bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclin-Dependent Kinase-9
Authors: Sano Motoaki , Schneider Michael D.
Published: October 2004

Over the past decade and a half, the paradigm has emerged of cardiac hypertrophy and ensuing heart failure as fundamentally a problem in signal transduction, impinging on the altered expression or function of gene-specific transcription factors and their partners, which then execute the hypertrophic phenotype. Strikingly, RNA polymerase II (RNAPII) is itself a substrate for two protein kinases—the cyclin-dependent kinases Cdk7 and Cdk9—that are activated by hypertrophic cues. Phosphorylation of RNAPII in the carboxyl terminal domain (CTD) of its largest subunit controls a number of critical steps subsequent to transcription initiation, among them enabling RNAPII to overcome its stalling in the promoter-proximal region and to engage in efficient transcription elongation. Here, we summarize our current understanding of the RNAPII-directed protein kinases in cardiac hypertrophy. Cdk9 activation is essential in tissue culture for myocyte enlargement and sufficient in transgenic mice for hypertrophy to occur and yet is unrelated to the “fetal” gene program that is typical of pathophysiological heart growth. Although this trophic effect of Cdk9 appears benign superficially, pathophysiological levels of Cdk9 activity render myocardium remarkably susceptible to apoptotic stress. Cdk9 interacts adversely with Gq-dependent pathways for hypertrophy, impairing the expression of numerous genes for mitochondrial proteins, and, in particular, suppressing master regulators of mitochondrial biogenesis and function, perioxisome proliferator-activated receptor-γ coactivator-1 (PGC-1), and nuclear respiratory factor-1 (NRF-1). Given the dual transcriptional roles of Cdk9 in hypertrophic growth and mitochondrial dysfunction, we suggest the potential usefulness of Cdk9 as a target in heart failure drug discovery.
Delayed Adaptation of the Heart to Stress
Authors: Stein Adam B. , Tang Xian-Liang , Guo Yiru , Xuan Yu-Ting , Dawn Buddhadeb , Bolli Roberto
Published: October 2004

The early phase of preconditioning (PC) lasts 2 to 3 hours and protects against myocardial infarction, but not against stunning. In contrast, the late phase of PC lasts for 3 to 4 days and protects against both myocardial stunning and infarction, making this phenomenon more clinically relevant. Late PC is a genetic reprogramming of the heart that involves the activation of several stress-responsive genes, which ultimately results in the development of a cardioprotective phenotype. Sublethal ischemic insults release chemical signals (nitric oxide [NO], adenosine, and reactive oxygen species) that trigger a series of signaling events (eg, activation of protein kinase C, Src protein tyrosine kinases, Janus kinases 1/2, and nuclear factor-κB) and culminates in increased synthesis of inducible NO synthase, cyclooxygenase-2, heme oxygenase-1, aldose reductase, Mn superoxide dismutase, and probably other cardioprotective proteins. In addition to ischemia, heat stress, exercise, and cytokines can also induce a similar series of events. Perhaps most importantly, many pharmacologic agents (eg, NO donors, adenosine receptor agonists, endotoxin derivatives, or opioid receptor agonists) can mimic the effects of ischemia in inducing the late phase of PC, suggesting that this phenomenon might be exploited therapeutically. The purpose of this review is to summarize the mechanisms that underlie the late phase of ischemic PC.
Recovery and Rehabilitation in Stroke
Authors: Lindvall Olle , Kokaia Zaal
Published: October 2004

The recent demostration that neurons for transplantation can be generated from stem cells and that the adult brain produces new neurons in response to stroke has raised hope for the development of a stem cell therapy for patients affected with this disorder. In this review we propose a road map to the clinic and describe the different scientific tasks that need to be accomplished to move stem cell–based approaches toward application in stroke patients.
RAGE (Yin) Versus LRP (Yang) Balance Regulates Alzheimer Amyloid β-Peptide Clearance Through Transport Across the Blood–Brain Barrier
Authors: Deane Rashid , Wu Zhenhua , Zlokovic Berislav V.
Published: October 2004

Accumulation of amyloid β-peptide (Aβ) in the central nervous system (CNS) may initiate pathogenic cascades mediating neurovascular and neuronal dysfunctions associated with the development of cerebral β-amyloidosis and cognitive decline in patients with Alzheimer disease (AD) and with related familial cerebrovascular disorders. Whether Aβ-related pathology in the CNS is reversible or not and what key therapeutic targets are controlling Aβ/amyloid levels in the aging brain remain debatable. In this article, we summarize recent evidence why the receptor for advanced glycation end products and low-density lipoprotein receptor related protein 1 in the vascular CNS barriers are critical for regulation of Aβ homeostasis in the CNS and how altered activities in these 2 receptors at the blood-brain barrier may contribute to the CNS Aβ accumulation resulting in neuroinflammation, disconnect between the cerebral blood flow and metabolism, altered synaptic transmission, neuronal injury, and amyloid deposition into parenchymal and neurovascular lesions. We briefly discuss the potential of advanced glycation end products and low-density lipoprotein receptor related protein 1–based therapeutic strategies to control brain Aβ in animal models of AD and ultimately in patients with AD and related familial cerebrovascular β-amyloidoses.
Elastin and Calcium Rather Than Collagen or Lipid Content Are Associated With Echogenicity of Human Carotid Plaques
Authors: Gonçalves Isabel , Lindholm Marie W. , Pedro Luís M. , Dias Nuno , Fernandes e Fernandes José , Fredrikson Gunilla Nordin , Nilsson Jan , Moses Jonatan , Ares Mikko P.S.
Published: October 2004

Background and Purpose—

Echolucent carotid plaques have been associated with increased risk for stroke. Histological studies suggested that echolucent plaques are hemorrhage- and lipid-rich, whereas echogenic plaques are characterized by fibrosis and calcification. This is the first study to relate echogenicity to plaque composition analyzed biochemically.

