bluuebunny/crossref_metadata_2025 huggingface dataset:
Glass transition behaviour of fructose
Authors: Truong Vinh , Bhandari Bhesh R. , Howes Tony , Adhikari Benu
Published: April 2004

The glass transition temperature and the second transition (the endothermic change between the glass transition and melting temperatures) of fructose were studied. The thermal history strongly affected both transitions of fructose. Storage for 10 days at 22 °C increased the dynamic glass transition temperature from 16 to 25 °C and decreased the second transition of fructose from 110 to 98 °C in the first differential scanning calorimetric (DSC) scan. The amplitude of the second transition increased slightly with storage time and reached 260% of the first transition for vacuum oven dried samples. The effect of thermal history on the glass transition temperature of fructose can be removed by scanning the sample in a DSC to 130 °C. The effects of water content, glucose and sucrose on the two transitions were also investigated.
The Impact of Public Infrastructure on the Productivity of the Chilean Economy
Authors: Albala‐Bertrand José M. , Mamatzakis Emmanuel C.
Published: April 2004

The aim of this study is to assess the effect of the change in infrastructure capital on the cost structure of the Chilean economy, and thereby on productivity, differentiating between two key institutional periods. A further aim is to establish the extent to which infrastructure capital formation affects private capital. The authors use an econometric estimation of the cost elasticity of infrastructure. Conclusions indicate that an increased infrastructure capital reduces the production cost of the economy, thereby increasing productivity, mostly in the second period. In turn, especially in this latter period, infrastructure capital formation appears to assert both a positive cost‐share effect on private capital and a negative cost‐share effect on labor. These effects can be explained to a large extent by the significant differences between the institutional structures of the two consecutive periods studied.
Non‐zero‐sum collaboration, reciprocity, and the preference for similarity: Developing an adaptive model of close relational functioning
Authors: Cole Tim , Bruno Teboul Jc.
Published: April 2004

An evolutionary framework was used to develop a model of relational functioning among friends. The proposed model focuses on the collaborative nature of close friendships and attempts to highlight two adaptive mechanisms important in creating non‐zero‐sum outcomes among highly interdependent parties. The model emphasizes the importance of reciprocity in creating mutually beneficial outcomes through social exchange, and it articulates how the preference for similarity is useful when creating non‐zero‐sum rewards through synergistic coordination. In particular, the focus is on the unique role that shared interests and mutual knowledge play when individuals attempt to pursue common goals through joint activity. The implications of the model are discussed with respect to a host of issues ranging from deceptive communication to relational satisfaction and commitment.
A Comparative Study Between Flow Visualization and Computational Fluid Dynamic Analysis for the Sun Medical Centrifugal Blood Pump
Authors: Yamane Takashi , Miyamoto Yusuke , Tajima Koki , Yamazaki Kenji
Published: April 2004

Abstract:  Flow visualization experiments and computational fluid dynamic (CFD) analyses were performed and the results were compared to clarify the detailed fluid dynamic characteristics for the prototype design of a centrifugal pump, namely, an implantable ventricular assist system from Sun Medical, whose hemocompatibility was previously demonstrated in a series of animal experiments. The flow visualization was conducted with particle tracking velocimetry, and the CFD analysis was performed with STAR‐CD software. The findings were as follows: (1) There were no flow separations around the curved open impeller. (2) Antithrombogenic design concepts for the inducer and the vane‐shaft clearance were effective in producing axial velocity along the shaft surface and generat‐ing suitable shear rates against the stationary fluid. (3) Unsteady vortex shedding in the outlet, which adversely affected the fluid dynamic efficiency, was observed clearly by flow visualization. Comparison of velocity distribution measured by flow visualization and CFD analysis showed reasonably good correlation. Our findings indicate that the impeller is suitable for an implantable artificial heart. The techniques of flow visualization and CFD analysis are complementary evaluation tools in research and development efforts.
Giving Artifacts a Voice? Bringing into Account Technology in Educational Analysis
Authors: Waltz Scott B.
Published: April 2004

Technologies increasingly shape educational settings and policies. Youth define the etiquette for communication devices even as engineers redefine what these devices are capable of doing. The what and how of technologies are being articulated all across the educational landscape, yet much of the discussion surrounding technologies in education continues to view them as additive rather than constitutive. The socio‐cultural work of persons is categorically privileged over the contributions of artifacts. Unfortunately, this division of objects from subjects obscures the very practical ways in which persons and technologies codetermine one another. This paper examines the theoretical grounding of the relationship between humans and nonhumans in light of recent work in Science and Technology Studies, and highlights the ways in which actor‐network theory might serve to level the playing field and give artifacts a voice.
New inhibitors for the neutral amino acid transporter ASCT2 reveal its Na+‐dependent anion leak
Authors: Grewer Christof , Grabsch Eva
Published: April 2004

