bluuebunny/crossref_metadata_2025 huggingface dataset:
Requirement for Pangolin/dTCF in
Drosophila
Wingless signaling
Authors: Schweizer Liang , Nellen Denise , Basler Konrad
Published: May 2003

The Wingless (Wg) protein is a secreted glycoprotein involved in intercellular signaling. On activation of the Wg signaling pathway, Armadillo is stabilized, causing target genes to be activated by the transcription factor Pangolin (Pan). This study investigated the roles of Pan in the developing wing of
Drosophila
by clonal analysis. Three different aspects of wing development were examined: cell proliferation, wing margin specification, and
wg
self-refinement. Our results indicate that Pan function is critically required for all three of these processes. Consequently, lack of
pan
causes a severe reduction in the activity of the Wg target genes
Distalless
and
vestigial
within their normal domain of expression. Loss of
pan
function does not, however, lead to a derepression of these genes outside this domain. Thus, although Pan is positively required for the induction of Wg targets in the wing imaginal disk, it does not appear to play a default repressor function in the absence of Wg input. In contrast, lack of zygotic
pan
function causes a milder phenotype than that caused by the lack of
wg
function in the embryo. We show that this difference cannot be attributed to maternally provided
pan
product, indicating that a Pan repressor function usually prevents the expression of embryonic Wg targets. Together, our results suggest that for embryonic patterning the activator as well as repressor forms of Pan play important roles, while for wing development Pan operates primarily in the activator mode.
Pore Structure Influences Gating Properties of the T-type Ca2+ Channel α1G
Authors: Talavera Karel , Janssens Annelies , Klugbauer Norbert , Droogmans Guy , Nilius Bernd
Published: May 2003

The selectivity filter of all known T-type Ca2+ channels is built by an arrangement of two glutamate and two aspartate residues, each one located in the P-loops of domains I–IV of the α1 subunit (EEDD locus). The mutations of the aspartate residues to glutamate induce changes in the conduction properties, enhance Cd2+ and proton affinities, and modify the activation curve of the channel. Here we further analyze the role of the selectivity filter in the gating mechanisms of T-type channels by comparing the kinetic properties of the α1G subunit (CaV3.1) to those of pore mutants containing aspartate-to-glutamate substitution in domains III (EEED) or IV (EEDE). The change of the extracellular pH induced similar effects on the activation properties of α1G and both pore mutants, indicating that the larger affinity of the mutant channels for protons is not the cause of the gating modifications. Both mutants showed alterations in several gating properties with respect to α1G, i.e., faster macroscopic inactivation in the voltage range from −10 to 50 mV, positive voltage shift and decrease in the voltage sensitivity of the time constants of activation and deactivation, decrease of the voltage sensitivity of the steady-state inactivation, and faster recovery from inactivation for long repolarization periods. Kinetic modeling suggests that aspartate-to-glutamate mutations in the EEDD locus of α1G modify the movement of the gating charges and alter the rate of several gating transitions. These changes are independent of the alterations of the selectivity properties and channel protonation.
Involvement of Hydrogen Peroxide and Nitric Oxide in Expression of the Ipomoelin Gene from Sweet Potato
Authors: Jih Pei-Ju , Chen Yu-Chi , Jeng Shih-Tong
Published: May 2003

The IPO (ipomoelin) gene was isolated from sweet potato (Ipomoea batatas cv Tainung 57) and used as a molecular probe to investigate its regulation by hydrogen peroxide (H2O2) and nitric oxide (NO) after sweet potato was wounded. The expression of the IPO gene was stimulated by H2O2 whether or not the plant was wounded, but its expression after wounding was totally suppressed by the presence of diphenylene iodonium, an inhibitor of NADPH oxidase, both in the local and systemic leaves of sweet potato. These results imply that a signal transduction resulting from the mechanical wounding of sweet potato may involve NADPH oxidase, which produces endogenous H2O2 to stimulate the expression of theIPO gene. The production of H2O2 was also required for methyl jasmonate to stimulate the IPO gene expression. On the contrary, NO delayed the expression of the IPO gene, whereas N  G-monomethyl-l-arginine monoacetate, an inhibitor of NO synthase, enhanced the expression of the IPO gene after the plant was wounded. This study also demonstrates that the production of H2O2stained with 3,3′-diaminobenzidine hydrochloride could be stimulated by wounding but was suppressed in the presence of NO. Meanwhile, the generation of NO was visualized by confocal scanning microscope in the presence of 4,5-diaminofluorescein diacetate after sweet potato was wounded. In conclusion, when sweet potato was wounded, both H2O2 and NO were produced to modulate the plant's defense system. Together, H2O2 and NO regulate the expression of the IPO gene, and their interaction might further stimulate plants to protect themselves from invasions by pathogens and herbivores.
Chloroplast Membrane Photostability in chlPTransgenic Tobacco Plants Deficient in Tocopherols
Authors: Havaux Michel , Lütz Cornelius , Grimm Bernhard
Published: May 2003