Methods—

Echogenicity of human carotid plaques was analyzed by standardized high-definition ultrasound and classified into echolucent, with gray-scale median (GSM) <32 and echogenic with GSM ≥32. The biochemical composition of the plaques was assessed by fast-performance liquid chromotography and high-performance thin-layer chromotography.

Results—

As assessed biochemically (milligrams per gram [mg/g]), echolucent plaques contained less hydroxyapatite (43.8 [SD 41.2] mg/g versus 121.6 [SD 106.2] mg/g;
P
=0.018), more total elastin (1.7 [SD 0.4] mg/g versus 1.2 [SD 0.4] mg/g;
P
=0.008), and more intermediate-size elastin forms (1.2 [SD 0.3] mg/g versus 0.8 [SD 0.4] mg/g;
P
=0.018). There was no difference in collagen amount between echogenic and echolucent plaques, neither biochemically (15.3 [SD 3.7] mg/g versus 14.4 [SD 3.4] mg/g) nor histologically (13.4 [SD 4.9] % versus 13.0 [SD 5.6] %). Cholesterol esters, unesterified cholesterol, and triglycerides were increased in plaques associated with symptoms (22.5 [SD 23.3] mg/g versus 13.3 [SD 3.2];
P
=0.04), but no differences were detected between echolucent and echogenic plaques (13.5 [SD 4.0] versus 20.2 [SD 21.5] mg/g). Similar results were obtained by Oil Red O staining (symptomatic 7.6 [SD 4.7] % versus asymptomatic 4.2 [SD 3.6] %;
P
=0.03; echolucent 5.9 [SD 4.1] % versus echogenic 5.0 [SD 4.0] % of area).

Conclusions—

Echogenicity of carotid plaques is mainly determined by their elastin and calcium but not collagen or lipid content. In addition, echolucency is associated to higher elastin content.
MERCI 1
Authors: Pierre Gobin Y. , Starkman Sidney , Duckwiler Gary R. , Grobelny Thomas , Kidwell Chelsea S. , Jahan Reza , Pile-Spellman John , Segal Alan , Vinuela Fernando , Saver Jeffrey L.
Published: October 2004

Background and Purpose—

To report the result of the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) 1 study, a phase 1 trial to evaluate the safety and efficacy of mechanical embolectomy in the cerebral vasculature.

Methods—

MERCI 1 enrolled 30 patients in 7 US centers. Main inclusion criteria were: National Institutes of Health Stroke Scale score (NIHSS) ≥10; treatment performed within 8 hours from symptoms onset and contra-indication to intravenous thrombolysis; no large hypodensity on computed tomography; and occlusion of a major cerebral artery on the angiogram. Safety was defined by the absence of vascular injury or symptomatic intracranial hemorrhage. Efficacy was assessed by recanalization rate and clinical outcome at 1 month. Significant recovery was defined as 30-day modified Rankin of 0 to 2 in patients with baseline NIHSS 10 to 20 and 30-day modified Rankin of 0 to 3 in patients with baseline NIHSS >20. The procedures were performed with the Merci Retrieval System, a system specially designed for intracranial embolectomy.

Results—

Twenty-eight patients were treated. Median NIHSS was 22. Median time from onset to completion of treatment was 6 hours and 15 minutes. Successful recanalization with mechanical embolectomy only was achieved in 12 (43%) patients, and with additional intra-arterial tissue plasminogen activator in 18 (64%) patients. There was one procedure related technical complication, with no clinical consequence. Twelve asymptomatic and no symptomatic intracranial hemorrhages occurred. At 1 month, 9 of 8 revascularized patients and 0 of 10 nonrevascularized patients had achieved significant recovery.

