bluuebunny/crossref_metadata_2025 huggingface dataset:
SPIRAL WAVE MEANDER AND SYMMETRY OF THE PLANE
Authors: BIKTASHEV V. N. , HOLDEN A. V. , NIKOLAEV E. V.
Published: October 2004

We present a general group-theoretic approach that explains the main qualitative features of the meander of spiral wave solutions on the plane. The approach is based on the well-known space reduction method and is used to separate the motions in the system into superposition of those ‘along’ orbits of the Euclidean symmetry group, and ‘across’ the group orbits. It can be interpreted as passing to a reference frame attached to the spiral wave’s tip. The system of ODEs governing the tip movement is obtained. It is the system that describes the movements along the group orbits. The motions across the group orbits are described by a PDE which lacks the Euclidean symmetry. Consequences of the Euclidean symmetry on the spiral wave dynamics are discussed. In particular, we explicitly derive the model system for bifurcation from rigid to biperiodic rotation, suggested earlier by Barkley [1994] from a priori symmetry considerations.
LORENZ EQUATION AND CHUA’S EQUATION
Authors: PIVKA LADISLAV , WU CHAI WAH , HUANG ANSHAN
Published: October 2004

The dynamical properties of two classical paradigms for chaotic behavior are reviewed—the Lorenz and Chua’s Equations—on a comparative basis. In terms of the mathematical structure, the Lorenz Equation is more complicated than Chua’s Equation because it requires two nonlinear functions of two variables, whereas Chua’s Equation requires only one nonlinear function of one variable. It is shown that most standard routes to cbaos and dynamical phenomena previously observed from the Lorenz Equation can be produced in Chua’s system with a cubic nonlinearity. In addition, we show other phenomena from Chua’s system which are not observed in the Lorenz system so far. Some differences in the topological geometric models are also reviewed. We present some theoretical results regarding Chua’s system which are absent for the Lorenz system. For example, it is known that Chua’s system is topologically conjugate to the class of systems with a scalar nonlinearity (except for a measure zero set) and is therefore canonical in this sense. We conclude with some reasons why Chua’s system can be considered superior or more suitable than the Lorenz system for various applications and studies.
THE CONLEY INDEX AND GLOBAL BIFURCATIONS II.: ILLUSTRATIVE APPLICATIONS
Authors: KAPPOS EFTHIMIOS
Published: October 2004

This paper continues the presentation of a set of tools based on the Conley index for studying global dynamics and bifurcations. The first part gives the basic theory and some fundamental results. In this second part, we give a number of examples in more detail to illustrate the way these tools are applied. They are chosen to address issues such as: how is an index pair selected? how do we deal with high dimension? etc. In addition, we present powerful algebraic methods for computing the Conley index: the method of forming the cone over a space and the use of exact sequences and excision. It is understood that the likely users of these methods are far from being familiar with these mathematical results, so the emphasis is in revealing exactly how information is extracted from them. The many figures will hopefully aid the understanding of these novel concepts.
TOPOLOGICAL ANALYSIS OF CHAOS IN EQUIVARIANT ELECTRONIC CIRCUITS
Authors: LETELLIER C. , GOUESBET G. , RULKOV N.F.
Published: October 2004

Chaotic oscillations in an electronic circuit are studied by recording two time series simultaneously. The chaotic dynamics is characterized by using topological analysis. A comparison with two models is also discussed. Some prescriptions are given in order to take into account the symmetry properties of the experimental system to perform the topological analysis.
ON THE BIRTH OF MULTIPLE LIMIT CYCLES IN NONLINEAR SYSTEMS
Authors: MOIOLA JORGE L. , CHEN GUANRONG
Published: October 2004

Degenerate (or singular) Hopf bifurcations of a certain type determine the appearance of multiple limit cycles under system parameter perturbations. In the study of these degenerate Hopf bifurcations, computational formulas for the stability indexes (i.e., curvature coefficients) are essential. However, such formulas are very difficult to derive, and so are usually computed by different approximation methods. Inspired by the feedback control systems methodology and the harmonic balance approximation technique, higher-order approximate formulas for such curvature coefficients are derived in this paper in the frequency domain setting. The results obtained are then applied to a study of nonlinear dynamical systems within the region of one periodic solution, bypassing a direct investigation of the multiple limit cycles and some tedious discussion of the complex multiplicity issue. Finally, we will show that several types of stability bifurcations can be controlled based on the results obtained in this paper.
FIRST HARMONIC ANALYSIS OF PLANAR LINEAR SYSTEMS WITH SINGLE SATURATED FEEDBACK
Authors: SUÁREZ RODOLFO , ALVAREZ-RAMIREZ JOSÉ , AGUIRRE BALTAZAR
Published: October 2004

A first harmonic approach (describing function method) is used here to analyze the dependence of periodic orbits on the control parameters of planar linear systems with single saturated feedback. It is shown that, if the open-loop system has at least one unstable eigenvalue, periodic orbits converge monotonically to an unstable equilibrium point as the control gains go to infinity.
THE DYNAMICAL SYSTEMS ASSOCIATED WITH CHEBYSHEV POLYNOMIALS IN TWO VARIABLES
Authors: UCHIMURA KEISUKE
Published: October 2004

