bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long QT syndrome: reduced repolarization reserve and the genetic link
Authors: RODEN D. M. 
Published: November 2005

Abstract.Marked QT prolongation and torsades de pointes can occur not only in the congenital long QT syndromes (LQTSs) but also as a consequence of environmental stimuli, notably administration of certain drugs. A key feature of this ‘acquired’ form of the LQTS has been its unpredictable nature. That is, although risk factors have been identified in series of patients, they have not been terribly useful in addressing risk in an individual patient. Normal cardiac repolarization depends critically on the interplay of multiple ion currents, and these provide some redundancy, or ‘reserve’, to protect against excessive QT prolongation by drugs. We have proposed that lesions in these repolarizing mechanisms can remain subclinical but nevertheless increase risk on drug exposure, and have termed this situation ‘reduced repolarization reserve’. The evidence in support of this concept is presented, and the known and potential contributions by genetic variants to risk is examined. Assessing variability in susceptibility to acquired LQTS provides a framework for analysis of other complex gene–environment interactions.
In vitroandin vivomodels for testing arrhythmogenesis in drugs
Authors: CARLSSON L. 
Published: November 2005

Abstract.The steadily increasing list of drugs associated with prolongation of the QT interval and torsades de pointes (TdP) constitute a medical problem of major concern. Hence, there is a need at an early stage to identify drug candidates with an inherent capacity to induce repolarization‐related proarrhythmias, avoiding exposure of large populations to potentially harmful drugs. Furthermore, the availability of clinically relevant and predictive animal models should reduce the risk that effective and potentially life‐saving drugs never reach the market. This review will discuss the pros and cons of somein vivoandin vitroanimal models for assessing proarrhythmia liability.
Population structure of brush‐tailed rock‐wallaby (Petrogale penicillata) colonies inferred from analysis of faecal DNA
Authors: PIGGOTT M. P. , BANKS S. C. , TAYLOR A. C. 
Published: November 2005

AbstractGenetic data obtained using faecal DNA were used to elucidate the population structure of four brush‐tailed rock‐wallaby (Petrogale penicillata) colonies located in Wollemi National Park, New South Wales. The results suggested that the four sampled colonies are genetically differentiated and do not form a panmictic unit. Based on assignment tests, approximately 5% of sampled individuals were inferred to be dispersers and both male and female migrants were detected. Multilocus spatial autocorrelation analyses provided evidence for increased philopatry among females compared to males within the largest colony in the valley. Females in close spatial proximity were more genetically similar than expected under a random distribution of females, and females separated by more than 400 m were less genetically similar than expected. In contrast, there was no evidence of a significant clustering of related males. This suggests that within‐colony dispersal is male biased. We also investigated the best strategies for conserving genetic diversity in this population. All of the four sampled colonies were found to contain distinct components of the genetic diversity of the Wolgan Valley P. penicillata population and loss of any colony is likely to result in the loss of unique alleles. Conservation and management plans should take into account that these colonies represent genetically differentiated discrete subpopulations. This approach is also the best strategy for maintaining the genetic diversity of the populations in this valley.
Testing phylogeographic predictions on an active volcanic island: Brachyderes rugatus (Coleoptera: Curculionidae) on La Palma (Canary Islands)
Authors: EMERSON BRENT C. , FORGIE SHAUN , GOODACRE SARA , OROMÍ PEDRO 
Published: November 2005

AbstractVolcanic islands with well‐characterized geological histories can provide ideal templates for generating and testing phylogeographic predictions. Many studies have sought to utilize these to investigate patterns of colonization and speciation within groups of closely related species across a number of islands. Here we focus attention within a single volcanic island with a well‐characterized geological history to develop and test phylogeographic predictions. We develop phylogeographic predictions within the island of La Palma of the Canary Islands and test these using 69 haplotypes from 570 base pairs of mitochondrial DNA cytochrome oxidase II sequence data for 138 individuals of Brachyderes rugatus rugatus, a local endemic subspecies of curculionid beetle occurring throughout the island in the forests of Pinus canariensis. Although geological data do provide some explanatory power for the phylogeographic patterns found, our network‐based analyses reveal a more complicated phylogeographic history than initial predictions generated from data on the geological history of the island. Reciprocal illumination of geological and phylogeographic history is also demonstrated with previous geological speculation gaining phylogeographic corroboration from our analyses.
Human CD56bright and CD56dim Natural Killer Cell Subsets Respond Differentially to Direct Stimulation with Mycobacterium bovis Bacillus Calmette‐Guérin
Authors: Batoni G. , Esin S. , Favilli F. , Pardini M. , Bottai D. , Maisetta G. , Florio W. , Campa M. 
Published: November 2005