Conclusion—

This phase 1 study shows that cerebral embolectomy with the Merci Retriever was safe and that successful recanalization could benefit a significant number of patients, even when performed in an extended 8-hour time window.
Clitic Positions and Restructuring in Italian
Authors: Cardinaletti Anna , Shlonsky Ur
Published: October 2004

Verbs can be introduced (merged) in either a lexical VP or a functional head, the latter position giving rise to restructuring contexts. We argue that there are two clitic positions in Italian “restructured” clauses: one associated with the (restructured) lexical verb and the other a clausal clitic position located in the functional domain. While restructuring can be recursive, clitics appear either on the restructured infinitive (no clitic climbing) or in the functional domain of the highest verb (full clitic climbing). There is no clitic climbing to an intermediate restructuring verb. We argue that only the lowest restructured verb makes a position for clitics available and that this position is the same as that of infinitive-final [e]. Finally, we show that the functional ∼ lexical dichotomy is too sharp and that a variety of verb classes must be admitted, whose properties correlate with the point in the structure in which they are merged.
Derivation in Optimality Theory: A Reply to Burzio
Authors: Rubach Jerzy
Published: October 2004

This article argues against Burzio's (2001) reanalysis of Rubach's (2000b) glide and glottal stop insertion in the Slavic languages. It is shown that the reanalysis cannot account for the range of attested facts and that it leads to unwarranted extensions of Optimality Theory by relying on unrestricted targeted constraints. The conclusion is that Optimality Theory must admit derivational levels.
De Gaulle, Moravcsik, and The Choice for Europe: Soft Sources, Weak Evidence
Authors: Lieshout Robert H. , Segers Mathieu L. L. , Vleuten Anna M. van der
Published: October 2004

In The Choice for Europe Andrew Moravcsik develops a “commercial” interpretation of Charles de Gaulle's European policies. Moravcsik claims that his revisionist analysis succeeds because he, as opposed to almost all other students of European Community policymaking, has relied not on “soft” sources but on hard primary sources. An investigation of his claim shows that it cannot be substantiated. Both the quality of his sources and his handling of them are poor. His commercial interpretation of de Gaulle's policy is based on a serious misreading of the two sources on which his argument depends. Finally, his restatement in 2000 of his original argument a restatement intended to overcome the problem that, as his critics pointed out, he failed to produce any direct supporting evidence leads only to further problems.
The Widening Socio-Economic Gap in UK Higher Education
Authors: Galindo-Rueda Fernando , Marcenaro-Gutierrez Oscar , Vignoles Anna
Published: October 2004

This paper provides up-to-date empirical evidence on the socio-economic gap in higher education (HE) participation, for the period spanning the introduction of tuition fees. We assess whether the gap has widened and ask whether the socio-economic gap emerges on entry into university or much earlier in the education system. We do this in two ways. Firstly we consider the likelihood of going to university for school leavers in poor neighbourhoods and analyse changes in this likelihood over time. Secondly, we use more detailed individual level data to model the determinants of HE participation, focusing on changes in the relationship between family background and HE participation over time. We find that the growth in HE participation amongst poorer students has been remarkably high, mainly because it was starting from such a low base. However, the gap between rich and poor, in terms of HE participation, has widened during the 1990s. Children from poor neighbourhoods have become relatively less likely to participate in HE since 1994/5, as compared to children from richer neighbourhoods. This trend started before the introduction of tuition fees. Much of the class difference in HE participation seems to reflect inequalities at earlier stages of the education system.
Weathering of the primary rock-forming minerals: processes, products and rates
Authors: Wilson M. J.
Published: October 2004

This paper describes the ways in which the major rock-forming primary minerals (olivine, pyroxenes, amphiboles, feldspars, micas and chlorites) break down during weathering, the products that develop during this breakdown and the rates at which this breakdown occurs. The perspective chosen to illustrate this vast topic is that of the residual soil weathering profile. Different physical and chemical conditions characterize the various parts of such a profile. Thus, in the slightly weathered rock at the base of the profile, mineral weathering will take place in microfissures and narrow solution channels and the capillary water in such spatially restricted volumes may be expected to be close to equilibrium with the primary mineral. In these circumstances, the weathering product formed may be closely related to the primary mineral both compositionally and structurally. The saprolite higher up in the weathering profile may or may not retain the fabric and structure of the original parent rock, but in either case the close relationship observed between primary mineral and weathering product in the slightly weathered rock may be lost. This part of the profile will usually be affected by freely flowing drainage waters, the composition of which will be far from equilibrium with specific primary minerals. Weathering products which do form are likely to reflect the interaction between bulk water and bulk parent material. In the soil profile, the situation will be further complicated by organic ligands derived from decomposing organic matter or from the direct activities of soil microbes or plant roots. Thus, biological weathering will assume a much greater significance in this part of the profile compared with the mainly inorganic processes dominating in the saprolite and the slightly weathered rock. The general nature of any particular weathering profile will reflect the interactions between climate, topography, parent material, soil biota and time and superimposed upon this complexity, when considering how individual primary minerals break down in detail, will be factors related to the nature of the mineral itself. Particularly important in this respect is the inherent susceptibility of the mineral to weathering, which is related to overall chemical composition and structure, as well as the distribution and density of defects, dislocations and exsolution features, which often control the progress of the weathering reaction.
Composition variation of illite-vermiculitesmectite mixed-layer minerals in a bentonite bed from Charente (France)
Authors: Meunier A. , Lanson B. , Velde B.
Published: October 2004

Mineralogical and chemical variations were studied in the upper half of a 1 m thick discontinuous bentonite bed interlaminated in the Lower Cenomanian sedimentary formations of the northern Aquitaine basin (France). X-ray diffraction patterns obtained from the <2 mm fraction in the Ca and K-saturated states were decomposed and compared to those calculated from decomposition parameters. They revealed the presence of two highly expandable illite-expandable (I-Exp) mixedlayer minerals (MLMs). The relative proportions of the two MLMs evolve steadily with depth leading to the decrease of the cation exchange capacity and of the (Na + Ca) content towards the centre of the bentonite bed. However, the system is essentially isochemical and Mg, Al, Si, K and Fe are roughly constant in the bulk samples. It is thought that the mineralogical zonation results from the initial stages of the smectite formation in an ash layer.

