menth-1-enes onto the C1–C2 double-bond carbons has led to a range of bicyclo[2.2.2] and bicyclo[3.2.1] products, together with the novel bicyclo[4.3.1]-1,3-oxazepine 9.
Synthesis and Fluorescence Properties of New Enaminenaphthalimides
Authors: McAdam C. John , Morgan Joy L. , Murray R. Eva , Robinson Brian H. , Simpson Jim
Published: May 2004

The first 4-enamine-N-methyl-1,8-naphthalimides (amine = piperidine, pyrrolidine, morpholine, Prn2NH, Pri2NH) are reported. The X-ray crystal structure of the piperidine derivative confirmed the E-stereochemistry and showed strong Π–Π stacking in the unit cell. The enamines are strongly fluorescent and quantum yields do not vary with the pKb of the amine. The solvent dependence of λ abs and λ flu is consistent with significant charge separation in the excited state.
Bipotential mouse embryonic liver stem cell lines contribute to liver regeneration and differentiate as bile ducts and hepatocytes
Authors: Strick-Marchand Hélène , Morosan Serban , Charneau Pierre , Kremsdorf Dina , Weiss Mary C.
Published: May 2004

Cell lines have many advantages: they can be manipulated genetically, expanded, and stockpiled for organ transplantation. Freshly isolated hepatocytes, oval cells, pancreatic cells, and hematopoietic stem cells have been shown to repopulate the damaged liver. Here we show that bipotential mouse embryonic liver (BMEL) stem cell lines participate in liver regeneration in albumin–urokinase plasminogen activator/severe combined immunodeficiency disease (Alb-uPA/SCID) transgenic mice. In the liver, BMEL-GFP cells proliferate and differentiate into both hepatocytes and bile ducts, forming small to large clusters detected throughout the 3–8 weeks analyzed after transplantation. Moreover, they respond like host cells to signals for growth, differentiation, and even zonal expression of metabolic enzymes, showing regulated expression of cytokeratins and liver-enriched transcription factors. Immunostaining for MHC class I molecules revealed that cells do not coexpress donor and recipient H-2 haplotypes, as would be the case had cell fusion occurred. This report shows that immortalized stem cell lines not only are competent to participate in the repair of a damaged tissue but also can differentiate into the two major epithelial cell types of a complex organ, hepatocytes and bile ducts.
A Model for a Proportional Treatment Effect on Disease Progression
Authors: Greene Tom
Published: May 2004

Summary. Treatments intended to slow the progression of chronic diseases are often hypothesized to reduce the rate of further injury to a biological system without improving the current level of functioning. In this situation, the treatment effect may be negligible for patients whose disease would have been stable without the treatment but would be expected to be an increasing function of the progression rate in patients with worsening disease. This article considers a variation of the Laird–Ware mixed effects model in which the effect of the treatment on the slope of a longitudinal outcome is assumed to be proportional to the progression rate for patients with progressive disease. Inference based on maximum likelihood and a generalized estimating equations procedure is considered. Under the proportional effect assumption, the precision of the estimated treatment effect can be increased by incorporating the functional relationship between the model parameters and the variance of the outcome variable, particularly when the magnitude of the mean slope of the outcome is small compared with the standard deviation of the slopes. An example from a study of chronic renal disease is used to illustrate insights provided by the proportional effect model that may be overlooked with models assuming additive treatment effects.
Controlling Test Size While Gaining the Benefits of an Internal Pilot Design
Authors: Coffey Christopher S. , Muller Keith E.
Published: May 2004

Summary. To compensate for a power analysis based on a poor estimate of variance, internal pilot designs use some fraction of the planned observations to reestimate error variance and modify the final sample size. Ignoring the randomness of the final sample size may bias the final variance estimate and inflate test size. We propose and evaluate three different tests that control test size for an internal pilot in a general linear univariate model with fixed predictors and Gaussian errors. Test 1 uses the first sample plus those observations guaranteed to be collected in the second sample for the final variance estimate. Test 2 depends mostly on the second sample for the final variance estimate. Test 3 uses the unadjusted variance estimate and modifies the critical value to bound test size. We also examine three sample‐size modification rules. Only test 2 can control conditional test size, align with a modification rule, and provide simple power calculations. We recommend it if the minimum second (incremental) sample is at least moderate (perhaps 20). Otherwise, the bounding test appears to have the highest power in small samples. Reanalyzing published data highlights some advantages and disadvantages of the various tests.
Mixed Effects Logistic Regression Models for Multiple Longitudinal Binary Functional Limitation Responses with Informative Drop‐Out and Confounding by Baseline Outcomes
Authors: Ten Have Thomas R. , Reboussin Beth A. , Miller Michael E. , Kunselman Allen
Published: May 2004

