bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Prescribing Guidelines for Inpatient Anticoagulation
Authors: Schumock Glen T , Blackburn Juan C , Nutescu Edith A , Walton Surrey M , Finley Jamie M , Lewis Richard K
Published: August 2004

BACKGROUND

Anticoagulants are widely used and represent a class of drugs that are problem-prone and have a high potential for adverse patient outcomes. As such, these drugs may be amenable to the use of prescribing guidelines. However, relatively little has been published on the effect of such guidelines on clinical outcomes or costs of care.

OBJECTIVE

To assess whether guidelines improve the appropriateness of prescribing, clinical outcomes, and costs associated with use of anticoagulants in a sample of community hospitals in the US.

METHODS

A retrospective analysis was performed of data voluntarily collected by 15 hospitals before (July—September 2001) and after (March—May 2002) implementation of anticoagulant prescribing guidelines. Statistical analyses of both patient- and hospital-level variables were conducted.

RESULTS

Implementation of the guidelines resulted in a significant increase in the proportion of anticoagulants that were prescribed appropriately (59.8% vs 86.9%; p < 0.001). The guidelines also resulted in a shift in the type of anticoagulants prescribed (decreased use of unfractionated heparin and increased use of low-molecular-weight heparins). There was suggestive evidence, although not statistically significant, that the guidelines resulted in fewer anticoagulant-associated adverse events (total bleeding RR 0.71) and lower costs (savings of $56.15 per patient per day).

CONCLUSIONS

While limitations existed with the study design, sufficient benefits were identified to warrant hospitals to consider use of these or similar guidelines on a routine basis. Clearly, additional study in this area would be useful.
The Truncated memories and fragmented pasts of contemporary Algeria: Salim Bachi’s Le Chien d’Ulysse
Authors: Orlando Valérie
Published: August 2004

Algerian Salim Bachi’s Le Chien d’Ulysse (2001) reveals a world that is caught in the overlapping of truth and myth, hampering the construction of what Pierre Nora describes as the lieux de mémoire necessary for the health of a society’s collective memory.
Principal protagonists, Hocine and his friends, are victims of a chaotic parable alluding to the sociocultural disarray which has reigned in Algeria in recent years. Their attempts to construct lieux de mémoire in order to discover the truth about their history and the memories on which
it is founded, fail. Hocine, like Salim Bachi, cannot explain how religious fundamentalism came to ravenous, overwhelming power in Algeria during the 1990s. Bachi’s tale is one of a society turned upside down, forced to live a reality that offers little possibility of historical, accurate
memory. Such a reality is and was during the 1990s, for the Algerian author, intellectual, journalist, and philosopher, one that had to be rejected.
Book Reviews
Authors: Koski Raija , Redouane Rabia , Bérard Sylvie
Published: August 2004

Lucie Hotte (dir.), La Littérature franco-ontarienne: voies nouvelles, nouvelles voix
Ottawa: Le Nordir, 2002

Yasmina Khadra, L’imposture des mots
Paris, Julliard, 2002, 177 pp.

Louise Dupré, Jaap Lintvelt et Janet M. Paterson,
Sexuation, espace, écriture: La littérature québécoise en transformation
Québec: Éditions Nota bene, 2002.
Consequences of Sales Management's Behavior- and Compensation-Based Control Strategies in Developing Countries
Authors: Piercy Nigel F. , Low George S. , Cravens David W.
Published: August 2004

The authors examine the consequences of sales management's behavior- and compensation-based control on important salesperson and organizational consequences from the sales manager's perspective. The few existing studies on this topic have been conducted in developed countries. The authors examine sales management control in three less developed countries: Greece, India, and Malaysia. The conceptual model considers the relationships among behavior-based control, compensation control, satisfaction with sales territory design, salesperson behavior and outcome performance, and sales unit effectiveness. Contrary to the prevailing conceptual logic, the findings from less developed countries provide no support that a combination of high levels of both behavior- and compensation-based control have a negative, conflicting impact on salesperson and organization consequences. The findings have several important implications for decisions about international sales operations.
Tigers, Dragons, and Others: Profiling High Performance in Asian Firms
Authors: Deshpandé Rohit , Farley John U. , Bowman Douglas
Published: August 2004

A comparison of samples of business-to-business firms based in major cities in China, Hong Kong, India, Japan, Thailand, and Vietnam finds significant differences across countries on several organizational dimensions, including innovativeness, market orientation, and organizational climate and culture. The work is framed in a modified competing values model that is based on theoretical work from the West, but the developmental work for empirical application was carried out in Japan. In general, the differences observed in Asia are consistent with the countries’ historical and cultural differences. Notably, however, the impact of the organizational dimensions on firm performance is statistically identical across the countries. Tests of hypotheses related to performance of firms in the Asian samples produced results that are qualitatively similar to a previous study of five industrial countries, but the importance weights of the individual factors are different. In particular, the significant effect of market orientation on performance is greater in Asia, whereas the similarly significant impact of innovativeness on performance is greater in the industrial countries.
The Impact of Control on International Joint Venture Performance: A Contingency Approach
Authors: Pangarkar Nitin , Klein Saul
Published: August 2004

