bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibitory Action of Ethanol on Cyclooxygenase‐2 Expression through Suppression of the Extracellular Signal‐Related Kinase‐Mediated Pathway in Rat Alveolar Macrophages
Authors: Kato Hirohisa , Negoro Munetaka , Wakabayashi Ichiro
Published: November 2004

Abstract: The purpose of the present study was to elucidate the effects of ethanol on expression of cyclooxygenase in alveolar macrophages. Rat alveolar macrophages were collected by bronchoalveolar lavage and stimulated by lipopolysaccharide. Lipopolysaccharide‐induced cyclooxygenase‐2 expression and prostaglandin E2 production were inhibited by ethanol (100–200 mM) in a concentration‐dependent manner. Ethanol at 100–200 mM concentration‐dependently inhibited cyclooxygenase‐2 mRNA expression. Lipopolysaccharide‐stimulated phosphorylation of both extracellular signal‐related kinase and p38 mitogen‐activated protein kinase was also significantly inhibited by ethanol (50–200 mM). Cyclooxygenase‐2 expression was significantly inhibited by U0126 but was not affected by SB203580. In the presence of SB203580, lipopolysaccharide‐induced cyclooxygenase‐2 expression was also inhibited by ethanol (50–200 mM). On the other hand, cyclooxygenase‐1 was expressed constitutively in alveolar macrophages and cyclooxygenase‐1 expression was affected neither by lipopolysaccharide nor ethanol. Lipopolysaccharide‐induced expression of inducible nitric oxide synthase in alveolar macrophages was not affected by ethanol at 50–200 mM. These results suggest that lipopolysaccharide‐induced expression of cyclooxygenase‐2 is mediated by extracellular signal‐related kinase but not by p38 kinase and that ethanol selectively attenuates cyclooxygenase‐2 expression mainly by inhibiting activation of extracellular signal‐related kinase.
NMDA receptors induce somatodendritic secretion in hypothalamic neurones of lactating female rats
Authors: De Kock Christiaan P. J. , Burnashev Nail , Lodder Johannes C. , Mansvelder Huibert D. , Brussaard Arjen B.
Published: November 2004

Many neurones in the mammalian brain are known to release the content of their vesicles from somatodendritic locations. These vesicles usually contain retrograde messengers that modulate network properties. The back‐propagating action potential is thought to be the principal physiological stimulus that evokes somatodendritic release. In contrast, here we show that calcium influx through NMDA receptor (NMDAR) channels, in the absence of postsynaptic cell firing, is also able to induce vesicle fusion from non‐synaptic sites in nucleated outside‐out patches of dorsomedial supraoptic nucleus (SON) neurones of adult female rats, in particular during their reproductive stages. The physiological significance of this mechanism was characterized in intact brain slices, where NMDAR‐mediated release of oxytocin was shown to retrogradely inhibit presynaptic GABA release, in the absence of postsynaptic cell firing. This implies that glutamatergic synaptic input in itself is sufficient to elicit the release of oxytocin, which in turn acts as a retrograde messenger leading to the depression of nearby GABA synapses. In addition, we found that during lactation, when oxytocin demand is high, NMDA‐induced oxytocin release is up‐regulated compared to that in non‐reproductive rats. Thus, in the hypothalamus, local signalling back and forth between pre‐ and postsynaptic compartments and between different synapses may occur independently of the firing activity of the postsynaptic neurone.
The effect of simulated ischaemia on spontaneous GABA release in area CA1 of the juvenile rat hippocampus
Authors: Allen Nicola J. , Attwell David
Published: November 2004

An early consequence of brain energy deprivation is an increase in the frequency of spontaneous inhibitory and excitatory postsynaptic currents (sIPSCs and sEPSCs), which may disrupt neural information processing. This increase in spontaneous transmitter release has been reported to occur in calcium‐free solution and has been attributed either to calcium release from internal stores or to a direct effect of hypoxia on the transmitter release mechanism. Here we investigate the mechanism of the increase in sIPSC frequency that occurs in area CA1 of rat hippocampus during simulated ischaemia, by making patch‐clamp recordings from CA1 pyramidal neurones. When recording in whole‐cell mode, exposure to ischaemic solution increased the sIPSC frequency 30‐fold (to 49 Hz) after 5 min, and doubled the sIPSC amplitude. Ischaemic sIPSCs were action potential independent, vesicular in origin and, contrary to the results of earlier studies which did not buffer extracellular calcium to a low level, dependent on extracellular calcium. The properties of the ischaemic sIPSCs were not affected by depleting intracellular stores of calcium or by blocking the neuronal GABA transporter GAT‐1. Recording from neurones using gramicidin‐perforated patch‐clamping showed a 10‐fold smaller, more transient increase in sIPSC frequency during ischaemia, with no change of sIPSC amplitude, suggesting that whole‐cell clamp recording increases the ischaemia‐induced sIPSC rate and amplitude by controlling the intracellular milieu.
Interhemispheric interaction between human dorsal premotor and contralateral primary motor cortex
Authors: Mochizuki Hitoshi , Huang Ying‐Zu , Rothwell John C.
Published: November 2004

