bluuebunny/crossref_metadata_2025 huggingface dataset:
Sodium Along With Low-Threshold Potassium Currents Enhance Coincidence Detection of Subthreshold Noisy Signals in MSO Neurons
Authors: Svirskis Gytis , Kotak Vibhakar , Sanes Dan H. , Rinzel John
Published: May 2004

Voltage-dependent membrane conductances support specific neurophysiological properties. To investigate the mechanisms of coincidence detection, we activated gerbil medial superior olivary (MSO) neurons with dynamic current-clamp stimuli in vitro. Spike-triggered reverse-correlation analysis for injected current was used to evaluate the integration of subthreshold noisy signals. Consistent with previous reports, the partial blockade of low-threshold potassium channels ( IKLT) reduced coincidence detection by slowing the rise of current needed on average to evoke a spike. However, two factors point toward the involvement of a second mechanism. First, the reverse correlation currents revealed that spike generation was associated with a preceding hyperpolarization. Second, rebound action potentials are 45% larger compared to depolarization-evoked spikes in the presence of an IKLT antagonist. These observations suggest that the sodium current ( INa) was substantially inactivated at rest. To test this idea, INa was enhanced by increasing extracellular sodium concentration. This manipulation reduced coincidence detection, as reflected by slower spike-triggering current, and diminished the hyperpolarization phase in the reverse-correlation currents. As expected, a small outward bias current decreased the pre-spike hyperpolarization phase, and TTX blockade of INa nearly eliminated the hyperpolarization phase in the reverse correlation current. A computer model including Hodgkin-Huxley type conductances for spike generation and for IKLT showed reduction in coincidence detection when IKLT was reduced or when INa was increased. We hypothesize that desirable synaptic signals first remove some inactivation of INa and reduce activation of IKLT to create a brief temporal window for coincidence detection of subthreshold noisy signals.
Effects of Search Efficiency on Surround Suppression During Visual Selection in Frontal Eye Field
Authors: Schall Jeffrey D. , Sato Takashi R. , Thompson Kirk G. , Vaughn Amanda A. , Juan Chi-Hung
Published: May 2004

Previous research has shown that visually responsive neurons in the frontal eye field of macaque monkeys select the target for a saccade during efficient, pop-out visual search through suppression of the representation of the nontarget distractors. For a fraction of these neurons, the magnitude of this distractor suppression varied with the proximity of the target to the receptive field, exhibiting more suppression of the distractor representation when the target was nearby than when the target was distant. The purpose of this study was to determine whether the variation of distractor suppression related to target proximity varied with target-distractor feature similarity. The effect of target proximity on distractor suppression did not vary with target-distractor similarity and therefore may be an endogenous property of the selection process.
Impact of Heterogeneous Perisomatic IPSC Populations on Pyramidal Cell Firing Rates
Authors: Aradi Ildiko , Santhakumar Vijayalakshmi , Soltesz Ivan
Published: May 2004

Previous computational modeling studies suggested a set of rules underlying the modulation of principal cell firing rates by heterogeneity in the synaptic parameters (peak amplitude and decay kinetics) of populations of GABAergic inputs. Here we performed dynamic clamp experiments in CA1 hippocampal pyramidal cells to test these ideas in biological neurons. In agreement with the simulation studies, the effects of increasing the event-to-event variance in a population of perisomatically injected inhibitory postsynaptic current (IPSC) peak conductances caused either an increase, decrease, or no change in the firing rates of CA1 pyramidal cells depending on the mean around which the scatter was introduced, the degree of the scatter, the depolarization that the pyramidal cell received, and the IPSC reversal potential. In contrast to CA1 pyramidal cells, both model and biological CA3 pyramidal cells responded with bursts of action potentials to sudden, step-wise alterations in input heterogeneity. In addition, injections of 40-Hz IPSC conductances together with θ-modulated depolarizing current inputs to CA1 pyramidal cells demonstrated that the principles underlying the modulation of pyramidal cell excitability by heterogeneous IPSC populations also apply during membrane potential oscillations. Taken together, these experimental results and the computational modeling data show the existence of simple rules governing the interactions of heterogeneous interneuronal inputs and principal cells.
Level of Arousal During the Small Irregular Activity State in the Rat Hippocampal EEG
Authors: Jarosiewicz Beata , Skaggs William E.
Published: May 2004

The sleeping rat cycles between two well-characterized hippocampal physiological states, large irregular activity (LIA) during slow-wave sleep (SWS) and theta activity during rapid-eye-movement sleep (REM). A third, less well-characterized electroencephalographic (EEG) state, termed “small irregular activity” (SIA), has been reported to occur when an animal is startled out of sleep without moving and during active waking when it abruptly freezes. We recently found that the hippocampal population activity of a spontaneous sleep state whose EEG resembles SIA reflects the rat's current location in space, suggesting that it is also a state of heightened arousal. To test whether this spontaneous SIA state corresponds to the SIA state reported in the literature and to compare the level of arousal during SIA to the other well-characterized physiological states, we recorded unit activity from ensembles of hippocampal CA1 pyramidal cells, EEG from the hippocampus and the neocortex, and electromyography (EMG) from the dorsal neck musculature in rats presented with auditory stimuli while foraging for randomly scattered food pellets and while sleeping. Auditory stimuli presented during sleep reliably induced SIA episodes very similar to spontaneous SIA in hippocampal and neocortical EEG amplitudes and power spectra, EMG amplitude, and CA1 population activity. Both spontaneous and elicited SIA exhibited neocortical desynchronization, and both had EMG amplitude comparable to that of waking LIA. We conclude based on this and other evidence that spontaneous SIA and elicited SIA correspond to a single state and that the level of arousal in SIA is higher than in the well-characterized sleep states but lower than the active theta state.
Principal and Independent Components of Macaque Vocalizations: Constructing Stimuli to Probe High-Level Sensory Processing
Authors: Averbeck Bruno B. , Romanski Lizabeth M.
Published: May 2004