The authors hypothesize that the exercise of control increases the performance of international joint ventures only when transaction costs are high and when there are large differences between partners and no prior business relationships. Using survey responses and secondary data, the authors find partial support for a contingent control–performance relationship.
A Conserved Role But Different Partners for the Transcriptional Corepressor CoREST in Fly and Mammalian Nervous System Formation
Authors: Dallman Julia E. , Allopenna Janet , Bassett Andrew , Travers Andrew , Mandel Gail
Published: August 2004

Identification of conserved proteins that act to establish the neuronal phenotype has relied predominantly on structural homologies of the underlying genes. In the case of the repressor element 1 silencing transcription factor (REST), a central player in blocking the neuronal phenotype in vertebrate non-neural tissue, the invertebrate homolog is absent, raising the possibility that distinct strategies are used to establish the CNS of invertebrates. Using a yeast two-hybrid screen designed specifically to identify functional analogs of REST, we show thatDrosophila melanogasteruses a strategy that is functionally similar to, but appears to have evolved independently of, REST. The gene at the center of the strategy in flies encodes the repressor Tramtrack88 (Ttk88), a protein with no discernable homology to REST but that nonetheless is able to interact with the same transcriptional partners. Ttk88 uses the REST corepressorDrosophilaCoREST to coordinately regulate a set of genes encoding the same neuronal hallmarks that are regulated by REST in vertebrates. Our findings indicate that repression is an important mechanism for regulating neuronal phenotype across phyla and suggest that co-option of a similar corepressor complex occurred to restrict expression of genes critical for neuronal function to a compartmentalized nervous system.
Endocytosis and Degradative Sorting of NMDA Receptors by Conserved Membrane-Proximal Signals
Authors: Scott Derek B. , Michailidis Ioannis , Mu Yuanyue , Logothetis Diomedes , Ehlers Michael D.
Published: August 2004

Regulation of the abundance of NMDA receptors (NMDARs) at excitatory synapses is critical during changes in synaptic efficacy underlying learning and memory as well as during synapse formation throughout neural development. However, the molecular signals that govern NMDAR delivery, maintenance, and internalization remain unclear. In this study, we identify a conserved family of membrane-proximal endocytic signals, two within the NMDAR type 1 (NR1) subunit and one within the NR2A and NR2B subunits, necessary and sufficient to drive the internalization of NMDARs. These endocytic motifs reside in the region of NMDAR subunits immediately after the fourth membrane segment, a region implicated in use-dependent rundown and NMDA channel inactivation. Although endocytosis driven by the distal C-terminal domain of NR2B is followed by rapid recycling, internalization mediated by membrane-proximal motifs selectively targets receptors to late endosomes and accelerates degradation. These results define a novel conserved signature of NMDARs regulating internalization and postendocytic trafficking.
Serotonergic Regulation of the Orexin/Hypocretin Neurons through the 5-HT1AReceptor
Authors: Muraki Yo , Yamanaka Akihiro , Tsujino Natsuko , Kilduff Thomas S. , Goto Katsutoshi , Sakurai Takeshi
Published: August 2004

Both orexin and serotonin (5-HT) have important roles in the regulation of sleep-wakefulness, as well as in feeding behavior. We examined the effects of 5-HT on orexin/hypocretin neurons, using hypothalamic slices prepared from orexin/enhanced green fluorescent protein (EGFP) transgenic mice in which EGFP is expressed exclusively in orexin neurons. Patch-clamp recording from EGFP-expressing cells showed that 5-HT hyperpolarized all orexin neurons in a concentration-dependent manner. The response was inhibited by the 5-HT1Areceptor antagonist WAY100635. A 5-HT1Areceptor agonist, 8-hydroxy-2-(dl-N-propyl-amino)tetralin, also evoked hyperpolarization on orexin neurons with potency comparable with 5-HT. A low concentration of Ba2+(30 μm) inhibited 5-HT-induced hyperpolarization. Single-channel recording revealed that the conductance of 5-HT-induced channel activity was 33.8 pS, which is in good agreement with that of the G-protein-coupled inward rectifier potassium channel (GIRK). Moreover, 5-HT1Areceptor-like immunoreactivity was observed on orexin neurons, and 5-HT transporter immunoreactive nerve endings are in close apposition to orexin neurons. Intracerebroventricular injection of the 5-HT1Areceptor-selective antagonist WAY100635 (100 ng) increased locomotor activity during the latter half of dark phase in wild-type mice but not inorexin/ataxin-3mice in which orexin neurons are specifically ablated, suggesting that activation of orexin neurons is necessary for the WAY100635-induced increase in locomotor activity. These results indicate that 5-HT hyperpolarizes orexin neurons through the 5-HT1Areceptor and subsequent activation of the GIRK and that this inhibitory serotonergic input to the orexin neurons is likely to be important for the physiological regulation of this neuropeptide system.
Disrupted Spermine Homeostasis: A Novel Mechanism in Polyglutamine-Mediated Aggregation and Cell Death
Authors: Colton C. A. , Xu Q. , Burke J. R. , Bae S. Y. , Wakefield J. K. , Nair A. , Strittmatter W. J. , Vitek M. P.
Published: August 2004