The phototolerance of three chlP transgenic tobacco (Nicotiana tabacum) lines, affected in geranylgeranyl reductase and, hence, deficient in tocopherols (vitamin E), was estimated by in vivo luminescence and fluorescence measurements and was compared with that of the wild type (WT). Exposure of leaf discs to high light (1 mmol photon m−2s−1) and low temperature (10°C) led to a rapid inhibition of photosystem II (PSII) photochemistry that showed little dependence on the tocopherol level. PSII photo-inhibition was followed by lipid peroxidation with a time delay of about 4 h, and this phenomenon was exacerbated in the tocopherol-deficient leaves. A linear correlation was observed in these short-term experiments between resistance to photooxidation and tocopherol content. When whole plants were exposed to the same treatment, PSII was severely photo-inhibited in mature leaves of all genotypes. Lipid peroxidation was also observed in all plants, but it occurred much more rapidly in tocopherol-deficient transgenic plants relative to WT plants. The time at which extensive lipid peroxidation occurred was correlated with the tocopherol content of the leaves. The present results show that tocopherols protect thylakoid membranes against photodestruction through lipid peroxidation. However, tocopherol deficiency was compensated in young, developing leaves that were able to photo-acclimate in the long term and did not suffer from photooxidative damage. Soluble antioxidants (glutathione and ascorbate) did not accumulate in photo-acclimated chlP transgenic leaves relative to WT leaves. In contrast, a selective accumulation of xanthophyll cycle pigments was observed in young transgenic leaves, and this could represent a compensatory mechanism for tocopherol deficiency.
Genetic Modification Removes an Immunodominant Allergen from Soybean,
Authors: Herman Eliot M. , Helm Ricki M. , Jung Rudolf , Kinney Anthony J.
Published: May 2003

The increasing use of soybean (Glycine max) products in processed foods poses a potential threat to soybean-sensitive food-allergic individuals. In vitro assays on soybean seed proteins with sera from soybean-sensitive individuals have immunoglobulin E reactivity to abundant storage proteins and a few less-abundant seed proteins. One of these low abundance proteins, Gly m Bd 30 K, also referred to as P34, is in fact a major (i.e. immunodominant) soybean allergen. Although a member of the papain protease superfamily, Gly m Bd 30 K has a glycine in the conserved catalytic cysteine position found in all other cysteine proteases. Transgene-induced gene silencing was used to prevent the accumulation of Gly m Bd 30 K protein in soybean seeds. The Gly m Bd 30 K-silenced plants and their seeds lacked any compositional, developmental, structural, or ultrastructural phenotypic differences when compared with control plants. Proteomic analysis of extracts from transgenic seed detected the suppression of Gly m Bd 30 K-related peptides but no other significant changes in polypeptide pattern. The lack of a collateral alteration of any other seed protein in the Gly m Bd 30 K-silenced seeds supports the presumption that the protein does not have a role in seed protein processing and maturation. These data provide evidence for substantial equivalence of composition of transgenic and non-transgenic seed eliminating one of the dominant allergens of soybean seeds.
Assessing life skills in young working adults – Part 1: the development of an alternative instrument
Authors: Jacoba van der Wal Rachel , van der Wal Ruurd
Published: May 2003

This research was motivated and initiated by a request from industry to present a life skills learning programme to supplement young workers’ training. Subsequently, the dilemma faced by facilitators and trainers to assess the learners’ attainment of the learning outcomes of a life skills learning programme provided the impetus to develop an alternative assessment method – the collage and the stimulus instruments. A model developed by the researchers guided the development of the alternative assessment method and the stimulus instruments. Taking into account the demands, requirements and characteristics of life skills, a collage consisting of ten pictures and ten verbal concepts was developed to assess the learners’ attainment of the learning outcomes of a particular life skills learning programme. The life skills learning programme was presented to 18 artisans employed in industry. The selected material in the collage depicts more than one life skill and reflects the learning outcomes of the programme. The article is published in two parts. Part 1 is outlined above. The second part of the article will report on the outcomes of the application of the assessment instrument with the subject group of young workers.
Saudisation and employment in Saudi Arabia
Authors: Madhi Salah T. , Barrientos Armando
Published: May 2003

The paper explores the conditions of employment and career development in Saudi Arabia, which are found to be strongly segmented across nationalities. It discusses the main factors shaping employment and career development in Saudi Arabia, including employment policy, education and training, labour regulations, and recent Saudisation policies aimed at reducing dependence on foreign labour by replacing non‐Saudi employees with Saudi nationals. The large inflows of foreign labour, and their conditions of employment, made possible rapid economic development in Saudi Arabia, while protecting the incomes and status of the Saudi labour force. The implementation of Saudisation faces important constraints, especially in the private sector, but signals an important change in employment policy and career development.
Policing Unauthorized Camping
Authors: Cowan Dave , Lomax Delia
Published: May 2003

We argue that the links between welfare, policing, and exclusion, though rarely made explicit, nevertheless form the undercurrent of the modern neo‐liberal state. In making this argument, we draw particularly upon the voluminous literature which amplifies the seminal work of Foucault, especially as it relates to government. Thereafter, we apply this set of understandings to the way in which the unauthorized encampments of Gypsies and Travellers are policed. We concentrate first on the construction of legislation and its legal aftermath. Subsequently, we draw upon case study evidence to illustrate our thesis, particularly focusing on the sorting processes of decision‐makers.
Justice for All: Putting Victims at the Heart of Criminal Justice?
Authors: Jackson John D.
Published: May 2003