Neurons in high-level sensory cortical areas respond to complex features in sensory stimuli. Feature elimination is a useful technique for studying these responses. In this approach, a complex stimulus, which evokes a neuronal response, is simplified, and if the cell responds to the reduced stimulus, it is considered selective for the remaining features. We have developed a feature-elimination technique that uses either the principal or the independent components of a stimulus to define a subset of features, to which a neuron might be sensitive. The original stimulus can be filtered using these components, resulting in a stimulus that retains only a fraction of the features present in the original. We demonstrate the use of this technique on macaque vocalizations, an important class of stimuli being used to study auditory function in awake, behaving primate experiments. We show that principal-component analysis extracts features that are closely related to the dominant Fourier components of the stimuli, often called formants in the study of speech perception. Conversely, independent-component analysis extracts features that preserve the relative phase across a set of harmonically related frequencies. We have used several statistical techniques to explore the original and filtered stimuli, as well as the components extracted by each technique. This novel approach provides a powerful method for determining the essential features within complex stimuli that activate higher-order sensory neurons.
Neural system-enriched gene expression: relationship to biological pathways and neurological diseases
Authors: Zhang Jianhua , Moseley Amy , Jegga Anil G. , Gupta Ashima , Witte David P. , Sartor Maureen , Medvedovic Mario , Williams Sarah S. , Ley-Ebert Cathy , Coolen Lique M. , Egnaczyk Gregory , Genter Mary Beth , Lehman Michael , Lingrel Jerry , Maggio John , Parysek Linda , Walsh Ryan , Xu Ming , Aronow Bruce J.
Published: May 2004

To understand the commitment of the genome to nervous system differentiation and function, we sought to compare nervous system gene expression to that of a wide variety of other tissues by gene expression database construction and mining. Gene expression profiles of 10 different adult nervous tissues were compared with that of 72 other tissues. Using ANOVA, we identified 1,361 genes whose expression was higher in the nervous system than other organs and, separately, 600 genes whose expression was at least threefold higher in one or more regions of the nervous system compared with their median expression across all organs. Of the 600 genes, 381 overlapped with the 1,361-gene list. Limited in situ gene expression analysis confirmed that identified genes did represent nervous system-enriched gene expression, and we therefore sought to evaluate the validity and significance of these top-ranked nervous system genes using known gene literature and gene ontology categorization criteria. Diverse functional categories were present in the 381 genes, including genes involved in intracellular signaling, cytoskeleton structure and function, enzymes, RNA metabolism and transcription, membrane proteins, as well as cell differentiation, death, proliferation, and division. We searched existing public sites and identified 110 known genes related to mental retardation, neurological disease, and neurodegeneration. Twenty-one of the 381 genes were within the 110-gene list, compared with a random expectation of 5. This suggests that the 381 genes provide a candidate set for further analyses in neurological and psychiatric disease studies and that as a field, we are as yet, far from a large-scale understanding of the genes that are critical for nervous system structure and function. Together, our data indicate the power of profiling an individual biologic system in a multisystem context to gain insight into the genomic basis of its structure and function.
Our Experience with Nifedipine and Prednisolone as Expulsive Therapy for Ureteral Stones
Authors: Saita A. , Bonaccorsi A. , Marchese F. , Condorelli S.V. , Motta M.
Published: May 2004

Objectives: We evaluated the effect of nifedipine associated with prednisolone in ureteral stone passage. Material and Methods: In our department we enrolled 50 patients with radiopaque ureteral stones. Stone size was 15 mm or less. The patients were divided into two groups: group I included 25 patients who received 30 mg oral treatment of slow – release nifedipine (for a maximum of 20 days) and 25 mg of prednisolone (for a maximum of 10 days) daily. Group II was made up of 25 patients who received 25 mg of prednisolone daily. On request, both groups could use non-steroidal anti-inflammatory drugs. Results: The mean expulsion time was 6 days in group I and 10 days in group II. The average stone size was 12 mm in group I and 12.8 mm in group II. Six patients suspended therapy in group I (5 erythema, 1 stomachache), and seven in group II (3 because of intolerable pain, 4 stomachache). The expulsion success rates were 68% in group I and 81% in group II. Conclusions: For ureteral stones that do not cause an emergency situation, such as obstructive uropathy, infection or intolerable pain, we suggest expulsive medical treatment with nifedipine and prednisolone, if there are no contraindications to drug use.
Mer Receptor Tyrosine Kinase Signaling Participates in Platelet Function
Authors: Chen Cailin , Li Quan , Darrow Andrew L. , Wang Yuanping , Derian Claudia K. , Yang Jing , de Garavilla Lawrence , Andrade-Gordon Patricia , Damiano Bruce P.
Published: May 2004

Objective—

Recently, mice made deficient in growth arrest–specific gene 6 product (Gas6) or in which Gas6 gene expression was inhibited were shown to have platelet dysfunction and to be less susceptible to thrombosis. The aim of this study was to define and characterize the relevant Gas6 receptor or receptors involved in platelet function.