In the Ca-saturated state, the expandable component of these MLMs was for the most part homogeneous with the presence of 2 sheets of ethylene glycol molecules in the interlayer. However, the heterogeneous hydration behaviour of these expandable layers was enhanced by the K-saturation test. From this test, the presence of three layer types with contrasting layer charge was evidenced from their contrasting swelling abilities. The C12-alkylammonium saturation test applied to samples in which the octahedral charge had previously been neutralized (Hofmann-Klemen treatment) showed that the tetrahedral charge is located on specific layers. These layers are responsible for the heterogeneous hydration behaviour. Low-charge smectite layers are mostly octahedrally substituted, whereas for intermediate- and high-charge layers this montmorillonitic charge is complemented by additional tetrahedral substitutions (0.30 and 0.35–0.40 charge per O10(OH)2, respectively).
TEM study of mineral transformations in fired carbonated clays: relevance to brick making
Authors: Bauluz B. , Mayayo M. J. , Yuste A. , Fernandez-Nieto C. , Gonzalez Lopez J. M.
Published: October 2004

This study uses transmission electron microscopy (TEM) and analytical electron microscopy (AEM) supported by X-ray diffraction (XRD) and scanning electron microscopy (SEM) to investigate the mineralogical and textural changes produced in carbonated clays by firing. Sample bars were prepared using raw clays composed of quartz, illite and carbonates with minor amounts of smectite, chlorite, feldspars and Fe oxides. The raw samples were then fired at temperatures of between 800 and 1050°C. The XRD data show that increases in firing temperature result in dehydroxylation of clay minerals, carbonate decomposition and the formation of Ca-bearing silicates (e.g. gehlenite, wollastonite, pyroxenes and anorthite). The sizes of the Ca-silicate crystals make the use of the SEM inappropriate since they lie below the resolution threshold. However, TEM/AEM do provide the required textural and compositional characterization, revealing that there is a broad range of pyroxene compositions, some of which resemble fassaite, and that Ca/Mg ratios increase with temperature. The TEM also shows significant dehydroxylation and vitrification of the clay-rich matrix at T of ~800°C. Observed mineralogical and textural changes probably occurred in a system with a local disequilibrium much like small-scale, high-temperature metamorphic reactions (i.e. pyrometamorphism). The importance of these results is that they enable the selection of more appropriate raw clay composition and firing dynamics (temperature, firing duration and cooling rate) for both the brickmaking industry and brick conservation in the field of cultural heritage.
Modification of kaolinite by controlled hydrothermal deuteration – a DRIFT spectroscopic study
Authors: Ming Hui
Published: October 2004

Kaolinites were modified by controlled hydrothermal deuteration. Both infrared and near infrared vibration spectra of deuterated kaolinite were investigated by Diffuse Reflectance Infrared Fourier Transform spectroscopy. The stretching vibrations (v) of deuteroxyl groups of the kaolinite were observed at 2726, 2709, 2697 and 2667 cm-1, respectively. The overtone bands (2n) of the deuteroxyl groups were visible in NIR regions at 5454, 5419, 5388 and 5342 cm-1, respectively. The lattice vibrations of the kaolinite taking part in deuteration included 937, 915, 792, 751 and 690 cm-1which are assigned to hydroxyl group-related deformation or translation-vibration mode. The hydroxyl band at 3435 cm-1with its deuteroxyl band at 2542 cm-1resulted from unevenly distributed structural defects, either due to the isomorphous substitution of foreign cations or the imperfections of the kaolinite lattice structure.
The platelet glycoprotein Ib–von Willebrand factor interaction activates the collagen receptor α2β1 to bind collagen: activation-dependent conformational change of the α2-I domain
Authors: Cruz Miguel A. , Chen Junmei , Whitelock Jody L. , Morales Liza D. , López José A.
Published: October 2004

Integrin α2β1 (glycoprotein [GP] Ia/IIa) is a major platelet receptor for collagen, containing its collagen-binding site within the α2 I domain. α2β1 changes conformation upon platelet activation, increasing its affinity for collagen. We observed that 2 antibodies known to bind within the α2I domain, 12F1 and 6F1, bound preferentially to adenosine diphosphate (ADP)–activated platelets. Interestingly, when whole blood was perfused over a surface coated with either 12F1 or 6F1, only 6F1 supported the adhesion of unstimulated platelets. To test whether the interaction of GP Ib with von Willebrand factor (VWF) directly activates α2β1, we used 12F1 as a probe of integrin activation. We perfused blood over a surface coated with a mixture of VWF-A1 domain (a GP Ib ligand) and 12F1 or VWF-A1 and mouse immunoglobulin G (IgG). Platelets rolled and did not attach stably on the A1/IgG surface, but they firmly bound and covered the A1/12F1 surface. We corroborated that 12F1 binds an active conformation of the I domain by showing that it binds with higher affinity to a gain-of-function mutant than to either wild-type I domain or a loss-of-function mutant. These results strongly suggest that the interaction of platelet GP Ib with VWF mediates the activation of α2β1, increasing its affinity for collagen.
Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells
Authors: Berger Carole L. , Tigelaar Robert , Cohen Justine , Mariwalla Kavita , Trinh Jennifer , Wang Nianci , Edelson Richard L.
Published: October 2004