The neutral amino acid transporter ASCT2 catalyses uncoupled anion flux across the cell membrane in the presence of transported substrates, such as alanine. Here, we report that ASCT2 conducts anions already in the absence of transported substrates through a leak anion‐conducting pathway. The properties of this leak anion conductance were studied by electrophysiological recording from ASCT2‐expressing HEK293 cells. We found that the leak anion conductance was inhibited by the binding of the newly characterized inhibitors benzylserine and benzylcysteine to ASCT2. These inhibitors competitively prevent binding of transported substrates to ASCT2, suggesting that they bind to the ASCT2 binding site for neutral amino acid substrates. The leak anion conductance exhibits permeation properties that are similar to the substrate‐activated anion conductance of ASCT2, preferring hydrophobic anions such as thiocyanate. Inhibition of the leak anion conductance by benzylserine requires the presence of extracellular, but not intracellular Na+. The apparent affinity of ASCT2 for extracellular Na+was determined as 0.3 mm. Interestingly, a Na+‐dependent leak anion conductance with similar properties was previously reported for the related excitatory amino acid transporters (EAATs), suggesting that this leak anion conductance is highly conserved within the EAAT protein family.
The favourable prognostic value of oestrogen receptor β immunohistochemical expression in breast cancer
Authors: Nakopoulou L , Lazaris A C , Panayotopoulou E G , Giannopoulou I , Givalos N , Markaki S , Keramopoulos A
Published: April 2004

Aims:Oestrogen receptor β (ERβ) is present in breast tumours, although its prognostic and pathophysiological roles remain to be established.

Methods:Standard immunohistochemistry with a specific monoclonal antibody was performed on paraffin wax embedded sections; 10% of strongly immunostained carcinoma cells was used as the cutoff point to classify tumours as ERβ positive. Statistical correlations were sought with clinicopathological variables (including hormone receptor status) and disease free (DFS) and overall survival (OS) in a well documented series of 181 invasive breast carcinomas. Cell proliferation was assessed immunohistochemically by topoisomerase IIa (TopoIIa) index; p53 protein accumulation and c-erbB-2 oncoprotein expression were also taken into account.

Results:ERβ immunoreactivity was detected in most specimens (71.2%); it was positively linked to ERα immunoreactivity and increased TopoIIα index, and inversely to c-erbB-2 overexpression. There were no correlations with p53 immunostaining or other clinicopathological parameters. A significant favourable impact of ERβ immunopositivity emerged with regard to DFS and OS in both univariate and multivariate analysis; ERβ immunopositivity retained its favourable significance with regard to DFS in the subgroups of stage I and II patients when they were examined separately. Progesterone receptor expression also had an independent favourable influence on survival, albeit with less significance. In contrast, survival was not significantly influenced by ERα status.

Conclusions:Because of the positive association between ERβ immunoreactivity and TopoIIα expression, the presence of ERβ in breast cancer cells could be considered an indication of increased proliferation. Nevertheless, ERβ immunoreactivity emerges as a valuable, independent indicator of favourable prognosis.
Expression of vascular endothelial growth factor, hypoxia inducible factor 1α, and carbonic anhydrase IX in human tumours
Authors: Jubb A M , Pham T Q , Hanby A M , Frantz G D , Peale F V , Wu T D , Koeppen H W , Hillan K J
Published: April 2004

Aims:To measure vascular endothelial growth factor (VEGF-A) mRNA in a large, diverse cohort of tumours and to investigate whether VEGF-A expression is associated with markers of hypoxia, including hypoxia inducible factor 1α (HIF-1α) and carbonic anhydrase IX (CA9).

Methods:The expression of VEGF-A and CA9 was assessed in 5067 fresh frozen human tissue samples and 238 cell lines by DNA microarray analysis. In addition, tissue microarrays were constructed from 388 malignancies to investigate the expression of VEGF-A and HIF-1α by in situ hybridisation and immunohistochemistry, respectively.

Results:VEGF-A was significantly upregulated in primary malignancies of the breast, cervix, colon and rectum, oesophagus, head and neck, kidney, ovary, skin, urinary system, and white blood cells by DNA microarray analysis. However, VEGF-A expression only correlated with CA9 expression in renal tissues. In the tissue microarrays, HIF-1α positive cores showed a significant increase in VEGF-A expression in lung, ovary, soft tissue, and thyroid malignancies.

Conclusions:The expression of VEGF-A is upregulated in a large proportion of human malignancies, and may be associated with markers of hypoxia. VEGF-A expression can be induced in the absence of hypoxia and hypoxia does not always provoke VEGF-A upregulation in tumours.
Epstein-Barr virus in gastric carcinomas and gastric stump carcinomas: a late event in gastric carcinogenesis
Authors: zur Hausen A , van Rees B P , van Beek J , Craanen M E , Bloemena E , Offerhaus G J A , Meijer C J L M , van den Brule A J C
Published: April 2004

Background:To determine at what stage during gastric carcinogenesis Epstein-Barr virus (EBV) enters the gastric epithelial cells, the presence of EBV was investigated in two pathogenetically related but distinct forms of adenocarcinoma of the stomach—gastric carcinoma of the intact stomach (GCIS) and gastric stump carcinoma (GSC)—and their presumed precursor lesions.

Patients and methods:Eleven patients with EBV positive GCIS and eight patients with EBV positive GSC, demonstrated by the highly sensitive EBV encoded RNA 1/2 (EBER1/2) RNA in situ hybridisation (RISH) technique, were studied. Paraffin wax embedded tissue available from preoperative gastric biopsies and tumour adjacent tissue from the resection specimens containing normal gastric mucosa, inflamed gastric mucosa, and preneoplastic lesions (intestinal metaplasia and dysplasia) was investigated by EBER1/2 RISH, in addition to EBV nuclear antigen 1 (EBNA-1) and latent membrane protein 1 (LMP-1) immunohistochemistry (IHC).

Results:In both GCIS and GSC and their precursor lesions EBER1/2 transcripts were restricted to the carcinoma cells. In addition, positivity of EBNA-1 IHC was also restricted to the tumour cells. IHC for LMP-1 was negative in all cases tested.