This article considers the claim in the government's White Paper, Justice for All, to put victims and witnesses at the heart of the criminal justice system and argues that there is an unresolved tension within the paper between instrumentalist crime control concerns and intrinsic concerns for the rights of victims and witnesses. It is argued that many of the proposals now contained in the latest Criminal Justice Bill are so preoccupied with rebalancing the system away from offenders that they risk doing injustice to defendants with little tangible benefit to victims and witnesses in terms of rights and remedies.
Reasoning In Bioethics
Authors: Gillett Grant
Published: May 2003

It is striking that some arguments in the bioethical literature seem implausible, counterintuitive, and even ridiculous when reported to competent moral agents. When examined, these arguments bear uncanny resemblances to the discourse of patients with debilitating mental disorders. I examine the kinds of irrationality involved, and discuss the fact that such irrationality is worrying in a discipline that purports to serve as a guide for real‐life practical reasoning. I offer some thoughts about correctives that we might use to temper some of the odd opinions that bedevil our subject in the name of ethical analysis. It seems that one ought to be suspicious of neatly rational arguments that produce counterintuitive conclusions, but the alternative seems to be that we explore new constructions of old problems in Bioethics such that our discussion of them does justice to what we regard as of fundamental significance to our lives together as human beings.
The derivation of R&D return indicators within a real options framework
Authors: Wörner Stefan D. , Grupp Hariolf
Published: May 2003

The purpose of this paper is to rework the building blocks of real option applications and to introduce a basket option framework. We find that the characteristic parameters of the risk neutral density function implied in observed share prices within the real option framework represent a novel category of R&D return indicators. Empirical evidence for a set of 13 US bio‐pharmaceutical companies is provided. The novel R&D return indicator can be used to analyse investor's expectations on R&D success of a particular firm. The implications of this indicator on decision making are mainly based on its information content on technological and market risk of the products under development in a particular firm. A proposal for a potential application of the stability index in innovation research is discussed as well. The study thus is at the interface between innovation research and (empirical) finance.
How well did the new Sumitomo Electric project ranking method predict performance?
Authors: Osawa Yoshitaka
Published: May 2003

The development and implementation of a new R&D project scoring method (NS‐method) within Sumitomo Electric Industries was introduced in a previous report. This paper evaluates the NS‐method's effectiveness by comparing the information generated by application to 146 projects in 1997 with the project achievements in 2000. The test results revealed that the NS‐method's evaluation scores were correlated to the performance indicators such as the gross profit and R&D productivity. It also showed that, when projects are classified into three groups (i.e., Top, Middle, Bottom) according to the forecast data generated by the NS‐method, the projects in the Top category had higher actual productivity ratios and success rates than those in the Bottom category.
‘(I am) Thinking’
Authors: Haldane John
Published: May 2003

The activity of thought is deeply perplexing. Anyone resistant to its consignment to the domain of sub‐personal psychology, or to quasi‐behaviouristic elimination, needs to address such matters as why it is that thinking seems to elude capture in consciousness, and what the nature of self‐ascription may be. This paper takes up from an earlier discussion by Claudio Costa (‘ “I’m Thinking” ’Ratio 2001) and argues that his account of thinking is flawed. It also argues, in opposition to Costa, that self‐reflexivity is real and is required to account for the ownership of thoughts. Finally, it identifies an argument from self‐awareness to the conclusion that the subject of thought is not a material object.
The Immortality Requirement for Life's meaning
Authors: Metz Thaddeus
Published: May 2003

Many religious thinkers hold the immortality requirement, the view that immortality of some kind is necessary for life to have meaning. After clarifying the nature of the immortality requirement, this essay examines three central arguments for it. The article establishes that existing versions of these arguments fail to entail the immortality requirement. The essay then reconstructs the arguments, and it shows that once they do plausibly support the immortality requirement, they equally support the God‐centred requirement, the view that God's existence is a necessary condition for life to be meaningful. The paper concludes by explaining why we should expect any argument for the immortality requirement also to constitute an argument for the God‐centred requirement.
The Sad Truth: Optimism, Pessimism, and Pragmatism
Authors: Waller Bruce N.
Published: May 2003

Pragmatists (such as William James) recommend optimism as a successful strategy, and recent psychological research has confirmed its value. But optimism comes at a price: optimists are less accurate in their assessments and expectations than are pessimists. Thus optimism ‘proves itself to be good in the way of belief’, and by pragmatic standards should count as true; but that makes the accuracy costs of optimism invisible (the problem is only exacerbated by Rorty's recommendation that pragmatists stop speaking of truth altogether). The problem prevents pragmatists from offering a Darwinian explanation of why pessimism survives, and also blocks any pragmatist account of the well‐documented and highly successful exploratory behavior of many animal species.
Evolution of Learning in Three Aplysiid Species: Differences in Heterosynaptic Plasticity Contrast with Conservation in Serotonergic Pathways
Authors: Marinesco Stéphane , Duran Kristy L. , Wright William G.
Published: May 2003