Summary. In the context of analyzing multiple functional limitation responses collected longitudinally from the Longitudinal Study of Aging (LSOA), we investigate the heterogeneity of these outcomes with respect to their associations with previous functional status and other risk factors in the presence of informative drop‐out and confounding by baseline outcomes. We accommodate the longitudinal nature of the multiple outcomes with a unique extension of the nested random effects logistic model with an autoregressive structure to include drop‐out and baseline outcome components with shared random effects. Estimation of fixed effects and variance components is by maximum likelihood with numerical integration. This shared parameter selection model assumes that drop‐out is conditionally independent of the multiple functional limitation outcomes given the underlying random effect representing an individual's trajectory of functional status across time. Whereas it is not possible to fully assess the adequacy of this assumption, we assess the robustness of this approach by varying the assumptions underlying the proposed model such as the random effects structure, the drop‐out component, and omission of baseline functional outcomes as dependent variables in the model. Heterogeneity among the associations between each functional limitation outcome and a set of risk factors for functional limitation, such as previous functional limitation and physical activity, exists for the LSOA data of interest. Less heterogeneity is observed among the estimates of time‐level random effects variance components that are allowed to vary across functional outcomes and time. We also note that, under an autoregressive structure, bias results from omitting the baseline outcome component linked to the follow‐up outcome component by subject‐level random effects.
Generalized Character Process Models: Estimating the Genetic Basis of Traits That Cannot Be Observed and That Change with Age or Environmental Conditions
Authors: Fletcher Scott D. , Jaffrezic Florence
Published: May 2004

Summary. The genetic analysis of characters that change as a function of some independent and continuous variable has received increasing attention in the biological and statistical literature. Previous work in this area has focused on the analysis of normally distributed characters that are directly observed. We propose a framework for the development and specification of models for a quantitative genetic analysis of function‐valued characters that are not directly observed, such as genetic variation in age‐specific mortality rates or complex threshold characters. We employ a hybrid Markov chain Monte Carlo algorithm involving a Monte Carlo EM algorithm coupled with a Markov chain approximation to the likelihood, which is quite robust and provides accurate estimates of the parameters in our models. The methods are investigated using simulated data and are applied to a large data set measuring mortality rates in the fruit fly, Drosophila melanogaster.
About the role of the various types of secondary electrons (SE1; SE2; SE3) on the performance of LVSEM
Authors: CAZAUX J.
Published: May 2004

The relative weight, δΒ, of the yield of secondary electrons, SE2, induced by the backscattered electrons, BSE, with respect to that, δP, of secondary electrons, SE1, induced by the primary electrons, PE, is deduced from simple theoretical considerations. At primary energies E0 larger than EM (where the total SE yield δ = δP + δB is maximum), the dominant role of the backscattering events is established. It is illustrated in SEM by a direct comparison of the contrast between SE images and BSE images obtained at E0 ∼ 5 keV and E0 ∼ 15 keV on a stratified specimen. At energies E0 less than EM, the dominant role of SE1 electrons with respect to SE2 (and SE3) is established. It is illustrated by the better practical resolution of diamond images obtained with an in‐lens detection in low voltage SEM E0 ∼ 0.2–1 keV range compared with that obtained with a lateral detector. The present contribution illustrates the improved performance of LVSEM in terms of contrast and of practical resolution as well as the importance of variable voltage methods for subsurface imaging. The common opinion that the practical lateral resolution is given by the incident spot diameter is also reconsidered in LVSEM.
MLJ Reviews
Authors: Liskin‐Gasparro Judith E.
Published: May 2004

Books reviewed in this article:

Branciforte, Suzanne, & Anna Grassi. Parliamo italiano!.

Cherry, Maurice C. (Ed.). Cyberspace and Foreign Languages: Making the Connection.

Chun, Dorothy M. Discourse Intonation in L2: From Theory and Research to Practice.

Cook, Manuela. Portuguese. A Complete Course in Understanding, Speaking and Writing.

Cordeiro, Emilce A., & Jane E. Rizzitano. Quiosco.

Fried–Booth, Diana. Project Work.

Grenfell, Michael. (Ed.). Modern Languages across the Curriculum.

Holliday, Adrian. Doing and Writing Qualitative Research.

Marinelli, Patti J., & Lizette Mujica Laughlin. Puentes: Spanish for Intensive and High Beginner Courses.

Marinelli, Patti J., Lizette Mujica Laughlin, & Elvira Swender. Puentes: Cuaderno de activiades y Gramática supplemental.

Okita, Toshie. Invisible Work: Bilingualism, Language Choice and Childrearing in Intermarried Families.

Porte, Graeme Keith. Appraising Research in Second Language Learning: A Practical Approach to Critical Analysis of Quantitative Research.

Ransdell, Sarah, & Marie–Laure Barbier. (Eds.). New Directions for Research in L2 Writing.

Scott, Virginia M., & Holly Tucker. (Eds.). SLA and the Literature Classroom: Fostering Dialogues.

Spreen, Carol Anne. (Ed.). New Technologies and Language Learning: Cases in the Less Commonly Taught Languages.

Vanpatten, Bill, James F. Lee, & Terry L. Ballman. Vistazos: Un curso breve.