Abstract Mycobacterium bovis bacillus Calmette‐Guérin (BCG) is capable of directly stimulating several effector functions of human natural killer (NK) cells in the absence of interleukin‐12 and professional antigen presenting cells. To assess the contribution of two main human NK‐cell subsets (CD56dim and CD56bright) to the overall in vitro NK‐cell response to BCG, peripheral blood mononuclear cells depleted of nylon wool‐adherent cells or purified NK cells were stimulated with live BCG. By combining intranuclear bromodeoxyuridine (BrdU) staining and analysis of CD56 marker intensity, statistically higher percentages of BrdU+ cells were found among the CD56bright subset than the CD56dim subset after 6 days of stimulation with BCG. Similarly, evaluation of intracellular interferon‐γ (IFN‐γ) revealed that CD56bright cells were those mainly involved in IFN‐γ production in response to BCG. In contrast, the CD56dim subset contained higher levels of perforin and granzyme A, two key molecules for exocytosis‐mediated cytotoxicity, than the CD56bright subset. Although 16–20‐h stimulation with BCG did not substantially alter the expression of cytotoxic molecules by the two subsets, a decrease in perforin content was observed in the CD56dim, but not in the CD56bright subset, following 4‐h incubation with the NK‐sensitive target K562 cell line. This decrease in perforin content correlated with the induction by BCG‐stimulated NK cells, of early markers of apoptosis on target cells to a greater extent than unstimulated cells suggesting a major role for the CD56dim subset in cytotoxic activity in response to BCG. Taken together, these results demonstrate that CD56bright and CD56dim human NK‐cell subsets exert different functional activities in response to a live bacterial pathogen.
Neutrophil Activation in Anti‐Proteinase 3‐Positive Vasculitis – a Prospective Study
Authors: Wikman A. , Lundahl J. , Jacobson S. H. 
Published: November 2005

Abstract In vitro studies have demonstrated that antineutrophil cytoplasmic antibodies (ANCA) have the capacity to activate neutrophils. Whether circulating neutrophils in patients with vasculitis are activated is under debate.Eight consecutive patients with antiproteinase 3 (PR3) positive acute vasculitis were included in this prospective study. Neutrophil expression of adhesion molecules, Fc‐receptors and the ANCA‐antigen PR3 was analysed and clinical characteristics were documented at inclusion and after 1, 3, 6 and 9 months in the same individuals. As additional markers of inflammation and endothelial activation interleukin‐8 and soluble vascular cell adhesion molecule‐1 in serum were analysed at the same time points.The expression of adhesion molecules on circulating neutrophils, CD62L and CD11b after in vitro N‐formyl‐methionyl‐leucyl‐phenylalanine stimulation was significantly decreased at diagnosis and after 1 month but returned to normal levels after 3–9 months. The neutrophil expression of Fc‐receptor IIIb (CD 16) was decreased at diagnosis but normalized after 1–9 months.The main finding was an activated neutrophil adhesion phenotype at diagnosis and after 1 month, with normalized expression of adhesion molecules at 3–9 months. A pathological regulation of adhesion molecules may have implications on the endothelial damage seen in vasculitis.
The Role of ERK5 in T‐Cell Signalling
Authors: Garaude J. , Kaminski S. , Cherni S. , Hipskind R. A. , Villalba M. 
Published: November 2005

AbstractThe mitogen‐activated protein kinase (MAPK) ERK5 plays an important role in mammary epithelial proliferation, endothelial cell survival and normal embryonic development. In nonhaematopoietic cells, mitogenic and stress signals activate the ERK5 cascade. Here, we investigated the role of the ERK5 pathway in T‐cell activation and show that primary and leukaemic T cells express ERK5, whose activating phosphorylation is induced by antibodies against CD3 but not by phorbol myristate acetate treatment. ERK5 localized in the cytosol and nucleus in quiescent and activated T cells. In the latter, ERK5 phosphorylation was mainly observed in the nucleus. Selective activation of the ERK5 cascade by transfecting constitutively active MEK5 and wildtype ERK5 induced a reporter gene driven by the IL‐2 promoter while barely affecting CD69 expression. These results suggest a new role for the ERK5 cascade in intracellular signalling in T cells.
Elevated Serum Levels of Soluble E‐Cadherin in Patients with Primary Sjögren's Syndrome
Authors: Jonsson M. V. , Salomonsson S. , Øijordsbakken G. , Skarstein K. 
Published: November 2005