We investigated the neurobiological basis of variation in sensitization between three aplysiid species: Aplysia californica, Phyllaplysia taylori and Dolabrifera dolabrifera. We tested two different forms of sensitization induced by a noxious tail shock: local sensitization, expressed near the site of shock, and general sensitization, tested at remote sites. Aplysia showed both local and general sensitization, whereas Phyllaplysia demonstrated only local sensitization, and Dolabrifera lacked both forms of learning. We then investigated a neurobiological correlate of sensitization, heterosynaptic modulation of sensory neuron excitability by tail‐nerve stimulation. We found (1) an increase in sensory neuron (SN) excitability after both ipsilateral and contralateral nerve stimulation in Aplysia, (2) a smaller and shorter‐lasting increase in Phyllaplysia, and (3) no effect in Dolabrifera. Because sensitization in Aplysia is strongly correlated with serotonergic (5‐HT) neuromodulation, we hypothesized that the observed interspecific variation in sensitization and SN neuromodulation might be correlated with variation in the anatomy and/or functional response of the serotonergic system. However, using immunohistochemistry, we found that all three species showed a similar pattern of 5‐HT innervation. Furthermore, they also showed comparable 5‐HT release evoked by tail‐nerve shock, as measured with chronoamperometry. These observations indicate that interspecific variation in learning is correlated with differences in SN heterosynaptic plasticity within a backgound of evolutionary conservation in the 5‐HT neuromodulatory pathway. We thus hypothesize that evolutionary changes in learning phenotype do not involve modifications of the 5‐HT pathway per se, but rather, changes in the response of SNs to the activation of this or other neuromodulatory pathways upon noxious stimulation.
Inward Rectification by Polyamines in Mouse Kir2.1 Channels: Synergy between Blocking Components
Authors: Xie Lai‐Hua , John Scott A. , Weiss James N.
Published: May 2003

We recently characterized two distinct mechanisms by which the polyamine spermine blocks Kir2.1 channels: (1) by reduction of negative surface charges in the cytoplasmicpore, thereby reducing single‐channel conductance, and (2) by direct open channel transmembrane pore block. The extent to which the surface charge reduction component is mediated by passive surface charge screening versus binding of polyamines to these charges, as well as the extent to which the surface charge reduction and pore block mechanisms are synergistic, versus simply additive, was not established. To address these issues, macroscopic currents were recorded from inside‐out giant patches from Xenopus oocytes and from single‐channel currents from COS7 cells expressing wild‐type and mutant Kir2.1 channels, during exposure to polyamines of varying length and charge. The surface charge reduction component was decreased when polyamine charge (at constant length) was decreased from 4 (spermine) to 2 (diamine 10, DA10). Moreover, the surface charge reduction component of block involved more than passive surface charge screening and required binding of polyamines to the cytoplasmic pore, since it was eliminated when polyamine length was shortened below six alkyl groups. Loss of surface charge reduction also dramatically affected open channel pore block. The latter consisted of two subcomponents with fast and slow kinetics, respectively. The slow subcomponent decreased as blocker length decreased (DA10, DA8 and DA6), whereas the fast subcomponent was sensitive to blocker charge (spermine vs. DA10). Neutralization of E224 and E299, which eliminated the surface charge reduction component of block, also eliminated the fast subcomponent of pore block. Neutralization of D172 had no effect on the surface charge reduction component, but weakened both of the subcomponents of pore block. These findings can be accounted for by a model in which the negative charges at E224, E299 and D172 act in a concerted manner to coordinate the surface charge reduction and open channel components of polyamine block. In this model, the binding of polyamines to surface charges E224 and E299 pre‐positions them in the cytoplasmic pore in a manner that directly facilitates their entry and exit from a transmembrane pore‐occluding site involving D172. A molecular model using the recently reported 1.8 Å resolution structure of the inward‐rectifier cytoplasmic pore, adapted to Kir2.1, is consistent with longer polyamines binding at their positively charged ends to the E224 and E299 positions in the same subunit, potentially accommodating four polyamine molecules per channel.
ELECTROTEXTILES: CONCEPTS AND CHALLENGES
Authors: WAGNER SIGURD , BONDEROVER EITAN , JORDAN WILLIAM B. , STURM JAMES C.
Published: May 2003

Electrotextiles (e-textiles) are fabrics made from yarns that carry electronic components. Circuits are made from such yarns by weaving. We describe the technical development of the concept of e-textiles, and briefly discuss three challenges: connectivity, materials and fabrication, and wear.
SEMICONDUCTOR UV SOURCES AND DETECTORS: SOME NON-CONSUMER APPLICATIONS
Authors: MUÑOZ ELIAS
Published: May 2003

UV emitters and photodetectors based on wide band-gap semiconductors are being investigated and may soon become commercially available. Solid state lighting and information storage are two main applications in the consumer area for these new semiconductor devices. Presently, III-nitrides seem to be the most promising materials for such near UV semiconductor devices. In this work some non-consumer applications are indicated. Biophotonics appears to be a very promising area for such devices.
Development of an Animal Model for Spontaneous Myocardial Infarction (WHHLMI Rabbit)
Authors: Shiomi Masashi , Ito Takashi , Yamada Satoshi , Kawashima Seinosuke , Fan Jianglin
Published: May 2003

Objective—

Coronary heart disease is the most common cause of death in developed countries. However, there are no suitable animal models that mimic spontaneous myocardial infarction in humans. In this study, we attempted to obtain a rabbit strain with spontaneous myocardial infarction by selective breeding of coronary atherosclerosis–prone Watanabe heritable hyperlipidemic (WHHL) rabbits, designated as WHHLMI rabbits.