Verhoeven, Ludo, & Sven Strömqvist. (Eds.). Narrative Development in a Multilingual Context.
The Role of Caregivers after a Stillbirth: Views and Experiences of Parents
Authors: Säflund Karin , Sjögren Berit , Wredling Regina
Published: May 2004

Abstract:  Background: The clinical role of the caregiver to parents in the event of a stillbirth has yet to be defined. The aim of this paper was to focus on the caregivers’ support as revealed by the parents’ experiences. Method: One or both parents of 31 stillborn infants (≥28 weeks) were interviewed twice, for a total of 57 interviews. The data analysis was conducted using a qualitative approach. Results: Parents identified the caregivers’ behavior and handling of the stillbirth as important. Findings showed that caregivers should support parents in moments of chaos and at other difficult times. The parents needed assistance in both facing and separating from the baby. The six “qualities” that summarized the findings were “support in chaos,”“support in the meeting with and separation from the baby,”“support in bereavement,”“explanation of the stillbirth,”“organization of the care,” and “understanding the nature of grief.” Findings indicate that the hospital is under an obligation to organize the care and make it possible for parents to see the same caregivers again, and to offer extra ultrasound investigations and checkups without unnecessary bureaucracy. Conclusion: We suggest that the “qualities” identified by the study findings should be implemented in clinical care, and could facilitate active guidance and counseling for bereaved parents who have experienced a stillbirth.
Metabolic control analysis and regulation of the conversion of sucrose to starch in growing potato tubers
Authors: GEIGENBERGER P. , STITT M. , FERNIE A. R.
Published: May 2004

Starch is of great importance both as a carbon storage reserve in plants and as a biotechnologically important product. The potato tuber is an attractive model system for the study of starch metabolism, because it is a relatively homogenous tissue in which conversion of sucrose to starch represents the dominant metabolic flux. All the major genes of the potato tuber sucrose to starch pathway have been cloned in recent years, allowing the generation of a suite of antisense transgenic lines to be produced in which the activity of each individual enzyme in the pathway is progressively decreased. Investigations of these plants have provided a complete picture of the distribution of control in this important pathway. Sucrose synthase, UGPase, hexokinase, cytosolic phosphoglucomutase, plastidial phosphoglucomutase, the amyloplastidial adenylate translocator, AGPase, starch synthase and starch branching enzyme have flux control coefficients (FCCs) of 0.10, approximating 0.00, approximating 0.00, 0.15, 0.23, 0.98, 0.35, 0.12 and approximating 0.00 for starch accumulation. These results show that the majority of the control on starch accumulation in potato tubers resides in the transfer of adenylate between the cytosol and the amyloplast, with a minor contribution being made by the first two steps of the plastidial starch synthesis pathway (the reactions catalysed by plastidial phosphoglucomutase and AGPase). This contrasts with leaves, in which the majority of the control has been found to reside in the reactions catalysed by plastidial phosphoglucomutase and AGPase. In leaves, ATP for starch synthesis is generated within the plastid via photophosphorylation. Several studies have attempted to increase the rate of starch synthesis by overexpressing pathway enzymes in tubers. The results of these studies and the role of other ATP producers in the starch synthetic process are reviewed. In the same time period methods of non‐aqueous fractionation have been adapted to potato tuber tissue in order to ascertain subcellular metabolite levels. Results obtained from these studies allow the calculation of mass action ratios of the constitutive enzymes of the sucrose to starch transition. When taken together with the known regulatory properties of these enzymes the combination of broad control analysis studies and assessment of the mass action ratios of the respective enzymes allows a comprehensive description of this important metabolic network. Some illustrative examples of how this network responds to environmental change are presented. Finally implications of this whole pathway evaluation for more general studies of plant metabolic pathways and networks are discussed.
A reinterpretation of the crustal N‐isotope record: evidence for a 15N‐enriched Archean atmosphere?
Authors: Jia Yiefei , Kerrich Robert
Published: May 2004

A new compilation of N‐isotope and abundance data for metasedimentary rocks, and hyrdothermal micas that proxy for bulk crust, show systematic patterns. (1) δ15N values of kerogen in Precambrian cherts are more negative relative to siliciclastic counterparts, probably due to a mantle hydrothermal component. (2) There is a secular trend from average δ15N 15.3 ± 1.8‰ in Archean shales, through intermediate values in the Proterozoic, to Phanerozoic counterparts where δ15N averages +3.5‰. (3) Hydrothermal micas in metamorphic hydrothermal systems of Palaeozoic and Mesozoic age that proxy for crust have δ15N within the range of contemporaneous sedimentary rocks. (4) Hydrothermal micas track the secular trend of δ15N for kerogen from 2.7 Ga to the Phanerozoic. (5) Within Precambrian datasets δ15N does not increase with decreasing N content; accordingly, high δ15N values cannot stem either from metamorphism or form Rayleigh fractionation. (6) Previous studies show isotopic shifts during metamorphism are only +1 to +3‰ up to amphibolite facies. Values of 10–24‰ are attributed to a high δ15N Archean atmosphere, a residual signature of CI carbonaceous chondrites where δ15N is +30‰ to + 42‰.
Late Ordovician glacial pavements revisited: a reappraisal of the origin of striated surfaces
Authors: Deynoux Max , Ghienne Jean‐François
Published: May 2004

