bluuebunny/crossref_metadata_2025 huggingface dataset:
Cholinergic receptor-mediated differential cytoskeletal recruitment of actin- and integrin-binding proteins in intact airway smooth muscle
Authors: Kim Hak Rim , Hoque Muntasir , Hai Chi-Ming
Published: July 2004

We tested the hypothesis that cholinergic receptor stimulation recruits actin- and integrin-binding proteins from the cytoplasm to the cytoskeleton-membrane complex in intact airway smooth muscle. We stimulated bovine tracheal smooth muscle with carbachol and fractionated the tissue homogenate into pellet (P) and supernatant (S) by ultracentrifugation. In unstimulated tissues, calponin exhibited the highest basal P-to-S ratio (P/S; 2.74 ± 0.47), whereas vinculin exhibited the lowest P/S (0.52 ± 0.09). Cholinergic receptor stimulation increased P/S of the following proteins in descending order of sensitivity: α-actinin > talin ≈ metavinculin > α-smooth muscle actin > vinculin ≈ calponin. Carbachol induced ERK1/2 phosphorylation by 300% of basal value. U0126 (10 μM) completely inhibited carbachol-induced ERK1/2 phosphorylation but did not significantly affect the correlation between α-actinin P/S and carbachol concentration. This observation indicates that cytoskeletal/membrane recruitment of α-actinin is independent of ERK1/2 mitogen-activated protein kinase activation. Metavinculin and vinculin are splice variants of a single gene, but metavinculin P/S was significantly higher than vinculin P/S. Furthermore, the P/S of metavinculin but not vinculin increased significantly in response to cholinergic receptor stimulation. Calponin and α-actinin both belong to the family of calponin homology (CH) domain proteins. However, unlike α-actinin, the calponin P/S did not change significantly in response to cholinergic receptor stimulation. These findings indicate differential cytoskeletal/membrane recruitment of actin- and integrin-binding proteins in response to cholinergic receptor stimulation in intact airway smooth muscle. α-Actinin, talin, and metavinculin appear to be key cytoskeletal proteins involved in the recruitment process.
Signals regulating trafficking of Menkes (MNK; ATP7A) copper-translocating P-type ATPase in polarized MDCK cells
Authors: Greenough M. , Pase L. , Voskoboinik I. , Petris M. J. , O'Brien A. Wilson , Camakaris J.
Published: July 2004

The Menkes protein (MNK; ATP7A) functions as a transmembrane copper-translocating P-type ATPase and plays a vital role in systemic copper absorption in the gut and copper reabsorption in the kidney. Polarized epithelial cells such as Madin-Darby canine kidney (MDCK) cells are a physiologically relevant model for systemic copper absorption and reabsorption in vivo. In this study, cultured MDCK cells were used to characterize MNK trafficking and enabled the identification of signaling motifs required to target the protein to specific membranes. Using confocal laser scanning microscopy and surface biotinylation we demonstrate that MNK relocalizes from the Golgi to the basolateral (BL) membrane under elevated copper conditions. As previously shown in nonpolarized cells, the metal binding sites in the NH2-terminal domain of MNK were found to be required for copper-regulated trafficking from the Golgi to the plasma membrane. These data provide molecular evidence that is consistent with the presumed role of this protein in systemic copper absorption in the gut and reabsorption in the kidney. Using site-directed mutagenesis, we identified a dileucine motif proximal to the COOH terminus of MNK that was critical for correctly targeting the protein to the BL membrane and a putative PDZ target motif that was required for localization at the BL membrane in elevated copper.
P2X7 receptor-mediated apoptosis of human cervical epithelial cells
Authors: Wang Qifang , Wang Liqin , Feng Ying-Hong , Li Xin , Zeng Robin , Gorodeski George I.
Published: July 2004

Normal human ectocervical epithelial (hECE) cells undergo apoptosis in culture. Baseline apoptosis could be increased by shifting cells to serum-free medium and blocked by lowering extracellular calcium. Treatment with the ATPase apyrase attenuated baseline apoptosis, suggesting that extracellular ATP and purinergic mechanisms control the apoptosis. Treatment with ATP and the P2X7 receptor analog 2′-3′- O-(4-benzoylbenzoyl)adenosine 5′-triphosphate (BzATP) increased apoptosis significantly, in a time- and dose-related manner. The threshold of ATP effect was 0.5 μM in hECE cells and ∼1 μM in CaSki cancer cells. The apoptotic effect of BzATP was additive in part to that of tumor necrosis factor (TNF)-α, and it could be attenuated by lowering extracellular calcium and by treatment with the caspase-9 inhibitor Leu-Glu-His-Asp- O-methyl-fluoromethylketone (LEHD-FMK). Treatment with BzATP activated caspase-9, and, in contrast to TNF-α, it had only a mild effect on caspase-8. Both BzATP and TNF-α activated caspase-3, suggesting that BzATP activates predominantly the mitochondrial apoptotic pathway. Both hECE and CaSki cells secrete ATP into the extracellular fluid, and mean ATP activity in conditioned medium was ∼0.5 μM, which is in the range of values that suffice to activate the P2X7 receptor. On the basis of these findings we propose a novel autocrine-paracrine mechanism of cervical cell apoptosis that operates by P2X7 receptor control of cytosolic calcium and utilizes the mitochondrial apoptotic pathway.
Impaired β-cell compensation to dexamethasone-induced hyperglycemia in women with polycystic ovary syndrome
Authors: Ehrmann David A. , Breda Elena , Corcoran Matthew C. , Cavaghan Melissa K. , Imperial Jacqueline , Toffolo Gianna , Cobelli Claudio , Polonsky Kenneth S.
Published: July 2004