The dynamical system given by [Formula: see text] is considered, where z is a complex variable and [Formula: see text] denotes the complex conjugate of it. The function F2(z) is related to Chebyshev polynomials in two variables. We show the chaoticity of this dynamical system on some closed domain and relations between the dynamics and a shift dynamical system. Besides we show that the dynamical system is related to the Sierpinsky gasket.
BEHAVIOR OF DYNAMICAL SYSTEMS SUBJECTED TO CONTINUOUS AND DISCONTINUOUS FORCING: APPLICATION TO LAMINAR CHAOTIC MIXING
Authors: PÉREZ A.T. , CHACÓN R. , CASTELLANOS A.
Published: October 2004

This paper studies the effect of continuous and discontinuous time dependent forcings onto dynamical systems. We compare these different forcings in the context of laminar chaotic mixing. It is shown that the response of a Hamiltonian two-dimensional system to a time periodic sinusoidal forcing differs qualitatively and quantitatively from the response to a square wave function of the same frequency. Consequently, the mixing efficiency of both types of forcings are different. Also a periodic function of the same shape as that of the velocity of the unperturbed system is tested as a forcing, its mixing efficiency being intermediate.
A SIMPLE METHOD TO REVEAL THE PARAMETERS OF THE LORENZ SYSTEM
Authors: STOJANOVSKI TONI , KOCAREV LJUPCO , PARLITZ ULRICH
Published: October 2004

In this paper we describe a simple method to reveal the parameters of the Lorenz system from time series of the x1 or x2 variable of the Lorenz system. The method is numerically tractable and extremely simple to apply. Furthermore, the method breaks secure communication systems like chaotic masking, chaos switching, and chaos modulation if they are based on the Lorenz system.
CHANNEL-INDEPENDENT CHAOTIC SECURE COMMUNICATION
Authors: YANG TAO , CHUA LEON O.
Published: October 2004

The generalized synchronization (GS) of two identical chaotic systems through an unknown channel is studied. First, some theoretical results of GS through an unknown channel are derived. Finally, an application of GS to channel-independent chaotic secure communication is presented.
Lipid and fatty acid profiles in the brain, liver, and stomach contents of neonatal rats: effects of hypoxia
Authors: Bruder Eric D. , Lee Ping C. , Raff Hershel
Published: October 2004

Neonatal hypoxia leads to clinically significant fatty liver, presumably due to disturbances in lipid metabolism. To fully evaluate lipid metabolism, the present study analyzed the complete lipid profile of the brain, liver, and ingested stomach contents of 7-day-old rats exposed to hypoxia from birth. Hypoxia had negligible direct effects on lipid metabolism in the brain. Conversely, hypoxia exhibited direct effects on hepatic lipid metabolism that could not be fully explained by changes in dietary intake. Triacylglyceride concentration was significantly increased in the hypoxic liver but remained unchanged in the brain and stomach contents. Diacylglyceride concentration was increased in both the brain and liver, and this was associated with increased diacylglyceride in the stomach contents. Most n-3 and n-6 fatty acids were increased in the liver, but not in the brain, of hypoxic pups. These changes did not reflect those measured in the stomach contents. Saturated fatty acid concentrations were increased in both the hypoxic brain and liver, and these changes reflected those in the stomach contents. Hypoxia also increased total phospholipid concentration in the brain and stomach contents. We conclude that neonatal hypoxia indirectly affects specific lipid and fatty acid concentrations in the brain and liver through alterations in the absorbed stomach contents. Hypoxia also exhibits some direct affects through modulation of metabolic pathways in situ, mostly in the liver. In this respect, the neonatal brain exhibits tighter control on lipid homeostasis than the liver during neonatal hypoxia.
Superoxide scavenging attenuates renal responses to ANG II during nitric oxide synthase inhibition in anesthetized dogs
Authors: Majid Dewan S. A. , Nishiyama Akira , Jackson Keith E. , Castillo Alexander
Published: October 2004

To assess the role of superoxide (O2−) and nitric oxide (NO) interaction in mediating the renal actions of ANG II, we examined the renal responses to intra-arterial infusion of ANG II (0.5 ng·kg−1·min−1) before and during administration of a superoxide dismutase mimetic, tempol (0.5 mg·kg−1·min−1), in the presence or absence of NO synthase inhibitor, nitro-l-arginine (NLA; 50 μg·kg−1·min−1), in anesthetized dogs pretreated with enalaprilat (33 μg·kg−1·min−1). In one group of dogs ( n = 7), ANG II infusion before tempol infusion caused decreases of 24 ± 4% in renal blood flow (RBF), 55 ± 7% in urine flow (V), and 53 ± 8% in urinary sodium excretion (UNaV) with a slight decrease in glomerular filtration rate (GFR; −7.8 ± 3.4%). Tempol infusion alone did not cause significant alterations in RBF, GFR, V, or UNaV; however, ANG II in the presence of tempol caused a smaller degree of decreases in RBF (−12 ± 2%), in V (−16 ± 5%), and in UNaV (−27 ± 10%) with a slight increase in GFR (6.6 ± 2.8%) than the responses observed before tempol. In another group of NLA-treated dogs ( n = 6), tempol infusion also caused significant attenuation in the ANG II-induced responses on RBF (−13 ± 3% vs. −22 ± 7%), GFR (−19 ± 5% vs. −33 ± 3), V (−15 ± 12% vs. −28 ± 4%), and UNaV (−11 ± 14% vs. −32 ± 7%). These data demonstrate that renal responses to ANG II are partly mediated by O2−generation and its interaction with NO. The sodium-retaining effect of ANG II is greatly influenced by O2−generation, particularly in the condition of NO deficiency.
Reduced tolerance of immature renal tubules to anoxia by HSF-1 decoy
Authors: Sreedharan Rajasree , Riordan Michael , Wang Shirley , Thulin Gunilla , Kashgarian Michael , Siegel Norman J.
Published: October 2004