We used transcranial magnetic stimulation (TMS) in a paired pulse protocol to investigate interhemispheric interactions between the right dorsal premotor (dPM) and left primary motor cortex (M1) using interstimulus intervals of 4, 6, 8, 10, 12, 16 and 20 ms in ten healthy subjects. A conditioning stimulus over right dPM at an intensity of either 90 or 110% resting motor threshold (RMT) suppressed motor‐evoked potentials (MEPs) evoked in the first dorsal interosseous (FDI) muscle by stimulation of left M1. Maximum effects occurred for interstimulus intervals (ISIs) of 8–10 ms. There was no effect if the conditioning stimulus was applied 2.5 cm lateral, anterior or medial to dPM. The effect differed from previously described M1 interhemispheric inhibition in that the threshold for the latter was greater than 90% RMT, whereas stimulation of the dPM at the same intensity led to significant inhibition. In addition, voluntary contraction of the left FDI (i.e. contralateral to the conditioning TMS) enhanced interhemispheric inhibition from right M1 but had no effect on the inhibition from right dPM. Finally, conditioning to right dPM at 90% RMT reduced short‐interval intracortical inhibition (SICI; at ISI = 2 ms) in left M1 whilst there was no effect if the conditioning stimulus was applied to right M1. We conclude that conditioning TMS over dPM has effects that differ from the previous pattern of interhemispheric inhibition described between bilateral M1s. This may reflect the existence of commissural fibres between dPM and contralateral M1 that may play a role in bimanual coordination.
Addressing students’ misconceptions of renal clearance
Authors: Richardson Daniel , Speck Dexter
Published: November 2004

Renal clearance is one of the more difficult concepts for students of physiology to learn. We hypothesized that this difficulty is rooted in a student’s misunderstanding of virtual volume. This was tested by having students select from several drawings the one they thought plasma would look like after a certain volume of it has been cleared of sodium by the kidneys. About half the participating students selected plasma pictured as having a certain volume of it devoid of sodium molecules. That is, their misconception of clearance seemed to be due to a lack of understanding about virtual volume, a deficiency which is reinforced by the classic definition of clearance. To address this misconception, a demonstration was devised in which a beaker of concentrated colored water was used to represent plasma before renal clearance, a beaker of the same concentrated colored water in which the top third had been replaced by clear mineral oil was used to represent what the definition of clearance said would happen to plasma after a third of it had been cleared of sodium, and a beaker of dilute colored water was used to represent what really happens to plasma when a certain volume of it is cleared of a solute. Incorporating this demonstration into discussions of renal clearance helped students to understand this concept, as evidenced by improved scores on related questions.
The targeted oral
Authors: Rangachari P. K.
Published: November 2004

An oral examination for assessing senior undergraduate students is described. The examinations were conducted in a room with a one-way mirror so that all students could learn from each other. This procedure was much appreciated by the participants.
Evolution of hominoids and the search for a genetic basis for creating humanness
Authors: Saitou N.
Published: November 2004

The phylogenetic relationship of human and apes are reviewed. The history of molecular phylogenetic studies in this field is then discussed, as is the role of natural selection at the molecular level. It is argued that approximately 10,000 genetic changes are responsible for creating human specific phenotypes. A genome-wide comparison is necessary to decipher those changes.
The dynamic nature and evolutionary history of subtelomeric and pericentromeric regions
Authors: Mewborn S.K. , Lese Martin C. , Ledbetter D.H.
Published: November 2004

The organization and evolution of the subtelomeric and pericentromeric regions of human chromosomes exhibit unique characteristics compared to other regions of the genome. As shown in Fig. 1 the functional elements of the centromere and telomere are comprised of highly repetitive DNA sequences, which are responsible for carrying out the main mechanistic duties of these two regions: chromosome segregation and end replication, respectively. The nature of the repeats in these two regions and their function have been reviewed separately and, therefore, will not be discussed in more detail here (Sullivan et al., 1996, 2001; McEachern et al., 2000; Henikoff et al., 2001). Adjacent to these functional element regions, the centromere and telomere regions share an interesting architecture as depicted in Fig. 1. For both pericentromeric and subtelomeric regions, blocks of recent genomic duplications form a zone of shared sequence homologies between certain subsets of human chromosomes. The dynamic nature and evolutionary history of these regions and the unique DNA sequence adjacent to them will be the focus of this review.
Primate phylogeny: molecular evidence from retroposons
Authors: Schmitz J. , Roos C. , Zischler H.
Published: November 2004

In these postgenomic times where aspects of functional genetics and character evolution form a focal point of human-mouse comparative research, primate phylogenetic research gained a widespread interest in evolutionary biology. Nevertheless, it also remains a controversial subject. Despite the surge in available primate sequences and corresponding phylogenetic interpretations, primate origins as well as several branching events in primate divergence are far from settled. The analysis of SINEs – short interspersed elements – as molecular cladistic markers represents a particularly interesting complement to sequence data. The following summarizes and discusses potential applications of this new approach in molecular phylogeny and outlines main results obtained with SINEs in the context of primate evolutionary research. Another molecular cladistic marker linking the tarsier with the anthropoid primates is also presented. This eliminates any possibility of confounding phylogenetic interpretations through lineage sorting phenomena and makes use of a new point of view in settling the phylogenetic relationships of the primate infraorders.
Tandem insertions of Alu elements
Authors: El-Sawy M. , Deininger P.
Published: November 2004