Deterioration in glucose tolerance occurs rapidly in women with polycystic ovary syndrone (PCOS), suggesting that pancreatic β-cell dysfunction may supervene early. To determine whether the compensatory insulin secretory response to an increase in insulin resistance induced by the glucocorticoid dexamethasone differs in women with PCOS and control subjects, we studied 10 PCOS and 6 control subjects with normal glucose tolerance. An oral glucose tolerance test (OGTT) and a graded glucose infusion protocol were performed at baseline and after subjects took 2.0 mg of dexamethasone orally. Basal (Φb), static (Φs), dynamic (Φd), and global (Φ) indexes of β-cell sensitivity to glucose were derived. Insulin sensitivity (Si) was calculated using the minimal model; a disposition index (DI) was calculated as the product of Si and Φ. PCOS and control subjects had nearly identical fasting and 2-h glucose levels at baseline. Φb was higher, although not significantly so, in the PCOS subjects. The Φd, Φs, and Φ indexes were 28, 19, and 20% higher, respectively, in PCOS subjects. The DI was significantly lower in PCOS (30.01 ± 5.33 vs. 59.24 ± 7.59) at baseline. After dexamethasone, control subjects averaged a 9% increase (to 131 ± 12 mg/dl) in 2-h glucose levels; women with PCOS had a significantly greater 26% increase to 155 ± 6 mg/dl. The C-peptide-to-glucose ratios on OGTT increased by 44% in control subjects and by only 15% in PCOS subjects. The accelerated deterioration in glucose tolerance in PCOS may result, in part, from a relative attenuation in the response of the β-cell to the demand placed on it by factors exacerbating insulin resistance.
Acute and chronic effects of FR-149175, a β3-adrenergic receptor agonist, on energy expenditure in Zucker fatty rats
Authors: Hatakeyama Yoshifumi , Sakata Yoshihiko , Takakura Shoji , Manda Toshitaka , Mutoh Seitaro
Published: July 2004

Clinical therapies for both obesity and obese non-insulin-dependent diabetes mellitus require maintenance of reduced body weight after the initial successful reduction resulting from calorie control, exercise, or medication. Although β3-adrenergic receptor (β3-AR) agonists have been shown to stimulate whole body energy expenditure and lipid mobilization, whether stimulatory effects on oxygen consumption and lipolysis are influenced by chronic exposure to agonists has not been fully characterized. We therefore examined the acute and chronic effects of FR-149175, a selective β3-AR agonist, on whole body oxygen consumption in genetically obese Zucker fatty rats. Chronic treatment with FR-149175 caused a decrease in both body weight gain and white fat pad weight at doses that induced lipolysis in acute treatment (1 and 3.2 mg/kg po). Single administration of FR-149175 (0.1, 1, and 3.2 mg/kg po) dose dependently increased whole body oxygen consumption. Repetitive administration did not cause attenuation of the thermogenic response at lower doses (0.1 and 1 mg/kg 2 times daily), whereas the highest dose (3.2 mg/kg 2 times daily) induced a progressive increase in oxygen consumption. PCR analyses of retroperitoneal white adipose tissue indicated little or no change in β3-AR mRNA levels. Uncoupling protein 1 gene expression increased at 1 mg/kg, and drastic upregulation was detected at 3.2 mg/kg. FR-149175 also increased HSL mRNA levels in a dose-related manner, whereas there was no effect on genes involved in β-oxidation. These results support that the thermogenic effect of β3-AR agonists is not attenuated by chronic exposure to agonists.
Role for CD14, TLR2, and TLR4 in bacterial product-induced anorexia
Authors: von Meyenburg C. , Hrupka B. H. , Arsenijevic D. , Schwartz G. J. , Landmann R. , Langhans W.
Published: July 2004

The cell surface component CD14 and the toll-like receptors 2 and 4 (TLR2 and TLR4) are important in mediating the immune responses to bacterial products in mammals. Using mice genetically deficient in CD14, TLR2, or TLR4, we studied the role of these molecules in the anorectic effects of LPS and muramyl dipeptide (MDP). CD14 or TLR2 knockout (KO) and TLR4-deficient (TLR4-DEF) mice as well as corresponding wild-type (WT) colittermates were injected intraperitoneally at dark onset with LPS (2 μg/mouse), MDP (10 mg/kg), interleukin-1β (IL-1β, 150 ng/mouse), or vehicle, and food intake was recorded. LPS and MDP reduced food intake in WT mice of all genotypes tested. The anorectic effect of LPS was attenuated ( P < 0.04) in CD14-KO and TLR4-DEF mice but not in TLR2-KO ( P > 0.05). The anorectic effect of MDP was blunted in CD14-KO and TLR2-KO ( P < 0.02) mice but not in TLR4-DEF mice. IL-1β reduced food intake similarly in all genotypes tested. These results indicate that CD14 is involved in mediating the anorectic effects of both LPS and MDP. Furthermore, TLR4 and TLR2 are specifically involved in mediating the anorectic effects of LPS and MDP, respectively. The results are consistent with the hypothesis that TLR4 functions as the true LPS receptor and that TLR2 is involved in recognition of gram-positive bacterial products.
Emerging role of relaxin in renal and cardiovascular function
Authors: Conrad Kirk P. , Novak Jacqueline
Published: July 2004