The recognition of ice‐related unconformities is of prime importance when dealing with the sequential architecture of pre‐Pleistocene glacial successions. Late Ordovician striated surfaces strikingly preserved in North Gondwana were long considered as abrasion surfaces at the sole of a grounded glacier overriding unlithified sediments, or having resulted from the scouring action of drifting icebergs. Field observations from Mauritania and Libya show that these striated surfaces require an alternative interpretation, which can be applied to similar surfaces described elsewhere, such as in Permo‐Carboniferous or Neoproterozoic glacial sequences. A new model is proposed that involves superimposed concurrent décollement planes within a subglacial brittle shear zone in unlithified sand beds. Shear zones in subglacial sediments are well known in Quaternary deposits but, to date, it has not been demonstrated that they may form striated surfaces occurring at continent scale with orientations consistent with palaeo ice‐flow reconstructions based on larger‐scale indicators.
A model of characteristic earthquakes and its implications for regional seismicity
Authors: López‐Ruiz Ricardo , Vázquez‐Prada Miguel , Gómez Javier B. , Pacheco Amalio F.
Published: May 2004

Regional seismicity (i.e. that averaged over large enough areas over long enough periods of time) has a size–frequency relationship, the Gutenberg–Richter law, which differs from that found for some seismic faults, the Characteristic Earthquake relationship. But all seismicity comes in the end from active faults, so the question arises of how one seismicity pattern could emerge from the other. The recently introduced Minimalist Model of Vázquez‐Prada et al. of characteristic earthquakes provides a simple representation of the seismicity originating from a single fault. Here, we show that a Characteristic Earthquake relationship together with a fractal distribution of fault lengths can accurately describe the total seismicity produced in a region. The resulting earthquake catalogue accounts for the addition of both all the characteristic and all the non‐characteristic events triggered in the faults. The global accumulated size–frequency relationship strongly depends on the fault length fractal exponent and, for fractal exponents close to 2, correctly describes a Gutenberg–Richter distribution with a b exponent compatible with real seismicity.
Nosocomial Spread of Ceftazidime-Resistant
Klebsiella pneumoniae
Strains Producing a Novel Class A β-Lactamase, GES-3, in a Neonatal Intensive Care Unit in Japan
Authors: Wachino Jun-ichi , Doi Yohei , Yamane Kunikazu , Shibata Naohiro , Yagi Tetsuya , Kubota Takako , Ito Hideo , Arakawa Yoshichika
Published: May 2004

Klebsiella pneumoniae
strain KG525, which showed high-level resistance to broad-spectrum cephalosporins, was isolated from the neonatal intensive care unit (NICU) of a Japanese hospital in March 2002. The ceftazidime resistance of strain KG525 was transferable to
Escherichia coli
CSH-2 by conjugation. Cloning and sequence analysis revealed that production of a novel extended-spectrum class A β-lactamase (pI 7.0), designated GES-3, which had two amino acid substitutions of M62T and E104K on the basis of the sequence of GES-1, was responsible for resistance in strain KG525 and its transconjugant. The
bla
GES-3
gene was located as the first gene cassette in a class 1 integron that also contained an
aacA1-orfG
fused gene cassette and one unique cassette that has not been described in other class 1 integrons and ended with a truncated 3′ conserved segment by insertion of IS
26
. Another five ceftazidime-resistant
K. pneumoniae
strains, strains KG914, KG1116, KG545, KG502, and KG827, which were isolated from different neonates during a 1-year period in the same NICU where strain KG525 had been isolated, were also positive for GES-type β-lactamase genes by PCR. Pulsed-field gel electrophoresis and enterobacterial repetitive intergenic consensus-PCR analyses displayed genetic relatedness among the six
K. pneumoniae
strains. Southern hybridization analysis with a GES-type β-lactamase gene-specific probe showed that the locations of
bla
GES
were multiple and diverse among the six strains. These findings suggest that within the NICU setting genetically related
K. pneumoniae
strains carrying the
bla
GES
gene were ambushed with genetic rearrangements that caused the multiplication and translocation of the
bla
GES
gene.
Epigallocatechin-Gallate Enhances the Activity of Tetracycline in Staphylococci by Inhibiting Its Efflux from Bacterial Cells
Authors: Sudano Roccaro Andrea , Blanco Anna Rita , Giuliano Francesco , Rusciano Dario , Enea Vincenzo
Published: May 2004

Epigallocatechin-gallate (EGCg), the major catechin present in green tea extracts, has been shown to have several antibacterial activities, limiting bacterial growth and invasion and acting in synergy with β-lactam antibiotics. In this article, we report that EGCg at doses half and below its calculated MIC of 100 μg/ml, is able to reverse tetracycline resistance in staphylococcal isolates expressing the specific efflux pump Tet(K) and appears to improve the MICs of tetracycline for susceptible staphylococcal isolates as well. The visible effect of EGCg is an increased accumulation of tetracycline inside bacterial cells. This effect is likely due to the inhibition of pump activity, and it is evident not only for Tet(K) pumps but also for efflux pumps of a different class [Tet(B)]. In summary, our data indicate that the observed dramatic enhancement by EGCg of tetracycline activity for resistant staphylococcal isolates is caused by impairment of tetracycline efflux pump activity and increased intracellular retention of the drug, suggesting a possible use of EGCg as an adjuvant in antibacterial therapy.
The Action of Bismuth against
Helicobacter pylori
Mimics but Is Not Caused by Intracellular Iron Deprivation
Authors: Bland Michael V. , Ismail Salim , Heinemann Jack A. , Keenan Jacqueline I.
Published: May 2004