Methods and Results—

WHHLMI rabbits were characterized by the high incidence of fatal myocardial infarction at ages 11 to 35 months, being increased from 23% to 97% after the selective breeding. The ECG on WHHLMI rabbits showed a typical feature of myocardial infarction. Histological examination of hearts from suddenly deceased WHHLMI rabbits revealed old myocardial infarction accompanied by fresh myocardial lesions. The culprit coronary arteries exhibited severe atheromatous plaques (>90% lumen area stenosis), suggesting that coronary atherosclerosis is responsible for myocardial infarction observed in WHHLMI rabbits. In addition, the coronary plaques showed vulnerable features including macrophage-rich thin cap and large necrotic core.

Conclusions—

To the best of our knowledge, this is the first report of spontaneous myocardial infarction in rabbits, and it is suggested that this WHHLMI rabbit strain will be a useful animal model to study human myocardial infarction.
Augmentation of Wall Shear Stress Inhibits Neointimal Hyperplasia After Stent Implantation
Authors: Carlier Stéphane G. , van Damme Luc C.A. , Blommerde Casper P. , Wentzel Jolanda J. , van Langehove Glenn , Verheye Stephan , Kockx Mark M. , Knaapen Michiel W.M. , Cheng Caroline , Gijsen Frank , Duncker Dirk J. , Stergiopulos Nikos , Slager Cornelis J. , Serruys Patrick W. , Krams Rob
Published: May 2003

Background—

Low wall shear stress (WSS) increases neointimal hyperplasia (NH) in vein grafts and stents. We studied the causal relationship between WSS and NH formation in stents by locally increasing WSS with a flow divider (Anti-Restenotic Diffuser, Endoart SA) placed in the center of the stent.

Methods and Results—

In 9 rabbits fed a high-cholesterol diet for 2 months to induce endothelial dysfunction, 18 stents were implanted in the right and left external iliac arteries (1 stent per vessel). Lumen diameters were measured by quantitative angiography before and after implantation and at 4-week follow-up, at which time, macrophage accumulation and interruption of the internal elastic lamina was determined. Cross sections of stent segments within the ARED (S+ARED), outside the ARED (S[minus]ARED), and in corresponding segments of the contralateral control stent (SCTRL) were analyzed. Changes in WSS induced by the ARED placement were derived by computational fluid dynamics. Computational fluid dynamics analysis demonstrated that WSS increased from 0.38 to 0.82 N/m
2
in the S+ARED immediately after ARED placement. This augmentation of shear stress was accompanied by (1) lower mean late luminal loss by quantitative angiography ([minus]0.23±0.22 versus [minus]0.58±0.30 mm,
P
=0.02), (2) reduction in NH (1.48±0.58, 2.46±1.25, and 2.36±1.13 mm
2
,
P
<0.01, respectively, for S+ARED, S[minus]ARED, and SCTRL), and (3) a reduced inflammation score and a reduced injury score. Increments in shear stress did not change the relationship between injury score and NH or between inflammation score and NH.

Conclusions—

The newly developed ARED flow divider significantly increases WSS, and this local increment in WSS is accompanied by a local reduction in NH and a local reduction in inflammation and injury. The present study is therefore the first to provide direct evidence for an important modulating role of shear stress in in-stent neointimal hyperplasia.
Safety and Feasibility of Catheter-Based Local Intracoronary Vascular Endothelial Growth Factor Gene Transfer in the Prevention of Postangioplasty and In-Stent Restenosis and in the Treatment of Chronic Myocardial Ischemia
Authors: Hedman Marja , Hartikainen Juha , Syvänne Mikko , Stjernvall Joachim , Hedman Antti , Kivelä Antti , Vanninen Esko , Mussalo Hanna , Kauppila Esa , Simula Sakari , Närvänen Outi , Rantala Arto , Peuhkurinen Keijo , Nieminen Markku S. , Laakso Markku , Ylä-Herttuala Seppo
Published: May 2003

Background—

Catheter-based intracoronary vascular endothelial growth factor (VEGF) gene transfer is a potential treatment for coronary heart disease. However, only limited data are available about local VEGF gene transfer given during angioplasty (PTCA) and stenting.