Although traditionally associated with reproductive processes, relaxin is emerging as an important player in renal and cardiovascular function. Much of our recently acquired understanding of relaxin in this new context has arisen from studies of maternal renal and cardiovascular adaptations to pregnancy in rats where the hormone is turning out to be an important mediator. First, we highlight the influence of relaxin on renal hemodynamics and glomerular filtration rate, as well as on other peripheral circulations. Second, we discuss the effect of relaxin on both the steady and pulsatile systemic arterial load, as well as on the heart, in particular, coronary blood flow. Third, we consider the impact of the hormone on cultured endothelial and vascular smooth muscle cells. Fourth, we address the interaction of relaxin with renal and cardiac disease, as well as its role in angiogenesis. Finally, in Perspectives, we point out several key research questions in need of investigation that relate to a potential autocrine/paracrine role of relaxin in renal and cardiovascular tissues. Furthermore, on the basis of its potent vasodilatory and matrix-degrading attributes, we speculate about the therapeutic potential of relaxin in renal and cardiovascular diseases.
Intracellular Measurements of Spatial Integration and the MAX Operation in Complex Cells of the Cat Primary Visual Cortex
Authors: Lampl Ilan , Ferster David , Poggio Tomaso , Riesenhuber Maximilian
Published: July 2004

We have examined the spatial integration properties of complex cells to determine whether some of their responses can be described by a maximum operation (MAX)-like computation, as suggested by Riesenhuber and Poggio's model of object recognition. Membrane potential was recorded from anesthetized cats while optimally oriented bars were presented, either alone or in pairs, in different parts of the cells' receptive field. In most cells, the membrane potential response to two bars presented simultaneously could not be predicted by the sum of the responses to individual bars. In many cells, however, the responses closely approximated a MAX-like model. That is, the response of the cell to two bars was similar to the larger of the two individual responses (“soft-MAX”). The degree of nonlinear summation varied from cell to cell and varied within single cells from one stimulus configuration to another but on average fit most closely to the MAX model. The firing response of the cells was also well predicted by the MAX-like model. The MAX-like behavior was independent of the distance between the bars (orthogonal to the preferred orientation), independent of the relative amplitude of the responses, and slightly less pronounced at low levels of contrast. This MAX-like behavior of a subset of complex cells may play an important role in invariant object recognition in clutter.
Diffusion of Epidermal Growth Factor in Rat Brain Extracellular Space Measured by Integrative Optical Imaging
Authors: Thorne Robert G. , Hrabětová Sabina , Nicholson Charles
Published: July 2004

Epidermal growth factor (EGF) stimulates proliferation, process outgrowth, and survival in the CNS. Understanding the actions of EGF necessitates characterizing its distribution in brain tissue following drug delivery or release from cellular sources. We used the integrative optical imaging (IOI) method to measure diffusion of fluorescently labeled EGF (6,600 Mr; 4 μg/ml) in the presence of excess unlabeled EGF (90 μg/ml) to compete off specific receptor binding and reveal the “true” EGF diffusion coefficient following injection in rat brain slices (400 μm). The effective diffusion coefficient was 5.18 ± 0.16 × 10−7(SE) cm2/s ( n = 22) in rat somatosensory cortex and the free diffusion coefficient, determined in dilute agarose gel, was 16.6 ± 0.12 × 10−7cm2/s ( n = 27). Tortuosity (λ), a parameter representing the hindrance imposed on EGF by the convoluted brain extracellular space (ECS), was 1.8, the lowest yet measured by IOI for a protein in brain. Control experiments with fluorescent dextran of similar molecular weight and tetramethylammonium confirmed EGF did not affect local ECS structure. We conclude that transport of smaller growth factors such as EGF through brain ECS is less hindered than that of larger proteins (>10,000 Mr, e.g., nerve growth factor) where typically λ > 2.1. Modeling was used to predict that low λ will allow EGF sources in the brain to be further from target cells and still elicit a biological response. High λ values for larger growth factors imply more constrained local biological effects than with smaller proteins such as EGF.
Parietal Representation of Hand Velocity in a Copy Task
Authors: Averbeck Bruno B. , Chafee Matthew V. , Crowe David A. , Georgopoulos Apostolos P.
Published: July 2004