Alu elements are non-autonomous, non-LTR retroposons that represent the most abundant mobile elements in the human genome (1.1 × 106 copies/genome). They preferentially insert adjacent to existing Alu elements. It has been proposed that Alu elements utilize LINE-1 machinery for their retroposition. The LINE-1 endonuclease cleaves at a loose consensus sequence. We have utilized a bioinformatics approach to show the order of insertion of pairs of young (Y) and old (S or J) Alu subfamily members. Our data suggest that the consensus LINE-1 endonuclease cleavage site used for insertion of the old Alu elements can be reused for integration of the younger ones inserting adjacent to them. However, there is also a preference at the 3′ end of Alu into a non-ideal cleavage site that may represent unique properties of the A-tail for integration. Alu elements inserting adjacent to one another may suggest the saturation of the optimal integration sites with existing Alu elements, rather than any innate preference for Alu elements to integrate adjacent to other Alus.
Molecular evolution of the human chromosome 15 pericentromeric region
Authors: Locke D.P. , Jiang Z. , Pertz L.M. , Misceo D. , Archidiacono N. , Eichler E.E.
Published: November 2004

We present a detailed molecular evolutionary analysis of 1.2 Mb from the pericentromeric region of human 15q11. Sequence analysis indicates the region has been subject to extensive interchromosomal and intrachromosomal duplications during primate evolution. Comparative FISH analyses among non-human primates show remarkable quantitative and qualitative differences in the organization and duplication history of this region – including lineage-specific deletions and duplication expansions. Phylogenetic and comparative analyses reveal that the region is composed of at least 24 distinct segmental duplications or duplicons that have populated the pericentromeric regions of the human genome over the last 40 million years of human evolution. The value of combining both cytogenetic and experimental data in understanding the complex forces which have shaped these regions is discussed.
Origins of primate chromosomes – as delineated by Zoo-FISH and alignments of human and mouse draft genome sequences
Authors: Froenicke L.
Published: November 2004

This review examines recent advances in comparative eutherian cytogenetics, including Zoo-FISH data from 30 non-primate species. These data provide insights into the nature of karyotype evolution and enable the confident reconstruction of ancestral primate and boreo-eutherian karyotypes with diploid chromosome numbers of 48 and 46 chromosomes, respectively. Nine human autosomes (1, 5, 6, 9, 11, 13, 17, 18, and 20) represent the syntenies of ancestral boreo-eutherian chromosomes and have been conserved for about 95 million years. The average rate of chromosomal exchanges in eutherian evolution is estimated to about 1.9 rearrangements per 10 million years (involving 3.4 chromosome breaks). The integrated analysis of Zoo-FISH data and alignments of human and mouse draft genome sequences allow the identification of breakpoints involved in primate evolution. Thus, the boundaries of ancestral eutherian conserved segments can be delineated precisely. The mapping of rearrangements onto the phylogenetic tree visualizes landmark chromosome rearrangements, which might have been involved in cladogenesis in eutherian evolution.
Reciprocal painting between humans, De Brazza’s and patas monkeys reveals a major bifurcation in the Cercopithecini phylogenetic tree
Authors: Stanyon R. , Bruening R. , Stone G. , Shearin A. , Bigoni F.
Published: November 2004

We report on reciprocal painting between humans and two Cercopithecini species, Erythrocebus patas (patas monkey) and Cercopithecus neglectus (De Brazza’s monkey). Both human and monkeys chromosome-specific probes were made by degenerate oligonucleotide primed PCR (DOP-PCR) from flow sorted chromosomes. Metaphases of both monkey species were first hybridized with human chromosome-specific probes and then human metaphases were hybridized with chromosome paints from each monkey species. The human paint probes detected 34 homologous segments on the C. neglectus karyotype, while the C. neglectus probes, including the Y, revealed 41 homologous segments on the human karyotype. The probes specific for human chromosomes detected 29 homologous segments in the E. patas karyotype, while the patas monkey probes painted 34 segments on the human karyotype. We tested various hypotheses of Cercopithecini phylogeny and taxonomy developed by morphologists, molecular biologists and cytogeneticists. Our hybridization data confirm that fissions (both Robertsonian and non-Robertsonian) are the main mechanism driving the evolutionary trend in Cercopithecini toward higher diploid numbers and strongly suggest an early phylogenetic bifurcation in Cercopithecini. One branch leads to Cercopithecus neglectus/Cercopithecus wolfi while the other line leads to Erythrocebus patas/Chlorocebus aethiops. Allenopithecus nigroviridis may have diverged prior to this major phylogenetic node.
Phylogenetic inferences of Atelinae (Platyrrhini) based on multi-directional chromosome painting in Brachyteles arachnoides, Ateles paniscus paniscus and Ateles b. marginatus
Authors: de Oliveira E.H.C. , Neusser M. , Pieczarka J.C. , Nagamachi C. , Sbalqueiro I.J. , Müller S.
Published: November 2004

We performed multi-directional chromosome painting in a comparative cytogenetic study of the three Atelinae species Brachyteles arachnoides, Ateles paniscus paniscus and Ateles belzebuth marginatus, in order to reconstruct phylogenetic relationships within this Platyrrhini subfamily. Comparative chromosome maps between these species were established by multi-color fluorescence in situ hybridization (FISH) employing human, Saguinus oedipus and Lagothrix lagothricha chromosome-specific probes. The three species included in this study and four previously analyzed species from all four Atelinae genera were subjected to a phylogenetic analysis on the basis of a data matrix comprised of 82 discrete chromosome characters. The results confirmed that Atelinae represent a monophyletic clade with a putative ancestral karyotype of 2n = 62 chromosomes. Phylogenetic analysis revealed an evolutionary branching sequence {Alouatta {Brachyteles {Lagothrix and Ateles}}} in Atelinae and {Ateles belzebuth marginatus {Ateles paniscus paniscus {Ateles belzebuth hybridus and Ateles geoffroyi}}} in genus Ateles. The chromosomal data support a re-evaluation of the taxonomic status of Ateles b. hybridus.
New insights into the evolution of chromosome 1
Authors: Weise A. , Starke H. , Mrasek K. , Claussen U. , Liehr T.
Published: November 2004