Helicobacter pylori
is highly susceptible to bismuth, a heavy metal with antimicrobial activity linked to its effect on bacterial iron uptake. Three strains of
H. pylori
were analyzed for indicators of iron limitation following exposure to the MIC of colloidal bismuth subcitrate (MIC
CBS
). Similar morphologic and outer membrane changes were observed following growth in iron-limiting medium and at the MIC
CBS
that inhibited the growth of all three strains. These changes, which were also observed for iron-limited bacteria, were alleviated by the addition of iron to the cultures.
H. pylori
ATP levels, reduced in iron-limiting medium, were below the limits of detection in two of the three strains following exposure to bismuth. The addition of iron partially restored bacterial ATP levels in these two strains, although not to normal concentrations. In contrast, exposure of the same strains to the MIC
CBS
failed to deplete intracellular levels of iron, which were significantly reduced by culturing in iron-limiting medium. Thus, the antimicrobial effect of bismuth and of iron limitation on
H. pylori
may be similar. However, the respective mechanisms of intracellular action would appear to be mediated by different pathways within the cell.
Evolution of Resistance to Sulfadoxine-Pyrimethamine in
Plasmodium falciparum
Authors: Gatton Michelle L. , Martin Laura B , Cheng Qin
Published: May 2004

The development of resistance to sulfadoxine-pyrimethamine by
Plasmodium
parasites is a major problem for the effective treatment of malaria, especially
P. falciparum
malaria. Although the molecular basis for parasite resistance is known, the factors promoting the development and transmission of these resistant parasites are less clear. This paper reports the results of a quantitative comparison of factors previously hypothesized as important for the development of drug resistance, drug dosage, time of treatment, and drug elimination half-life, with an in-host dynamics model of
P. falciparum
malaria in a malaria-naïve host. The results indicate that the development of drug resistance can be categorized into three stages. The first is the selection of existing parasites with genetic mutations in the dihydrofolate reductase or dihydropteroate synthetase gene. This selection is driven by the long half-life of the sulfadoxine-pyrimethamine combination. The second stage involves the selection of parasites with allelic types of higher resistance within the host during an infection. The timing of treatment relative to initiation of a specific anti-
P. falciparum
EMP1 immune response is an important factor during this stage, as is the treatment dosage. During the third stage, clinical treatment failure becomes prevalent as the parasites develop sufficient resistance mutations to survive therapeutic doses of the drug combination. Therefore, the model output reaffirms the importance of correct treatment of confirmed malaria cases in slowing the development of parasite resistance to sulfadoxine-pyrimethamine.
Clade-Specific Flucytosine Resistance Is Due to a Single Nucleotide Change in the
FUR1
Gene of
Candida albicans
Authors: Dodgson Andrew R. , Dodgson Kirsty J. , Pujol Claude , Pfaller Michael A. , Soll David R.
Published: May 2004

Population studies have indicated that natural resistance to flucytosine (5FC) in
Candida albicans
is limited to one of the five major clades, clade I. In addition, while 73% of clade I isolates are less susceptible to 5FC (MIC ≥ 0.5 μg/ml), only 2% of non-clade I isolates are less susceptible. In order to determine the genetic basis for this clade-specific resistance, we sequenced two genes involved in the metabolism of 5FC that had previously been linked to resistance (cytosine deaminase and uracil phosphoribosyltransferase), in 48 isolates representative of all clades. Our results demonstrate that a single nucleotide change from cytosine to thymine at position 301 in the uracil phosphoribosyltransferase gene (
FUR1
) of
C. albicans
is responsible for 5FC resistance. The mutant allele was found only in group I isolates. The 5FC MICs for strains without copies of the mutant allele were almost exclusively ≤0.25 μg/ml, those for strains with one copy of the mutant allele were ≥0.5 μg/ml, and those for strains with two copies of the mutant allele were ≥16 μg/ml. Thus, the two alleles were codominant. The presence of this allele is responsible for clade I-specific resistance to 5FC within the
C. albicans
population and thus by inference is likely to be the major underlying 5FC resistance mechanism in
C. albicans
. This represents the first description of the genetic mutation responsible for 5FC resistance.
MAGNETIC BACKGROUNDS AND NONCOMMUTATIVE FIELD THEORY
Authors: SZABO RICHARD J.
Published: May 2004

This paper is a rudimentary introduction, geared at nonspecialists, to how noncommutative field theories arise in physics and their applications to string theory, particle physics and condensed matter systems.
EG‐VEGF: A Novel Mediator of Endocrine‐Specific Angiogenesis, Endothelial Phenotype, and Function
Authors: LECOUTER JENNIFER , LIN RUI , FERRARA NAPOLEONE
Published: May 2004