We recorded neural activity from ensembles of neurons in areas 5 and 2 of parietal cortex, while two monkeys copied triangles, squares, trapezoids, and inverted triangles and used both linear and nonlinear models to predict the hand velocity from the neural activity of the ensembles. The linear model generally outperformed the nonlinear model, suggesting a reasonably linear relation between the neural activity and the hand velocity. We also found that the average transfer function of the linear model fit to individual cells was a low-pass filter because the neural response had considerable high-frequency power, whereas the hand velocity only had power at frequencies below ∼5 Hz. Increasing the width of the transfer function, up to a width of 700–800 ms, improved the fit of the model. Furthermore, the Rsqr of the linear model improved monotonically with the number of cells in the ensemble, saturating at 60–80% for a filter width of 700 ms. Finally, it was found that including an interaction term, which allowed the transfer function to shift with the eye position, did not improve the fit of the model. Thus ensemble neural responses in superior parietal cortex provide a high-fidelity, linear representation of hand kinematics within our task.
Contributions of Mossy Fiber and CA1 Pyramidal Cell Sprouting to Dentate Granule Cell Hyperexcitability in Kainic Acid–Treated Hippocampal Slice Cultures
Authors: Bausch Suzanne B. , McNamara James O.
Published: July 2004

Axonal sprouting like that of the mossy fibers is commonly associated with temporal lobe epilepsy, but its significance remains uncertain. To investigate the functional consequences of sprouting of mossy fibers and alternative pathways, kainic acid (KA) was used to induce robust mossy fiber sprouting in hippocampal slice cultures. Physiological comparisons documented many similarities in granule cell responses between KA- and vehicle-treated cultures, including: seizures, epileptiform bursts, and spontaneous excitatoty postsynaptic currents (sEPSCs) >600pA. GABAergic control and contribution of glutamatergic synaptic transmission were similar. Analyses of neurobiotin-filled CA1 pyramidal cells revealed robust axonal sprouting in both vehicle- and KA-treated cultures, which was significantly greater in KA-treated cultures. Hilar stimulation evoked an antidromic population spike followed by variable numbers of postsynaptic potentials (PSPs) and population spikes in both vehicle- and KA-treated cultures. Despite robust mossy fiber sprouting, knife cuts separating CA1 from dentate gyrus virtually abolished EPSPs evoked by hilar stimulation in KA-treated but not vehicle-treated cultures, suggesting a pivotal role of functional afferents from CA1 to dentate gyrus in KA-treated cultures. Together, these findings demonstrate striking hyperexcitability of dentate granule cells in long-term hippocampal slice cultures after treatment with either vehicle or KA. The contribution to hilar-evoked hyperexcitability of granule cells by the unexpected axonal projection from CA1 to dentate in KA-treated cultures reinforces the idea that axonal sprouting may contribute to pathologic hyperexcitability of granule cells.
Hydroxylation of HIF-1: Oxygen Sensing at the Molecular Level
Authors: Semenza Gregg L.
Published: July 2004

The ability to sense and respond to changes in oxygenation represents a fundamental property of all metazoan cells. The discovery of the transcription factor HIF-1 has led to the identification of protein hydroxylation as a mechanism by which changes in Po2 are transduced to effect changes in gene expression.
Postural Stability During Treadmill Locomotion as a Function of the Visual Polarity and Rotation of a Three-Dimensional Virtual Environment
Authors: Richards Jason T. , Mulavara Ajitkumar P. , Bloomberg Jacob J.
Published: July 2004

Visual inputs provide us with important cues for orientation and self-movement perception during locomotion. The purpose of the present study was to better understand and quantify the effects of visual scene variables: visual polarity and visual scene rotation on postural stability during treadmill locomotion. During 60 s trials, subjects walked at 4.0 km/h while viewing a monoscopic, passive-immersive, 3D virtual room environment that contained either polarized or nonpolarized content and was back-projected onto a screen 1.5 m in front of them, one at a time. Scenes remained static for the first 30 s, then rotated about the roll, pitch, or yaw axis of the room at a constant rate of 30°/s for the remaining 30 s. Each subject saw each combination of visual polarity (polarized, nonpolarized) and scene rotation direction (roll, pitch, yaw) for three separate trials. There was a main effect of visual polarity on variability in torso linear X (fore–aft) position and torso roll and pitch angular orientations with polarized scenes causing more variability than nonpolarized scenes. For the polarized scenes only, variability in torso roll, pitch, and yaw angular orientations was increased for corresponding scene rotation directions, respectively. In general, rotating visual scenes caused increased variability in torso motion compared to static scenes. Visual polarity is an important consideration when designing virtual environment motion simulations.
Concurrency Control Mechanisms for Closely Coupled Collaboration in Multithreaded Peer-to-Peer Virtual Environments
Authors: Linebarger John M. , Kessler G. Drew
Published: July 2004

As collaboration in virtual environments becomes more object-focused and closely coupled, the frequency of conflicts in accessing shared objects can increase. In addition, two kinds of concurrency control “surprises” become more disruptive to the collaboration. Undo surprises can occur when a previously visible change is undone because of an access conflict. Intention surprises can happen when a concurrent action by a remote session changes the structure of a shared object at the same perceived time as a local access of that object, such that the local user might not get what they expect because they have not had time to visually process the change. A hierarchy of three concurrency control mechanisms is presented in descending order of collaborative surprises, which allows the concurrency scheme to be tailored to the tolerance for such surprises. One mechanism is semioptimistic; the other two are pessimistic. Designed for peer-to-peer virtual environments in which several threads have access to the shared scene graph, these algorithms are straightforward and relatively simple. They can be implemented using C/C++ and Java, under Windows and Unix, on both desktop and immersive systems. In a series of usability experiments, the average performance of the most conservative concurrency control mechanism on a local LAN was found to be quite acceptable.
Geometric Message-Filtering Protocols for Distributed Multiagent Environments
Authors: Goldin Alexander , Gotsman Craig
Published: July 2004

Message filtering is important for distributed multiagent systems, where a large number of dynamic agents participate in the system activity, but a typical agent is interested in only a very small dynamic subset of the other agents. The agent must be constantly informed on the status of this subset, and this is achieved by message passing between relevant agents. Message filtering is required to reduce the communications load on the system, which could be prohibitive if each agent must communicate with all others in order to obtain the information it needs.