Conclusions:The absence of EBER1/2 transcripts in preneoplastic gastric lesions (intestinal metaplasia and dysplasia) and their presence in two distinct types of gastric carcinoma strongly suggest that EBV can only infect neoplastic gastric cells and thus is a late event in gastric carcinogenesis.
STOCHASTIC RESONANCE AND OPTIMAL CLUSTERING FOR ASSEMBLIES OF ION CHANNELS
Authors: SCHMID G. , GOYCHUK I. , HÄNGGI P. , ZENG S. , JUNG P.
Published: April 2004

We consider the statistical properties of action potentials generated by clusters of sodium and potassium channels due to channel noise and/or external stimulation. Since the fluctuations are related to the cluster size, a size-resonance effect — analog to stochastic resonance — is observed that facilitates optimal decoding of small external stimuli at optimal cluster sizes. Furthermore, in analogy to the coherence resonance effect, the channel-noise induced firing patterns exhibit a resonant-like temporal coherence as a function of the cluster size even in the absence of a periodic stimulus. In the presence of additional synaptic noise, SR occurs only for large cluster sizes which possess suboptimal internal noise levels.
NONLINEAR SIGNAL DETECTION IN THE TIME DOMAIN: LEVEL CROSSING STATISTICS AND NOISE-MEDIATED MINIMIZATION OF THE MEASUREMENT ERROR
Authors: NIKITIN A. , STOCKS N. G. , BULSARA A. R.
Published: April 2004

We study the problem of detecting a small dc signal by quantifying its effect on the mean difference ΔT in residence times in the stable steady states of a bistable dynamical measurement device, in the presence of a noise-floor and a known time-sinusoidal bias signal. Errors in the measurement process occur due to a finite observation time that is present in most practical scenarios; in turn, noise degrades the measurement. Adjusting the bias signal amplitude to a slightly subthreshold operating regime, leads to a non-monotonic dependence of the (suitably defined) error on the noise intensity; at a critical noise intensity, the error is minimized. This phenomenon, reminiscent of the well-known Stochastic Resonance effect [1–4], appears to be most pronounced for subthreshold bias signals in the strongly nonlinear response regime. The results can be applied to a variety of nonlinear systems, including neurons, that operate in the time-domain.
STATE-DEPENDENT NOISE AND HUMAN BALANCE CONTROL
Authors: CABRERA JUAN LUIS , BORMANN RONALD , EURICH CHRISTIAN , OHIRA TORU , MILTON JOHN
Published: April 2004

The fluctuations observed in the task of stick balancing at the fingertip exhibit many of the properties predicted to occur in parametric stochastic dynamical systems, namely intermittency, truncated Lévy flights and truncated Lévy distributions. The development of virtual balancing tasks that involve the interplay between a human and computer and that exhibit the same dynamical properties as seen for stick balancing opens the door for experimental investigations into the nature of the neural motor control mechanisms that underlie these phenomena.
STOCHASTIC DYNAMICS OF ELECTRORECEPTORS IN PADDLEFISH
Authors: NEIMAN ALEXANDER B. , RUSSELL DAVID F.
Published: April 2004

Electroreceptors in paddlefish serve as accessible and well-defined biological models for studying the functional roles in sensory nervous systems of noisy oscillations and the nonlinear phenomena associated with them, including synchronization, noise-induced transitions, and noise-induced bursting. The spontaneous dynamics of paddlefish electroreceptors show two oscillatory modes: one associated with 26 Hz oscillations in the sensory epithelia, and another with 30-65 Hz periodicities of afferent terminals. This novel type of organization of peripheral sensory receptors, with two distinct types of embedded oscillators, results in stochastic biperiodic firing patterns of primary afferents. The biperiodicity can be explained qualitatively in terms of a simple model based on a stochastic circle map. Stimulation with broadband Gaussian noise changes the tonic firing pattern of electroreceptors to a bursting mode, indicating a noise-induced transition. This qualitative change in dynamics leads to burst synchronization among different electroreceptors.
FERMI RESONANCE — NEW APPLICATIONS OF AN OLD EFFECT
Authors: EBELING WERNER , KARGOVSKY ALEXEY , NETREBKO ALEXEY , ROMANOVSKY YURI
Published: April 2004

We consider here the effect of Fermi resonance on the rate of stochastic transitions over potential barriers. As a typical phenomenon for Fermi resonance we investigate the fading of the energy between the oscillations in different degrees of freedom. Due to this fading phenomenon we see from time to time rather large amplitudes of oscillations along the reaction path which may support transitions over reaction barriers in the underdamped regime. As as an application we study the influence of Fermi resonance on enzyme reactions. In particular we investigate the possible effect of Fermi resonance on the breaking of peptide bonds.
INSTANTANEOUS PHASE METHOD IN STUDYING CHAOTIC AND STOCHASTIC OSCILLATIONS AND ITS LIMITATIONS
Authors: ANISHCHENKO VADIM S. , VADIVASOVA TATJANA E. , STRELKOVA GALINA I.
Published: April 2004

We study the behavior of an instantaneous phase and mean frequency of chaotic self-sustained oscillations and noise-induced stochastic oscillations. The results obtained by using various methods of the phase definition are compared to each other. We also compare two methods for describing synchronization of chaotic self-sustained oscillations, namely, instantaneous phase locking and locking of characteristic frequencies in power spectra. It is shown that the technique for diagnostics of the chaos synchronization based on the instantaneous phase locking is not universal.
Impaired nitric oxide synthase-2 signaling pathway in cystic fibrosis airway epithelium
Authors: Zheng Shuo , Xu Weiling , Bose Santanu , Banerjee Amiya K. , Haque S. Jaharul , Erzurum Serpil C.
Published: April 2004