Abstract: Angiogenesis is the focus of therapeutic efforts to promote new vessel development in damaged tissues. Conversely, inhibiting endothelial cell growth and survival is a strategy to treat various proliferative diseases. Much evidence indicates that VEGF is a key mediator of angiogenesis. Recently, a novel angiogenic mitogen with tissue‐specific expression and target selectivity was characterized. Human endocrine gland derived vascular endothelial growth factor (EG‐VEGF) is selectively expressed in steroidogenic glands and promotes growth of endocrine gland endothelium. The identification of tissue‐selective angiogenic factors raises the possibility that other secreted molecules in this class exist. The potential advantage of tissue‐specific angiogenic therapeutics may be the reduction of systemic side effects. Additionally, these peptides or their receptors may be attractive targets for inhibition in several disorders.
Molecular Mechanisms of Gastrin‐Dependent Gene Regulation
Authors: HÖCKER MICHAEL
Published: May 2004

Abstract: The peptide hormone gastrin is the key regulator of gastric acid secretion. Gastrin exerts its effects as acid secretagogue through functional activation of gastric enterochromaffin‐like (ECL) cells, which control acid secretion through biosynthesis and release of histamine. In ECL cells, concerted activation of histidine decarboxylase (HDC), vesicular monoamine transporter 2 (VMAT2), and chromogranin A (CgA) genes by gastrin is a prerequisite for proper acid control. To elucidate the molecular pathways underlying gastrin‐dependent control of ECL cell genes, we recently analyzed the signaling cascades, regulatory promoter elements, and transcription factors mediating the transcriptional effects of gastrin. Our studies identified the Raf>MEK1>ERK 1/‐2 kinase module as the common signaling pathway mediating gastrin‐dependent ECL cell gene transcription. In contrast to this uniform signaling cascade, pronounced heterogeneity was detected between cis‐ and trans‐activating regulatory factors conferring gastrin responsiveness. The molecular diversity of transcription factors and regulatory enhancer elements transmitting gastrin‐triggered gene transcription offers the molecular basis for synergistic, but differential, regulation of HDC, VMAT2, and CgA genes during a secretory challenge of ECL cells by gastrin and possibly other acid secretagogues.
Programmed Cell Death Protein 4 (PDCD4) Acts As a Tumor Suppressor in Neuroendocrine Tumor Cells
Authors: GÖKE RÜDIGER , GREGEL CORNELIA , GÖKE ALEXANDRA , ARNOLD RUDOLF , SCHMIDT HARALD , LANKAT‐BUTTGEREIT BRIGITTE
Published: May 2004

Abstract: PDCD4 is a new tumor suppressor gene. In the current study, we show that overexpression of PDCD4 in carcinoid cells results in inhibition of cell proliferation. This is most likely caused by a PDCD4‐induced downregulation of carbonic anhydrase type II which catalyzes the production of bicarbonate, a fundamental substrate for many cellular pathways.
Strategies for Optimizing Antiepileptic Drug Therapy in Elderly People
Authors: Lackner Thomas E.
Published: May 2004

The elderly take more antiepileptic drugs (AEDs) than all other adults. This extensive use directly correlates with an increased prevalence of epilepsy in a growing population of older people, as well as other neuropsychiatric conditions such as neuropathic pain and behavioral disorders associated with dementia and for which AEDs are administered. The agents account for nearly 10% of all adverse drug reactions in the elderly and are the fourth leading cause of adverse drug reactions in nursing home residents. Numerous factors associated with advanced age contribute to the high frequency of untoward drug effects in this population; however, strategies are available to ensure optimal outcomes.
Clinical Outcomes of Critical Illness Polyneuropathy
Authors: Kane Sandra L. , Dasta Joseph F.
Published: May 2004

It is often difficult to isolate the origin of acute weakness in the critically ill population because of multiple etiologies. Aminoglycosides, corticosteroids, and neuromuscular blockers frequently are implicated as the source of acute weakness. Recently, critical illness polyneuropathy (CIP), a syndrome of unknown etiology, was added to the differential diagnosis. The frequency of CIP is approximately 70% in patients with sepsis. Early studies of CIP, which were mostly retrospective, underestimated its frequency due to the complexity of the diagnosis and unfamiliarity with the syndrome. Prospective studies have explored the causality and clinical outcomes of CIP. Clinical outcomes of patients with CIP include difficulty weaning from mechanical ventilation, increased length of stay, prolonged recovery, and an overall mortality rate of 26–71%. The association of CIP with sepsis, multiorgan failure, and drugs is still unclear.
Tobramycin as a Pharmacologic Tracer to Compare Airway Deposition from Nebulizers
Authors: Asmus Michael J. , Stewart Barbara A. , Milavetz Gary , Teresi Mary E. , Han Seung‐Ho , Wang Deli , Ahrens Richard C.
Published: May 2004

Study Objective. To assess the utility of inhaled tobramycin as a pharmacologic tracer for comparing lung deposition from a prototypic breath‐actuated jet nebulizer connected to an electronic pressure sensor designed to coordinate nebulization with inspiration with that from a continuously operating standard jet nebulizer.

Design. Prospective open‐label study.