Methods and Results—

Using RT-PCR and Western blot analysis we found that mer was the predominantly expressed subtype in mouse and human platelets, whereas axl and rse were not detected. We generated mer-deficient mice by targeted disruption of the mer receptor gene. Platelets derived from mer-deficient mice had decreased platelet aggregation in responses to low concentrations of collagen, U46619, and PAR4 thrombin receptor agonist peptide in vitro. However, the response to ADP was not different from wild-type platelets. Knockout of the mer gene protected mice from collagen/epinephrine–induced pulmonary thromoembolism and inhibited ferric chloride–induced thrombosis in vivo. Tail bleeding times, coagulation parameters, and peripheral blood cell counts in mer-deficient mice were similar to wild-type mice.

Conclusions—

Our data provide the first evidence that mer, presumably through activation by its ligand Gas6, participates in regulation of platelet function in vitro and platelet-dependent thrombosis in vivo.
CCL11 (Eotaxin) Induces CCR3-Dependent Smooth Muscle Cell Migration
Authors: Kodali Ravindra B. , Kim William J.H. , Galaria Irfan I. , Miller Christine , Schecter Alison D. , Lira Sergio A. , Taubman Mark B.
Published: May 2004

Objective—

CCL11 (Eotaxin) is a potent eosinophil chemoattractant that is abundant in atheromatous plaques. The major receptor for CCL11 is CCR3, which is found on leukocytes and on some nonleukocytic cells. We sought to determine whether vascular smooth muscle cells (SMCs) possessed functional CCR3.

Methods and Results—

CCR3 mRNA (by RT-PCR) and protein (by Western blot analysis and flow cytometry) were present in mouse aortic SMCs. CCL11 induced concentration-dependent SMC chemotaxis in a modified Boyden chamber, with maximum effect seen at 100 ng/mL. SMC migration was markedly inhibited by antibody to CCR3, but not to CCR2. CCL11 also induced CCR3-dependent SMC migration in a scrape-wound assay. CCL11 had no effect on SMC proliferation. CCR3 and CCL11 staining were minimal in the normal arterial wall, but were abundant in medial SMC and intimal SMC 5 days and 28 days after mouse femoral arterial injury, respectively, times at which SMCs possess a more migratory phenotype.

Conclusion—

These data demonstrate that SMCs possess CCR3 under conditions associated with migration and that CCL11 is a potent chemotactic factor for SMCs. Because CCL11 is expressed abundantly in SMC-rich areas of the atherosclerotic plaque and in injured arteries, it may play an important role in regulating SMC migration.
Chronic Hyperglycemia Attenuates Coronary Collateral Development and Impairs Proliferative Properties of Myocardial Interstitial Fluid by Production of Angiostatin
Authors: Weihrauch Dorothee , Lohr Nicole L. , Mraovic Boris , Ludwig Lynda M. , Chilian William M. , Pagel Paul S. , Warltier David C. , Kersten Judy R.
Published: May 2004

Background—

Development of coronary collateral vessels is impaired in patients with diabetes mellitus. We tested the hypothesis that hyperglycemia alone attenuates collateral development and abolishes proliferative properties of myocardial interstitial fluid (MIF) by enhancing expression of matrix metalloproteinases (MMP) and angiostatin.

Methods and Results—

Chronically instrumented dogs were randomly assigned to receive an infusion of normal saline (control; n=9) or 70% dextrose in water to increase blood glucose to 350 to 400 mg/dL for 8 h/d (hyperglycemia; n=7) in the presence or absence (sham; n=9) of brief (2 minutes), repetitive coronary artery occlusions (1/h; 8/d for 21 days). Collateral perfusion increased to 41±11% and 49±6% of normal zone flow in control dogs on days 14 and 21 (
P
<0.05) but remained unchanged over 21 days in hyperglycemic and sham dogs (12±3% and 13±3%, respectively). A progressive reduction of the postocclusive peak reactive hyperemic response was also observed in control dogs (16±1 to 10±1 Hz · 10
2
on days 1 and 21, respectively) but not in hyperglycemic (17±2 to 20±2) or sham (17±2 to 16±1) dogs. Endothelial cell tube formation was produced by MIF obtained from control dogs but not hyperglycemic or sham dogs. Coincubation of MIF from hyperglycemic dogs with an angiostatin antibody restored endothelial cell tube formation. MMP-9 activity and expression of angiostatin were increased in dogs receiving exogenous glucose compared with controls

Conclusions—

Chronic hyperglycemia abolishes development of coronary collateral vessels by increasing MMP-9 activity and angiostatin expression in dogs.
C-Reactive Protein Promotes Monocyte Chemoattractant Protein-1—Mediated Chemotaxis Through Upregulating CC Chemokine Receptor 2 Expression in Human Monocytes
Authors: Han Ki Hoon , Hong Kyung-Hee , Park Jae-Hyeong , Ko Jesang , Kang Duk-Hyun , Choi Kee-Joon , Hong Myeong-Ki , Park Seong-Wook , Park Seung-Jung
Published: May 2004

Background—

Inflammation plays a crucial role in atherosclerosis. An elevated serum C-reactive protein (CRP) level is a strong marker for future atherosclerotic cardiovascular diseases. In addition, recent data suggest that CRP may directly promote atherogenesis. In this study, we investigated whether CRP can directly activate human circulating monocytes.