Our data suggest a novel mechanism whereby pathological-length polyglutamine (polyQ) proteins promote the spermine synthetic pathway, increasing polyQ-aggregation and cell death. As detected in a cell-free turbidity assay, spermine promotes aggregation of thio-polyQ62 in a dose-dependent manner. Using a stable neuronal cell line expressing pathological-length [polyQ57-yellow fluorescent protein (YFP) (Q57)] or non-pathological-length [polyQ19-YFP (Q19)] polyglutamine protein, we show that multiple steps in the production of polyamines are affected in Q57 cells, suggesting dysfunctional spermine homeostasis. As the building block for spermine synthesis, arginine transport is significantly increased in neuronal cell lines stably expressing Q57. Q57 lines displayed upregulated basal and inducible arginase I activities that were not seen in polyQ19-YFP lines. Normal induction of spermidine/spermineN-acetyltransferase in Q19 lines regulating back-conversion of spermine, thereby reducing spermine levels, however, was not observed in Q57 lines. Pharmacological activation of ornithine decarboxylase (ODC), a key enzyme of the polyamine synthetic pathway, increased cellular aggregates and increased cell death in Q57 cells not observed in Q19 cells. Inhibition of ODC by difluoromethylornithine prevented basal and induced cell death in Q57 cells, demonstrating a central role for polyamines in this process.
Perceived Controllability Modulates the Neural Response to Pain
Authors: Salomons Tim V. , Johnstone Tom , Backonja Misha-Miroslav , Davidson Richard J.
Published: August 2004

The response to painful stimulation depends not only on peripheral nociceptive input but also on the cognitive and affective context in which pain occurs. One contextual variable that affects the neural and behavioral response to nociceptive stimulation is the degree to which pain is perceived to be controllable. Previous studies indicate that perceived controllability affects pain tolerance, learning and motivation, and the ability to cope with intractable pain, suggesting that it has profound effects on neural pain processing. To date, however, no neuroimaging studies have assessed these effects. We manipulated the subjects' belief that they had control over a nociceptive stimulus, while the stimulus itself was held constant. Using functional magnetic resonance imaging, we found that pain that was perceived to be controllable resulted in attenuated activation in the three neural areas most consistently linked with pain processing: the anterior cingulate, insular, and secondary somatosensory cortices. This suggests that activation at these sites is modulated by cognitive variables, such as perceived controllability, and that pain imaging studies may therefore overestimate the degree to which these responses are stimulus driven and generalizable across cognitive contexts.
GABAAReceptor Phospho-Dependent Modulation Is Regulated by Phospholipase C-Related Inactive Protein Type 1, a Novel Protein Phosphatase 1 Anchoring Protein
Authors: Terunuma Miho , Jang Il-Sung , Ha Sang Hoon , Kittler Josef T. , Kanematsu Takashi , Jovanovic Jasmina N. , Nakayama Keiichi I. , Akaike Norio , Ryu Sung Ho , Moss Stephen J. , Hirata Masato
Published: August 2004

GABAAreceptors are critical in controlling neuronal activity. Here, we examined the role for phospholipase C-related inactive protein type 1 (PRIP-1), which binds and inactivates protein phosphatase 1α (PP1α) in facilitating GABAAreceptor phospho-dependent regulation usingPRIP-1-/-mice. In wild-type animals, robust phosphorylation and functional modulation of GABAAreceptors containing β3 subunits by cAMP-dependent protein kinase was evident, which was diminished inPRIP-1-/-mice.PRIP-1-/-mice exhibited enhanced PP1α activity compared with controls. Furthermore, PRIP-1 was able to interact directly with GABAAreceptor β subunits, and moreover, these proteins were found to be PP1α substrates. Finally, phosphorylation of PRIP-1 on threonine 94 facilitated the dissociation of PP1α-PRIP-1 complexes, providing a local mechanism for the activation of PP1α. Together, these results suggest an essential role for PRIP-1 in controlling GABAAreceptor activity via regulating subunit phosphorylation and thereby the efficacy of neuronal inhibition mediated by these receptors.
Direct Interactions between the Basolateral Amygdala and Nucleus Accumbens Core Underlie Cocaine-Seeking Behavior by Rats
Authors: Di Ciano Patricia , Everitt Barry J.
Published: August 2004

An insidious feature of drug craving and drug seeking in humans is that it can be induced and maintained by conditioned stimuli after a prolonged drug-free period. Understanding the neural basis of this control over addictive behavior may aid in the development of treatments targeting drug seeking and thereby be beneficial in preventing drug use. In the present study, we used a well established animal model to investigate the functional importance of amygdala-nucleus accumbens interactions in cocaine seeking under the control of drug-associated conditioned reinforcers. To probe the direct neuroanatomical relationship between these structures within a functional corticostriatal loop, we used a neuropharmacological disconnection procedure. Thus, infusing a dopamine receptor antagonist unilaterally into the basolateral amygdala (which had no effect on its own) and an AMPA-kainate (KA) receptor antagonist into the contralateral nucleus accumbens core (which also had no effect on its own) greatly reduced cocaine seeking. We also show that bilateral infusions of the DA receptor antagonist into the amygdala, but not nucleus accumbens, or of the AMPA-KA receptor antagonist in the nucleus accumbens, but not the amygdala, also greatly reduced cocaine seeking. The results of this study demonstrate an amygdala-nucleus accumbens system that critically underlies stimulus-controlled cocaine seeking and indicate possible neurochemical targets for relapse-prevention medication.
Identification and Characterization of Metallothionein-1 and -2 Gene Expression in the Context of (±)3,4-Methylenedioxymethamphetamine-Induced Toxicity to Brain Dopaminergic Neurons
Authors: Xie Tao , Tong Liqiong , McCann Una D. , Yuan Jie , Becker Kevin G. , Mechan Annis O. , Cheadle Christopher , Donovan David M. , Ricaurte George A.
Published: August 2004