This paper deals with the case of a multiagent virtual environment, where each agent has a location in 2D space, and is interested in a small subset of the other agents, either those within a fixed range—as treated by previous authors, or the k other agents nearest to it—treated here for the first time. Furthermore, we treat the case of a fully distributed system, where no central server(s) are available to coordinate between the agents. The main challenge is then to design protocols that perform significant message filtering, yet enable each agent to maintain a consistent image of the other agents it is interested in. These protocols are useful in multi-agent games, simulations, and other virtual environments in which the geometric relationships between agents are important. They could also be useful for mobile-commerce and cellphone-based gaming applications.
Transatlantic Touch: A Study of Haptic Collaboration over Long Distance
Authors: Kim Jung , Kim Hyun , Tay Boon K. , Muniyandi Manivannan , Srinivasan Mandayam A. , Jordan Joel , Mortensen Jesper , Oliveira Manuel , Slater Mel
Published: July 2004

The extent to which the addition of haptic communication between human users in a shared virtual environment (SVE) contributes to the shared experience of the users has not received much attention in the literature. In this paper we describe a demonstration of and an experimental study on haptic interaction between two users over a network of significant physical distance and a number of network hops. A number of techniques to mitigate instability of the haptic interactions induced by network latency are presented. An experiment to evaluate the use of haptics in a collaborative situation mediated by a networked virtual environment is examined. The experimental subjects were to cooperate in lifting a virtual box together under one of four conditions in a between-groups design. Questionnaires were used to report the ease with which they could perform the task and the subjective levels of presence and copresence experienced. This extends earlier work by the authors to consider the possibility of haptic collaboration under real network conditions with a number of improvements. Using the technology described in this paper, transatlantic touch was successfully demonstrated between the Touch Lab at Massachusetts Institute of Technology, USA and Virtual Environments and Computer Graphics (VECG) lab at University College London (UCL), UK in 2002. It was also presented at the Internet II demonstration meeting in 2002 between University of Southern California and the Massachusetts Institute of Technology.
The CIA and the Polish Crisis of 1980–1981
Authors: Davies Richard T.
Published: July 2004

The crisis in Poland in 1980–1981 imposed great demands on the U.S. intelligence community. On the one hand, U.S. intelligence analysts sought to determine whether the Soviet Union might send troops into Poland to crush the Solidarity movement. On the other hand, a small group of senior intelligence and national security officials who were privy to reports from Colonel Ryszard Kukliński, a senior officer on the Polish General Staff who was secretly working for the United States, had to decide how best to use the enormously valuable information the colonel was providing. These issues and others pertaining to the activities of the U.S. Central Intelligence Agency (CIA) during the Polish crisis are examined in a new book by Douglas J. MacEachin, a former CIA deputy director who oversaw the agency's efforts vis-à-vis Poland and the Soviet Union. MacEachin's book, as this essay shows, provides an astute and refreshingly candid evaluation of the CIA's performance.
Captives, Children and Conversion: A Case from Late Naṣrid Granada
Authors: el Hour Rachid , Marín Manuela
Published: July 2004

Around 894/1488-89, a legal opinion on the case of a child living in the Naṣrid Kingdom of Granada, who came under the double threat of captivity and forced conversion to Christianity, was demanded by its father from jurists in Tlemcen. The text of this case is presented here and analysed from two points of view: the historical context of Muslim captives in Christian Spain, and the legal theory applied in the North African answer to the question posed by the Andalusi father. In the historical part of the article, cases of Andalusi Muslim captives (from the 6th/12th century to the 9th/15th century) are examined. Special attention is given to the possible ways used to put an end to captivity: ransoms and those who paid for them, bequests and pious fundations, etc., as well as tales of escape from Christians. Finally, the Muslim religious view of captivity is considered. In the second part, the case posed to the North African jurists is reviewed in detail. The two responses given by Ibn Zakarīyāʾ (d. 899/1493) and al-Sanūsī (d. 895/1490) both agree that the child could be separated from its mother and removed to a safe country. The motives given by both jurists to justify their opinions differ, but they follow the Mālikite school of law and reflect the historical and social developments of their time.
On (mis)interpreting Plato's Ion
Authors: Stern-Gillet Suzanne
Published: July 2004