Cystic fibrosis (CF) airway epithelial cells are more susceptible to viral infection due to impairment of the innate host defense pathway of nitric oxide (NO). NO synthase-2 (NOS2) expression is absent, and signal transducer and activator of transcription (STAT) 1 activation is reduced in CF. We hypothesized that the IFN-γ signaling pathway, which leads to NOS2 gene induction in CF airway epithelial cells, is defective. In contrast to a lack of NOS2 induction, the major histocompatibility complex class 2, an IFN-γ-regulated delayed-responsive gene, is similarly induced in CF and non-CF airway epithelial (NL) cells, suggesting an NOS2-specific defect in the IFN-γ signaling pathway. STAT1 and activator protein-1, both required for NOS2 gene expression, interact normally in CF cells. Protein inhibitor of activated STAT1 is not increased in CF cells. IFN-γ induces NOS2 expression in airway epithelial cells through an autocrine mechanism involving synthesis and secretion of IFN-γ-inducible mediator(s), which activates STAT1. Here, CF cells secrete IFN-γ-inducible factor(s), which stimulate NOS2 expression in NL cells, but not in CF cells. In contrast, IFN-γ-inducible factor(s) similarly inhibit virus in CF and NL cells. Thus autocrine activation of NOS2 is defective in CF cells, but IFN-γ induction of antiviral host defense is intact.
Renal epithelial cells constitutively produce a protein that blocks adhesion of crystals to their surface
Authors: Kumar Vivek , Yu Shihui , Farell Gerard , Toback F. Gary , Lieske John C.
Published: April 2004

Attachment of newly formed crystals to renal tubular epithelial cells appears to be a critical step in the development of kidney stones. The present study was undertaken to identify autocrine factors released from renal epithelial cells into the culture medium that inhibit adhesion of calcium oxalate crystals to the cell surface. A 39-kDa glycoprotein that is constitutively secreted by renal cells was purified by gel filtration chromatography. Amino acid microsequencing revealed that it is novel and not structurally related to known inhibitors of calcium oxalate crystallization. Hence, it was named crystal adhesion inhibitor, or CAI. Immunoreactive CAI was detected in diverse rat tissues, including kidney, heart, pancreas, liver, and testis. Immunohistochemistry revealed that CAI is present in the renal cell cytosol and is also on the plasma membrane. Importantly, CAI is present in normal human urine, from which it can be purified using calcium oxalate monohydrate crystal affinity chromatography. CAI could be an important defense against crystal attachment to tubular cells and the subsequent development of renal stones in vivo.
Preclinical models of human peripheral arterial occlusive disease: implications for investigation of therapeutic agents
Authors: Waters Richard E. , Terjung Ronald L. , Peters Kevin G. , Annex Brian H.
Published: April 2004

Peripheral arterial occlusive disease (PAOD) is now recognized as a combination of clinical syndromes that are associated with significant morbidity and mortality. The primary pathophysiology of PAOD is impaired perfusion to the lower extremity. Effective pharmacotherapy designed to increase perfusion in PAOD is lacking, and revascularization options are suboptimal. New and more efficacious therapies that improve blood flow are definitely needed, and thus designing, describing, and validating these new therapies in preclinical PAOD models will be essential. This study describes the various preclinical PAOD models presently in use, correlates the models to human PAOD, and reviews the available end points that can be used to detect a response to therapy.
Comparing Perceptual Signals of Single V5/MT Neurons in Two Binocular Depth Tasks
Authors: Krug K. , Cumming B. G. , Parker A. J.
Published: April 2004

Neurons in the extrastriate visual area V5/MT show perceptually relevant signals in binocular depth tasks, which can be measured as a choice probability (CP) for the neuron. The presence of a CP in a particular paradigm may be an indicator that the neuron is generally part of the substrate for the perception of binocular depth. We compared the responses of those single neurons that show CPs in one stereoscopic depth task with their responses in another stereo task. Each neuron was tested for the presence of 1) CPs during a task in which macaques responded to the sign of binocular depth in a structure-from-motion stimulus, to judge its direction of three-dimensional rotation and 2) a consistent response to the stereo disparity of binocularly anti-correlated stimuli. Previous work, confirmed here, shows that changing the disparity of these binocularly anti-correlated stimuli often fails to yield a coherent change in the depth percept. For each test alone, there are V5/MT neurons that carry signals that are congruent with the perceptual effects. However, on comparing tests, there is no fixed pool of neurons that can account for the binocular depth percept. Excitation of neurons with a measurable CP does not necessarily lead to a change in perception. The cortical circuitry must be able to make dynamic changes in the pools of neurons that underlie perceptual judgments according to the demands of the task.
Location and Magnitude of Conductance Changes Produced by Renshaw Recurrent Inhibition in Spinal Motoneurons
Authors: Maltenfort Mitchell G. , McCurdy Martha L. , Phillips Carrie A. , Turkin Vladimir V. , Hamm Thomas M.
Published: April 2004