In mice, the recreational drug (±)3,4-methylenedioxymethamphetamine [MDMA (“ecstasy”)] produces a selective toxic effect on brain dopamine (DA) neurons. Using cDNA microarray technology in combination with an approach designed to facilitate recognition of relevant changes in gene expression, the present studies sought to identify genes potentially involved in murine MDMA-induced toxicity to DA neurons. Of 15,000 mouse cDNA fragments studied, metallothionein (Mt)-1andMt2emerged as candidate genes possibly involved in MDMA-induced toxicity to DA neurons. Northern blot analysis confirmed the microarray findings and revealed a dynamic upregulation ofMt1andMt2mRNA in the ventral midbrain within 4-12 hr after MDMA treatment. Western blot analysis showed a similar increase in MT protein levels, with peak times occurring subsequent to increases in mRNA levels.Mt1-2double knock-out mice were more vulnerable to MDMA-induced toxicity to DA neurons than corresponding wild-type mice. Stimulation of endogenous expression of MT protein with zinc acetate conferred complete protection against MDMA-induced toxicity to DA neurons, and administration of exogenous MT protein afforded partial protection. Collectively, these results indicate that MDMA-induced toxicity to DA neurons is associated with increasedMt1andMt2gene transcription and translation, possibly as part of a neuroprotective mechanism. The present findings may have therapeutic implications for neuropathological conditions involving DA neurons.
Deafness inClaudin 11-Null Mice Reveals the Critical Contribution of Basal Cell Tight Junctions to Stria Vascularis Function
Authors: Gow Alexander , Davies Caroline , Southwood Cherie M. , Frolenkov Gregory , Chrustowski Mark , Ng Lily , Yamauchi Daisuke , Marcus Daniel C. , Kachar Bechara
Published: August 2004

Generation of a strong electrical potential in the cochlea is uniquely mammalian and may reflect recent evolutionary advances in cellular voltage-dependent amplifiers. This endocochlear potential is hypothesized to dramatically improve hearing sensitivity, a concept that is difficult to explore experimentally, because manipulating cochlear function frequently causes rapid degenerative changes early in development. Here, we examine the deafness phenotype in adultClaudin 11-null mice, which lack the basal cell tight junctions that give rise to the intrastrial compartment and find little evidence of cochlear pathology. Potassium ion recycling is normal in these mutants, but endocochlear potentials were below 30 mV and hearing thresholds were elevated 50 dB sound pressure level across the frequency spectrum. Together, these data demonstrate the central importance of basal cell tight junctions in the stria vascularis and directly verify the two-cell hypothesis for generation of endocochlear potential. Furthermore, these data indicate that endocochlear potential is an essential component of the power source for the mammalian cochlear amplifier.
Memantine Protects Hippocampal Neuronal Function in Murine Human Immunodeficiency Virus Type 1 Encephalitis
Authors: Anderson Eric R. , Gendelman Howard E. , Xiong Huangui
Published: August 2004

Memantine, a low-to-moderate-affinity NMDA receptor antagonist, can be used to treat cognitive impairment associated with Alzheimer's disease. However, its potential neuroprotective effects for human immunodeficiency virus type 1-associated (HIV-1-associated) dementia are less well appreciated. To this end we studied hippocampal synaptic function in a severe combined immunodeficient (SCID) mouse model of HIV-1 encephalitis (HIVE). Human monocyte-derived macrophages (MDMs) infected with HIV-1ADAwere injected stereotactically into the caudate and putamen of SCID mice, generating HIVE. These brain subregions are among those most affected in humans. Impaired synaptic transmission and long-term potentiation (LTP) were detected in the CA1 region of hippocampal brain slices of HIVE mice. Memantine-treated HIVE mice showed significant improvements in synaptic function during frequency facilitation tests and LTP induced by high-frequency stimulation when compared with untreated animals. Immunocytochemical measures of neuronal antigens mirrored the neuronal physiological tests. These results demonstrate that memantine attenuates hippocampal synaptic impairment in murine HIVE and provide a rationale for its use in infected humans who experience cognitive decline.
Octopamine Modulates the Axons of Modulatory Projection Neurons
Authors: Goaillard Jean-Marc , Schulz David J. , Kilman Valerie L. , Marder Eve
Published: August 2004

Octopamine increases the cycle frequency of the pyloric rhythm in the crabCancer borealisby acting at multiple sites within the stomatogastric nervous system. The junction between the stomatogastric nerve (stn) and the superior esophageal nerve (son) shows synaptic structures. When applied only to thestn-sonjunction, octopamine induced action potentials in the axons of the modulatory commissural neuron 5 (MCN5) that project from the commissural ganglia to the stomatogastric ganglion (STG). The activation of the MCN5 neurons was correlated with an increase in the pyloric rhythm frequency. Additionally, octopamine had direct effects on the STG, including the activation of the pyloric dilator and pyloric neurons, an increase in the pyloric frequency, and a change in the phase relationships of the pyloric neurons. Thus, the same modulator can influence the pyloric rhythm by acting at multiple sites, including the axons of identified modulatory neurons that project to the STG. These data demonstrate that axonal propagation may be influenced locally by neuromodulators acting on axonal receptors, therefore altering the conduction of information from different command and integrating centers.
Ecto-Nucleotidases and Nucleoside Transporters Mediate Activation of Adenosine Receptors on Hippocampal Mossy Fibers by P2X7Receptor Agonist 2′-3′-O-(4-Benzoylbenzoyl)-ATP
Authors: Kukley Maria , Stausberg Pia , Adelmann Giselind , Chessell Iain P. , Dietrich Dirk
Published: August 2004