Plato's Ion, despite its frail frame and traditionally modest status in the corpus, has given rise to large exegetical claims. Thus some historians of aesthetics, reading it alongside page 205 of the Symposium, have sought to identify in it the seeds of the post-Kantian notion of 'art' as non-technical making, and to trace to it the Romantic conception of the poet as a creative genius. Others have argued that, in the Ion, Plato has Socrates assume the existence of a technē of poetry. In this article, these claims are challenged on exegetical and philosophical grounds. To this effect, Plato's use of poiētēs and poiēsis in the Symposium is analysed, the defining criteria of technē in the Ion and other dialogues are identified and discussed, and the 'Romantic' interpretation of the dialogue is traced to Shelley's tendentious translation of it. These critical developments lead to what is presented as a more faithful reading of the dialogue. In the Ion, it is claimed, Plato seeks to subvert the traditional status of poetry by having Socrates argue that poetry is both non-rational and non-cognitive in nature. In the third part of the article, suggestions are offered as to the contribution made by the Ion to the evolution of Plato's reflections on poetic composition, and particularly as to the reasons which later induced Plato to substitute the concept of mimesis for that of inspiration in his account of poetry.
Socrates' Avowals of Knowledge
Authors: Wolfsdorf David
Published: July 2004

The paper examines Socrates' avowals and disavowals of knowledge in the standardly accepted early Platonic dialogues. All of the pertinent passages are assembled and discussed. It is shown that, in particular, alleged avowals of knowledge have been variously misinterpreted. The evidence either does not concern ethical knowledge or its interpretation has been distorted by abstraction of the passage from context or through failure adequately to appreciate the rhetorical dimensions of the context or the author's dramaturgical interests. Still, six sincere Socratic avowals or assumptions of ethical knowledge occur among the early dialogues. Moreover, it is maintained that in a number of these texts Socrates is committed to the epistemological priority of definitional knowledge of excellence for pertinent non-definitional knowledge (for example, that knowledge of the definition of justice is necessary for knowledge of instances of justice). Thus, there are inconsistencies among Socrates' avowals and disavowals of ethical knowledge. It is argued that the most important recent attempts to resolve Socrates' avowals and disavowals of knowledge (for example, Vlastos's) fail. A novel interpretation is then offered that depends upon a fundamental adjustment in the interpretation of Socrates' utterances in the texts. The practice of assembling all of Socrates' topic-relevant utterances, divorced from context, and attempting to distill from these consistent philosophical principles is rejected as naïve. In contrast, it is argued that Plato uses Socrates in various ways in various texts in order to achieve certain pedagogical objectives. Accordingly, Socrates' utterances do not all have the same hermeneutic status. On this depends the correct interpretation of Socrates' occasional avowals of ethical knowledge as well as the general epistemological, specifically ethical epistemological commitments that Plato intended to advance in the early dialogues. The paper concludes with an explanation of the function of Socrates' occasional avowals of ethical knowledge as well as an account of the ethical epistemological commitments that Plato intended to advance among the early dialogues.
Piracy and law in medieval Genoa: the consilia of Bartolomeo Bosco
Authors: Tai Emily
Published: July 2004

This essay contextualizes a series of learned legal opinions, or consilia, authored primarily by the Genoese jurist Bartolomeo Bosco (d. 1437) on the subject of maritime theft, or piracy, by referring to contemporaneous records for the practice of maritime theft in the Mediterranean, archival records in the Archivio di Stato for Bosco's career, and related consilia authored by Bosco. It argues that Bosco's opinions on matters related to the practice of piracy, overlooked despite revived scholarly interest in his work, illustrate the applications and limitations of consilia as practical documents in medieval civic governance, and suggest a divide between commercial and administrative perspectives in the maritime republics of late medieval Europe. Finally, it proposes that Bartolomeo Bosco be numbered among the "economic humanists" of the fifteenth century.
A protease activated receptor-2 (PAR-2) activating peptide, tc-LIGRLO-NH2, induces protease release from mast cells: role in TNF degradation
Authors: Alshurafa Hashem N , Stenton Grant R , Wallace John L , Hollenberg Morley D , Dean Befus A , Vliagoftis Harissios
Published: July 2004

Background

Mast cell (MC)-derived serine proteases have been implicated in a variety of inflammatory processes. We have previously shown that rat peritoneal MC (PMC) express mRNA for protease activated receptor 2 (PAR-2), a G-coupled receptor activated by trypsin-like proteases. Recent evidence also suggests that MC-induced inflammation can be mediated through PAR. Therefore, we hypothesized that specific PAR-2 agonist peptides (PAR-2ap) induce protease release from PMC.

Results

Western blot analysis of PMC supernatants revealed that a PAR-2ap, tc-LIGRLO (10 μM), stimulated the release of rat MC protease (RMCP)-1, RMCP-5 and carboxypeptidase-A. The release was evident by 20 min but further increased up to 8 h. To study the biological effects of protease release we tested supernatants from tc-LIGRLO, tc-OLRGIL (inactive control peptide) and antigen-activated PMC for proteolytic activity by seeding with TNF (150 pg/ml), incubating for 8 h at 37°C, and measuring TNF remaining in the supernatants. Supernatants from tc-LIGRLO-stimulated PMC degraded 44 % of seeded TNF (n = 5). Moreover, this TNF proteolysis was dependent on the concentration of tc-LIGRLO used to stimulate PMC, and was significantly inhibited (94 %) by soybean trypsin inhibitor. Antigen and tc-OLRGIL induced no significant release of such proteolytic activity.