The mean location of Renshaw synapses on spinal motoneurons and their synaptic conductance were estimated from changes in impedance magnitude produced by sustained recurrent inhibition. Motoneuron impedance was determined by injecting quasi-white noise current into lumbosacral motoneurons of pentobarbital-anesthetized cats. Synaptic location and conductance were estimated by comparing observed impedance changes to simulation results obtained using standard motoneuron models and compartmental models fit to each impedance function. Estimated synaptic locations ranged from 0.10 to 0.41λ, with a mean of 0.19 or 0.24λ, depending on the estimation method. Average dendritic path length was 262 μm. Average synaptic conductance was 23 to 27 nS (range: 6.7 to 57.9 nS), corresponding to conductance changes of 78 to 88% of resting membrane conductance. Estimated accuracy was supported by consistency using different estimation methods, agreement with Fyffe's 1991 morphological data, and comparisons of observed and simulated recurrent IPSP amplitudes. Synaptic location, but not synaptic conductance, was correlated with rheobase, a measure of motoneuron excitability. Synaptic conductance did not depend on synaptic location. A regression analysis demonstrated that synaptic conductance and cell impedance were the principal factors determining recurrent IPSP amplitude. Simulations using the observed values and locations of Renshaw conductance demonstrate that recurrent inhibition can require as much as an additional 14 to 18% sustained excitatory synaptic conductance to depolarize motoneurons sufficiently to activate somatic or dendritic inward currents and recruit motoneurons or amplify excitatory synaptic currents.
Genetic Cross‐Talk During Head Development in Drosophila
Authors: Amin Amr
Published: April 2004

The dorsal head vertex of Drosophila is specified
mainly by the orthodenticle (otd) gene. The
expression and the function of otd are regulated by the
concerted action of many genes including hedgehog
(hh) and notch (N). These genes are
components of a meshwork of signaling transduction pathways that
interact to form the dorsal head capsule of the fruit fly.
Loss‐of‐function Hh mutants lack ocelli; however,
loss‐of‐function N mutants lack a different domain of
the dorsal head vertex. This report provides new evidence that
the Hh and N pathways are two epistatic
signaling cascades that act genetically upstream of the dorsal
head capsule specification gene.
Cardiovascular Biology of the Asymmetric Dimethylarginine:Dimethylarginine Dimethylaminohydrolase Pathway
Authors: Vallance Patrick , Leiper James
Published: April 2004

An increasing number of reports indicate that endogenously produced inhibitors of nitric oxide synthase, particularly asymmetric dimethylarginine (ADMA), regulate nitric oxide generation in disease states. This article describes the biology of ADMA and the implications for cardiovascular physiology and pathophysiology.
Determinants of Blood Pressure Response to Quinapril in Black and White Hypertensive Patients
Authors: Mokwe Evan , Ohmit Suzanne E. , Nasser Samar A. , Shafi Tariq , Saunders Elijah , Crook Errol , Dudley Amanda , Flack John M.
Published: April 2004

Race has been considered an important factor in determining blood pressure response to treatment and selection of antihypertensive drug therapy. Data collected during a clinical trial that evaluated rapidity of medication up-titration with blood pressure response to monotherapy with the angiotensin-converting enzyme (ACE) inhibitor quinapril were used to characterize response in 533 black and 2046 white participants. Our objectives were to examine the influence of race and other factors on blood pressure response and to assess the degree to which nonrace factors account for apparent racial differences in response. Average systolic and diastolic blood pressure responses (baseline minus follow-up) to treatment were assessed with treatment groups combined. Crude systolic and diastolic blood pressure responses averaged 4.7 and 2.4 mm Hg less, respectively, in black compared with white participants; however, the response distributions largely overlapped. In multivariate linear regression models adjusted for study design variables and measured participant characteristics, the racial difference in systolic response was reduced by 51% to 2.3 mm Hg, and diastolic response by 21% to 1.9 mm Hg. In these models, participant characteristics, including age, gender, body size, and pretreatment blood pressure severity, significantly predicted either attenuated or enhanced blood pressure response to treatment. Our findings demonstrate that a large source of variability of blood pressure response to treatment is within, not between, racial groups, and that factors that vary at the level of the individual contribute to apparent racial differences in response to treatment.
Human Cytomegalovirus Causes Endothelial Injury Through the Ataxia Telangiectasia Mutant and p53 DNA Damage Signaling Pathways
Authors: Shen Y.H. , Utama B. , Wang J. , Raveendran M. , Senthil D. , Waldman W.J. , Belcher J.D. , Vercellotti G. , Martin D. , Mitchelle B.M. , Wang X.L.
Published: April 2004

Atherosclerosis is the leading cause of death in the United States, and human cytomegalovirus (HCMV), a member of the herpes virus family, may play a role in the development of the disease. We previously showed that HCMV regulated endothelial apoptosis. In this study, we investigated the induction of apoptosis and signal transduction pathways regulating this process in HCMV-infected endothelial cells. As observed previously, HCMV induced a typical cytopathic effect in human aortic endothelial cells (HAECs), ie, the formation of single nucleated or multinucleated giant cells. Although infected HAECs were resistant to apoptosis at earlier stages of infection, they became apoptotic with prolonged infection as demonstrated by positive staining using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). This apoptotic process was mediated by the caspase-dependent mitochondrial apoptotic pathway as indicated by increased expression and cleavage of caspases 3 and 9 as well as increased expressions of pro-apoptotic molecules Bax and Bak. Blocking caspases 3 or 9 significantly inhibited the HCMV-induced apoptosis. Further exploration of the upstream pathway demonstrated upregulation of the tumor suppressor p53 gene and activation of the ataxia telangiectasia mutant (ATM) pathway in the infected cells. Blocking p53 inhibited HCMV-stimulated Bax and Bak expression as well as caspase-3 activation and blocking the ATM pathway inhibited HCMV-stimulated p53 activation. Although early infection may render cells antiapoptotic, prolonged infection, however, induced endothelial apoptosis through ATM and p53-dependent activation of the mitochondrial death pathway. This proapoptotic effect may be relevant to endothelial dysfunction and HCMV-associated vascular diseases.
Functional Relevance of the Stretch-Dependent Slow Force Response in Failing Human Myocardium
Authors: von Lewinski Dirk , Stumme Burkhard , Fialka Florian , Luers Claus , Pieske Burkert
Published: April 2004