AbstractThe aim of this study was to investigate serum levels of soluble E‐cadherin (sE‐cadherin) in relation to lymphocytic organization and to characterize the expression of E‐cadherin and integrin αEβ7/CD103 in salivary gland epithelium of patients with Sjögren's syndrome (SS). Serum levels of sE‐cadherin were significantly increased in SS compared to non‐SS and nonsignificantly in germinal centre (GC)+ compared to GC– patients. Membrane‐bound E‐cadherin was detected on the majority of acinar and ductal epithelial cells in both SS and non‐SS. αEβ7/CD103‐positive cells were found scattered in focal infiltrates and GC, and in small clusters close to ductal and acinar epithelium at an increased level in SS compared to non‐SS. Interestingly, E‐cadherin‐positive cells were detected randomly dispersed in focal lymphocytic infiltrates in 10/21 patients. By double‐labelling, the cells with the E‐cadherin‐positive component were identified as CD68+ macrophages. Elevated serum levels of sE‐cadherin indicate an increased epithelial cell turnover and shedding, and sE‐cadherin deserves further analysis as a potential diagnostic tool for SS.
Predicting the pathway to wind pollination: heritabilities and genetic correlations of inflorescence traits associated with wind pollination in Schiedea salicaria (Caryophyllaceae)
Authors: Weller S. G. , Sakai A. K. , Culley T. M. , Campbell D. R. , Dunbar-wallis A. K. 
Published: November 2005

Abstract
The transition from biotic to abiotic pollination was investigated using Schiedea, a genus exhibiting a remarkable diversity of inflorescence architecture associated with pollination biology. Heritabilities and genetic correlations of inflorescence traits were estimated in gynodioecious Schiedea salicaria (Caryophyllaceae), a species that has likely undergone a recent transition to wind-pollination. Using a partial diallel crossing design, significant narrow-sense heritabilities were detected for inflorescence condensation (h2 = 0.56 to 0.68 in the two sexes) and other traits related to the extent of wind pollination in Schiedea species. Heritabilities were generally higher in hermaphrodites than in females. Strong genetic correlations may constrain the evolution of some inflorescence traits that facilitate wind pollination, such as simultaneous shortening of inflorescence length and elongation of the subtending internode. The presence of significant narrow-sense heritabilities for traits associated with wind pollination suggests, however, that selection for more effective wind pollination in the windy, pollinator-limited environments where S. salicaria grows could lead to the evolution of the highly condensed inflorescences characteristic of other wind-pollinated species of Schiedea.
Health needs in rural areas and the efficacy and cost‐effectiveness of doctors and nurses
Authors: Vlastos Ioannis M. , Mpatistakis Antonios G. , Gkouskou Kalliopi K. 
Published: November 2005

AbstractObjective:  Because of a lack of GPs in rural areas of Greece it is mandatory for junior doctors to offer medical service in those areas for a year. The aim of this study is to determine the possibility of replacement of internships with nurses and to suggest the most cost‐effective way of covering health needs in remote areas. Design:  Regional survey. Setting and participants:  Patients of primary care offices in two remote areas of Crete, Greece within a year. Main outcome measures:  Comparative analysis of the level of preventive medicine (estimated by questionnaires) and health needs in the two areas. The reasons for visiting medical offices, references rates, percentages of glucose and blood pressure regulation are also studied. Results:  Prescription of drugs for chronic diseases and blood pressure counting were the main reasons for office visits (2868/4594). Respiratory track infections (364/4594) follow. Apart from the high percentages of uncontrolled patients with blood pressure (34%) and diabetes mellitus (14%) there is a high percentage of ignorance or wrong opinions concerning preventive medicine, for example only 63% knew the value of a pap test. Conclusions:  More than two‐thirds of ‘medical’ visits in rural areas were for acts that nurses could easily do. The easy access to a junior doctor did not promote preventive medicine. Replacement of junior doctors with properly trained nurses cooperating with GPs responsible for greater regions would be more cost‐effective than junior doctors improving health in rural areas. Legislation should change, mainly with regard to repeat prescriptions, in order to reduce house visits.
The effect of angle on dovetail fretting experiments in Ti‐6Al‐4V
Authors: GOLDEN P. J. , NICHOLAS T. 
Published: November 2005