Conclusions

These data indicate that a PAR-2ap induces the release of proteases from mast cells, which may degrade extracellular cytokines and other substrates thus modulating the inflammatory response.
Treatment of mechanically-induced vasospasm of the carotid artery in a primate using intra-arterial verapamil: a technical case report
Authors: Coon Alexander L , Colby Geoffrey P , Mack William J , Feng Lei , Meyers Philip , Sander Connolly E
Published: July 2004

Background

Despite improvements in the safety and efficacy of endovascular procedures, considerable morbidity may still be attributed to vasospasm. Vasospasm has proven amenable to pharmacological intervention such as nitrates, intravenous calcium channel blockers (CCBs), and intra-arterial papaverine, particularly in small vessels. However, few studies have focused on medium to large vessel spasm. Here we report the use of an intra-arterial CCB, verapamil, to treat flow-limiting mechanically-induced spasm of the common carotid artery (CCA) in a primate. We believe this to be the first such report of its kind.

Case presentation

As part of a study assessing the placement feasibility and safety of a catheter capable of delivering intra-arterial cerebroprotective therapy, a female 16 kg baboon prophylaxed with intravenous nitroglycerin underwent transfemoral CCA catheterization with a metallic 6-Fr catheter without signs of acute spasm. The protocol dictated that the catheter remain in the CCA for 12 hours. Upon completion of the protocol, arteriography revealed a marked decrease in CCA size (mean cross-sectional area reduction = 31.6 ± 1.9%) localized along the catheter length. Intra-arterial verapamil (2 mg/2cc) was injected and arteriography was performed 10 minutes later. Image analysis at 6 points along the CCA revealed a 21.0 ± 1.7% mean increase in vessel diameter along the length of the catheter corresponding to a 46.7 ± 4.0% mean increase in cross-sectional area. Mean systemic blood pressure did not deviate more than 10 mm Hg during the procedure.

Conclusions

Intraluminal CCBs like verapamil may constitute an effective endovascular treatment for mechanically-induced vasospasm in medium to large-sized vessels such as the CCA.
Assessing harmful effects in systematic Reviews
Authors: McIntosh Heather M , Woolacott Nerys F , Bagnall Anne-Marie
Published: July 2004

Background

Balanced decisions about health care interventions require reliable evidence on harms as well as benefits. Most systematic reviews focus on efficacy and randomised trials, for which the methodology is well established. Methods to systematically review harmful effects are less well developed and there are few sources of guidance for researchers. We present our own recent experience of conducting systematic reviews of harmful effects and make suggestions for future practice and further research.

Methods

We described and compared the methods used in three systematic reviews. Our evaluation focused on the review question, study designs and quality assessment.

Results

One review question focused on providing information on specific harmful effects to furnish an economic model, the other two addressed much broader questions. All three reviews included randomised and observational data, although each defined the inclusion criteria differently. Standard methods were used to assess study quality. Various practical problems were encountered in applying the study design inclusion criteria and assessing quality, mainly because of poor study design, inadequate reporting and the limitations of existing tools. All three reviews generated a large volume of work that did not yield much useful information for health care decision makers. The key areas for improvement we identified were focusing the review question and developing methods for quality assessment of studies of harmful effects.

Conclusions

Systematic reviews of harmful effects are more likely to yield information pertinent to clinical decision-making if they address a focused question. This will enable clear decisions to be made about the type of research to include in the review. The methodology for assessing the quality of harmful effects data in systematic reviews requires further development.
Effects of chemokines on proliferation and apoptosis of human mesangial cells
Authors: Wörnle Markus , Schmid Holger , Merkle Monika , Banas Bernhard
Published: July 2004

Background

Proliferation and apoptosis of mesangial cells (MC) are important mechanisms during nephrogenesis, for the maintenance of glomerular homeostasis as well as in renal disease and glomerular regeneration. Expression of chemokines and chemokine receptors by intrinsic renal cells, e.g. SLC/CCL21 on podocytes and CCR7 on MC is suggested to play a pivotal role during these processes. Therefore the effect of selected chemokines on MC proliferation and apoptosis was studied.

Methods

Proliferation assays, cell death assays including cell cycle analysis, hoechst stain and measurement of caspase-3 activity were performed.

Results

A dose-dependent, mesangioproliferative effect of the chemokine SLC/CCL21, which is constitutively expressed on human podocytes was seen via activation of the chemokine receptor CCR7, which is constitutively expressed on MC. In addition, in cultured MC SLC/CCL21 had a protective effect on cell survival in Fas-mediated apoptosis. The CXCR3 ligands IP-10/CXCL10 and Mig/CXCL9 revealed a proproliferative effect but did not influence apoptosis of MC. Both the CCR1 ligand RANTES/CCL5 and the amino-terminally modified RANTES analogue Met-RANTES which blocks CCR1 signalling had no effect on proliferation and apoptosis.

Conclusions

The different effects of chemokines and their respective receptors on proliferation and apoptosis of MC suggest highly regulated, novel biological functions of chemokine/chemokine receptor pairs in processes involved in renal inflammation, regeneration and glomerular homeostasis.
Irinotecan plus folinic acid/continuous 5-fluorouracil as simplified bimonthly FOLFIRI regimen for first-line therapy of metastatic colorectal cancer
Authors: Teufel Andreas , Steinmann Silke , Siebler Jürgen , Zanke Christiane , Hohl Herbert , Adami Bernd , Schroeder M , Klein O , Höhler Thomas , Galle Peter R , Heike Michael , Moehler Markus
Published: July 2004

Background

Combination therapy of irinotecan, folinic acid (FA) and 5-fluorouracil (5-FU) has been proven to be highly effective for the treatment of metastatic colorectal cancer. However, in light of safety and efficacy concerns, the best combination regimen for first-line therapy still needs to be defined. The current study reports on the bimonthly FOLFIRI protocol consisting of irinotecan with continuous FA/5-FU in five German outpatient clinics, with emphasis on the safety and efficiency, quality of life, management of delayed diarrhea, and secondary resection of regressive liver metastases.