Immature animals demonstrate an amplified heat shock response following a variety of insults compared with that seen in mature animals (M). The potential role of the heat shock response in modulating immature tolerance to injury was compared between rat pups, 10 postnatal days of age ( P10), and M. Baseline levels of the heat shock transcription factor (HSF-1) were substantially elevated in P10 compared with M animals. In uninjured P10 pups, HSF-1 level was comparable to that of M animals subjected to 45 min of ischemia. As anticipated, the integrity of suspensions of tubules exposed to anoxia was preserved in P10 animals (23% LDH release) compared with M (40%), P < 0.01. The effect of targeted inhibition of HSF-1 on tubular integrity was studied using a cyclic oligonucleotide decoy. The HSF-1 decoy increased the severity of anoxic injury in P10 pups to a level comparable with M animals. LDH release was 33% in decoy-treated P10 tubules compared with 40% in M. When P10 tubules were treated with scrambled decoy, resistance to anoxia remained intact (24%). The increased vulnerability of the tubular suspension to injury was specific to the HSF-1 decoy and proportional to the dose of decoy applied. This study demonstrates maturation in the abundance of HSF-1 in the immature rat kidney. The loss of resistance of immature tubules to anoxia with specific inhibition of HSF-1 may be due to its effect on the heat shock response or other signaling pathways of critical pathobiological importance in renal cell injury.
On the nature of proteinuria with acute renal injury in patients with chronic kidney disease
Authors: Agarwal Rajiv
Published: October 2004

Albuminuria is an excellent marker of cardiovascular and renal prognosis. Commercially available tests of immunodetectable albumin in the urine may not identify posttranslationally modified albumin that makes it undetectable to antibodies. Also, it is unclear whether albumin is degraded to smaller fragments, such as through proteolysis, in the course of acute renal injury. In 20 men with chronic kidney disease, we measured excretion rates of urinary protein (pyragallol red), immundetectable urinary albumin (immunoturbidimetry), and urinary total intact albumin (HPLC) after a single dose of 100 mg intravenous iron sucrose administered over 5 min. Fragmentation of urinary albumin and carbonylation of urinary proteins were assessed by immunoblotting. Results showed that iron infusion increased carbonylation of plasma and urinary proteins in a time-dependent manner. A transient increase in urinary excretion rates of total protein, immunodetectable urinary albumin, and total intact albumin was seen. Fragmentation and loss of immunoreactivity of albumin paralleled the changes in total protein excretion. In conclusion, fragmentation, loss of immunoreactivity, and oxidation of albumin in a time-dependent manner may underestimate the extent of injury with the immunoreactive microalbumin assay. Measurement of total intact albumin may better quantify acute renal injury.
Passive Movements of the Head Do Not Abolish Anticipatory Firing Properties of Head Direction Cells
Authors: Bassett Joshua P. , Zugaro Michaël B. , Muir Gary M. , Golob Edward J. , Muller Robert U. , Taube Jeffrey S.
Published: October 2004

Neurons in the anterior dorsal thalamic nucleus (ADN) of the rat selectively discharge in relation to the animal's head direction (HD) in the horizontal plane. Temporal analyses of cell firing properties reveal that their discharge is optimally correlated with the animal's future directional heading by ∼24 ms. Among the hypotheses proposed to explain this property is that ADN HD cells are informed of future head movement via motor efference copy signals. One prediction of this hypothesis is that when the rat's head is moved passively, the anticipatory time interval (ATI) will be attenuated because the motor efference signal reflects only the active contribution to the movement. The present study tested this hypothesis by loosely restraining the animal and passively rotating it through the cell's preferred direction. Contrary to our prediction, we found that ATI values did not decrease during passive movement but in fact increased significantly. HD cells in the postsubiculum did not show the same effect, suggesting independence between the two sites with respect to anticipatory firing. We conclude that it is unlikely that a motor efference copy signal alone is responsible for generating anticipatory firing in ADN HD cells.
Cortical Neurons Lacking KCC2 Expression Show Impaired Regulation of Intracellular Chloride
Authors: Zhu Lei , Lovinger David , Delpire Eric
Published: October 2004

As excitable cells, neurons experience constant changes in their membrane potential due to ion flux through plasma membrane channels. They maintain their transmembrane cation concentrations through robust Na+/K+-ATPase pump activity. During synaptic transmission and spread of action potentials, the concentration of the major anion, Cl−, is also under constant challenge from membrane potential changes. Moreover, intracellular Cl− is also affected by ligand-gated Cl− channels such as GABAA and glycine receptors. To regulate intracellular Cl− in an electrically silent manner, neurons couple the movement of Cl− with K+. In this study, we have used gene-targeted KCC2−/− mice to provide strong evidence that KCC2, the neuronal-specific K-Cl co-transporter, drives neuronal Cl− to low concentrations, shifting the GABA reversal potential toward more negative potentials, thus promoting hyperpolarizing GABA responses. Cortical neurons lacking KCC2, not only fail to show a developmental decrease in [Cl−]i, but also are unable to regulate [Cl−]i on Cl− loading or maintain [Cl]i during membrane depolarization. These data are consistent with the central role of KCC2 in promoting inhibition and preventing hyperexcitability.
Differential modulation of baroreflex control of heart rate by neuron- vs. glia-derived angiotensin II
Authors: Sakai Koji , Chapleau Mark W. , Morimoto Satoshi , Cassell Martin D. , Sigmund Curt D.
Published: October 2004