Setting. University‐affiliated research center.

Subjects. Six healthy adult volunteers.

Intervention. All subjects received inhaled tobramycin 80, 160, and 320 mg from each nebulizer during six visits, as well as oral tobramycin 32 mg at a seventh visit to confirm the absence of significant gastrointestinal absorption. During each visit, urine was collected before drug administration and in 12‐hour segments throughout the first 48 hours after administration.

Measurements and Main Results. Lung deposition of tracer after each of the seven treatments was quantified by measuring urinary tobramycin excretion over 48 hours with use of an enzyme‐multiplied immunoassay technique. The ratio of tobramycin excreted after breath‐actuated nebulization to that after standard nebulization, normalized for dose, was used to compare lung deposition by the two devices. Urinary excretion of tobramycin was linear and proportional to dose for both nebulizers. For every 1 mg of tobramycin that the standard nebulizer deposited into the lungs, the breath‐actuated nebulizer deposited 1.22 mg (95% confidence interval 1.04–1.43).

Conclusions. Tobramycin can be used as a pharmacologic tracer for comparison of relative airway deposition by nebulizers.
Serum Bactericidal Activity of Extended‐Release Clarithromycin Against Macrolide‐Resistant Strains of Streptococcus pneumoniae
Authors: Stein Gary E. , Schooley Sharon
Published: May 2004

Study Objective. To investigate the serum bactericidal activity (SBA) over time of extended‐release clarithromycin against moderately resistant strains of Streptococcus pneumoniae.

Design. Prospective, single‐dose pharmacodynamic study.

Setting. University‐affiliated research center.

Subjects. Eleven healthy male volunteers.

Intervention. All volunteers received a single dose of extended‐release clarithromycin as two 500‐mg tablets, and blood samples were obtained at 0, 2, 6, 12, and 24 hours after administration of the dose.

Measurements and Main Results. For each blood sample, a serum bactericidal titer (SBT) was determined against S. pneumoniae strains with minimum inhibitory concentrations (MICs) of 0.5, 1.0, 2.0, 4.0, and 8.0 μg/ml to clarithromycin. The median SBT was determined for each time period. The extended‐release formulation of clarithromycin exhibited SBA for 24 hours against pneumococcal strains with MICs of 0.5, 1.0, and 2.0 μg/ml. No SBA was observed against isolates with MICs of 4.0 or 8.0 μg/ml.

Conclusion. The extended‐release formulation of clarithromycin, taken once/day, will provide SBA for 24 hours against strains of S. pneumoniae with MICs of 2.0 μg/ml or less.
Syndrome of Inappropriate Antidiuretic Hormone‐Induced Hyponatremia Associated with Amiodarone
Authors: Patel Gourang P. , Kasiar Jennifer B.
Published: May 2004

The syndrome of inappropriate antidiuretic hormone (SIADH), the most common cause of euvolemic hyponatremia, is due to nonphysiologic release of arginine vasopressin from the posterior pituitary. Hyponatremia induced by SIADH can be caused by several conditions, such as central nervous system disorders, malignancies, various nonmalignant lung diseases, hypoadrenalism, and hypothyroidism. A 67‐year‐old man developed hyponatremia consistent with SIADH. Although common comorbid conditions associated with SIADH were excluded as possible causes, his medical history and drug regimen were extensive. However, he had been taking spironolactone, amiodarone, and simvastatin for less than 3 months. Amiodarone was discontinued based on a case report suggesting that this drug can cause SIADH‐induced hyponatremia. The patient's serum sodium level began to rise within 3 days of discontinuation and returned to normal within 1 month. Although SIADH‐induced hyponatremia occurs only rarely, it should be recognized as a possible adverse effect of amiodarone.
Impact of a Critical Pathway on Acute Myocardial Infarction Quality Indicators
Authors: Bestul Megan B. , McCollum Marianne , Stringer Kathleen A. , Burchenal Jeb
Published: May 2004

Study Objective. To determine the impact of a critical pathway on acute myocardial infarction (AMI) quality indicators.

Design. Retrospective chart review.

Setting. Large university hospital.

Patients. One hundred seventy‐five patients who underwent primary percutaneous transluminal angioplasty for AMI (control group 89 patients, intervention group 86 patients).

Measurements and Main Results. The medical records of the control group (1998–1999) were reviewed for door‐to‐balloon (DtB) time (the time between the patient's arrival at the emergency department and the first balloon inflation during a percutaneous transluminal coronary angioplasty procedure). Drug therapy prescribed at hospital discharge (aspirin, β‐blocker, angiotensin‐converting enzyme [ACE] inhibitor, and lipid‐lowering therapy) was also reviewed. The data collected for the control group were compared with the intervention group data (2000–2001). The impact of the pathway was evaluated using the Wilcoxon rank sum test, odds ratios (ORs), and χ2 tests. The DtB time was significantly lower in the intervention group versus the control group (91.5 vs 108 min, p<0.01), and fewer intervention patients exceeded the guidelines with a DtB time longer than 120 minutes (OR 0.38, p<0.01). In addition, the intervention group was more likely than the control group to be prescribed an ACE inhibitor (OR 3.7, p<0.01) or lipid‐lowering therapy (OR 3.7, p=0.02) at discharge. Aspirin and β‐blockers were not prescribed differently in the intervention versus control groups (aspirin 95.2% vs 96.2%, β‐blockers 93.5% vs 92.6%).