Methods

A total of 35 patients were treated for metastatic colorectal cancer. All patients received first-line treatment according to the FOLFIRI regimen, consisting of irinotecan (180 mg/m2), L-FA (200 mg/m2) and 5-FU bolus (400 mg/m2) on day 1, followed by a 46-h continuous infusion 5-FU (2400 mg/m2). One cycle contained three fortnightly administrations. Staging was performed after 2 cycles. Dosage was reduced at any time if toxicity NCI CTC grade III/IV was observed. Chemotherapy was administered only to diarrhea-free patients.

Results

The FOLFIRI regimen was generally well tolerated. It was postponed for one-week in 51 of 415 applications (12.3%). Dose reduction was necessary in ten patients. Grade III/IV toxicity was rare, with diarrhea (14%), nausea/vomiting (12%), leucopenia (3%), neutropenia (9%) and mucositis (3%). The overall response rate was 31% (4 CR and 7 PR), with disease control in 74%. After primary chemotherapy, resection of liver metastases was achieved in three patients. In one patient, the CR was confirmed pathologically. Median progression-free and overall survival were seven and 17 months, respectively.

Conclusions

The FOLFIRI regimen proved to be safe and efficient. Outpatient treatment was well tolerated. Since downstaging was possible, combinations of irinotecan and continuous FA/5-FU should further be investigated in neoadjuvant protocols.
Identification of astrocytoma associated genes including cell surface markers
Authors: Boon Kathy , Edwards Jennifer B , Eberhart Charles G , Riggins Gregory J
Published: July 2004

Background

Despite intense effort the treatment options for the invasive astrocytic tumors are still limited to surgery and radiation therapy, with chemotherapy showing little or no increase in survival. The generation of Serial Analysis of Gene Expression (SAGE) profiles is expected to aid in the identification of astrocytoma-associated genes and highly expressed cell surface genes as molecular therapeutic targets. SAGE tag counts can be easily added to public expression databases and quickly disseminated to research efforts worldwide.

Methods

We generated and analyzed the SAGE transcription profiles of 25 primary grade II, III and IV astrocytomas [1]. These profiles were produced as part of the Cancer Genome Anatomy Project's SAGE Genie [2], and were used in an in silico search for candidate therapeutic targets by comparing astrocytoma to normal brain transcription. Real-time PCR and immunohistochemistry were used for the validation of selected candidate target genes in 2 independent sets of primary tumors.

Results

A restricted set of tumor-associated genes was identified for each grade that included genes not previously associated with astrocytomas (e.g. VCAM1, SMOC1, and thymidylate synthetase), with a high percentage of cell surface genes. Two genes with available antibodies, Aquaporin 1 and Topoisomerase 2A, showed protein expression consistent with transcript level predictions.

Conclusions

This survey of transcription in malignant and normal brain tissues reveals a small subset of human genes that are activated in malignant astrocytomas. In addition to providing insights into pathway biology, we have revealed and quantified expression for a significant portion of cell surface and extra-cellular astrocytoma genes.
Smoking cigarettes of low nicotine yield does not reduce nicotine intake as expected: a study of nicotine dependency in Japanese males
Authors: Nakazawa Atsuko , Shigeta Masako , Ozasa Kotaro
Published: July 2004

Background

Many Japanese believe that low-yield cigarettes are less hazardous than regular cigarettes, and many smokers consume low-yield cigarettes to reduce their risks from smoking. We evaluate the association between actual nicotine intake and brand nicotine yield, and the influence of nicotine dependence on this association.

Methods

The study subjects included 458 Japanese male smokers, aged 51.2 ± 9.9 years, who participated in health check-ups in a hospital in 1998 and 2000. Each subject filled out a self-administered smoking questionnaire and the score of each on the Fagerström Test for Nicotine Dependence was calculated. Urinary cotinine concentration was measured at the time of participation.

Results

The geometric mean of urinary cotinine concentration was 535 ng/mgCr for those who smoked brands with the lowest nicotine (0.1 mg on the package), compared with 1010 ng/mgCr for those who smoked brands with the highest (0.9–2.4 mg, weighted mean of 1.1 mg). Thus, despite the 11-fold ratio of nicotine yield on the packages, the ratio of urinary cotinine level was less than twofold. Both nicotine yield on the package and nicotine dependence significantly increased urinary cotinine concentration, and the negative interaction between them almost attained statistical significance. Cotinine concentration in heavily dependent smokers was consistently high regardless of the nicotine yield of brands.

Conclusions

The nicotine yield of cigarettes measured by machine-smoking does not reliably predict the exposure of smokers. Smokers consuming low-yield nicotine cigarettes did not reduce actual intake of nicotine to the level that might be expected, especially for those heavily dependent on nicotine. Current labeling practices are misleading for the two-third of smokers who are moderately or highly dependent on nicotine.