We developed transgenic mice with targeted expression of human renin (hREN) and human angiotensinogen (hAGT) to either neurons (N-AII mice) or glia (G-AII mice) to test the hypothesis that neuronal and glial ANG II may have differential function. Since baseline blood pressure (BP) did not differ between the models (109 ± 3 vs. 114 ± 4 mmHg), we stressed the BP regulatory pathway by measuring the heart rate (HR) (baroreflex) response to phenylephrine- and nitroprusside-induced changes in arterial BP. The midpoint of the baroreflex curve (BP50) was reset to a significantly higher BP in N-AII mice (131 ± 5 mmHg) compared with littermate controls (115 ± 3 mmHg). Baroreflex gain (slope of BP-HR relation) was similar in N-AII and control mice (12 ± 1 vs. 14 ± 2 beats·min−1·mmHg−1). In contrast, G-AII mice exhibited less of an increase in BP50 (125 ± 5 mmHg) but a larger decrease in baroreflex gain (8 ± 1 beats·min−1·mmHg−1) compared with both control and N-AII mice. Differences in BP50 and gain between N-AII, G-AII, and control mice persisted after parasympathetic blockade with atropine but were eliminated after sympathetic blockade with propranolol, indicating the effects of ANG II were selective for cardiosympathetic arm of the reflex. ANG II-like immunoreactivity was observed more prominently around the paraventricular nucleus and nucleus tractus solitarii in G-AII mice but more prominently in the ventrolateral medulla in N-AII mice. We conclude that ANG II differentially modulates baroreflex control of HR in mice producing ANG II in neurons vs. glia, and its differential function may reflect regional differences in the production of ANG II in cardiovascular control nuclei of the brain.
Target ablation-induced regulation of macrophage recruitment into the olfactory epithelium ofMip-1α−/−mice and restoration of function by exogenous MIP-1α
Authors: Kwong Kevin , Vaishnav Radhika A. , Liu Yushu , Subhedar Nishikant , Stromberg Arnold J. , Getchell Marilyn L. , Getchell Thomas V.
Published: October 2004

The chemokine macrophage inflammatory protein (MIP)-1α recruits macrophages to sites of epithelial remodeling. We showed previously that mRNA and protein levels of MIP-1α in the olfactory epithelium (OE) increased significantly at 3 days after bilateral olfactory bulbectomy (OBX). The first aim of this study was to investigate the effect of the absence of MIP-1α on macrophage recruitment to the OE 3 days after OBX in Mip-1α−/−mice compared with C57BL/6 mice and to test whether chemokine function could be restored by MIP-1α protein injection into Mip-1α−/−mice. OBX was performed on C57BL/6 and Mip-1α−/−mice. The mice received six subcutaneous injections at 12-h intervals of either 10 μg/ml MIP-1α protein in carrier or carrier only. Macrophage recruitment was evaluated with antibodies to CD68 for all macrophages and F4/80 for activated macrophages. Compared with C57BL/6 mice, at 3 days post-OBX the numbers of CD68+and F4/80+macrophages were significantly lower in carrier-injected Mip-1α−/−mice and were comparable in MIP-1α protein-injected Mip-1α−/−mice. The second aim was to determine the identity of genes regulated at 3 days post-OBX in the OE of carrier-injected Mip-1α−/−mice compared with carrier-injected C57BL/6 mice. Total RNA from the OE was hybridized to Affymetrix microarrays. A number of chemokine-, cytokine-, and growth factor-related genes were significantly regulated in the Mip-1α−/−mice and were restored in MIP-1α protein-injected Mip-1α−/−mice. The results illustrated that MIP-1α played a key role in recruitment of macrophages to the OE and provided insight into the genomic regulation involved in OE remodeling.
Gene expression profiling in chronic copper overload reveals upregulation ofPrnpandApp
Authors: Armendariz Angela D. , Gonzalez Mauricio , Loguinov Alexander V. , Vulpe Christopher D.
Published: October 2004

The level at which copper becomes toxic is not clear. Several studies have indicated that copper causes oxidative stress; however, most have tested very high levels of copper exposure. We currently have only a limited understanding of the protective systems that operate in cells chronically exposed to copper. Additionally, the limits of homeostatic regulation are not known, making it difficult to define the milder effects of copper excess. Furthermore, a robust assay to facilitate the diagnosis of copper excess and to distinguish mild, moderate, and severe copper overload is needed. To address these issues, we have investigated the effects on steady-state gene expression of chronic copper overload in a cell culture model system using cDNA microarrays. For this study we utilized cells from genetic models of copper overload: fibroblast cells from two mouse mutants, C57BL/6- Atp7aMobrand C57BL/6- Atp7aModap. These cell lines accumulate copper to abnormally high levels in normal culture media due to a defect in copper export from the cell. We identified 12 differentially expressed genes in common using our outlier identification methods. Surprisingly, our results show no evidence of oxidative stress in the copper-loaded cells. In addition, candidate components perhaps responsible for a copper-specific homeostatic response are identified. The genes that encode for the prion protein and the amyloid-β precursor protein, two known copper-binding proteins, are upregulated in both cell lines.
The Archive, Disciplinarity, and Governing: Cultural Studies and the Writing of History
Authors: Robertson Craig
Published: October 2004