A complex low-repetitive human DNA probe (BAC RP11-35B4) together with two microdissection-derived region-specific probes of the multicolor banding (MCB) probe-set for chromosome 1 were used to re-analyze the evolution of human chromosome 1 in comparison to four ape species. BAC RP11-35B4 derives from 1q21 and contains 143 kb of non-repetitive DNA; however, it produces three specific FISH signals in 1q21, 1p12 and 1p36.1 of Homo sapiens (HSA). Human chromosome 1 was studied in comparison to its homologues in Hylobates lar (HLA), Pongo pygmaeus (PPY), Gorilla gorilla (GGO) and Pan troglodytes (PTR). A duplication of sequences homologous to human 1p36.1 could be detected in PPY plus an additional signal on PPY 16q. The region homologous to HSA 1p36.1 is also duplicated in HLA, and split onto chromosomes 7q and 9p; the region homologous to HSA 1q21/1p12 is present as one region on 5q. Additionally, the breakpoint of a small pericentric inversion in the evolution of human chromosome 1 compared to other great ape species could be refined. In summary, the results obtained here are in concordance with previous reports; however, there is evidence for a deletion of regions homologous to human 1p34.2→p34.1 during evolution in the Pongidae branch after separation of PPY.
Evolutionary breakpoints are co-localized with fragile sites and intrachromosomal telomeric sequences in primates
Authors: Ruiz-Herrera A. , García F. , Giulotto E. , Attolini C. , Egozcue J. , Ponsà M. , Garcia M.
Published: November 2004

The concentration of evolutionary breakpoints in primate karyotypes in some particular regions or chromosome bands suggests that these chromosome regions are more prone to breakage. This is the first extensive comparative study which investigates a possible relationship of two genetic markers (intrachromosomal telomeric sequences [TTAGGG]n, [ITSs] and fragile sites [FSs]), which are implicated in the evolutionary process as well as in chromosome rearrangements. For this purpose, we have analyzed: (a) the cytogenetic expression of aphidicolin-induced FSs in Cebus apella and Cebus nigrivittatus (F. Cebidae, Platyrrhini) and Mandrillus sphinx (F. Cercopithecidae, Catarrhini), and (b) the intrachromosomal position of telomeric-like sequences by FISH with a synthetic (TTAGGG)n probe in C. apella chromosomes. The multinomial FSM statistical model allowed us to determinate 53 FSs in C. apella, 16 FSs in C. nigrivittatus and 50 FSs in M. sphinx. As expected, all telomeres hybridized with the probe, and 55 intrachromosomal loci were also detected in the Cebus apella karyotype. The χ2 test indicates that the coincidence of the location of Cebus and Mandrillus FSs with the location of human FSs is significant (P < 0.005). Based on a comparative cytogenetic study among different primate species we have identified (or described) the chromosome bands in the karyotypes of Papionini and Cebus species implicated in evolutionary reorganizations. More than 80% of these evolutionary breakpoints are located in chromosome bands that express FSs and/or contain ITSs.
Inter- and intra-specific gene-density-correlated radial chromosome territory arrangements are conserved in Old World monkeys
Authors: Tanabe H. , Küpper K. , Ishida T. , Neusser M. , Mizusawa H.
Published: November 2004

Recently it has been shown that the gene-density correlated radial distribution of human 18 and 19 homologous chromosome territories (CTs) is conserved in higher primates in spite of chromosomal rearrangements that occurred during evolution. However, these observations were limited to apes and New World monkey species. In order to provide further evidence for the evolutionary conservation of gene-density-correlated CT arrangements, we extended our previous study to Old World monkeys. They comprise the remaining species group to be analyzed in order to obtain a comprehensive overview of the nuclear topology of human 18 and 19 homologous CTs in higher primates. In the present study we investigated four lymphoblastoid cell lines from three species of Old World monkeys by three-dimensional fluorescence in situ hybridization (3D-FISH): two individuals of Japanese macaque (Macaca fuscata), crab-eating macaque (Macaca fascicularis), and an interspecies hybrid individual between African green monkey (Cercopithecus aethiops) and Patas monkey (Erythrocebus patas). Our data demonstrate that gene-poor human 18 homologous CTs are located preferentially close to the nuclear periphery, whereas gene-dense human 19 homologous CTs are oriented towards the nuclear center in all cell lines analyzed. The gene-density-correlated positioning of human 18 and 19 homologous CTs is evolutionarily conserved throughout all major higher primate lineages, despite chromosomal inversions, fusions, fissions or reciprocal translocations that occurred in the course of evolution in these species. This remarkable preservation of a gene-density-correlated chromatin arrangement gives further support for a functionally relevant higher-order chromatin architecture.
Retrieval of Sea Surface Temperature from Space, Based on Modeling of Infrared Radiative Transfer: Capabilities and Limitations
Authors: Merchant Christopher J. , Le Borgne Pierre
Published: November 2004