Conclusion. These data suggest that in the current era of published treatment guidelines, implementation of a critical pathway can further improve AMI quality indicators and clinical care.
Changing Strategies for the Management of Invasive Fungal Infections
Authors: Rapp Robert P.
Published: May 2004

The frequency of invasive fungal infections (IFIs) has increased with the increase in number of high‐risk patients. United States trends in mortality due to invasive mycoses showed a striking increase in the past 2 decades. Human immunodeficiency virus–associated opportunistic mycoses accounted for part of the increase, as did mycoses in other immunocompromised populations. Those at‐risk populations include recipients of solid organ transplants or hematopoietic stem cell transplants, those with hematologic malignancies, and others receiving immunosuppressive treatment. Infections due to Candida sp are the most common fungal infections. The mortality rate due to invasive aspergillosis has risen steadily, with a 357% increase from 1980–1997. Depending on whether an IFI is possible, probable, or proved, three treatment strategies are available: prophylactic, empiric, and specific. Options for preventing and treating IFIs have increased, with four classes of antifungal agents available: polyenes, azoles, nucleoside analogs, and echinocandins. The effectiveness of the polyene amphotericin B deoxycholate (the standard for > 40 yrs) is limited by toxic effects, notably renal and infusion‐related toxicity. Three lipid formulations are approved for the treatment of IFIs in patients refractory to or intolerant of amphotericin B: amphotericin lipid complex, amphotericin B colloidal dispersion, and liposomal amphotericin B. The nucleoside analog class contains only flucytosine—an antimetabolite targeting the nucleus of the fungal cell and generally not given as monotherapy because of frequent development of resistance. The azoles debuted with ketoconazole, followed by fluconazole, itraconazole, and voriconazole. Fluconazole is largely active against Candida sp and Cryptococcus neoformans; itraconazole's activity is largely against moulds, such as Aspergillus, and dimorphic fungi, such as Histoplasma and Blastomyces; and voriconazole is active against both yeasts and moulds. The echinocandin class has one drug approved for clinical use—caspofungin, which targets the fungal cell wall. Deciding which antifungal agent to use involves weighing such clinical factors as mycoses susceptibility and drug toxicity, as well as pharmacoeconomic considerations. Besides the price of the drug, the cost of antifungal therapy includes costs of mortality associated with failed treatment, prolonged hospitalization and treatment related to complications, and additional antifungal treatment to compensate for primary treatment failure.
Evaluation of the US Oncology Network's Recommended Guidelines for Therapeutic Substitution with Darbepoetin alfa 200 μg Every 2 Weeks in Both Naïve Patients and Patients Switched from Epoetin alfa
Authors: Thames William A. , Smith Sandra L. , Scheifele Andrew C. , Yao Bin , Giffin Suzana A. , Alley Julie L.
Published: May 2004

Study Objective. To evaluate the efficacy of darbepoetin alfa 200 μg subcutaneously every 2 weeks after therapeutic substitution for epoetin alfa.

Design. Retrospective multicenter chart review.

Setting. Three US Oncology–affiliated outpatient sites.

Patients. Three hundred thirty anemic patients with nonmyeloid malignancies, of whom 174 had been treated previously with epoetin alfa (switched group) and 156 had not been treated recently with epoetin alfa (naïve group).

Interventions. Therapeutic substitution with darbepoetin alfa was started according to the US Oncology Pharmacy and Therapeutics Committee's recommended dosing guidelines: anemic patients with cancer received a starting dosage of darbepoetin alfa 200 μg every 2 weeks regardless of whether or not they had previously received epoetin alfa. Hematologic and darbepoetin alfa usage data were abstracted from consecutive medical records dated from May 2002–March 2003.

Measurements and Main Results. Median exposure to darbepoetin alfa was 10 weeks (25th quartile 6 wks, 75th quartile 17 wks) and 10 weeks (25th quartile 5 wks, 75th quartile 18 wks) for the naïve and switched groups, respectively. The week before the switch to darbepoetin alfa, the 174 patients receiving epoetin alfa were administered the following weekly doses: less than 40,000 U (9%), 40,000 U (50%), or 45,000–90,000 U (41%). Mean hemoglobin level increased from baseline (wk 0) in both the naïve and switched groups. The proportion of patients receiving a red blood cell transfusion in the darbepoetin alfa treatment phase was low (15% in each group). No variation in transfusion rates was observed across weight categories in patients who received a fixed dosage of darbepoetin alfa. Darbepoetin alfa was well tolerated. A detailed usage algorithm was validated by these results and is being used in these three US Oncology–affiliated practices.

Conclusion. A darbepoetin alfa starting dosage of 200 μg subcutaneously every 2 weeks administered according to US Oncology–recommended dosing guidelines is effective in treating chemotherapy‐induced anemia in both epoetin alfa–naïve patients and those switched from epoetin alfa.