ABSTRACTThe objective of this work was to compare the fretting fatigue performance of Ti‐6Al‐4V dovetail specimens on Ti‐6Al‐4V pads having various contact angles typical of engine hardware; 35°, 45° and 55° dovetail angles were considered. The dovetail fixtures were instrumented with strain gages so that the local normal and shear contact forces could be calculated. The contact force hysteresis loops were recorded showing the stick‐slip history. At R= 0.1, gross slip was observed for several thousand cycles followed by partial slip after the average coefficient of friction increased. At R= 0.5, gross slip was present only during the first half cycle. During partial slip, the slope of the shear versus normal force was a function of the dovetail angle. The local contact loads, therefore, differed for the same remotely applied force. Despite this, the fretting fatigue life depended primarily on the remotely applied load not dovetail angle.
Dynamic initiation and propagation behaviour of sub‐interfacial cracks in PMMA/aluminium bi‐material system
Authors: YAO X. F. , YEH H. Y. , XU W. 
Published: November 2005

ABSTRACTThe paper describes studies on the dynamic initiation and growth of sub‐interfacial cracks in a PMMA/aluminium bi‐material system using high‐speed photography combined with the method of caustics. Dynamic fracture phenomena such as crack propagation trajectories, crack velocity, phase angle and stress intensity factor were determined from recordings of a series of dynamic caustic patterns surrounding the propagating sub‐interfacial crack tip.. There is a considerable influence of the distance between the interface and the crack on fracture characterization.
Rhythms in clock proteins in the mouse pars tuberalis depend on MT1 melatonin receptor signalling
Authors: Jilg Antje , Moek Juliane , Weaver David R. , Korf Horst‐Werner , Stehle Jörg H. , Von Gall Charlotte 
Published: November 2005

AbstractMelatonin provides a rhythmic neuroendocrine output, driven by a central circadian clock that encodes information about phase and length of the night. In the hypophyseal pars tuberalis (PT), melatonin is crucial for rhythmic expression of the clock genes mPer1 and mCry1, and melatonin acting in the PT influences prolactin secretion from the pars distalis. To examine further the possibility of a circadian clockwork functioning in the PT, and the impact of melatonin on this tissue, we assessed circadian clock proteins by immunohistochemistry and compared the diurnal expression in the PT of wild type (WT), and MT1 melatonin receptor‐deficient (MT1–/–) mice. While in the PT of WT mice mPER1, mPER2, and mCRY1 showed a pronounced rhythm, mCRY2, CLOCK, and BMAL1 were constitutively present. Despite reported differences in maximal levels and timing of mCry1, mPer1, and mPer2 RNAs, the corresponding protein levels peaked simultaneously during late day, suggesting a codependency for their stabilization and/or nuclear entry. MT1–/– mice had reduced levels of mPER1, mCRY1, CLOCK and BMAL1, consistent with the earlier reported reduction in mRNA expression of these clock genes. Surprisingly, mPER2‐immunoreaction was constitutively low, although mPer2 was rhythmically expressed in the PT of MT1–/– mice. This suggests that mPER2 is degraded due to the reduced levels of its stabilizing interaction partners mPER1 and mCRY1. The results show that melatonin, acting through the MT1, determines availability of the circadian proteins mPER1, mPER2 and mCRY1 and thus plays a crucial role in regulating rhythmicity in PT cells.
Afferent–target interactions during olivocerebellar development: transcommissural reinnervation indicates interdependence of Purkinje cell maturation and climbing fibre synapse elimination
Authors: Lohof Ann M. , Mariani Jean , Sherrard Rachel M. 
Published: November 2005