Methods and Results—

Incubation of THP-1 monocytes with CRP (10 μg/mL) increased CC chemokine receptor 2 (CCR2) expression at both the protein and transcript levels, which in turn enhanced chemotaxis mediated by monocyte chemoattractant protein-1 (MCP-1) up to 2-fold. The CRP-induced upregulation of CCR2 expression involved binding of CRP to the FcγR, most notably FcγRI, and phospholipase D1 activation. Serum high-sensitivity CRP levels in 52 normocholesterolemic human subjects were positively correlated with CCR2 surface expression on circulating monocytes (
r
=0.62,
P
<0.001) and MCP-1–mediated monocyte chemotaxis (
r
=0.53,
P
<0.001).

Conclusions—

Elevated blood CRP levels may promote accumulation of monocytes in the atherogenic arterial wall by increasing chemotactic activities of monocytes in response to MCP-1.
At the Crossroads of Evolutionary Computation and Music: Self-Programming Synthesizers, Swarm Orchestras and the Origins of Melody
Authors: Miranda Eduardo Reck
Published: May 2004

This paper introduces three approaches to using Evolutionary Computation (EC) in Music (namely, engineering, creative and musicological approaches) and discusses examples of representative systems that have been developed within the last decade, with emphasis on more recent and innovative works. We begin by reviewing engineering applications of EC in Music Technology such as Genetic Algorithms and Cellular Automata sound synthesis, followed by an introduction to applications where EC has been used to generate musical compositions. Next, we introduce ongoing research into EC models to study the origins of music and detail our own research work on modelling the evolution of melody.
Ideal Evaluation from Coevolution
Authors: Jong Edwin D. de , Pollack Jordan B.
Published: May 2004

In many problems of interest, performance can be evaluated using tests, such as examples in concept learning, test points in function approximation, and opponents in game-playing. Evaluation on all tests is often infeasible. Identification of an accurate evaluation or fitness function is a difficult problem in itself, and approximations are likely to introduce human biases into the search process. Coevolution evolves the set of tests used for evaluation, but has so far often led to inaccurate evaluation.

We show that for any set of learners, a Complete Evaluation Set can be determined that provides ideal evaluation as specified by Evolutionary Multi-Objective Optimization. This provides a principled approach to evaluation in coevolution, and thereby brings automatic ideal evaluation within reach. The Complete Evaluation Set is of manageable size, and progress towards it can be accurately measured. Based on this observation, an algorithm named DELPHI is developed. The algorithm is tested on problems likely to permit progress on only a subset of the underlying objectives. Where all comparison methods result in overspecialization, the proposed method and a variant achieve sustained progress in all underlying objectives. These findings demonstrate that ideal evaluation may be approximated by practical algorithms, and that accurate evaluation for test-based problems is possible even when the underlying objectives of a problem are unknown.
Comparing Sectarian Practice and Organization: the Qumran Sects in Light of the Regulations of the Shakers, Hutterites, Mennonites and Amish
Authors: Regev Eyal
Published: May 2004

This article tries to demonstrate that the unique regulations of the Qumran (Dead Sea Scrolls) sect are derived from its social character as a sect, not from scriptural exegesis or Hellenistic influence. In order to achieve this goal, the article introduces practices that are typical of introversionist sects, and shows that they can also be found in Qumran. Thus the evidence from Qumran contributes to the understanding of the sectarian practices and organization in general. The article compares the regulations from Qumran to those of the Shakers, the Hutterites, the Mennonites and the Amish and also makes inferences concerning the practices of these different sects. The comparison pertains to the procedures of joining the sect, admission to adulthood, annual or semi-annual ceremonial communions, sanctions and punishments, confessions, economical organization and organizational patterns, especially the tendency of keeping the local community small, as well as gender relations and social hierarchy within the sect.
Syndecan-1 up-regulated by ephrinB2/EphB4 plays dual roles in inflammatory angiogenesis
Authors: Yuan Kuo , Hong Tse-Ming , Chen Jeremy J. W. , Tsai Wan Hua , Lin Ming T.
Published: May 2004

EphrinB2 and EphB4, its cognate receptor, are important in the vascular development of the mouse embryo. Their roles in human inflammatory angiogenesis, however, are not well understood. By examining hyperinflammatory lesions, we saw that ephrinB2 was predominantly expressed in macrophage-like cells and EphB4 in small venules. Because macrophages usually transmigrate through postcapillary venules during inflammation, we wanted to explore the downstream effects of EphB4 after binding to ephrinB2. By using cDNA microarray technique and following reverse transcriptase–polymerase chain reaction (RT-PCR), we found that syntenin and syndecan-1 were up-regulated in EphB4-positive endothelial cells dose dependently and time dependently after stimulation with preclustered ephrinB2. In vitro, ephrinB2 suppressed the angiogenic effects of basic fibroblast growth factor (bFGF) on EphB4-positive endothelial cells, partially due to syndecan-1's competition with fibroblast growth factor receptor (FGFR) for bFGF. However, ephrinB2 exhibited angiogenic effects in vivo, possibly due to an inflammation-associated enzyme—heparanase. The enzymes could convert the inhibitory effect of ephrinB2 on EphB4-positive endothelial cells to an activating effect by removing poorly sulfated side chains of up-regulated syndecan-1 ectodomain. Depending on the presence of heparanases, the roles of syndecan-1 may be opposite in different physiological settings.
Expression of the chemokine receptor CCR2 on immature B cells negatively regulates their cytoskeletal rearrangement and migration
Authors: Flaishon Liat , Becker-Herman Shirly , Hart Gili , Levo Yoram , Kuziel William A. , Shachar Idit
Published: May 2004