Stretch induces immediate and delayed inotropic effects in mammalian myocardium via distinct mechanosensitive pathways, but these effects are poorly characterized in human cardiac muscle. We tested the effects of stretch on immediate and delayed force response in failing human myocardium. Experiments were performed in muscle strips from 52 failing human hearts (37°C, 1 Hz, bicarbonate buffer). Muscles were stretched from 88% of optimal length to 98% of optimal length. The resulting immediate and delayed (ie, slow force response [SFR]) increases in twitch force were assessed without and after blockade of the sarcoplasmic reticulum (SR; cyclopiazonic acid and ryanodine), stretch-activated ion channels (SACs; gadolinium, streptomycin),
l
-type Ca
2+
-channels (diltiazem), angiotensin II type-1 (AT
1
) receptors (candesartan), endothelin (ET) receptors (PD145065 or BQ123), Na
+
/H
+
exchange (NHE1; HOE642), or reverse-mode Na
+
/Ca
+
exchange (NCX; KB-R7493). We also tested the effects of stretch on SR Ca
2+
load (rapid cooling contractures [RCCs]) and intracellular pH (in BCECF-loaded trabeculae). Stretch induced an immediate (<10 beats), followed by a slow (5 to 10 minutes), force response. Twitch force increased to 232±6% of prestretch value during the immediate phase, followed by a further increase to 279±8% during the SFR. RCC amplitude significantly increased, but pHi did not change during SFR. Inhibition of SACs,
l
-type Ca
2+
channels, AT
1
receptors, or ET receptors did not affect the stretch-dependent immediate or SFR. In contrast, the SFR was reduced by NHE1 inhibition and almost completely abolished by reverse-mode NCX inhibition or blockade of sarcoplasmic reticulum function. The data demonstrate the existence of a functionally relevant, SR-Ca
2+
–dependent SFR in failing human myocardium, which partly depends on NHE1 and reverse-mode NCX activation.
Role of the Endothelial Lining in Recurrences After Coil Embolization
Authors: Raymond Jean , Guilbert François , Metcalfe Annick , Gévry Guylaine , Salazkin Igor , Robledo Olivier
Published: April 2004

Background and Purpose—

Endovascular treatment can improve the outcome of patients treated for ruptured intracranial aneurysms as compared with surgical clipping, but angiographic recurrences are frequent. Endothelial denudation before coil embolization may prevent recanalization and improve results of endovascular treatment.

Methods—

We compared angiographic and pathological results 3 months after coil occlusion of paired canine arteries (n=16), with or without previous denudation of the endothelial lining using an endovascular device. The technique was then used to denude the neck of carotid venous pouch bifurcation aneurysms before coil embolization in 8 dogs, and the angiographic evolution at 12 weeks was compared with 7 control aneurysms treated by coiling only. Qualitative scoring systems were used to compare angiographic results with time and neointimal coverage at the neck of aneurysm after necropsy. The evolution of angiographic scores was analyzed using Wilcoxon signed rank tests whereas angiographic and neointimal scores of the 2 groups were compared using the Mann–Whitney test.

Results—

All arteries embolized with platinum coils recanalized, whereas most arteries (12/16 or 75%) denuded before coil embolization remained occluded at 3 and 12 weeks (
P
<0.001). Aneurysms treated with coils without previous denudation tended to recur, with angiographic scores significantly worse at 12 weeks as compared with T
0
(
P
=0.015). Median angiographic and neointimal scores were significantly better at 12 weeks with endothelial denudation (
P
=0.011 and 0.026, respectively).

Conclusion—

Endothelial denudation can prevent recanalization after coil embolization.
Protein Z Deficiency in Antiphospholipid-Negative Sneddon’s Syndrome
Authors: Ayoub Nakhlé , Esposito Gaetan , Barete Stéphane , Soria Claudine , Piette Jean-Charles , Francès Camille
Published: April 2004

Background—

Sneddon’s syndrome is characterized by the association of ischemic cerebrovascular events and widespread livedo racemosa. The pathophysiology of Sneddon’s syndrome remains elusive, but various prothrombotic abnormalities have been previously reported in this setting. Low levels of protein Z, a downregulator of coagulation, have been recently linked to an increased risk of arterial thrombosis. The purpose of this study was to investigate the levels of protein Z in a series of Sneddon’s syndrome patients without circulating antiphospholipid antibodies in comparison with an age- and sex-matched control population.

Methods—

Twenty-six patients and 78 healthy controls had determination of their protein Z blood levels by an enzyme-linked immunoassay test. Patients’ thrombotic and vascular risk factors, including tobacco smoking, arterial hypertension, oral contraceptive agents, dyslipidemia, factor V Leiden, and factor II mutation were recorded.

Results—

Protein Z plasma levels were significantly lower in patients (mean 1.47 mg/L) than in controls (mean 1.93 mg/L) (
P
=0.02). Prevalence of protein Z deficiency (level <1 mg/L) was significantly higher (
P
=0.001) among patients (31%) than among controls (3.8%). Factor V Leiden and heavy smoking were observed in 4 and 7 patients, respectively.