The ionotropic and cytolytic P2X7receptor is typically found on immune cells, where it is involved in the release of cytokines. Recently, P2X7receptors were reported to be localized to presynaptic nerve terminals and to modulate transmitter release. In the present study, we reassessed this unexpected role of P2X7receptors at hippocampal mossy fiber-CA3 synapses. In agreement with previous findings, the widely used P2X7agonist 2′-3′-O-(4-benzoylbenzoyl)-adenosine-5′-triphosphate (BzATP) clearly depressed field potentials (fEPSPs); however, no evidence for an involvement of P2X7receptors could be obtained. First, depression of fEPSPs by BzATP was unchanged in P2X7-/-mice. Second, experiments using P2X7-/-mice, immunohistochemistry, and electron microscopy showed that the antigen detected by frequently used P2X7antibodies is not compatible with a plasmalemmal P2X7receptor. Third, BzATP did not alter Ca2+levels in synaptic terminals. In contrast, the depression of fEPSPs by BzATP was fully blocked by adenosine (A1) receptor antagonists. Furthermore, the application of BzATP also activated postsynaptic A1receptor-coupled K+channels. This effect of BzATP was mimicked by ATP and adenosine and was completely prevented by enzymes specifically degrading adenosine. Activation of A1-coupled K+channels by BzATP was dependent on ecto-nucleotidases, extracellular enzymes that convert ATP to adenosine. Moreover, the opening of A1-coupled K+channels by BzATP was dependent on nucleoside transporters. Taken together, our results indicate that BzATP is extracellularly catabolized to Bz-adenosine and subsequently hetero-exchanged for intracellular adenosine and then depresses mossy fiber fEPSPs through presynaptic A1receptors rather than through P2X7receptors. Thus, the present study casts doubts on the neuronal localization of P2X7receptors in rodent hippocampus.
A Role ofath5in InducingneuroDand the Photoreceptor Pathway
Authors: Ma Wenxin , Yan Run-Tao , Xie Wenlian , Wang Shu-Zhen
Published: August 2004

Photoreceptors in the vertebrate retina are light-sensitive neurons, and their degeneration results in irreversible visual loss. Understanding how photoreceptor fate is determined is a prerequisite for developing photoreceptor replacement therapies. Previous studies identified two basic helix-loop-helix genes,neurogenin2(ngn2) andneuroD, participating in a genetic pathway leading to photoreceptor genesis. Here we present experimental data suggesting thatath5, which is known for its critical role in retinal ganglion cell development, may also lead to photoreceptor production. In the developing retina,ath5expression was detected in two zones of cells, and coexpression withneuroDwas observed in the zone adjacent to young photoreceptor cells accumulating on the retinal pigment epithelial side. Retroviral-driven misexpression ofath5in retinal cells increased the population of photoreceptor cells, as well as ganglion cells, in a developmental stage-dependent manner that is consistent withath5being involved in the development of multiple types of retinal neurons. Ectopicath5expression in cultures of non-neural retinal pigment epithelial cells elicited transdifferentiation into cells that expressed photoreceptor-specific genes and displayed photoreceptor-like morphologies. Gene expression analysis showed thatngn2did not induceath5, andath5did not inducengn2, but both inducedneuroDandRaxL. These data suggest a pathway of “ath5→neuroD→ photoreceptor genes” separate from yet convergent with thengn2pathway.
Signaling from Integrins to Fyn to Rho Family GTPases Regulates Morphologic Differentiation of Oligodendrocytes
Authors: Liang Xiquan , Draghi Nicole A. , Resh Marilyn D.
Published: August 2004

Differentiation of oligodendrocyte progenitor cells requires activation of the Src family kinase Fyn. The signals that are upstream and downstream of Fyn in oligodendrocytes remain essentially unknown. Here we show that extracellular matrix engagement regulates the morphology of oligodendrocytes and activates Fyn. Infection of primary oligodendrocyte cultures with recombinant adenovirus revealed that expression of Fyn or its downstream target p190RhoGAP induced process extension. This phenotypic change was not observed when kinase-inactive Fyn or GAP-defective p190 mutants were expressed. Because Rho family proteins are regulated by p190, we monitored the effects of introducing dominant-negative (DN) or constitutively activated (CA) versions of Rho, Rac1, or Cdc42 into primary oligodendrocyte cultures. Expression of DN Rho, CA Rac1, or CA Cdc42 induced outgrowth of oligodendrocyte processes, whereas introduction of CA Rho, DN Rac1, or DN cdc42 inhibited oligodendrocyte differentiation, indicating that Rho and Cdc42-Rac1 exert opposing effects on oligodendrocyte differentiation. Direct measurement of Rho family activity revealed that RhoA was downregulated, and Cdc42 and Rac1 were upregulated during differentiation of primary oligodendrocytes. Moreover, inhibition of integrin engagement or of Fyn activation blocked activation of Rac1 and cdc42 as well as myelin basic protein expression. Taken together, these results suggest a linear signal transduction pathway of integrin-Fyn-Rho family GTPases that controls morphologic differentiation of oligodendrocytes.
Debt, Epistemology and Ecotheology
Authors: Goodchild Philip
Published: August 2004