Studies in an in vitro model of cutaneous T-cell lymphoma (CTCL) demonstrated that CTCL cell proliferation is stimulated by direct contact with autologous, immature dendritic cells (DCs), suggesting that CD4+ CTCL cell division is driven by antigens presented by DC major histocompatibility complex (MHC) class 2. We now report that the T-cell receptor (TCR) of the CD4+ CTCL cells is triggered after interaction with DCs loaded with apoptotic CTCL cells, as shown by reduced membrane expression of CD3 and the TCR, up-regulation of cytotoxic T lymphocyte antigen-4 (CTLA-4), and calcium mobilization. CTCL cells adopt a T-regulatory (Treg) phenotype expressing CD25/CTLA-4 and FoxP3 and secreting interleukin-10 (IL-10) and transforming growth factor-β (TGF-β). Treg CTCL cells suppress normal T-cell antigen-driven secretion of IL-2 and interferon-γ (IFN-γ). Blocking DC MHC class 2 expression or transport inhibited CTCL cell adoption of a Treg phenotype. Allogeneic CTCL cells or normal CD4 T cells served as sources of apoptotic material for CTCL cell conversion to a Treg phenotype. Conversion of CTCL cells to Treg cells may explain the anergic, immunosuppressive nature of the malignancy. (Blood. 2005;105:1640-1647)
Combining gene expression data from different generations of oligonucleotide arrays
Authors: Hwang Kyu-Baek , Kong Sek Won , Greenberg Steve A , Park Peter J
Published: October 2004

Background

One of the important challenges in microarray analysis is to take full advantage of previously accumulated data, both from one's own laboratory and from public repositories. Through a comparative analysis on a variety of datasets, a more comprehensive view of the underlying mechanism or structure can be obtained. However, as we discover in this work, continual changes in genomic sequence annotations and probe design criteria make it difficult to compare gene expression data even from different generations of the same microarray platform.

Results

We first describe the extent of discordance between the results derived from two generations of Affymetrix oligonucleotide arrays, as revealed in cluster analysis and in identification of differentially expressed genes. We then propose a method for increasing comparability. The dataset we use consists of a set of 14 human muscle biopsy samples from patients with inflammatory myopathies that were hybridized on both HG-U95Av2 and HG-U133A human arrays. We find that the use of the probe set matching table for comparative analysis provided by Affymetrix produces better results than matching by UniGene or LocusLink identifiers but still remains inadequate. Rescaling of expression values for each gene across samples and data filtering by expression values enhance comparability but only for few specific analyses. As a generic method for improving comparability, we select a subset of probes with overlapping sequence segments in the two array types and recalculate expression values based only on the selected probes. We show that this filtering of probes significantly improves the comparability while retaining a sufficient number of probe sets for further analysis.

Conclusions

Compatibility between high-density oligonucleotide arrays is significantly affected by probe-level sequence information. With a careful filtering of the probes based on their sequence overlaps, data from different generations of microarrays can be combined more effectively.
Reuse of imputed data in microarray analysis increases imputation efficiency
Authors: Kim Ki-Yeol , Kim Byoung-Jin , Yi Gwan-Su
Published: October 2004

Background

The imputation of missing values is necessary for the efficient use of DNA microarray data, because many clustering algorithms and some statistical analysis require a complete data set. A few imputation methods for DNA microarray data have been introduced, but the efficiency of the methods was low and the validity of imputed values in these methods had not been fully checked.

Results

We developed a new cluster-based imputation method called sequential K-nearest neighbor (SKNN) method. This imputes the missing values sequentially from the gene having least missing values, and uses the imputed values for the later imputation. Although it uses the imputed values, the efficiency of this new method is greatly improved in its accuracy and computational complexity over the conventional KNN-based method and other methods based on maximum likelihood estimation. The performance of SKNN was in particular higher than other imputation methods for the data with high missing rates and large number of experiments.

Application of Expectation Maximization (EM) to the SKNN method improved the accuracy, but increased computational time proportional to the number of iterations. The Multiple Imputation (MI) method, which is well known but not applied previously to microarray data, showed a similarly high accuracy as the SKNN method, with slightly higher dependency on the types of data sets.

Conclusions

Sequential reuse of imputed data in KNN-based imputation greatly increases the efficiency of imputation. The SKNN method should be practically useful to save the data of some microarray experiments which have high amounts of missing entries. The SKNN method generates reliable imputed values which can be used for further cluster-based analysis of microarray data.
Implications for domain fusion protein-protein interactions based on structural information
Authors: Chia Jer-Ming , Kolatkar Prasanna R
Published: October 2004

Background

Several in silico methods exist that were developed to predict protein interactions from the copious amount of genomic and proteomic data. One of these methods is Domain Fusion, which has proven to be effective in predicting functional links between proteins.