AbstractWe have used a model of postlesional reinnervation to observe the interactions between synaptic partners during neosynaptogenesis to determine how the developmental states of the pre‐ and postsynaptic cells influence circuit maturation. After unilateral transection of the neonatal rat olivocerebellar pathway (pedunculotomy), axons from the remaining ipsilateral inferior olive grow into the denervated hemicerebellum and develop climbing fibre (CF) terminal arbors on Purkinje cells (PCs) at a later stage of development than normal. However, the significance of delayed CF‐PC interactions on subsequent circuit maturation remains poorly defined. To examine this question, we recorded CF‐induced currents in PCs and analysed PC morphology during the first two postnatal weeks in control animals and following left unilateral inferior cerebellar pedunculotomy on postnatal day (P)3. Our results show that transcommissural olivary axons multiply‐reinnervate PCs in the denervated hemisphere over 4 days following pedunculotomy. Each PC received fewer CFs than did age‐matched controls and the maximal multi‐reinnervation was reached on P7, 2 days later than in controls. Consequently, the onset of CF synapse elimination in reinnervated PCs was delayed, but then proceeded in parallel with controls so that all PCs were monoinnervated by P15. Furthermore, reinnervated PCs had delayed dendritic maturation and subsequent dendritic abnormalities consistent with the role of CF innervation in PC dendritic growth. Thus, within the olivocerebellar system, our data suggest that target neurons depend upon sufficient afferent investment arriving at the correct time for their normal development, and maturation of the target neuron regulates afferent selection and therefore circuit maturation.
Deficits in the mid‐brain raphe nuclei and striatum of the AS/AGU rat, a protein kinase C‐γ mutant
Authors: Al‐Fayez M. , Russell D. , Wayne Davies R. , Shiels P. G. , Baker P. J. , Payne A. P. 
Published: November 2005

AbstractThe AS/AGU rat carries a recessive mutation (agu) in the gene coding for the gamma isoform of protein kinase C. The rat is characterized by disordered locomotion and progressive dysfunction of the nigrostriatal dopaminergic (DA) system. This dysfunction begins with a failure to release DA within the striatum and culminates in cell loss within the substantia nigra pars compacta. The present study examines another midbrain aminergic system with input to the basal ganglia, the serotonergic (5‐HT) raphe–striatal system originating in the dorsal raphe nucleus. By 3 months after birth, there is a very substantial reduction in the extracellular levels of 5‐HT in the dorsal caudate‐putamen of the mutants compared with controls (c. 70%). This is accompanied by a proportional increase in the levels of the 5‐HT metabolite 5‐hydroxyindole acetic acid (5‐HIAA). At a later age, there are reductions in whole tissue 5‐HT (and increases in 5‐HIAA) in both the striatum and the region containing the dorsal raphe nucleus, as well as numbers of 5‐HT‐immunoreactive cells in the dorsal raphe nucleus. The median raphe appears to be unaffected. The results are seen in terms of an initial dysfunction in transmitter release leading to cell death, perhaps through the formation of free radicals or neurotoxins.
5‐Bromo‐2′‐deoxyuridine is selectively toxic to neuronal precursors in vitro
Authors: Caldwell Maeve A. , He Xiaoling , Svendsen Clive N. 
Published: November 2005

AbstractThe effect of 5‐bromo‐2′‐deoxyuridine (BrdU) incorporation on the phenotype of progeny derived from expanded E18 rat striatal precursors was examined. BrdU was administered to cultures for 24 h prior to differentiation. Results revealed that there was selective toxicity of this compound to developing TuJ1+ neurons, but not glia, at concentrations used in most labelling studies. Therefore, a BrdU dose–response curve from 0.2 µm to 10 µm was established. The optimum dose of BrdU for labelling cells was 0.2 µm, well below the 1–10 µm recommended concentration. This dose resulted in the survival of significantly more newborn BrdU/TuJ1+ double‐labelled neurons and eliminated the toxic effects of BrdU. Administration of 10 µm BrdU resulted in a significant decrease in extracellular regulated kinase (ERK) phosphorylation compared with untreated cultures, this could be completely restored by the administration of either N‐methyl‐d‐aspartate (NMDA) receptor antagonists such as MK801 or the nitric oxide synthesis inhibitor l‐methyl‐arginine methyl ester (L‐NAME). Our results show that high levels of BrdU are selectively toxic to neurons through a mechanism that activates classical cell death pathways. This has implications for labelling studies both in vivo and in vitro.