Immature B cells are targeted to specific areas in the spleen, where a fraction of these cells receive signals that induce them to mature and participate in the immune response. In this study, we show that the C-C chemokine receptor 2 (CCR2) is transcribed in immature B cells, while its message is dramatically down-regulated at the mature stage. CCR2-deficient cells exhibit up-regulation of chemokine-induced actin polymerization, migration, and homing to the lymph nodes of immature B cells. In addition, we demonstrate that control of homing by CCR2 is mediated by its ligand, CCL2/JE, which is secreted by B cells and down-regulates the stromal derived factor-1 (SDF-1) signaling cascade. Thus, this study describes an additional, previously uncharacterized, role for CCR2 and its ligand as negative regulators of the homing of immature B cells.
Megakaryocytes express functional Aurora-B kinase in endomitosis
Authors: Geddis Amy E. , Kaushansky Kenneth
Published: May 2004

Endomitosis (EnM) in megakaryocytes (MKs) is characterized by abortion of mitosis in late anaphase and failure of cytokinesis; subsequent reinitiation of DNA synthesis results in polyploidy. Ablation of chromosomal passenger proteins including Aurora-B kinase causes defects in late anaphase and cytokinesis in diploid cells; thus one hypothesis is that the expression or function of these proteins in polyploid MKs is abnormal. It has been reported that Aurora-B kinase mRNA is decreased in polyploid megakaryocytic cells, suggesting that deficiency of Aurora-B kinase is responsible for EnM. We examined the localization of Aurora-B kinase and additional members of the chromosomal passenger protein and aurora kinase families in MKs. We found that in EnM MKs (1) Aurora-B kinase is present and appropriately localized to centromeres in early EnM; (2) in low-ploidy human MKs, centromeric localization of survivin and inner centromere protein (INCENP) can also be demonstrated; (3) the function of Aurora-B kinase, as measured by Ser10 phosphorylation of histone H3, is intact; and (4) aurora-A kinase localizes appropriately to centrosomes in EnM. These results suggest that EnM MKs appropriately express functional Aurora-B kinase and related proteins in early anaphase, making a simple deficiency of this protein an unlikely explanation for polyploidy in this cell type.
Human bone marrow megakaryocytes and platelets express PPARγ, and PPARγ agonists blunt platelet release of CD40 ligand and thromboxanes
Authors: Akbiyik Filiz , Ray Denise M. , Gettings Kelly F. , Blumberg Neil , Francis Charles W. , Phipps Richard P.
Published: May 2004

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor important in lipid metabolism, diabetes, and inflammation. We evaluated whether human platelets and megakaryocytes express PPARγ and whether PPARγ agonists influence platelet release of bioactive mediators. Although PPARγ is mainly considered a nuclear receptor, we show that enucleate platelets highly express PPARγ protein as shown by Western blotting, flow cytometry, and immunocytochemistry. Meg-01 megakaryocyte cells and human bone marrow megakaryocytes also express PPARγ. Platelet and Meg-01 PPARγ bound the PPARγ DNA consensus sequence, and this was enhanced by PPARγ agonists. Platelets are essential not only for clotting, but have an emerging role in inflammation in part due to their release or production of the proinflammatory and proatherogenic mediators CD40 ligand (CD40L) and thromboxanes (TXs). Platelet incubation with a natural PPARγ agonist, 15d-PGJ2, or with a potent synthetic PPARγ ligand, rosiglitazone, prevented thrombin-induced CD40L surface expression and release of CD40L and thromboxane B2 (TXB2). 15d-PGJ2 also inhibited platelet aggregation and adenosine triphosphate (ATP) release. Our results show that human platelets express PPARγ and that PPARγ agonists such as the thiazolidinedione class of antidiabetic drugs have a new target cell, the platelet. This may represent a novel mechanism for treatment of inflammation, thrombosis, and vascular disease in high-risk patients.
‘Hard health’ and ‘soft schools’: research designs to evaluate SLT work in schools
Authors: McCartney Elspeth
Published: May 2004

While systems approaches are useful for evaluating speech and language therapists' (SLT) work in individual school contexts, there is a need to undertake studies detailing in a replicable format the interventions offered to children and for studies at all levels to assess whether these interventions work, using validated scientific techniques. There is a demandfor such studies to meet the National Health Service objective of using evidence-based approaches, which offer the best interventions available. Education researchers are being asked to address similar issues, and an overview is given of the type and levels of research used in the two sectors. It is suggested that health and education research are moving closer together and that SLTs in schools should undertake exploratory, group and cohort studies to further develop effective therapies.
The role of phonological representation in decoding skills of young readers
Authors: Hester Elizabeth , Hodson Barbara Williams
Published: May 2004