The retrieval (estimation) of sea surface temperatures (SSTs) from space-based infrared observations is increasingly performed using retrieval coefficients derived from radiative transfer simulations of top-of-atmosphere brightness temperatures (BTs). Typically, an estimate of SST is formed from a weighted combination of BTs at a few wavelengths, plus an offset. This paper addresses two questions about the radiative transfer modeling approach to deriving these weighting and offset coefficients. How precisely specified do the coefficients need to be in order to obtain the required SST accuracy (e.g., scatter <0.3 K in week-average SST, bias <0.1 K)? And how precisely is it actually possible to specify them using current forward models? The conclusions are that weighting coefficients can be obtained with adequate precision, while the offset coefficient will often require an empirical adjustment of the order of a few tenths of a kelvin against validation data. Thus, a rational approach to defining retrieval coefficients is one of radiative transfer modeling followed by offset adjustment. The need for this approach is illustrated from experience in defining SST retrieval schemes for operational meteorological satellites. A strategy is described for obtaining the required offset adjustment, and the paper highlights some of the subtler aspects involved with reference to the example of SST retrievals from the imager on the geostationary satellite GOES-8.
Improving Wind Profiler–Measured Winds Using Coplanar Spectral Averaging
Authors: Schafer Robert , Avery Susan K. , Gage Kenneth S. , Johnston Paul E. , Carter D. A.
Published: November 2004

A method is presented that increases the detectability of weak clear-air signals by averaging Doppler spectra from coplanar wind profiler beams. The method, called coplanar spectral averaging (CSA), is applied to both simulated wind profiler spectra and to 1 yr of archived spectra from a UHF profiler at Christmas Island (1 October 1999–30 September 2000). A collocated 50-MHz wind profiler provides a truth for evaluating the CSA technique.

In the absence of precipitation, it was found that CSA, when combined with a fuzzy logic quality control, increases the height coverage of the 1-hourly averaged UHF profiler winds by over 600 m (two range gates). CSA also increased the number of good wind estimates at each observation range by about 10%–25% over the standard consensus method.
A Wireless Network for Collection and Synthesis of Mobile Mesoscale Weather Observations
Authors: Ziegler Conrad L. , Kennedy Douglas , Rasmussen Erik N.
Published: November 2004

This paper reports the development of a wireless network of instrumented vehicles and aircraft for the real-time collection and synthesis of their mobile weather observations in mesoscale field experiments. The mobile digital network (MDN) utilizes 900-MHz radio frequency modem technology, enabling real-time data transmissions at up to 115 kbit s−1 across a domain of about 40 km on a side. The effective throughput of the network of multiple mobile units is about 40 kbit s−1 due to overhead from data quality checking and acknowledgment that data have been received. After gathering data from mobile observing platforms at a centrally located mobile command post, both image products and data are then uplinked via geostationary satellite at about 80 kbit s−1 and served to the Internet. The first application of the MDN was to mobile field observations obtained during the International H2O Project (IHOP).
Meteosat and GOES-East Imager Visible Channel Calibration
Authors: Le Borgne Pierre , Legendre Gérard , Marsouin Anne
Published: November 2004

As a preliminary step to solar irradiance calculations, the Centre de Météorologie Spatiale (CMS) has developed a pragmatic approach to calibrate the visible channels of Meteosat and GOES-East imagers. The responsivity of the Meteosat visible channel has been monitored with three desert targets from 1989 to 2002. The annual degradation rate has been estimated to 1.8% for Meteosat-4, 1.4% for Meteosat-5, and 1.9% for Meteosat-7. A reference calibration coefficient for Meteosat-7 has been derived from a comparison with Clouds and Earth's Radiant Energy System (CERES) data in summer 1998. Meteosat and GOES-East data corresponding to homogenous pixels along longitude 37.5°W and around 1200 LST have been compared on a monthly basis, leading to a calibration of GOES-East visible channel. GOES-8 data have been processed from June 1998 to December 2002 and the annual degradation rate obtained during this period is 4.0%. GOES-12 data have been processed from April to August 2003. During this short period, no degradation rate can be estimated but only a mean value of the calibration coefficient, which corresponds to a 7% increase of the prelaunch coefficient.
Analgesic Effect of Sustained‐Release Flurbiprofen Administered at the Site of Tissue Injury in the Oral Surgery Model
Authors: Dionne Raymond A. , Haynes Duncan , Brahim Jaime S. , Rowan Janet S. , Guivarc'h Pol‐Henri
Published: November 2004

Nonsteroidal anti‐inflammatory drugs produce their analgesic and adverse effects through interaction with cyclooxygenase in a variety of tissues. The authors evaluated the therapeutic potential of administering a sustained‐release formulation of flurbiprofen into a surgical wound following oral surgery to produce analgesia at the site of injury while minimizing exposure to potential targets for toxicity. Subjects (N = 98) received 1 of 8 treatments: flurbiprofen in a microparticle formulation in doses of 3.125 mg, 6.25 mg, 12.5 mg, 25 mg, or 50 mg; PO flurbiprofen 25 mg or 50 mg; or placebo. The flurbiprofen microparticle formulation or matching placebo was placed into the extraction sites at the end of surgery (removal of 2 lower impacted third molars). The sum of the pain visual analog scale over the 6‐hour observation period demonstrated significantly less pain (P < .05) for flurbiprofen microparticle in comparison with placebo. Fewer subjects remedicated in the flurbiprofen microparticle drug groups, primarily for the 12.5‐mg and higher doses. The incidence of adverse effects and local complications did not differ across groups. These data suggest that direct administration of flurbiprofen in a microparticle formulation at a site of tissue injury delays the onset and lowers the intensity of postoperative pain at lower doses than usually administered orally.
The Effect of Food on the Pharmacokinetics of a Dual Angiotensin‐Converting Enzyme/Neutral Endopeptidase Inhibitor, M100240
Authors: Cirillo Iolanda , Martin Nancy E. , Brennan Barbara , Barrett Jeffrey S.
Published: November 2004