Results

Analyzing the structures of multi-domain single-chain peptides, we found that domain pairs located less than 30 residues apart on a chain are almost certain to share a physical interface. The majority of these interactions are also conserved across separate chains. We make use of this observation to improve domain fusion based protein interaction predictions, and demonstrate this by implementing it on a set of Saccharomyces cerevisiae proteins.

Conclusion

We show that existing structural data supports the domain fusion hypothesis. Empirical information from structural data also enables us to refine and assess domain fusion based protein interaction predictions. These interactions can then be integrated with downstream biochemical and genetic assays to generate more reliable protein interaction data sets.
Real-time PCR quantitation of glucocorticoid receptor alpha isoform
Authors: Melo Murilo R , Faria Cláudia DC , Melo Keli C , Rebouças Nancy A , Longui Carlos A
Published: October 2004

Background

The expression of glucocorticoid-receptor (GR) seems to be a key mechanism in the regulation of glucocorticoid (GC) sensitivity and is potentially involved in cases of GC resistance or hypersensitivity. The aim of this study is to describe a method for quantitation of GR alpha isoform (GRα) expression using real-time PCR (qrt-PCR) with analytical capabilities to monitor patients, offering standard-curve reproducibility as well as intra- and inter-assay precision.

Results

Standard-curves were constructed by employing standardized Jurkat cell culture procedures, both for GRα and BCR (breakpoint cluster region), as a normalizing gene. We evaluated standard-curves using five different sets of cell culture passages, RNA extraction, reverse transcription, and qrt-PCR quantification. Intra-assay precision was evaluated using 12 replicates of each gene, for 2 patients, in a single experiment. Inter-assay precision was evaluated on 8 experiments, using duplicate tests of each gene for two patients. Standard-curves were reproducible, with CV (coefficient of variation) of less than 11%, and Pearson correlation coefficients above 0,990 for most comparisons. Intra-assay and inter-assay were 2% and 7%, respectively.

Conclusion

This is the first method for quantitation of GRα expression with technical characteristics that permit patient monitoring, in a fast, simple and robust way.
Development of the time course for processing conflict: an event-related potentials study with 4 year olds and adults
Authors: Rueda M Rosario , Posner Michael I , Rothbart Mary K , Davis-Stober Clintin P
Published: October 2004

Background

Tasks involving conflict are widely used to study executive attention. In the flanker task, a target stimulus is surrounded by distracting information that can be congruent or incongruent with the correct response. Developmental differences in the time course of brain activations involved in conflict processing were examined for 22 four year old children and 18 adults. Subjects performed a child-friendly flanker task while their brain activity was registered using a high-density electroencephalography system.

Results

General differences were found in the amplitude and time course of event-related potentials (ERPs) between children and adults that are consistent with their differences in reaction time. In addition, the congruency of flankers affected both the amplitude and latency of some of the ERP components. These effects were delayed and sustained for longer periods of time in the children compared to the adults.

Conclusions

These differences constitute neural correlates of children's greater difficulty in monitoring and resolving conflict in this and similar tasks.
Tracheal adenoid cystic carcinoma masquerading asthma: A case report
Authors: Kokturk Nurdan , Demircan Sedat , Kurul Cuneyt , Turktas Haluk
Published: October 2004

Background

Tracheal tumors are often misdiagnosed as asthma and are treated with inhaled steroids and bronchodilators without resolution.

Case Presentation

Here, a patient with tracheal adenoid cystic carcinoma who had been previously diagnosed with difficult asthma was reported. The possibility of the presence of localized airway obstruction was raised when the flow-volume curve suggesting fixed airway obstruction, was obtained.

Conclusion

The presenting case report emphasizes the fact that not all wheezes are asthma. It is critical to bear in mind that if a patient does not respond to appropriate anti-asthma therapy, localized obstructions should be ruled out before establishing the diagnosis of asthma.
Effects of lornoxicam on the physiology of severe sepsis
Authors: Memiş Dilek , Karamanlıoğlu Beyhan , Turan Alparslan , Koyuncu Onur , Pamukçu Zafer
Published: October 2004

Introduction

The purpose of the present study was to evaluate the effects of intravenous lornoxicam on haemodynamic and biochemical parameters, serum cytokine levels and patient outcomes in severe sepsis.

Methods

A total of 40 patients with severe sepsis were included, and were randomly assigned (20 per group) to receive either lornoxicam (8 mg administered intravenously every 12 hours for six doses) or placebo. For both groups the following were recorded: haemodynamic parameters (heart rate, mean arterial pressure), nasopharyngeal body temperature, arterial blood gas changes (pH, partial oxygen tension, partial carbon dioxide tension), plasma cytokine levels (IL-1β, IL-2 receptor, IL-6, IL-8, tumour necrosis factor-α), biochemical parameters (lactate, leucocytes, trombocytes, creatinine, total bilirubin, serum glutamate oxalate transaminase), length of stay in the intensive care unit, duration of mechanical ventilation and mortality. All measurements were obtained at baseline (before the start of the study) and at 24, 48 and 72 hours from the start of lornoxicam/placebo administration.