The roots of the contemporary ecological crisis demand theological re-description: economic globalisation, driven by debt, is founded on a poor epistemology constructed around a theology of money. Modern and postmodern epistemologies with a humanistic frame of reference, as well as more traditional epistemologies with a naturalistic frame of reference, are inadequate to address the contemporary predicament as well as restrictive in the space they construct for theology. An ecotheology, liberated from secular humanist constraints, is necessary to construct an adequate epistemology.
Bioethics after Posthumanism
Authors: Graham Elaine
Published: August 2004

Three recent books by prominent social and political theorists (Francis Fukuyama, Gregory Stock and Jürgen Habermas) have engaged with the impact of biotechnology on our very concepts of human nature, and the corresponding challenges to ethical discourse of the so-called ‘posthuman condition’.
All three writers raise important questions about the role of concepts of ‘human nature’ in moral discourse, and the paper will subject their claims to theological critique. I conclude by proposing, after Peter Scott (2003), that to consider humanity as ‘un/natural’ serves to affirm human interdependence with, rather than transcendence or dominion over, nature; but that similarly, talk of nature itself as ‘post/human’ restores to it a divinely-conferred integrity, liberated from the self-serving interests of technoscientific objectification.
We Have Never Been Gods
Authors: Scott Peter Manley
Published: August 2004

This article offers a theological response to the postmodern affirmation of hybridity, that is, the ‘mixing up’ of nature and humanity by technology. Drawing on the doctrine of creation, specifically the interpretation of creation as creatio ex nihilo, it argues that Christianity—contrary to either its instinctual aversion to or learned fascination with technology—should accept the reality of hybridity. Furthermore, it is argued that the concept of imago dei can be extended to encompass such hybridity. Refusing Elaine Graham’s turn to immanence in her recent work (Graham 2002), the theme of creatio ex nihilo is further explored by reference to transcendence and contingency. The article concludes that transcendence and contingency offer a theological context for the consideration of hybridity. This context is practical: concerned primarily with the distribution of God’s goodness through hybridity and hybrid practices, and with human participation in that distribution.
Deconstructing Autonomy
Authors: Reader John
Published: August 2004

The aim of the article is to argue that a version of Habermas’s concept of communicative reason, expanded using the work of the postmodern philosophers Derrida, Levinas and Irigaray, is a requirement for theology as it responds to environmental concerns. In particular the notion of human autonomy as presupposed by Habermas can be deconstructed in order to establish that humans also operate at a pre-autonomous level and with the messianic promise of a post-autonomous level through the search for an open identity. This forms part of a wider argument which identifies four locations where there is the possibility of a renewed relationship between the Enlightenment concept of reason as reconfigured by Habermas and the ‘others’ of reason, including faith. Key ideas are Derrida’s concept of the messianic and deconstruction as a means of acknowledging the hidden ‘other’, Levinas’s tension between the Saying and the Said, and Irigaray’s demand for a new ontology. Each of these points theology towards a critique of autonomy and the search for a yet-to-be-glimpsed new relationship with non-human nature.
Pharmacovigilance in the 21st Century: New Systematic Tools for an Old Problem
Authors: Szarfman Ana , Tonning Joseph M. , Doraiswamy P. Murali
Published: August 2004

The large number of adverse‐event reports generated by marketed drugs and devices argues for the application of validated computerized algorithms to supplement traditional methods of detecting adverse‐event signals. Difficulties in accurately estimating patient exposure and background rates for a given event in a specific population hinder risk estimation in spontaneous adverse‐event databases. The United States Food and Drug Administration (FDA) is evaluating a Bayesian data mining system called Multi‐item Gamma Poisson Shrinker (MGPS) to enhance the FDA's ability to monitor the safety of drugs, biologics, and vaccines after they have been approved for use. The MGPS computes adjusted higher‐than‐expected reporting relationships between drugs and adverse events across 35 years of data relative to internal background rates. The MGPS can also adjust for random noise by using a model derived from the data, and corrects for temporal trends and confounding related to age, sex, and other variables by stratifying over 900 categories. Signals can then be compared with or used in conjunction with other sources (e.g. clinical trials, general practice databases) to further study the adverse‐event risk. The example of pancreatitis risk with atypical antipsychotics, valproic acid, and valproate is used to discuss the strengths and limitations of MGPS versus traditional methods. Validated data mining techniques offer great promise to enhance pharmacovigilance practices.
Pharmacoepidemiology II: The Nested Case‐Control Study—A Novel Approach in Pharmacoepidemiologic Research
Authors: Etminan Mahyar
Published: August 2004

This article on pharmacoepidemiology, the second of two parts, is a more focused discussion of the methodology of cohort studies and case‐control studies, the basic methodologies of which were discussed in part I. The nested case‐control study incorporates the strengths of both the cohort and case‐control studies but may alleviate some of the methodologic challenges inherent in both types of studies. In a nested case‐control study, a cohort of individuals is followed during certain time periods until a certain outcome is reached. The analysis is conducted as a case‐control study in which cases are matched to only a sample of control subjects. Matching allows for control of potential confounding variables such as age, calendar time, and disease duration. Also, the time dependency of an exposure can be quantified without complicated statistical techniques. Matching the cases and controls by time allows the investigator to stratify exposure based on current, past, or intermittent use. By using the principles of epidemiology, the nested case‐control study allows for the control of confounding variables, as well as better quantification of time‐dependent exposures.
Pharmacokinetics and Pharmacodynamics of Methadone Enantiomers After Coadministration with Amprenavir in Opioid‐Dependent Subjects
Authors: Hendrix Craig W. , Wakeford John , Wire Mary Beth , Lou Yu , Bigelow George E. , Martinez Elizabeth , Christopher Jared , Fuchs Edward J. , Snidow Jerry W.
Published: August 2004

Study Objective. To investigate the steady‐state pharmacokinetics of methadone enantiomers when coadministered with amprenavir.