Phonological awareness reflects the strength of a child's ability to represent linguistic information cognitively at the phonological level. Although the role of phonological awareness in early reading decoding has been well documented, its relationship to other factors affecting reading decoding has yet to be fully examined. In this study, the relative strength of phonological representation was assessed through real word production, nonword repetition and phonological manipulation. The contribution of phonological representation to reading decoding was compared to the contribution of working memory, nonverbal intelligence and receptive vocabulary. Multiple regression analysis indicated that a complex phonological manipulation task, pig Latin, explained far more of the variance in reading decoding than any of the other predictor variables. Working memory, measured through a concurrent processing task, was not a significant predictor.
The nature of referred subtypes of primary speech disability
Authors: Broomfield Jan , Dodd Barbara
Published: May 2004

Of 1100 children referred to a mainstream paediatric speech and language therapy service in a 15-month period (January 1999 to April 2000), 320 had primary speech impairment. No referred child had significant hearing impairment, learning disability or physical disability. This paper describes the nature of the subtypes of speech disability referred. The results showed that of 320 children, 57.5% had phonological delay, 20.6% consistently made non-developmental errors, 9.4% made inconsistent errors on the same lexical item and 12.5% had articulation disorder; no child was diagnosed with develop-mental verbal dyspraxia. An estimate of the referral incidence of primary speech disability in a single year, calculated from referrals who attended, was 6.4% (estimated as 48000 children per year in the UK). The findings inform speech and language therapy service planning.
An atypical articulatory setting as learned behaviour: a videofluorographic study
Authors: Ball Martin , Manuel Rachel , Muller Nicole
Published: May 2004

We describe the case of a child with severely unintelligible speech, referred to our clinic after unsuccessful therapy elsewhere. Thomas's speech was char-acterized by deapicalization and velodorsal articulations, together with hypernasality. Unusually, Thomas was also able to produce a small number of items normally. His speech was investigated by videofluorography as previous impressionistic transcription had been inconclusive. Thomas's history suggested that these speech characteristics were learned behaviour, adopted because of irritation in the upper oro-pharynx. Previous therapy had concentrated on articulatory drills with little success. A new strategy of a contextually embedded, meaning-based approach to speech remediation was undertaken, and within a short time Thomas was using mainly intelligible speech with age-appropriate phonological patterns.
Language acquisition by children with Down syndrome: a naturalistic approach to assisting language acquisition
Authors: Vilaseca Rosa Maria , Del Rio Maria-José
Published: May 2004

Many child language studies emphasize the value of verbal and social support, of ‘scaffolding’ processes and mutual adjustments that naturally occur in adult-child interactions in everyday contexts. Based on such theories, this study attempted to improve the language and communication skills in children with special educational needs through naturalistic intervention. The results showed positive changes in the targeted language components of three children with Down syndrome. We consider that child language gains were best maintained after intervention if the mothers received at the same time specific advice about verbal interaction at home.
Severe Pulmonary Toxicity in Patients With Advanced-Stage Hodgkin's Disease Treated With a Modified Bleomycin, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone, and Gemcitabine (BEACOPP) Regimen Is Probably Related to the Combination of Gemcitabine and Bleomycin: A Report of the German Hodgkin's Lymphoma Study Group
Authors: Bredenfeld Henning , Franklin Jeremy , Nogova Lucia , Josting Andreas , Fries S. , Mailänder Volker , Oertel Joachim , Diehl Volker , Engert Andreas
Published: May 2004

Purpose

To investigate a new effective, nonleukemogenic polychemotherapy regimen, BAGCOPP (bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, gemcitabine) in a phase I/II dose-escalation study in patients with advanced-stage Hodgkin's disease (HD).

Patients and Methods

Patients in clinical stages IIB with risk factors III and IV were enrolled in this nonrandomized, multicenter trial aimed at defining the maximum-tolerated dose of gemcitabine within a modified escalated BEACOPP regimen. Gemcitabine was given at a starting dose of 800 mg/m2 on days 1 and 4 of each cycle.

Results

Twenty-seven patients (eight female, 19 male) were enrolled with a median age of 33 years (range, 19 to 65 years). Due to a higher than expected hematotoxicity, the day-4 application of gemcitabine was omitted after 14 patients were included and 59 cycles were given. A total of eight patients developed lung toxicity, mainly pneumonitis (six of eight), which led to the termination of the study. With a median follow-up of 27 months, 25 patients are in continuing complete remission.

Conclusion

The substitution of etoposide by gemcitabine in the escalated BEACOPP schema is not feasible and leads to severe pulmonary toxicity. This toxicity is probably related to the concomittant application of gemcitabine and bleomycin.
Opposing inputs by Hedgehog and Brinker define a stripe ofhairyexpression in theDrosophilaleg imaginal disc
Authors: Kwon Chulan , Hays Rebecca , Fetting Jennifer , Orenic Teresa V.
Published: May 2004