Results

No significant differences were found between the intravenous lornoxicam and placebo groups in major cytokines, duration of ventilation and length of intensive care unit stay, and inspired fractional oxygen/arterial oxygen tension ratio (P > 0.05).

Conclusion

In these patients with severe sepsis, we found intravenous lornoxicam to exert no effect on haemodynamic and biochemical parameters, cytokine levels, or patient outcomes. Because of the small number of patients included in the study and the short period of observation, these findings require confirmation by larger clinical trials of intravenous lornoxicam, administered in a dose titrated manner.
Spatial patterns of transcriptional activity in the chromosome of Escherichia coli
Authors: Jeong Kyeong Soo , Ahn Jaeyong , Khodursky Arkady B
Published: October 2004

Background

Although genes on the chromosome are organized in a fixed order, the spatial correlations in transcription have not been systematically evaluated. We used a combination of genomic and signal processing techniques to investigate the properties of transcription in the genome of Escherichia coli K12 as a function of the position of genes on the chromosome.

Results

Spectral analysis of transcriptional series revealed the existence of statistically significant patterns in the spatial series of transcriptional activity. These patterns could be classified into three categories: short-range, of up to 16 kilobases (kb); medium-range, over 100-125 kb; and long-range, over 600-800 kb. We show that the significant similarities in gene activities extend beyond the length of an operon and that local patterns of coexpression are dependent on DNA supercoiling. Unlike short-range patterns, the formation of medium and long-range transcriptional patterns does not strictly depend on the level of DNA supercoiling. The long-range patterns appear to correlate with the patterns of distribution of DNA gyrase on the bacterial chromosome.

Conclusions

Localization of structural components in the transcriptional signal revealed an asymmetry in the distribution of transcriptional patterns along the bacterial chromosome. The demonstration that spatial patterns of transcription could be modulated pharmacologically and genetically, along with the identification of molecular correlates of transcriptional patterns, offer for the first time strong evidence of physiologically determined higher-order organization of transcription in the bacterial chromosome.
Assembly and characterization of heterochromatin and euchromatin on human artificial chromosomes
Authors: Grimes Brenda R , Babcock Jennifer , Rudd M Katharine , Chadwick Brian , Willard Huntington F
Published: October 2004

Background

Human centromere regions are characterized by the presence of alpha-satellite DNA, replication late in S phase and a heterochromatic appearance. Recent models propose that the centromere is organized into conserved chromatin domains in which chromatin containing CenH3 (centromere-specific H3 variant) at the functional centromere (kinetochore) forms within regions of heterochromatin. To address these models, we assayed formation of heterochromatin and euchromatin on de novo human artificial chromosomes containing alpha-satellite DNA. We also examined the relationship between chromatin composition and replication timing of artificial chromosomes.

Results

Heterochromatin factors (histone H3 lysine 9 methylation and HP1α) were enriched on artificial chromosomes estimated to be larger than 3 Mb in size but depleted on those smaller than 3 Mb. All artificial chromosomes assembled markers of euchromatin (histone H3 lysine 4 methylation), which may partly reflect marker-gene expression. Replication timing studies revealed that the replication timing of artificial chromosomes was heterogeneous. Heterochromatin-depleted artificial chromosomes replicated in early S phase whereas heterochromatin-enriched artificial chromosomes replicated in mid to late S phase.

Conclusions

Centromere regions on human artificial chromosomes and host chromosomes have similar amounts of CenH3 but exhibit highly varying degrees of heterochromatin, suggesting that only a small amount of heterochromatin may be required for centromere function. The formation of euchromatin on all artificial chromosomes demonstrates that they can provide a chromosome context suitable for gene expression. The earlier replication of the heterochromatin-depleted artificial chromosomes suggests that replication late in S phase is not a requirement for centromere function.
Solving Ethically Difficult Care Situations in Nursing Homes
Authors: Slettebø Åshild , Bunch Eli Haugen
Published: October 2004

Patients in nursing homes sometimes give accounts of episodes in which they feel their autonomy and/or self-respect are violated as a result of the care they receive from nursing staff. In these ethically difficult care situations nurses use strategies such as negotiation, explanation and, in some cases, restraint. This study investigates how nurses apply these strategies to resolve ethical dilemmas in such a way that patients experience respect rather than violation. Critical issues that will be discussed include the definition of ethically difficult care situations in nursing homes and the identification of strategies for resolving such situations. Examples of the use of three strategies are presented. The use of negotiation, restraint and explanation are discussed in order to ensure respect for patients’ autonomy and thus to optimize health care outcomes.
Nursing Care of Elderly People at Home and Ethical Implications: an experience from Istanbul
Authors: Doğan Hanzade , Değer Mebrure
Published: October 2004