This article historicizes the archive as a mechanism of exclusion. It focuses on three archival sites (the development of archival rationalization in the 19th century, national archives and the collecting of government documents, and the discipline of history) to analyze their shared logics of classification, identity, evidence, and authenticity. These three sites are connected through the author’s attempts to research and write a history of the passport within cultural studies. The archive, therefore, provides a site from which to clarify what is at stake in the claims of cultural studies to be an interdisciplinary project.
Beyond Belief: Religious Fundamentalism and Cultural Politics in the Age of George W. Bush
Authors: Giroux Henry A.
Published: October 2004

This article looks at the increasing way in which evangelical religion has shaped the cultural politics and policies of the United States and the presidency of George W. Bush. The author argues that under the Bush administration, there is an ongoing attempt to collapse the divisions between religion and the state and that the implications for such changes threaten not only freedom of religion but the very nature of democracy.
Speak Memory! Morae Sigye and the Politics of Social Melodrama in Contemporary South Korea
Authors: Lee Keehyeung
Published: October 2004

This article is composed of two parts. The first part presents a brief survey of cinematic and television melodramas in South Korea and describes how melodrama has unevenly reflected a range of socio-cultural transformations. It traces the ways melodrama has embodied the changing social and gender norms against the backdrop of highly compressed modernization and the persistent patriarchal authority in South Korea. The second part analyzes various textual strategies in Morae Sigye as a social melodrama by examining the generic specificity and radical differences seen in Morae Sigye versus mainstream television dramas. In particular, this article assesses Morae Sigye’s representation of actual historical events and its pedagogical usefulness as a vehicle of cultural remembering. The article as a whole explores the potential of social melodrama as a useful televisual subgenre that can articulate melodramatic pathos with desire to summon popular memory surrounding the traumatic historical events in the past.
Trolox selectively enhances arsenic-mediated oxidative stress and apoptosis in APL and other malignant cell lines
Authors: Diaz Zuanel , Colombo Myrian , Mann Koren K. , Su Haixiang , Smith Kamilah N. , Bohle D. Scott , Schipper Hyman M. , Miller Wilson H.
Published: October 2004

Although arsenic trioxide (As2O3) is an effective therapy in acute promyelocytic leukemia (APL), its use in other malignancies is limited by the toxicity of concentrations required to induce apoptosis in non-APL tumor cells. We looked for agents that would synergize with As2O3 to induce apoptosis in malignant cells, but not in normal cells. We found that trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), a widely known antioxidant, enhances As2O3-mediated apoptosis in APL, myeloma, and breast cancer cells. Treatment with As2O3 and trolox increased intracellular oxidative stress, as evidenced by heme oxygenase-1 (HO-1) protein levels, c-Jun terminal kinase (JNK) activation, and protein and lipid oxidation. The synergistic effects of trolox may be specific to As2O3, as trolox does not add to toxicity induced by other chemotherapeutic drugs. We explored the mechanism of this synergy using electron paramagnetic resonance and observed the formation of trolox radicals when trolox was combined with As2O3, but not with doxorubicin. Importantly, trolox protected nonmalignant cells from As2O3-mediated cytotoxicity. Our data provide the first evidence that trolox may extend the therapeutic spectrum of As2O3. Furthermore, the combination of As2O3 and trolox shows potential specificity for tumor cells, suggesting it may not increase the toxicity associated with As2O3 monotherapy in vivo.
A case for developing North-South partnerships for research in sickle cell disease
Authors: Weatherall David , Hofman Karen , Rodgers Griffin , Ruffin John , Hrynkow Sharon
Published: October 2004

For a better understanding of the pathophysiology and mechanisms of phenotypic diversity of sickle cell disease, and for the improvement of its management globally, there is a strong case for developing sustainable research partnerships between rich and poor countries.
Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy
Authors: Barker Juliet N. , Weisdorf Daniel J. , DeFor Todd E. , Blazar Bruce R. , McGlave Philip B. , Miller Jeffrey S. , Verfaillie Catherine M. , Wagner John E.
Published: October 2004

Limited umbilical cord blood (UCB) cell dose compromises the outcome of adult UCB transplantation. Therefore, to augment graft cell dose, we evaluated the safety of the combined transplantation of 2 partially human leukocyte antigen (HLA)–matched UCB units. Twenty-three patients with high-risk hematologic malignancy (median age, 24 years; range, 13-53 years) received 2 UCB units (median infused dose, 3.5 × 107 nucleated cell [NC]/kg; range, 1.1-6.3 × 107 NC/kg) after myeloablative conditioning. All evaluable patients (n = 21) engrafted at a median of 23 days (range, 15-41 days). At day 21, engraftment was derived from both donors in 24% of patients and a single donor in 76% of patients, with 1 unit predominating in all patients by day 100. Although neither nucleated or CD34+ cell doses nor HLA-match predicted which unit would predominate, the predominating unit had a significantly higher CD3+ dose (P < .01). Incidences of grades II-IV and III-IV acute GVHD were 65% (95% confidence interval [CI], 42%-88%) and 13% (95% CI, 0%-26%), respectively. Disease-free survival was 57% (95% CI, 35%-79%) at 1 year, with 72% (95% CI, 49%-95%) of patients alive if they received transplants while in remission. Therefore, transplantation of 2 partially HLA-matched UCB units is safe, and may overcome the cell-dose barrier that limits the use of UCB in many adults and adolescents.
Both perforin and Fas ligand are required for the regulation of alloreactive CD8+ T cells during acute graft-versus-host disease
Authors: Maeda Yoshinobu , Levy Robert B. , Reddy Pavan , Liu Chen , Clouthier Shawn G. , Teshima Takanori , Ferrara James L. M.
Published: October 2004