Design. Prospective, open‐label, within‐subject pharmacokinetic study.

Setting. University research center.

Subjects. Nineteen opioid‐dependent, methadone‐maintained, healthy individuals were enrolled.

Intervention. On study day 1, subjects received their usual once‐daily dose of methadone alone. On study days 2–11, they received the same once‐daily methadone dose plus amprenavir 1200 mg twice/day Serial blood samples were collected over 24 hours on study days 1 and 11 for measurement of plasma R‐ and S‐methadone, and over 12 hours on day 11 for serum amprenavir concentrations.

Measurements and Main Results. Standard pharmacokinetic parameters were determined from the concentrations and compared between the two treatments (methadone alone vs methadone with amprenavir). Subjects served as their own control for methadone comparisons, and amprenavir comparisons were made by using a historic control group (38 healthy men). Opioid‐effect measures were assessed throughout the study. Coadministration of amprenavir with methadone resulted in a 3–4‐hour delay in plasma R‐ and S‐methadone enantiomer peak concentrations at steady state (Cmax‐ss). The active R‐methadone enantiomer area under the plasma concentration–time curve during a dosing interval (AUCτ‐ss), Cmax‐ss, and the minimum plasma concentration at steady state (Cmin‐ss) were decreased by 13%, 25%, and 21%, respectively, after coadministration of methadone and amprenavir. The inactive S‐enantiomer AUCτ‐ss, Cmax‐ss, and Cmin‐ss were decreased by 40%, 48%, and 52%, respectively. No clinically significant changes were noted in opioid pharmacodynamic effects, and there was no evidence of opioid withdrawal. No methadone dosage was changed in any subject.

Conclusion. No a priori adjustment in methadone dosage is required during coadministration with amprenavir as there is only a small effect on R‐methadone exposure and no evidence of opioid withdrawal.
Application of an Empiric Bayesian Data Mining Algorithm to Reports of Pancreatitis Associated with Atypical Antipsychotics
Authors: Hauben Manfred
Published: August 2004

Study Objective. To compare the results from one frequently cited data mining algorithm with those from a study which was published in a peer‐reviewed journal, that examined the association of pancreatitis with selected atypical antipsychotics observed by traditional rule‐based methods of signal detection.

Design. Retrospective pharmacovigilance study.

Intervention. The widely studied data mining algorithm known as the Multi‐item Gamma Poisson Shrinker (MGPS) was applied to adverse‐event reports from the United States Food and Drug Administration's Adverse Event Reporting System database through the first quarter of 2003 for clozapine, olanzapine, and risperidone to determine if a significant signal of pancreatitis would have been generated by this method in advance of their review or the addition of these events to the respective product labels.

Measurements and Main Results. Data mining was performed by using nine preferred terms relevant to drug‐induced pancreatitis from the Medical Dictionary for Regulatory Activities (MedDRA). Results from a previous study on the antipsychotics were reviewed and analyzed. Physicians' Desk References (PDRs) starting from 1994 were manually reviewed to determine the first year that pancreatitis was listed as an adverse event in the product label for each antipsychotic. This information was used as a surrogate marker of the timing of initial signal detection by traditional criteria. Pancreatitis was listed as an adverse event in a PDR for all three atypical antipsychotics. Despite the presence of up to 88 reports/drug‐event combination in the Food and Drug Administration's Adverse Event Reporting System database, the MGPS failed to generate a signal of disproportional reporting of pancreatitis associated with the three antipsychotics despite the signaling of these drug‐event combinations by traditional rule‐based methods, as reflected in product labeling and/or the literature. These discordant findings illustrate key principles in the application of data mining algorithms to drug safety surveillance.

Conclusion. The optimal place of data mining algorithms in the pharmacovigilance tool kit remains to be determined, requires consideration of numerous factors that may affect their performance, and is highly situation dependent.
Evaluation of Gastric pH and Guaiac Measurements in Neonates Receiving Acid Suppression Therapy During Extracorporeal Membrane Oxygenation
Authors: Crill Catherine M. , Bugnitz Mark C. , Hak Emily B.
Published: August 2004

Study Objectives.To assess gastric pH measurements, evaluate the frequency of guaiac‐positive gastric aspirates, and characterize the appearance of gastric aspirates in neonates receiving acid suppression therapy during extracorporeal membrane oxygenation (ECMO).

Design.Retrospective, observational study.

Setting.Intensive care unit in a 225‐bed tertiary care pediatric referral hospital.

Subjects.Thirteen neonates receiving ECMO.