Conclusions—

Sneddon’s syndrome could be viewed as the peculiar clinical expression of various and sometimes associated coagulation abnormalities. Low levels of protein Z may account, at least partly, for the thrombotic events observed in Sneddon’s syndrome and shed a new light on its pathophysiology. Clinical implications for protein Z deficiency in this setting deserve further investigations.
Plasminogen Activator Inhibitor-1 4G Allele in the 4G/5G Promoter Polymorphism Increases the Occurrence of Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage
Authors: Vergouwen M.D.I. , Frijns C.J.M. , Roos Y.B.W.E.M. , Rinkel G.J.E. , Baas F. , Vermeulen M.
Published: April 2004

Background and Purpose—

In several acute life-threatening diseases, the 4G-allele in the 4G/5G-promotor polymorphism in the plasminogen activator inhibitor-1 (PAI-1) gene is associated with higher PAI-1 levels and increased poor outcome, probably by promoting the formation of microthrombi. The aim of the present study was to investigate whether the PAI-1 4G/5G polymorphism is associated with the occurrence of cerebral ischemia, rebleeding, and other events, and clinical outcome after aneurysmal subarachnoid hemorrhage.

Methods—

DNA was collected and analyzed in 126 patients with aneurysmal subarachnoid hemorrhage admitted to the Academic Medical Centre Amsterdam and University Medical Centre Utrecht in the Netherlands. All episodes of deterioration were classified according to predefined criteria. Causes of poor outcome and functional outcome were assessed 3 months after the initial bleeding according to the 5-point Glasgow Outcome Scale (GOS).

Results—

Secondary ischemia occurred more often in patients with the 4G genotype than in patients homozygous for the 5G allele (RR: 3.3; 95% CI: 1.1 to 10.0). No significant differences were found between the groups for rebleeding or other events. Patients with the 4G genotype tended to have a higher risk for poor outcome than patients with the 5G/5G genotype (RR 1.2; 95% CI 0.7 to 2.2).

Conclusion—

The 4G allele in the PAI-1 gene increases the risk for cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH) and probably also the risk for poor outcome. After early aneurysm occlusion, treatment aimed at enhancing fibrinolysis might be effective to prevent and treat cerebral ischemia in patients with aneurysmal SAH.
Algunas variables predictoras de las actitudes del alumnado ante la integración escolar
Authors: Navas Leandro , Torregrosa Germán , Mula Antonio
Published: April 2004

Este trabajo persigue conocer cómo se pueden predecir las actitudes de los alumnos hacia la integración escolar y si están asociadas al conocimiento mutuo, a las actitudes de los padres, a las actitudes de los profesores o a otras variables. La muestra la componen 1.061 alumnos y alumnas de la provincia de Alicante y de las respuestas de éstos al cuestionario con el que se evalúan sus actitudes se obtienen tres factores: “Prejuicios negativos”, “Aceptación de las diferencias” y “Disposición a la interacción”. Con la puntuación total en estos factores se realiza un análisis de regresión múltiple que permite destacar el papel relevante que presenta la comunicación de los hijos con los padres en la formación de actitudes de los estudiantes hacia la integración en el aula de alumnos con necesidades educativas especiales.
El concepto de emoción en Árabe Clásico
Authors: Casado Cristina
Published: April 2004

El presente artículo trata de obtener el equivalente del concepto de emoción en árabe Clásico (àl-fushà). Este estudio muestra la difícil obtención del concepto emoción en su versión clásica o estándar. Concluimos que a pesar de constituir una referencia fundamental en la literatura sobre emoción, dicho sustantivo no posee una fácil traducción en idiomas tan importantes como el árabe, utilizado por unos 250 millones de personas en todo el mundo.
Enforced expression of cyclin D2 enhances the proliferative potential of myeloid progenitors, accelerates in vivo myeloid reconstitution, and promotes rescue of mice from lethal myeloablation
Authors: Sasaki Yutaka , Jensen Christina T. , Karlsson Stefan , Jacobsen Sten Eirik W.
Published: April 2004

Severe and prolonged cytopenias represent a considerable problem in clinical stem cell transplantations. Cytokine-induced ex vivo expansion of hematopoietic stem and progenitor cells has been intensively explored as a means of accelerating hematopoietic recovery following transplantation but have so far had limited success. Herein, overexpression of D-type cyclins, promoting G0/G1 to S transition, was investigated as an alternative approach to accelerate myeloid reconstitution following stem cell transplantation. With the use of retroviral-mediated gene transfer, cyclin D2 was overexpressed in murine bone marrow progenitor cells, which at limited doses showed enhanced ability to rescue lethally ablated recipients. Competitive repopulation studies demonstrated that overexpression of cyclin D2 accelerated myeloid reconstitution following transplantation, and, in agreement with this, cyclin D2–transduced myeloid progenitors showed an enhanced proliferative response to cytokines in vitro. Furthermore, cyclin D2–overexpressing myeloid progenitors and their progeny were sustained for longer periods in culture, resulting in enhanced and prolonged granulocyte production in vitro. Thus, overexpression of cyclin D2 confers myeloid progenitors with an enhanced proliferative and granulocyte potential, facilitating rapid myeloid engraftment and rescue of lethally ablated recipients.
Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo
Authors: Dietz Allan B. , Souan Lina , Knutson Gaylord J. , Bulur Peggy A. , Litzow Mark R. , Vuk-Pavlović Stanimir
Published: April 2004