Fas ligand (FasL) and perforin pathways not only are the major mechanisms of T cell–mediated cytotoxicity but also are involved in homeostatic regulation of these T cells. In the present study, we tested whether CD8+ donor T cells that are deficient in both perforin and FasL (cytotoxic double deficient [cdd]) could induce graft-versus-host disease (GVHD) in a major histocompatibility complex class I–mismatched lethally irradiated murine model. Interestingly, recipients of cdd CD8+ T cells demonstrated significantly greater serum levels of interferon gamma and tumor necrosis factor alpha and histopathologic damage from GVHD than wild-type (wt) T cells on day 30 after allogeneic bone marrow transplantation (P < .05). Wt and either perforin-deficient or FasL-deficient CD8+ T cells expanded early after transplantation followed by a contraction phase in which the majority of expanded CD8+ T cells were eliminated. In contrast, cdd CD8+ T cells exhibited prolonged expansion and reduced apoptosis to alloantigen stimulation in vivo and in vitro. Together these results suggest that donor cdd CD8+ T cells expand continuously and cause lethal GVHD, and that both perforin and FasL are required for the contraction of allo-reactive CD8+ T cells.
Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis
Authors: Lisman Ton , de Groot Philip G. , Meijers Joost C.M. , Rosendaal Frits R.
Published: October 2004

The role of the fibrinolytic system in the development of deep vein thrombosis (DVT) is unclear. We determined the plasma fibrinolytic potential of patients enrolled in the Leiden Thrombophilia Study (LETS), a population-based case-control study on risk factors for DVT. Plasma fibrinolytic potential was determined in 421 patients and 469 control subjects by means of a tissue factor–induced and tissue-type plasminogen activator (tPA)–induced clot lysis assay. Using clot lysis times above the 70th, 80th, 90th, 95th, and 99th percentiles of the values found in control subjects as cut-off levels, we found a dose-dependent increase in risk for DVT in patients with hypofibrinolysis (odds ratios of 1.4, 1.6, 1.9, 2.1, and 2.2, respectively). This indicates a 2-fold increased risk of DVT in subjects with clot lysis times above the 90th percentile. The risk increase was not affected by age or sex (adjusted odds ratio for 90th percentile, 2.0), and after correction for all possible confounders (age, sex, and levels of procoagulant proteins shown to associate with clot lysis times in the control population), the risk estimate was marginally reduced (odds ratio, 1.6 for 90th percentile). Taken together, these results indicate that plasma hypofibrinolysis constitutes a risk factor for venous thrombosis, with a doubling of the risk at clot lysis times that are present in 10% of the population.
HLA-G expression is associated with an unfavorable outcome and immunodeficiency in chronic lymphocytic leukemia
Authors: Nückel Holger , Rebmann Vera , Dürig Jan , Dührsen Ulrich , Grosse-Wilde Hans
Published: October 2004

The human leukocyte antigen G (HLA-G) molecule exhibits limited tissue distribution and exerts multiple immunoregulatory functions. Recent studies indicate an ectopic up-regulation in tumor cells that may favor their escape from antitumor immune responses. The role of HLA-G in B-cell chronic lymphocytic leukemia (B-CLL) has not been defined. HLA-G expression was studied retrospectively in circulating B-CLL cells from 47 patients by flow cytometry using the anti-HLA-E specific monoclonal antibody MEM/G9. The proportion of leukemic cells expressing HLA-G varied from 1% to 54%. Patients with 23% or fewer HLA-G-positive cells (according to receiver operating characteristics [ROC] analysis; designated as HLA-G-negative group) had a significantly longer progression-free survival (PFS) time than patients with more than 23% positive cells (median PFS: 120 versus 23 months; P = .0001). In multivariate analysis, HLA-G expression (hazard ratio: 4.8; P = .002) was an even better independent prognostic factor than the zeta-associated protein 70 (ZAP-70) or CD38 status. Humoral and cellular immunosuppression were significantly more prominent in the HLA-G-positive compared with the HLA-G-negative patient group. In B-CLL, the level of HLA-G expression is correlated with the degree of immunosuppression and prognosis. HLA-G may contribute to the impairment of immune responses against tumor cells and infections. Thus, these findings need to be confirmed in a prospective study. (Blood. 2005;105:1694-1698)
Polyadenylation of ribosomal RNA by Candida albicans also involves the small subunit
Authors: Fleischmann Jacob , Liu Hong , Wu Chieh-Pin
Published: October 2004

Background

Candida albicans is a polymorphic fungus causing serious infections in immunocompromised patients. It is capable of shifting from yeast to germinating forms such as hypha and pseudohypha in response to a variety of signals, including mammalian serum. We have previously shown that some of the large 25S components of ribosomal RNA in Candida albicans get polyadenylated, and this process is transiently intensified shortly after serum exposure just prior to the appearance of germination changes.