Measurements and Main Results.Gastric pH measurements, guaiac test results, appearance of gastric aspirates, and ranitidine and antacid dosing were recorded. On ECMO day 1, mean ± SD gastric pH was 4.3 ± 2.8 in the five neonates whose pH was documented. Intravenous ranitidine 2.9 ± 0.4 mg/kg/day was started in all neonates by ECMO day 2. Gastric pH was less than 4.0 in seven neonates; these low pH values accounted for only 10% of gastric pH measurements. The frequency of positive guaiac results in neonates with pH measurements below 4.0 was 27% compared with 41% for neonates with a gastric pH of 4.0 or greater (p=0.125). Guaiac tests were positive in 69 (42%) aspirates in 11 neonates. Of the guaiac‐positive aspirates that had a corresponding pH measurement, 94% had a pH of 4.0 or greater. Guaiac‐positive aspirates had evidence of bile (49%), antacid (17%), and blood (7%) in gastric fluid. In six patients, ranitidine dosages were increased to 3.9 ± 0.6 mg/kg/day due to low pH and/or positive guaiac results. In two of these neonates, gastric pH remained below 4.0 in nine of 35 pH measurements despite increased ranitidine dosing. Guaiac results remained positive in all subsequent aspirates in five out of six of these neonates. No neonates developed clinically significant upper gastrointestinal bleeding (UGIB).

Conclusions.Gastric pH is variable in neonates receiving histamine2‐receptor antagonist and antacid therapy during ECMO, and gastric pH of 4.0 or greater does not decrease the frequency of guaiac‐positive aspirates. Higher gastric pH measurements are confounded by duodenogastric reflux and the presence of blood and/or antacid in gastric fluid. Motility agents in combination with acid suppression therapy for prevention of UGIB may be necessary in this setting based on gastric pH measurements, appearance of gastric aspirates, and guaiac testing.
Impact of Nesiritide on Health Care Resource Utilization and Complications in Patients with Decompensated Heart Failure
Authors: Lenz Thomas L. , Foral Pamela A. , Malesker Mark A. , Hunter Claire B. , Hilleman Daniel E. , Dr. Lucas
Published: August 2004

Study Objective. To determine the impact of nesiritide on health care resource utilization and complications in patients hospitalized with decompensated heart failure.

Design. Retrospective case‐control study.

Setting. United States hospitals.

Patients. Two hundred sixteen patients hospitalized for decompensated heart failure.

Measurements and Main Results. One hundred eight patients who received a nesiritide infusion for a minimum of 12 hours during the first 48 hours after hospital admission were matched with 108 patients not receiving nesiritide. Health care resource utilization, consisting of hospital length of stay (LOS), rate of rehospitalization within 90 days, concomitant drugs administered, and laboratory and diagnostic tests, was determined for each hospital admission. Rates of adverse events also were recorded. Patients receiving nesiritide had a significantly shorter LOS in a critical care unit (p=0.03). General medical ward or step‐down unit LOS was not different between the treatment groups. A favorable trend toward a lower rate of rehospitalization over the 90‐day follow‐up period was observed with nesiritide (p=0.07). The number of patients who developed life‐threatening ventricular arrhythmias and hypotension was similar for both treatment groups. However, in patients receiving nesiritide, significantly less atrial fibrillation (p=0.03) and renal dysfunction (p=0.04) occurred compared with patients not receiving nesiritide.

Conclusion. Nesiritide therapy is associated with significant reductions in both health care resource utilization and complications in patients with decompensated heart failure.
Extended‐Release Divalproex Sodium for Mood Stabilization
Authors: Stoner Steven C. , Dubisar Beth M. , Lea Jessica W. , Marken Patricia A. , Ramlatchman Leonard V. , Reynolds James B.
Published: August 2004

Study Objective. To evaluate the efficacy, safety, and tolerability of extended‐release divalproex sodium.

Design. Prospective, open‐label, 4‐week study.

Setting. Long‐term care facility of the Missouri Department of Mental Health.

Patients. Ten hospitalized patients (mean age 39.4 yrs) with mood or thought disorders who were experiencing adverse effects from delayed‐release divalproex sodium.

Intervention. All participants were switched from delayed‐release to extended‐release divalproex sodium.

Measurements and Main Results. Efficacy was monitored with the Brief Psychiatric Rating Scale (BPRS), and safety and tolerability were monitored with the Systematic Assessment for Treatment Emergent Events (SAFTEE). Frequently reported adverse effects before conversion were sedation, stomach upset, and tremor. At study conclusion, no differences were seen in total BPRS scores or individual BPRS items, although a trend pointed to decreased somatic complaints (p=0.057). The mean serum concentration of valproic acid among participants did not change significantly in the transition from the delayed‐release formulation to an equivalent dose‐adjusted extended‐release formulation (90.5 mg/L vs 95.5 mg/L, p=0.493). At study conclusion, significant decreases in low‐density lipoprotein cholesterol (p=0.010) and potassium (p=0.043) levels were identified. Three categories of adverse effects decreased significantly after patients switched to the extended‐release form of divalproex sodium: sedation (p=0.022), stomach or abdominal discomfort (p=0.045), and tremor (p=0.004).

Conclusion. This preliminary investigation suggests that patients receiving delayed‐release divalproex sodium for mood lability can be converted successfully to extended‐release divalproex sodium. Moreover, these findings imply that this transition is associated with a reduction in some of the adverse effects associated with divalproex sodium.