M100240 is a thioester of MDL 100,173, a dual angiotensin‐converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor. Clinical studies have shown that M100240 is capable of decreasing ACE activity and angiotensin II concentrations while increasing plasma renin activity and potentiating the effects of atrial natriuretic peptide. This may result in a unique treatment benefit in disease states characterized by intravascular volume or sodium overload or increased venous pressure. The pharmacokinetics of MDL 100,173 were evaluated in 30 healthy subjects in an open‐label, randomized, 2‐period crossover design. Subjects received a single oral dose of 50 mg of M100240 administered with a high‐fat meal and separately under fasted conditions. Serial plasma concentrations of M100240 and MDL 100,173 were analyzed, and pharmacokinetic parameters were calculated with noncompartmental methods. The intrasubject percent coefficient of variation for MDL 100,173 Cmax and AUC0–24h were less than 20%, indicating that this agent is a moderately variable drug. Although AUC0–24h was within the protocol‐defined range of 80% to 125%, the lower limit of the 90% confidence interval for Cmax fell outside of the 70% to 143% range. Absence of a food effect on the pharmacokinetic profile of 50 mg of M100240 could therefore not be demonstrated. This finding is not surprising based on the documented food effect with the sulfhydryl‐containing ACE inhibitor, captopril. Clinical significance of this pharmacokinetic food effect is unlikely, as the magnitude of pharmacodynamic response is probably better correlated with AUC than a single‐point determination of Cmax. Single oral doses of 50 mg of M100240 were safe and well tolerated under fed and fasted conditions.
Assessment of In Vivo CYP2D6 Activity: Differential Sensitivity of Commonly Used Probes to Urine pH
Authors: Özdemir Mahmut , Crewe Kim H. , Tucker Geoffrey T. , Rostami‐Hodjegan Amin
Published: November 2004

Drug/metabolite ratios (MRs) are used as in vivo markers of enzyme activity. The ratios are potentially confounded by the renal clearance of the drug (urine‐based MRs) or metabolite (plasma‐based MRs). The authors have investigated the relative sensitivity of urinary MR of 3 in vivo probe substrates of CYP2D6 debrisoquine (DB), dextromethorphan (DM), and metoprolol (MP) to changes in urine pH. Three groups of healthy volunteers each comprising 12 individuals were given DB (10 mg), DM (25 mg), or MP (100 mg) on 3 occasions. In 1 study arm, urine was acidified by the oral intake of ammonium chloride; in another, it was alkalinized by intake of sodium bicarbonate; and in the third, urine pH was uncontrolled. Urinary MP/α‐hydroxy‐MP, DM/dextrorphan, and DB/4‐hydroxy‐DB ratios were calculated. The meangeo MR for DB was not significantly different in any of the study arms, whereas those for MP and DM were significantly different under acidified and alkalinized urine conditions compared to uncontrolled urine pH (P < .01) and were correlated with urine pH (P < .001). Without control of urine pH, in vivo estimates of CYP2D6 metabolic activity are likely to be less precise using DM or MP as probe substrates compared to DB. Although this is unlikely to cause any problem in distinguishing the large functional differences in CYP2D6 in poor metabolizer (PM) and extensive metabolizer (EM) phenotypes, this may contribute to difficulties in differentiating in vivo metabolic activity among allelic variants within the overall CYP2D6 EM phenotype using MP or DM. However, because DB is not available in many countries (eg, United States), alternative in vivo markers of CYP2D6 with low sensitivity to urine pH should be sought.
Pharmacokinetics, Safety, and Tolerability of R411, a Dual α4β1‐α4β7 Integrin Antagonist After Oral Administration at Single and Multiple Once‐Daily Ascending Doses in Healthy Volunteers
Authors: Hijazi Youssef , Welker Horst , Dorr Albert E. , Tang Jian‐Ping , Blain Roger , Renzetti Louis M. , Abbas Richat
Published: November 2004

R411 is a dual α4β1‐α4β7 integrin antagonist under development for the treatment of chronic asthma. The objective of this study was to investigate the pharmacokinetics and safety of R411 and its active metabolite, RO0270608, in humans. A 3‐part phase I trial was conducted in 132 healthy volunteers: (1) 12 subjects received 200 mg R411 as a single oral dose or 100 mg RO0270608 as an intravenous infusion in a 1‐sequence crossover design; (2) 7 groups of 10 subjects received 1 of 7 single oral doses of R411 (10–1200 mg) in a parallel, placebo‐controlled, ascending adaptive dose design; and (3) 5 groups of 10 subjects each received repeated oral qd doses of R411 (50–900 mg) for up to 3 weeks in a parallel, placebo‐controlled, ascending adaptive dose design. The absolute bioavailability of RO0270608 (mean ± standard deviation) after oral administration of R411 was 27% ± 4%, and the terminal half‐life was 7.33 ± 2.29 hours. After IV infusion of RO0270608, total clearance (mean ± standard deviation) was 19.4 ± 7.1 L/h, and the volume of distribution was 93.1 ± 36.1 L. After single ascending oral doses of R411, area under the concentration‐time curve from 0 to infinity of active metabolite RO0270608 increased proportionally from 150 to 1200 mg (P < .05). Following repeated administration, the oral clearance was independent of time. No drug accumulation was observed, and no safety concerns were revealed up to a dose of 900 mg after up to 3 weeks of treatment.
Dose‐Dependent Alternations in the Pharmacokinetics of Olanzapine During Coadministration of Fluvoxamine in Patients With Schizophrenia
Authors: Chiu Chih‐Chiang , Lane Hsien‐Yuan , Huang Ming‐Chyi , Liu Hui‐Ching , Jann Michael W. , Hon Yuen‐Yi , Chang Wen‐Ho , Lu Mong‐Liang
Published: November 2004