Methods and Results—

Patients with coronary heart disease (n=103; Canadian Cardiovascular Society class II to III; mean age, 58±6 years) were recruited in this randomized, placebo-controlled, double-blind phase II study. PTCA was performed with standard methods, followed by gene transfer with a perfusion-infusion catheter. Ninety percent of the patients were given stents; 37 patients received VEGF adenovirus (VEGF-Adv, 2×10
10
pfu), 28 patients received VEGF plasmid liposome (VEGF-P/L; 2000 μg of DNA with 2000 μL of DOTMA:DOPE [1:1 wt/wt]), and 38 control patients received Ringer’s lactate. Follow-up time was 6 months. Gene transfer to coronary arteries was feasible and well tolerated. The overall clinical restenosis rate was 6%. In quantitative coronary angiography analysis, the minimal lumen diameter and percent of diameter stenosis did not significantly differ between the study groups. However, myocardial perfusion showed a significant improvement in the VEGF-Adv-treated patients after the 6-month follow-up. Some inflammatory responses were transiently present in the VEGF-Adv group, but no increases were detected in the incidences of serious adverse events in any of the study groups.

Conclusions—

Gene transfer with VEGF-Adv or VEGF-P/L during PTCA and stenting shows that (1) intracoronary gene transfer can be performed safely (no major gene transfer-related adverse effects were detected), (2) no differences in clinical restenosis rate or minimal lumen diameter were present after the 6-month follow-up, and (3) a significant increase was detected in myocardial perfusion in the VEGF-Adv-treated patients.
AT
1
Receptor Blockade Improves Vasorelaxation in Experimental Renal Failure
Authors: Kööbi Peeter , Kalliovalkama Jarkko , Jolma Pasi , Rysä Jaana , Ruskoaho Heikki , Vuolteenaho Olli , Kähönen Mika , Tikkanen Ilkka , Fan Meng , Ylitalo Pauli , Pörsti Ilkka
Published: May 2003

It is not known whether angiotensin II type 1 receptor antagonists can influence the function and morphology of small arteries in renal failure. We investigated the effect of 8-week losartan therapy (20 mg/kg per day) on isolated mesenteric resistance arteries by wire and pressure myographs in 5/6 nephrectomized rats. Plasma urea nitrogen was elevated 1.6-fold after nephrectomy, and ventricular synthesis of atrial and B-type natriuretic peptides was increased 2.2-fold and 1.7-fold, respectively, whereas blood pressure was not affected. Losartan did not influence these variables. The endothelium-mediated relaxation to acetylcholine was impaired in nephrectomized rats in the absence and presence of nitric oxide synthase and cyclooxygenase inhibition. Blockade of calcium-activated potassium channels by charybdotoxin and apamin reduced the remaining acetylcholine response, and this effect was less marked in nephrectomized than in sham-operated rats. Relaxation to levcromakalim, a vasodilator acting through adenosine triphosphate-sensitive potassium channels, was also impaired after nephrectomy. The arteries of nephrectomized rats showed eutrophic inward remodeling: Wall-to-lumen ratio was increased without change in wall cross-sectional area. All changes in arterial relaxation and morphology were normalized by losartan therapy. Aortic ACE content, measured by autoradiography, directly correlated to the plasma level of urea nitrogen, suggesting that renal failure has an enhancing influence on the vascular renin-angiotensin system. Losartan normalized relaxation and morphology of resistance arteries in experimental renal failure, independent of its influence on blood pressure, impaired kidney function, or volume overload. The mechanism of improved vasodilation by losartan may include enhanced relaxation through potassium channels.
Subcortical Loop Activation during Selection of Currently Relevant Memories
Authors: Treyer Valerie , Buck Alfred , Schnider Armin
Published: May 2003

Clinical studies on spontaneous confabulation and imaging studies with healthy subjects indicate that the anterior limbic system, in particular, the orbitofrontal cortex (OFC), is necessary to adjust thought and behavior to current reality. It appears to achieve this by continuously suppressing activated memories that do not pertain to ongoing reality, even before their content is consciously recognized. In the present study, we explored through what anatomical connections the OFC exerts this influence. Healthy subjects were scanned with H2 15O PET as they performed four blocks of continuous recognition tasks, each block composed of a different type of stimuli (meaningful designs, geometric designs, words, nonwords). Within each block, three runs composed of exactly the same picture series, arranged in different order each time, were made. Subjects were asked to indicate item recurrences only within the currently ongoing run and to disregard familiarity from previous runs. In the combined first runs, in which all items were initially new and responses could be based on familiarity judgement (with repeated items) alone, we found medial temporal and right orbitofrontal activation. In the combined third runs, when all items were already known and selection of currently relevant memories was required, we found left orbitofrontal activation contingent with distinct activation of the ventral striatum, head and body of the caudate nucleus, substantia nigra, and medial thalamus. The study indicates that the OFC influences the cortical representation of memories through subcortical connections including the basal ganglia and the thalamus. The data are compatible with a role of the dopaminergic reward system in the monitoring of ongoing reality in thinking.
cAC10-vcMMAE, an anti-CD30–monomethyl auristatin E conjugate with potent and selective antitumor activity
Authors: Francisco Joseph A. , Cerveny Charles G. , Meyer Damon L. , Mixan Bruce J. , Klussman Kerry , Chace Dana F. , Rejniak Starr X. , Gordon Kristine A. , DeBlanc Ron , Toki Brian E. , Law Che-Leung , Doronina Svetlana O. , Siegall Clay B. , Senter Peter D. , Wahl Alan F.
Published: May 2003