Results

We now present data that this process also involves the small 18S subunit of ribosomal RNA in this organism. Unlike the large 25S subunit, polyadenylation sites near the 3' end are more variable and no polyadenylation was found at the reported maturation site of 18S. Similar to 25S, one or more polyadenylated mature sized 18S molecules get intensified transiently by serum just prior to the appearance of hypha.

Conclusions

The transient increase in polyadenylation of both the large and the small subunits of ribosomal RNA just prior to the appearance of hypha, raises the possibility of a role in this process.
Participant characteristics associated with withdrawal from a large randomized trial of spermicide effectiveness
Authors: Raymond Elizabeth G , Chen Pai Lien , Pierre-Louis Bosny , Luoto Joanne , Barnhart Kurt T , Bradley Lynn , Creinin Mitchell D , Poindexter Alfred , Wan Livia , Martens Mark , Schenken Robert , Nicholas Cate F , Blackwell Richard
Published: October 2004

Background

In most recent large efficacy trials of barrier contraceptive methods, a high proportion of participants withdrew before the intended end of follow-up. The objective of this analysis was to explore characteristics of participants who failed to complete seven months of planned participation in a trial of spermicide efficacy.

Methods

Trial participants were expected to use the assigned spermicide for contraception for 7 months or until pregnancy occurred. In bivariable and multivariable analyses, we assessed the associations between failure to complete the trial and 17 pre-specified baseline characteristics. In addition, among women who participated for at least 6 weeks, we evaluated the relationships between failure to complete, various features of their first 6 weeks of experience with the spermicide, and characteristics of the study centers and population.

Results

Of the 1514 participants in this analysis, 635 (42%) failed to complete the study for reasons other than pregnancy. Women were significantly less likely to complete if they were younger or unmarried, had intercourse at least 8 times per month, or were enrolled at a university center or at a center that enrolled fewer than 4 participants per month. Noncompliance with study procedures in the first 6 weeks was also associated with subsequent early withdrawal, but dissatisfaction with the spermicide was not. However, many participants without these risk factors withdrew early.

Conclusions

Failure to complete is a major problem in barrier method trials that seriously compromises the interpretation of results. Targeting retention efforts at women at high risk for early withdrawal is not likely to address the problem sufficiently.
Radiotherapy fractionation for the palliation of uncomplicated painful bone metastases – an evidence-based practice guideline
Authors: Wu Jackson Sai-Yiu , Wong Rebecca KS , Lloyd Nancy S , Johnston Mary , Bezjak Andrea , Whelan Timothy ,   the Supportive Care Guidelines Group of Cancer Care Ontario
Published: October 2004

Background

This practice guideline was developed to provide recommendations to clinicians in Ontario on the preferred standard radiotherapy fractionation schedule for the treatment of painful bone metastases.

Methods

A systematic review and meta-analysis was performed and published elsewhere. The Supportive Care Guidelines Group, a multidisciplinary guideline development panel, formulated clinical recommendations based on their interpretation of the evidence. In addition to evidence from clinical trials, the panel also considered patient convenience and ease of administration of palliative radiotherapy. External review of the draft report by Ontario practitioners was obtained through a mailed survey, and final approval was obtained from the Practice Guidelines Coordinating Committee.

Results

Meta-analysis did not detect a significant difference in complete or overall pain relief between single treatment and multifraction palliative radiotherapy for bone metastases. Fifty-nine Ontario practitioners responded to the mailed survey (return rate 62%). Forty-two percent also returned written comments. Eighty-three percent of respondents agreed with the interpretation of the evidence and 75% agreed that the report should be approved as a practice guideline. Minor revisions were made based on feedback from the external reviewers and the Practice Guidelines Coordinating Committee. The Practice Guidelines Coordinating Committee approved the final practice guideline report.

Conclusion

For adult patients with single or multiple radiographically confirmed bone metastases of any histology corresponding to painful areas in previously non-irradiated areas without pathologic fractures or spinal cord/cauda equine compression, we conclude that:

• Where the treatment objective is pain relief, a single 8 Gy treatment, prescribed to the appropriate target volume, is recommended as the standard dose-fractionation schedule for the treatment of symptomatic and uncomplicated bone metastases.

Several factors frequently considered in clinical practice when applying this evidence such as the effect of primary histology, anatomical site of treatment, risk of pathological fracture, soft tissue disease and cord compression, use of antiemetics, and the role of retreatment are discussed as qualifying statements.

Our systematic review and meta-analysis provided high quality evidence for the key recommendation in this clinical practice guideline. Qualifying statements addressing factors that should be considered when applying this recommendation in clinical practice facilitate its clinical application. The rigorous development and approval process result in a final document that is strongly endorsed by practitioners as a practice guideline.
Efficacy of two once-daily methylphenidate formulations compared across dose levels at different times of the day: Preliminary indications from a secondary analysis of the COMACS study data
Authors: Sonuga-Barke Edmund JS , Swanson James M , Coghill David , DeCory Heleen H , Hatch Simon J
Published: October 2004

Background

Methylphenidate (MPH) is commonly prescribed in the treatment of Attention-Deficit/Hyperactivity Disorder or ADHD. Concerta and Metadate CD are once-daily formulations of MPH using different delivery mechanisms resulting in different pharmacokinetic profiles. A recent study (COMACS) showed that for near-milligram (mg) equivalent daily doses, Metadate CD provides greater symptom control in the morning (1.5 through 4.5 hours post-dose), while Concerta provides greater control in the early evening (12 hours post-dose). Non-inferential comparison of effects for different dose levels of the two formulations suggested that equivalent levels of morning symptom control could be obtained with lower daily doses of Metadate CD than Concerta; the situation being reversed in the evening. The current paper presents a secondary analysis that provides a statistical test of these observations.