The sensory organs of the Drosophila adult leg provide a simple model system with which to investigate pattern-forming mechanisms. In the leg,a group of small mechanosensory bristles is organized into a series of longitudinal rows, a pattern that depends on periodic expression of the hairy gene (h) and the proneural genes achaete(ac) and scute (sc). Expression of ac in longitudinal stripes in prepupal leg discs defines the positions of the mechanosensory bristle rows. The ac/sc expression domains are delimited by the Hairy repressor, which is itself periodically expressed. In order to gain insight into the molecular mechanisms involved in leg sensory organ patterning, we have analyzed a Hedgehog (Hh)- and Decapentaplegic(Dpp)-responsive enhancer of the h gene, which directs expression of h in a narrow stripe in the dorsal leg imaginal disc (the D-h stripe). Our studies suggest that the domain of D-hexpression is defined by the overlap of Hh and high-level Dpp signaling. We find that the D-h enhancer consists of a Hh-responsive activation element (HHRE) and a repression element (REPE), which responds to the transcriptional repressor Brinker (Brk). The HHRE directs expression of h in a broad stripe along the anteroposterior (AP) compartment boundary. HHRE-directed expression is refined along the AP and dorsoventral axes by Brk1, acting through the REPE. In D-h-expressing cells, Dpp signaling is required to block Brk-mediated repression. This study elucidates a molecular mechanism for integration of the Hh and Dpp signals, and identifies a novel function for Brk as a repressor of Hh-target genes.
Multiple points of interaction between retinoic acid and FGF signaling during embryonic axis formation
Authors: Shiotsugu Jason , Katsuyama Yu , Arima Kayo , Baxter Allison , Koide Tetsuya , Song Jihwan , Chandraratna Roshantha A. S. , Blumberg Bruce
Published: May 2004

Anteroposterior (AP) patterning of the developing CNS is crucial for both regional specification and the timing of neurogenesis. Several important factors are involved in AP patterning, including members of the WNT and FGF growth factor families, retinoic acid receptors, and HOX genes. We have examined the interactions between FGF and retinoic signaling pathways. Blockade of FGF signaling downregulates the expression of members of the RAR signaling pathway, RARα, RALDH2 and CYP26. Overexpression of a constitutively active RARα2rescues the effects of FGF blockade on the expression of XCAD3 and HOXB9. This suggests that RARα2 is required as a downstream target of FGF signaling for the posterior expression of XCAD3 and HOXB9. Surprisingly, we found that posterior expression of FGFR1 and FGFR4 was dependent on the expression of RARα2. Anterior expression was also altered with FGFR1 expression being lost, whereas FGFR4 expression was expanded beyond its normal expression domain. RARα2 is required for the expression of XCAD3 and HOXB9, and for the ability of XCAD3 to induce HOXB9 expression. We conclude that RARα2 is required at multiple points in the posteriorization pathway, suggesting that correct AP neural patterning depends on a series of mutually interactive feedback loops among FGFs, RARs and HOX genes.
The epithelial-mesenchymal transition of theDrosophilamesoderm requires the Rho GTP exchange factor Pebble
Authors: Smallhorn Masha , Murray Michael J. , Saint Robert
Published: May 2004

Drosophila pebble (pbl) encodes a Rho-family GTP exchange factor (GEF) required for cytokinesis. The accumulation of high levels of PBL protein during interphase and the developmentally regulated expression of pbl in mesodermal tissues suggested that the primary cytokinetic mutant phenotype might be masking other roles. Using various muscle differentiation markers, we found that Even skipped (EVE) expression in the dorsal mesoderm is greatly reduced in pbl mutant embryos. EVE expression in the dorsalmost mesodermal cells is induced in response to DPP secreted by the dorsal epidermal cells. Further analysis revealed that this phenotype is likely to be a consequence of an earlier defect. pblmutant mesodermal cells fail to undergo the normal epithelial-mesenchymal transition (EMT) and dorsal migration that follows ventral furrow formation. This phenotype is not a secondary consequence of failed cytokinesis, as it is rescued by a mutant form of pbl that does not rescue the cytokinetic defect. In wild-type embryos, newly invaginated cells at the lateral edges of the mesoderm extend numerous protrusions. In pbl mutant embryos,however, cells appear more tightly adhered to their neighbours and extend very few protrusions. Consistent with the dependence of the mesoderm EMT and cytokinesis on actin organisation, the GTP exchange function of the PBL RhoGEF is required for both processes. By contrast, the N-terminal BRCT domains of PBL are required only for the cytokinetic function of PBL. These studies reveal that a novel PBL-mediated intracellular signalling pathway operates in mesodermal cells during the transition from an epithelial to migratory mesenchymal morphology during gastrulation.
Recruitment of Pyk2 and Cbl to lipid rafts mediates signals important for actin reorganization in growing neurites
Authors: Haglund Kaisa , Ivankovic-Dikic Inga , Shimokawa Noriaki , Kruh Gary D. , Dikic Ivan
Published: May 2004

Protein tyrosine kinase Pyk2 and multifunctional adaptor protein Cbl are implicated in the regulation of the cytoskeleton in several cell types. We report that Pyk2 and Cbl form a signaling complex that is translocated to lipid rafts and is enriched in growth cones of differentiating PC12 cells following growth factor stimulation. We found that Pyk2 and Cbl interacted with the adaptor protein ArgBP2, which also bound to flotillin-1, a component of lipid raft microdomains. These interactions contributed to recruitment of the Pyk2/Cbl complex to lipid raft compartments. In addition, Pyk2, Cbl and ArgBP2 were found co-localized with actin in axons and growth cones of differentiated PC12 cells. Moreover, co-expression of Pyk2, ArgBP2 and Cbl facilitated growth factor-induced formation of lamellipodia at the tip of neurites. Formation of these growth cone lamellipodia was dependent on intact lipid rafts and the Cbl-associated effectors Crk and phosphatidylinositol 3 (PI 3)-kinase. Our results indicate that recruitment of Pyk2/Cbl complexes to lipid rafts participates in growth factor-induced regulation of the actin cytoskeleton in growing neurites.
Using sweep to extend the stall-free operational range in axial fan rotors
Authors: Corsini A , Rispoli F
Published: May 2004