The chimeric monoclonal antibody cAC10, directed against CD30, induces growth arrest of CD30+ cell lines in vitro and has pronounced antitumor activity in severe combined immunodeficiency (SCID) mouse xenograft models of Hodgkin disease. We have significantly enhanced these activities by conjugating to cAC10 the cytotoxic agent monomethyl auristatin E (MMAE) to create the antibody-drug conjugate cAC10-vcMMAE. MMAE, a derivative of the cytotoxic tubulin modifier auristatin E, was covalently coupled to cAC10 through a valine-citrulline peptide linker. The drug was stably attached to the antibody, showing only a 2% release of MMAE following 10-day incubation in human plasma, but it was readily cleaved by lysosomal proteases after receptor-mediated internalization. Release of MMAE into the cytosol induced G2/M-phase growth arrest and cell death through the induction of apoptosis. In vitro, cAC10-vcMMAE was highly potent and selective against CD30+ tumor lines (IC50 less than 10 ng/mL) but was more than 300-fold less active on antigen-negative cells. In SCID mouse xenograft models of anaplastic large cell lymphoma or Hodgkin disease, cAC10-vcMMAE was efficacious at doses as low as 1 mg/kg. Mice treated at 30 mg/kg cAC10-vcMMAE showed no signs of toxicity. These data indicate that cAC10-vcMMAE may be a highly effective and selective therapy for the treatment of CD30+ neoplasias.
Hair follicles serve as local reservoirs of skin mast cell precursors
Authors: Kumamoto Tadashi , Shalhevet David , Matsue Hiroyuki , Mummert Mark E. , Ward Brant R. , Jester James V. , Takashima Akira
Published: May 2003

Several leukocyte populations normally reside in mouse skin, including Langerhans cells and γδ T cells in the epidermis and macrophage and mast cells in the dermis. Interestingly, these skin resident leukocytes are frequently identified within or around hair follicles (HFs), which are known to contain stem cell populations that can generate the epidermal architecture or give rise to the melanocyte lineage. Thus, we reasoned that HFs might serve as a local reservoir of the resident leukocyte populations in the skin. When vibrissal follicles of adult mice were cultured in the presence of stem cell factor (SCF), interleukin 3 (IL-3), IL-7, granulocyte-macrophage colony-stimulating factor, and Flt3 ligand, CD45+/lineage–/c-kit+/FcϵRI+ cells became detectable on the outgrowing fibroblasts in 10 days and expanded progressively thereafter. These HF-derived leukocytes showed characteristic features of connective tissue-type mast cells, including proliferative responsiveness to SCF, metachromatic granules, mRNA expression for mast cell proteases-1, -4, -5, and -6, and histamine release on ligation of surface IgE or stimulation with substance P or compound 48/80. These results, together with our findings that HFs contain c-kit+ cells and produce SCF mRNA and protein, suggest that HFs provide a unique microenvironment for local development of mast cells.
Effect of muscle length on strength and dexterity after stroke
Authors: Ada Louise , Canning Colleen , Dwyer Tiffany
Published: May 2003

Objective: The effect of muscle length on strength and dexterity after stroke was investigated. The aim was to determine if poor function at a particular muscle length could be attributed solely to differential weakness at this joint angle or whether an additional problem of differential dexterity exists.

Design: This descriptive research study measured elbow flexor and extensor strength as well as dexterity at three elbow joint angles: 30°, 60° and 90° flexion. Dexterity was measured independently of strength.

Subjects: Fifteen (seven female, eight male) chronic stroke patients (mean age 67 years) who could actively flex and extend their affected elbow participated. Ten neurologically normal control subjects (mean age 67 years) acted as controls.

Main outcome measures: Strength was measured as peak elbow flexor and extensor torque at three angles; and dexterity was measured as coherence for slow and fast tracking also at three angles.

Results: Dexterity was not affected by muscle length but strength was and this finding was the same for both stroke and controls. While the magnitude of the torque-angle curves was not significantly different between stroke and controls, the shape of torque-angle curves was altered after stroke so that both the elbow flexors ( p < 0.05) and extensors ( p < 0.05) tested weaker in the testing position where they were shortest.

Conclusion: Since there was no differential loss of dexterity, it appears that differential loss of strength, especially in the shortened range, may explain the clinical observation of poorer function at one muscle length than another after stroke. Specific training to strengthen the muscles in these ranges is therefore of clinical importance for rehabilitation.
Functional deterioration in adults with cerebral palsy
Authors: Ando Norihiko , Ueda Satoshi
Published: May 2003

Objective: To examine the problem of functional deterioration of patients with cerebral palsy.

Subjects: Adults with cerebral palsy who work at community workshops throughout Japan.

Settings: Interviews combined with physical examinations. In the first part of the study a survey was conducted, to which 686 patients responded. In the second part, physicians conducted physical examinations on 163 patients. In the third part, the patients who had been examined in the second part were studied.

Results: Functional deterioration was noted in approximately 35% of adult patients with cerebral palsy; it was higher among those with involuntary movements of the head and neck and abnormal movement patterns during locomotion. Deterioration was also noted among those who reported an inadequate work environment, such as poor posture during work and unsuitability of the desk, chairs and tools. Deterioration over a five-year period was noted in 8 of 122 patients.