Imatinib mesylate (STI571, imatinib) inhibited DNA synthesis in primary human T cells stimulated with allogeneic mature dendritic cells or phytohemagglutinin (PHA) but did not induce apoptosis. The values for the concentration that inhibits 50% (IC50) of T-cell proliferation stimulated by dendritic cells and PHA were 3.9 μM and 2.9 μM, respectively, that is, within the concentration range found in patients treated with imatinib mesylate. Interestingly, imatinib mesylate did not inhibit expression of T-cell activation markers CD25 and CD69, although it reduced the levels of activated nuclear factor-κB (NF-κB) and changed phosphorylation or protein levels of Lck, ERK1/2, retinoblastoma protein, and cyclin D3. When T cells were washed free of imatinib mesylate, they proliferated in response to PHA, demonstrating that inhibition is reversible. Treatment with imatinib mesylate led to accumulation of the cells in G0/G1 phase of the cell cycle. The in vitro observations were confirmed in vivo in a murine model of delayed-type hypersensitivity (DTH). In mice treated with imatinib mesylate, DTH was reduced in comparison to sham-injected controls. However, the number of splenic T cells was not reduced showing that, similarly to in vitro observations, imatinib mesylate inhibited T-cell response, but did not cause apoptosis. These findings indicate that long-term administration of high-dose imatinib mesylate might affect immunity.
Interleukin-17 regulates expression of the CXC chemokine LIX/CXCL5 in osteoblasts: implications for inflammation and neutrophil recruitment
Authors: Ruddy Matthew J , Shen Fang , Smith Jeffrey B , Sharma Ashu , Gaffen Sarah L
Published: April 2004

Interleukin (IL)-17 is the founding member of an emerging family of inflammatory cytokines whose functions remain poorly defined. IL-17 has been linked to the pathogenesis of rheumatoid arthritis, and numerous studies implicate this cytokine in inflammation-induced bone loss. It is clear that a major function of IL-17 is to amplify the immune response by triggering production of chemokines, cytokines, and cell-surface markers, ultimately leading to neutrophil chemotaxis and inflammation. As an IL-17 signaling deficiency in mice causes a dramatic reduction in neutrophil chemotaxis and a consequent increased susceptibility to bacterial infection, it is important to define gene targets involved in IL-17-mediated neutrophil trafficking. Here, we demonstrate that IL-17 and tumor necrosis factor α (TNF-α) cooperatively induce the lipopolysaccharide-inducible CXC chemokine (LIX; a.k.a., CXC chemokine ligand 5, Scya5, or murine granulocyte chemotactic protein-2) in the preosteoblast cell line MC3T3. LIX is induced rapidly at the mRNA and protein levels, likely through the activation of new gene transcription. Conditioned media from MC3T3 cells treated with IL-17 and/or TNF-α stimulates neutrophil mobility potently, and LIX is a significant contributing factor to this process. In addition, IL-17 cooperates with bacterial components involved in periodontal disease to up-regulate LIX expression. This study is the first demonstration of LIX expression in bone cells and has implications for inflammatory bone diseases such as arthritis and periodontal disease.
Patched controls the Hedgehog gradient by endocytosis in a dynamin-dependent manner, but this internalization does not play a major role in signal transduction
Authors: Torroja Carlos , Gorfinkiel Nicole , Guerrero Isabel
Published: April 2004

The Hedgehog (Hh) morphogenetic gradient controls multiple developmental patterning events in Drosophila and vertebrates. Patched (Ptc), the Hh receptor, restrains both Hh spreading and Hh signaling. We report how endocytosis regulates the concentration and activity of Hh in the wing imaginal disc. Our studies show that Ptc limits the Hh gradient by internalizing Hh through endosomes in a dynamin-dependent manner, and that both Hh and Ptc are targeted to lysosomal degradation. We also found that the ptc14 mutant does not block Hh spreading, as it has a failure in endocytosis. However, this mutant protein is able to control the expression of Hh target genes as the wild-type protein, indicating that the internalization mediated by Ptc is not required for signal transduction. In addition, we noted that both in this mutant and in those not producing Ptc protein, Hh still occurred in the endocytic vesicles of Hh-receiving cells,suggesting the existence of a second, Ptc-independent, mechanism of Hh internalization.
A regulatory network of T-box genes and theeven-skippedhomologuevab-7controls patterning and morphogenesis inC. elegans
Authors: Pocock Roger , Ahringer Julie , Mitsch Michael , Maxwell Sara , Woollard Alison
Published: April 2004

T-box genes form a large family of conserved transcription factors with diverse roles in animal development, but so far functions for only a few have been studied in detail. Here we show that four Caenorhabditis elegansT-box genes and the even-skipped-like homeobox gene vab-7function within a regulatory network to control embryonic patterning and morphogenesis. tbx-8 and tbx-9 have functionally redundant roles in the intercalation of posterior dorsal hypodermal cells, in muscle cell positioning and in intestinal development. Inhibiting tbx-9alone using RNA interference (RNAi) produces worms that have a thickened,`bobbed tail' phenotype, similar to that seen in mutants of vab-7,which itself has been shown to pattern posterior muscle and hypodermal cells. In support of the view that these genes function in the same pathway, we find that tbx-8 and tbx-9 are both necessary and sufficient for vab-7 expression. In addition, a third T-box gene, tbx-30,acts to repress vab-7 expression in the anterior of embryos. We further show that vab-7 itself represses the T-box gene mab-9 in posterior cells. Thus, during posterior patterning in C. elegans, there are multiple interactions between T-box genes and the vab-7 homeobox gene. Evolutionary parallels in other organisms suggest that regulatory interactions between T-box genes and even-skipped homologues are conserved.