Olanzapine, an atypical antipsychotic agent, is a substrate of the cytochrome P4501A2 (CYP1A2) enzyme. Administration of a potent CYP1A2 inhibitor (eg, fluvoxamine) may alter the pharmacokinetics of olanzapine. This study investigated the pharmacokinetic interactions between olanzapine and fluvoxamine in patients with schizophrenia. Ten male smokers were administrated a single dose of olanzapine 10 mg at baseline, followed by 2 weeks of fluvoxamine 50 mg/day and another 2 weeks of fluvoxamine 100 mg/day. Olanzapine 10 mg was given at day 10 during each fluvoxamine treatment. After pretreatment with fluvoxamine, the area under the curve, maximal plasma concentration, and half‐time of olanzapine were significantly increased by 30% to 55%, 12% to 64%, and 25% to 32%, respectively. Volume of distribution and apparent clearance were significantly reduced by 4% to 26% and 26% t O 38%, respectively, after administration of fluvoxamine. Increases in area under the plasma concentration‐time curve from time 0 to infinity appear to be dose dependent. Presumably, altered olanzapine pharmacokinetics are attributed to the inhibition of CYP1A2. Patients treated with the combination of olanzapine and fluvoxamine should be monitored carefully.
Sensitized Photoluminescence of Eu3+ and Gd3+-Doped Y3Al5O12 Phosphors Prepared via a Reverse Microemulsion Process
Authors: Lu Chung-Hsin , Huang Chien-Hao
Published: November 2004

Europium-ion and gadolinium-ion codoped Y3Al5O12 phosphors were synthesized via a reverse microemulsion process. The emission intensity and quantum yield of Y3Al5O12: Eu3+ depend on the codoping concentration of gadolinium ions. The significant enhancement in the luminance and quantum yield via codoping of Gd3+ ions imply efficient energy transfer from Gd3+ ions to Eu3+ activators. The microemulsion-derived Y3Al5O12: Eu3+, Gd3+ phosphors with small particle sizes and enhanced luminescence efficiency are demonstrated to hold application potential for flat panel displays.
Platinum Thin Film with a Highly Ordered Mesostructure by Contact Plating
Authors: Yamauchi Yusuke , Yokoshima Tokihiko , Momma Toshiyuki , Osaka Tetsuya , Kuroda Kazuyuki
Published: November 2004

By a contact plating technique using a galvanic reaction between Al and Au in the presence of Pt complex, we have for the first time succeeded in the formation of a highly ordered mesostructured Pt film on a Au surface by reduction of Pt ions in the presence of lyotropic liquid crystals.
Templateless Hydrothermal Synthesis of Aligned ZnO Nanorods
Authors: Zhao Yongnan , Kwon Young-Uk
Published: November 2004

Aligned single crystalline ZnO nanorods with sharp end were synthesized hydrothermally starting from metallic zinc powders; investigations reveal that only metal powders can give rise to nanorods under suitable conditions.
Formation of [Cu(η2-H2)]+ Species in MFI-type Zeolite and Resulting H–D Exchange Reaction with Hydrogen on Brønsted Acid Sites at 300 K
Authors: Kuroda Yasushige , Okamoto Takae , Mori Toshinori , Yoshikawa Yuzo
Published: November 2004

We examined the adsorption feature of the CuMFI sample for H2 adsorption and found a specific interaction between Cu+ exchanged in MFI and H2 even at 300 K, the formation of η2-type H2-adsorbed species in MFI-type zeolite; it caused H–D exchange reaction with hydrogen on Brønsted acid sites even at 300 K.
Aminopropyl–Glucose Sequentially Grafted Mesoporous Silica Nanocomposite as a Novel Boron Adsorbent
Authors: Yasui Masataka , Ikeda Masataka , Takimiya Kazuo , Ohshita Joji , Yamanaka Shoji , Inumaru Kei
Published: November 2004

Aminopropyl groups and glucose molecules were sequentially grafted on mesoporous silica (ca. 5 nm in diameter) to synthesize a glucamine group analogue in the nanospaces. The grafted nanocomposite material showed a high capacity for adsorption of boric acid/borate from water.
Pathway to Insoluble Aggregates on the Refolding of a Single-chain Fv Antibody: Morphological Changes of Aggregated Protein on Refolding
Authors: Umetsu Mitsuo , Ashish Kumar , Tsumoto Kouhei , Kumagai Izumi
Published: November 2004

In vitro aggregated single-chain Fv antibody (scFv) was analyzed by attenuated total reflectance Fourier transform infrared spectra and scanning electron microscope images. The spectroscopic results demonstrate that the formation of β-strands is a first trigger to the off-pathway toward insoluble aggregates, which is independent of redox condition; however, the morphology of the insoluble aggregates is strongly influenced by the environment in which scFv is aggregated.
Efficient Acetalization of Epoxy Rings on a Fullerene Cage
Authors: Shigemitsu Yasuo , Kaneko Masayoshi , Tajima Yusuke , Takeuchi Kazuo
Published: November 2004