Conclusion: Although the factors intrinsic to cerebral palsy are often responsible for the functional deterioration, environmental factors are not to be taken lightly if functional deterioration is to be prevented.
A comparison of two approaches in the treatment of perceptual problems after stroke
Authors: Edmans J A , Webster J , Lincoln N B
Published: May 2003

Objective: To compare the effectiveness of the transfer of training and functional approaches in improving perceptual and functional abilities after stroke.

Design: Patients identified as having perceptual problems were randomly allocated to either the transfer of training approach or the functional approach for perceptual treatment. On completion of six weeks of treatment, each patient was reassessed for perceptual and functional abilities.

Subjects and setting: Eighty inpatients on the Nottingham Stroke Unit.

Interventionsy: Perceptual treatment was given for 2.5 hours per week for six weeks.

Main outcome measures: Rivermead Perceptual Assessment Battery, Barthel ADL Index and Edmans ADL index.

Results: There was no significant difference between the treatment groups on patient characteristics or impairments. The results also showed no significant difference between the treatment groups before and after treatment on perceptual ability total scores, individual perceptual subtest scores, or functional ability total scores (Mann–Whitney U 642.5–798.0, p > 0.05). Wilcoxon matched pairs signed ranks tests showed a significant improvement in both groups after treatment on perceptual and functional abilities (perceptual z = 6.02, p < 0.001, functional z = 6.72, p < 0.001).

Conclusions: These results indicated that the improvement in perceptual abilities was equivalent using either of the two approaches. This could be due to spontaneous recovery or the effects of the Stroke Unit.
Low TENS treatment on post-stroke paretic arm: a three-year follow-up
Authors: Sonde L , Kalimo H , Fernaeus S E , Viitanen M
Published: May 2003

Objective: To determine whether stroke patients with initial increases in arm motor recovery following low-frequency transcutaneous electrical nerve stimulation (low TENS) treatment go on to show long-term benefits. Also whether the same therapy results in long-term improvements in motor function, spasticity or activities of daily living (ADL).

Design: A three-year follow-up study.

Subjects: Twenty-eight stroke patients, who had participated in a randomized trial of daily treatment with low-frequency (1.7 Hz) transcutaneous electrical nerve stimulation (low TENS) on the paretic arm for three months starting 6–12 months after stroke.

Outcomes: Fugl-Meyer Motor Performance Scale for evaluation of changes in arm motor function. A 6-point Ashworth Scale to measure spasticity. Barthel Index to evaluate performance in ADL.

Results: Motor function of the paretic arm had deteriorated in both treatment and control groups. Increased spasticity was seen in both groups. ADL score remained at a similar level in the low TENS group, whereas the control group had deteriorated during the same time period.

Conclusions: Low TENS stimulation started 6–12 months after stroke may not have a specific effect on arm motor function years after completion of treatment.
Stress and coping in spouses of persons with spinal cord injuries
Authors: Chan Raymond CK
Published: May 2003

Objective: To examine the sources of stress and the patterns of coping of spouses of persons with spinal cord injuries (SCI) among Hong Kong Chinese.

Design: A cross-sectional correlation design. A set of structured questionnaires and semi-structured interviews were administered.

Subjects: Forty spouses of persons with SCI were recruited and interviewed.

Outcome measures: These included coping strategies, depression, care-giving burden, life satisfaction and marital adjustment.

Results: The most stressful situations reported by the participants concerned health issues of their injured partners, the family and marital interactions, and the care-giving burden imposed on them. Cluster analysis indicated a potential at-risk group, characterized by high scores in external locus of control, inadequate coping modes and limited social support. They were noted to manifest high levels of depression, care-giving burden, low levels of life satisfaction and marital adjustment.

Conclusion: The identification of the potential at-risk group indicates that spouses of persons with SCI suffer levels of stress comparable to those of their injured partners. Rehabilitation plans should include this potential at-risk group to help them release the stress and to prevent them from developing clinically significant mental disorders.
Preventing falls on an elderly care rehabilitation ward
Authors: Donald I P , Pitt K , Armstrong E , Shuttleworth H
Published: May 2003

Objective: Comparison of two flooring types – carpet and vinyl – in the bed areas, and two modes of physiotherapy – conventional therapy and additional leg strengthening exercises – in avoiding falls.

Design: Randomized 2 × 2 controlled trial.

Setting: Elderly care rehabilitation ward in a community hospital.

Subjects: Fifty-four consecutive patients referred for rehabilitation.

Outcome measures: The incidence of falls, and the change in strength.

Results: There were 10 falls on carpet, and only a single fall on vinyl floor covering (relative risk 8.3, 95% confidence interval 0.95–73, p = 0.05). There were four falls in those receiving additional exercise, and seven falls in those receiving only conventional physiotherapy (relative risk 0.21, 95% confidence interval 0.04–1.2, p = 0.12). Fifty-nine per cent of patients were able to complete strength measurements on admission and discharge. In these, handgrip strength improved more in those given additional exercise than conventional physiotherapy (2.1 kg versus – 0.3 kg, p < 0.05).

Conclusion: There is no evidence to support either intervention in preventing falls on a rehabilitation ward, but within this low-powered study, there was a strong trend towards vinyl being superior.