The paper discusses the use of sweep as a remedial strategy to control the aerodynamic limits in low-speed axial fan rotors. In this respect, the present work contributes to the understanding of the potential effect of blade lean on the shifting of the rotor stall margin. Numerical investigations have been undertaken on highly loaded fans of non-free vortex design, with the ideal total head rise coefficient typical of the industrial application range. Two rotors with identical nominal design parameters and, respectively, with 35° forward swept blades and unswept blades have been studied. The investigation has been carried out using an accurate in-house developed multilevel parallel finite element RANS solver, with the adoption of a non-isotropic two-equation turbulence closure. The pay-off derived from the sweep technology has been assessed with respect to the operating range improvement. To this end, the flow structure developing through the blade passages and downstream of the rotors, as well as loss distributions, have been analysed at design and near-peak pressure operating conditions. The analyses of three-dimensional flow structures showed that, sweeping forward the blade, the non-free vortex spanwise secondary flows are attenuated, and a control on the onset of stall is recovered. Moreover, the swept rotor features a reduced sensitivity to leakage flow effects. Consequently, it operates more efficiently approaching the throttling limit.
Aerodynamics of human-powered vehicles
Authors: Kyle C. R. , Weaver M. D.
Published: May 2004

Since the invention of the modern bicycle in the late 1880s, human-powered cycles have been used for racing. Air resistance can be over 90 per cent of the total retarding force on a bicycle, and consequently the aerodynamics has been a critical factor in increasing racing speeds. This paper reviews the history of aerodynamics in cycling and the physical factors that influence speed. A discussion of the aerodynamic design of both conventional racing bicycles and completely streamlined human-powered vehicles (HPVs) is included. A mathematical model that predicts vehicle speed when human power input and the other key properties are known is presented. At a steady speed of 50km/h, a modern racing bicycle would require about 420 W of power input, while a modern HPV requires only about 75 W, 18 per cent as much. The top speed for a conventional racing bicycle for 200m is about 72km/h, while for an HPV it is about 130km/h (180 per cent greater). At 130km/h a conventional bicycle would require about 5800W (humanly impossible), while a modern HPV requires only 350W, or 6 per cent as much. Reduced aerodynamic drag is almost entirely responsible for these extraordinary differences in power and speed.
Numerical investigation of a high-speed centrifugal compressor with hub vane diffusers
Authors: Liu Ruitao , Xu Zhong
Published: May 2004

Hub vane diffusers can obtain higher pressure recovery and efficiency compared with the vaneless diffuser and a wider operating range compared with the vane diffuser. To improve the performance of high pressure ratio centrifugal compressors it is necessary to understand the flow phenomena in the hub vane diffusers. Although some research work on hub vane diffuser flow has been published, many unknown flow physics and disputed questions still remain. A computational analysis of the flowfield in a high-speed centrifugal compressor with a backswept unshrouded impeller and wedge vane channel diffuser is presented. In order to obtain the optimum hub vane height, the pressure and velocity fields were numerically simulated for eight kinds of hub vane, which are varied as follows: h/b = 0 (vaneless), 0.2, 0.3, 0.4, 0.5, 0.6, 0.8 and 1 (vane). The advanced Navier-Stokes solver EURANUS/TURBO is applied with a Baldwin-Lomax model for closure. The calculations are performed with a central space discretization scheme, with second- and fourth-order artificial dissipation terms. The numerical procedure applied a four-stage explicit Runge-Kutta scheme, coupled to local time stepping. The good agreement of the computed stage performance and the experimental data of the stage with the vane diffuser shows that the solver is effective and reasonable. Numerical results show that the maximum flowrate attained by the stage with the vane diffuser is about 12.5 per cent less than with the hub vane diffusers. The stage efficiency reaches its maximum value for the hub vane diffuser with an h/b ratio of 0.5 at lower flowrate and for the hub vane diffuser with an h/b ratio of 0.4 at higher flowrate. The hub vane diffusers have a wider operating range than the vane diffuser. The hub vane diffuser with an h/b ratio of 0.3 shows a higher mass-averaged static pressure coefficient up to a flow coefficient φ = 0.16. The hub vane diffuser with an h/b ratio of 0.4 shows a slightly higher mass-averaged static pressure coefficient over an operating range of φ = 0.18–0.28, but it falls beyond φ = 0.3 below that of the vaneless diffuser. The performance of the centrifugal compressor with the shroud vane diffuser is better than that with the hub vane diffuser for the same height of the vane.
Rotordynamic characteristics of a rotor with labyrinth gas seals. Part 1: comparison with Childs’ experiments
Authors: Huang Diangui , Li Xuesong
Published: May 2004

A numerical method based on three-dimensional unsteady compressible Navier-Stokes equations with moving boundaries is employed to predict the fluid reaction forces and the rotordynamic coefficients of labyrinth gas seals. A large number of simulations under various conditions have been conducted. Comparison of the values from an experimental, two-control-volume model and current unsteady computational fluid dynamics (CFD) under different conditions shows that the computer code works well for most of the simulations.