Fullerene epoxides react with benzaldehyde derivatives in the presence of a pyridinium hexafluoroantimonate to give corresponding 1,3-dioxolane derivatives of [60]fullerene in excellent yields. The activation energy for the reaction of fullerene monoepoxide with benzaldehyde was determined to be 112.7 kJ mol−1. This result shows that fullerene epoxides undergo the stepwise SN1-like acetalization reaction.
Social Contagion and Income Heterogeneity in New Product Diffusion: A Meta-Analytic Test
Authors: Van den Bulte Christophe , Stremersch Stefan
Published: November 2004

Standard diffusion models capture social contagion only coarsely and do not allow one to operationalize different contagion mechanisms. Moreover, there is increasing skepticism about the importance of contagion and, as has long been known, S-shaped diffusion curves can also result from heterogeneity in the propensity to adopt. We present hypotheses about conditions under which specific contagion mechanisms and income heterogeneity are more pronounced, and test these hypotheses using a meta-analysis of the q/p ratio in applications of the Bass diffusion model. The ratio is positively associated with the Gini index of income inequality in a country, supporting the heterogeneity-in-thresholds interpretation. The ratio also varies as predicted by the Gamma-Shifted Gompertz diffusion model, but the evidence vanishes after controlling for national culture. As to contagion, the q/p ratio varies with the four Hofstede dimensions of national culture—for three of them in a direction consistent with the social contagion interpretation. Furthermore, products with competing standards have a higher q/p ratio, which is again consistent with the social contagion interpretation. Finally, we find effects of national culture only for products without competing standards, suggesting that technological effects and culturally moderated social contagion effects might not operate independently from each other.
Customizing Promotions in Online Stores
Authors: Zhang Jie , Krishnamurthi Lakshman
Published: November 2004

The main objective of this paper is to provide a decision-support system of micro-level customized promotions, primarily for use in online stores. Our proposed approach utilizes the one-on-one and interactive nature of the Internet shopping environment and provides recommendations on when to promote how much to whom. We address the issue by first constructing a joint purchase incidence-brand choice-purchase quantity model that incorporates how variety-seeking/inertia tendency differs among households and change over time for the same household. Based on the model, we develop an optimization procedure to derive the optimal amount of price discount for each household on each shopping trip. We demonstrate that the proposed customization method could greatly improve the effectiveness of current promotion practices, and discuss the implications for retailers and consumer packaged goods companies in the age of Internet technology.
Using Online Conversations to Study Word-of-Mouth Communication
Authors: Godes David , Mayzlin Dina
Published: November 2004

Managers are very interested in word-of-mouth communication because they believe that a product's success is related to the word of mouth that it generates. However, there are at least three significant challenges associated with measuring word of mouth. First, how does one gather the data? Because the information is exchanged in private conversations, direct observation traditionally has been difficult. Second, what aspect of these conversations should one measure? The third challenge comes from the fact that word of mouth is not exogenous. While the mapping from word of mouth to future sales is of great interest to the firm, we must also recognize that word of mouth is an outcome of past sales. Our primary objective is to address these challenges. As a context for our study, we have chosen new television (TV) shows during the 1999–2000 seasons. Our source of word-of-mouth conversations is Usenet, a collection of thousands of newsgroups with diverse topics. We find that online conversations may offer an easy and cost-effective opportunity to measure word of mouth. We show that a measure of the dispersion of conversations across communities has explanatory power in a dynamic model of TV ratings.
Reply to “Do Returns Policies Intensify Retail Competition?”
Authors: Padmanabhan V. , Png I. P. L.
Published: November 2004

Returns policies are common in many sectors of retail distribution. Padmanabhan and Png (1997) showed that with demand uncertainty, a returns policy could improve manufacturer profitability under certain conditions. Wang (2004) showed that returns policies do not change manufacturer profitability when demand is certain and retailing is competitive. We show that returns policies do increase manufacturer profitability by attenuating retailer price competition when demand is low and intensifying competition when demand is high. Importantly, this effect holds only in the presence of demand uncertainty. Further, the conditions under which a returns policy raises the manufacturer's profit are weaker when retailing is a duopoly than when retailing is a monopoly. This suggests that returns policies serve both to manage competition and mitigate demand uncertainty.
The Impact of Advancing Technology on Marketing and Academic Research
Authors: Shugan Steven M.
Published: November 2004

Academic research in marketing often and rightfully tends to either build on well-established past research topics or follow well-established practices in industry. However, as technology advances, it might be possible to foresee some more enduring trends and focus research on future issues rather than on past issues.

One approach would be to study emerging technologies with rapidly declining costs. Each of these emerging technologies spawns myriad applications that have the potential to dramatically impact existing markets. Interesting research topics include the study of the impact of these applications on different market participants (e.g., final consumers, the seller, the seller of complementary services, intermediaries, information providers, competitors, other industries). Research topics also include the optimal structure for products and services, given these new applications, as well as which intermediary should offer particular services. Research topics also include the interactive ability to rapidly customize marketing strategy by identifying individuals at particular points in time and under particular demand conditions. Five of these technologies include enhanced search services, biometrics and smart cards, enhanced computational speed, M-commerce, and GPS tracking.