Method

The COMACS study was a multi-center, double-blind crossover study of Metadate CD, Concerta and placebo with each treatment administered for 1 week. Children were assigned on the basis of their pre-trial dosage to either high (Metadate CD 60 mg; Concerta 54 mg), medium (Metadate CD 40 mg; Concerta 36 mg) or low doses (Metadate CD 20 mg; Concerta 18 mg) of MPH, and attended a laboratory school on the 7th day for assessment at 7 sessions across the day. For the post-hoc comparisons across dose levels presented here, total SKAMP scores with the active treatments (adjusted for placebo response) were analyzed using an analysis of covariance, with a combined measure modeling placebo response across all time period as the covariate.

Results

Symptom control from 1.5 through 6.0 hours post-dose was as good with lower doses of Metadate CD (20 and 40 mg) as with higher doses of Concerta (36 and 54 mg, respectively). Lower daily doses of Concerta (18 and 36 mg) and higher doses of Metadate CD (40 and 60 mg, respectively) gave equivalent control at 7.5 and 12 hours with Metadate CD giving better control from1.5 through 6.0 hours post-dose.

Conclusions

Different delivery profiles of Metadate CD and Concerta can be exploited to limit total daily exposure to MPH while at the same targeting a specific, especially clinically significant, period of the day. These results need to be confirmed in a study in which children are randomly allocated to different dose levels of the two formulations and plasma MPH concentrations are assessed simultaneously.
New sorting nexin (SNX27) and NHERF specifically interact with the 5-HT4(a) receptor splice variant: roles in receptor targeting
Authors: Joubert Lara , Hanson Brendon , Barthet Gaël , Sebben Michèle , Claeysen Sylvie , Hong Wanjin , Marin Philippe , Dumuis Aline , Bockaert Joël
Published: October 2004

The 5-hydroxytryptamine type 4 receptor (5-HT4R) is involved in learning, feeding, respiratory control and gastrointestinal transit. This receptor is one of the G-protein-coupled receptors for which alternative mRNA splicing generates the most variants that differ in their C-terminal extremities. Some 5-HT4R variants (a, e and f) express canonical PDZ ligands at their C-termini. Here, we have examined whether some mouse 5-HT4R variants associate with specific sets of proteins, using a proteomic approach based on peptide-affinity chromatography, two-dimensional electrophoresis and mass spectrometry. We have identified ten proteins that interact specifically with the 5-HT4(a)R and three that only associate with the 5-HT4(e)R. Most of them are PDZ proteins. Among the proteins that associated specifically with the 5-HT4(a)R variant, NHERF greatly modified its subcellular localization. Moreover, NHERF recruited the 5-HT4(a)R to microvilli, where it localized with activated ezrin, consistent with the role of 5-HT4(a)R in cytoskeleton remodelling. The 5-HT4(a)R also interacted with both the constitutive and inducible (upon methamphetamine treatment) forms of the recently cloned sorting nexin 27 (SNX27a and b, respectively). We found that SNX27a redirected part of 5-HT4(a)R to early endosomes. The interaction of the 5-HT4R splice variants with distinct sets of PDZ proteins might specify their cellular localization as well as their signal transduction properties.
Nuclear localisation of the G-actin sequestering peptide thymosin β4
Authors: Huff Thomas , Rosorius Olaf , Otto Angela M. , Müller Christian S. G. , Ballweber Edda , Hannappel Ewald , Mannherz Hans Georg
Published: October 2004

Thymosin β4 is regarded as the main G-actin sequestering peptide in the cytoplasm of mammalian cells. It is also thought to be involved in cellular events like cancerogenesis, apoptosis, angiogenesis, blood coagulation and wound healing. Thymosin β4 has been previously reported to localise intracellularly to the cytoplasm as detected by immunofluorescence. It can be selectively labelled at two of its glutamine-residues with fluorescent Oregon Green cadaverine using transglutaminase; however, this labelling does not interfere with its interaction with G-actin. Here we show that after microinjection into intact cells, fluorescently labelled thymosin β4 has a diffuse cytoplasmic and a pronounced nuclear staining. Enzymatic cleavage of fluorescently labelled thymosin β4 with AsnC-endoproteinase yielded two mono-labelled fragments of the peptide. After microinjection of these fragments, only the larger N-terminal fragment, containing the proposed actin-binding sequence exhibited nuclear localisation, whereas the smaller C-terminal fragment remained confined to the cytoplasm. We further showed that in digitonin permeabilised and extracted cells, fluorescent thymosin β4 was solely localised within the cytoplasm, whereas it was found concentrated within the cell nuclei after an additional Triton X100 extraction. Therefore, we conclude that thymosin β4 is specifically translocated into the cell nucleus by an active transport mechanism, requiring an unidentified soluble cytoplasmic factor. Our data furthermore suggest that this peptide may also serve as a G-actin sequestering peptide in the nucleus, although additional nuclear functions cannot be excluded.