Elderly people are a particularly vulnerable group in society and have special health problems. The world population of older people is increasing. People who are 65 years or older constitute 6% of the Turkish population, 90% of whom have chronic health problems. In Turkey, there is a high possibility that elderly people’s requirements are not met by today’s health care system in the way they would wish. They prefer not to be hospitalized when they have health problems. From a wider perspective, various countries are still seeking how to provide the best care for elderly people. Our goal was to characterize home-based care for elderly people using an ethical approach as an area of interest for nurses and other health care professionals now and in the future, both for Turkey specifically and from a global perspective. We studied four case histories and then prepared a composite scenario and a short questionnaire for elderly people living in a specific district of Istanbul to evaluate their expectations from the health care system. We compared our findings with situations in other countries and have proposed some practical solutions. The results showed that these older people preferred to receive nursing care at home instead of in hospital in Turkey, and also in many other countries. In this article we discuss our findings, comparing them with those in the literature, and suggest that there should be nursing care at home with insurance coverage while using a proper ethical approach.
Dignity and Respect for Dignity - Two Key Health Professional Values: implications for nursing Practice
Authors: Gallagher Ann
Published: October 2004

It is argued that dignity can be considered both subjectively, taking into account individual differences and idiosyncrasies, and objectively, as the foundation of human rights. Dignity can and should also be explored as both an other-regarding and a self-regarding value: respect for the dignity of others and respect for one’s own personal and professional dignity. These two values appear to be inextricably linked. Aristotle’s doctrine of the mean enables nurses to reflect on the appropriate degree of respect for the dignity of others and of respect for themselves. To develop an understanding of the rationale for and the significance and implications of dignity in health care practice, a view of human nature is proposed that implies vulnerability and fallibility, and that urges that an ethic of aspiration is embraced. Anonymized vignettes are included to illustrate points about the everyday nature of dignity.
Why Cancer Patients Enter Randomized Clinical Trials: Exploring the Factors That Influence Their Decision
Authors: Wright James R. , Whelan Timothy J. , Schiff Susan , Dubois Sacha , Crooks Dauna , Haines Patricia T. , DeRosa Diane , Roberts Robin S. , Gafni Amiram , Pritchard Kathleen , Levine Mark N.
Published: October 2004

Purpose

Few interventions have been designed and tested to improve recruitment to clinical trials in oncology. The multiple factors influencing patients' decisions have made the prioritization of specific interventions challenging. The present study was undertaken to identify the independent predictors of a cancer patient's decision to enter a randomized clinical trial.

Methods

A list of factors from the medical literature was augmented with a series of focus groups involving cancer patients, physicians, and clinical research associates (CRAs). A series of questionnaires was developed with items based on these factors and were administered concurrently to 189 cancer patients, their physicians, and CRAs following the patient's decision regarding trial entry. Forward logistic regression modeling was performed using the items significantly correlated (by univariate analysis) with the decision to enter a clinical trial.

Results

A number of items were significantly correlated with the patient's decision. In the multivariate logistic regression model, the patient's perception of personal benefit was the most important, with an odds ratio (OR) of 3.08 (P < .05). CRA-related items involving supportive aspects of the decision-making process were also important. These included whether the CRA helped with the decision (OR = 1.71; P < .05), and whether the decision was hard for the patient to make (OR = 0.52; P < .05).

Conclusion

Strategies that better address the potential benefits of trial entry may result in improved accrual. Interventions or aids that focus on the supportive aspects of the decision-making process while respecting the need for information and patient autonomy may also lead to meaningful improvements in accrual.
Early Deaths and Treatment-Related Mortality in Children Undergoing Therapy for Acute Myeloid Leukemia: Analysis of the Multicenter Clinical Trials AML-BFM 93 and AML-BFM 98
Authors: Creutzig Ursula , Zimmermann Martin , Reinhardt Dirk , Dworzak Michael , Stary Jan , Lehrnbecher Thomas
Published: October 2004

Purpose

The rates of early death (ED) and treatment-related mortality (TRM) are unacceptably high in children undergoing intensive chemotherapy for acute myeloid leukemia (AML). Better strategies of supportive care might help to improve overall survival in these children.

Patients and Methods

In a retrospective study, we analyzed incidence, clinical features, and risk factors for lethal complications of 901 children enrolled onto the multicenter trials Acute Myeloid Leukemia-Berlin-Frankfurt-Muenster (AML-BFM) 93 and AML-BFM 98.

Results

One hundred four patients (11.5%) enrolled onto the clinical trials AML-BFM 93 and AML-BFM 98 died shortly after diagnosis or as a result of treatment-related complications. Thirty-two patients (3.5%) died before (six patients) or during (26 patients) the first 14 days of treatment, mainly as a result of bleeding or leukostasis. Low performance status, hyperleukocytosis, and French-American-British type M5 were the main risk factors for a lethal event before day 15. After day 15, the predominant causes of death were complications caused by infections, particularly bacterial and fungal infections. The incidence of lethal infections was highest during induction therapy and decreased thereafter. When comparing both clinical trials, significantly fewer patients died within the first 6 weeks in AML-BFM 98 than in AML-BFM 93 (14 [3.5%] of 430 patients v 35 [7.4%] of 471 patients; P = .01).

Conclusion

To reduce the high incidence of ED and TRM in children with AML, early diagnosis and adequate treatment of complications are needed. Children with AML should be treated in specialized pediatric cancer centers only. Prophylactic and therapeutic regimens for better treatment management of bleeding disorders and infectious complications have to be assessed in future trials to ultimately improve overall survival in children with AML.