bluuebunny/crossref_metadata_2025 huggingface dataset:
An algorithm for interpolation in the pyramid domain‡
Authors: Guitton Antoine , Claerbout Jon
Published: March 2010

With the pyramid transform, 2D dip spectra can be characterized by 1D prediction‐error filters (pefs) and 3D dip spectra by 2D pefs. These filters, contrary to pefs estimated in the frequency‐space domain (ω, x), are frequency independent. Therefore, one pef can be used to interpolate all frequencies. Similarly, one pef can be computed from all frequencies, thus yielding robust estimation of the filter in the presence of noise. This transform takes data from the frequency‐space domain (ω, x) to data in a frequency‐velocity domain (ω, u=ω·x) using a simple mapping procedure that leaves locations in the pyramid domain empty. Missing data in (ω, x)‐space create even more empty bins in (ω, u)‐space. We propose a multi‐stage least‐squares approach where both unknown pefs and missing data are estimated. This approach is tested on synthetic and field data examples where aliasing and irregular spacing are present.
Understanding the HER family in breast cancer: interaction with ligands, dimerization and treatments
Authors: Barros Fabrício F T , Powe Desmond G , Ellis Ian O , Green Andrew R
Published: March 2010

Barros F F T, Powe D G, Ellis I O & Green A R (2010) Histopathology56, 560–572

Understanding the HER family in breast cancer: interaction with ligands, dimerization and treatments

Breast carcinoma is the most frequent type of cancer affecting women. Among the recently described molecular and phenotypic classes of breast cancer, human epidermal growth factor receptor 2 (HER2)‐positive tumours are associated with a poor prognosis. HER2 plays an important role in cancer progression being targeted to provide predictive and prognostic information. Moreover, HER2 is related to cancer resistance against a variety of therapies; however, trastuzumab (herceptin) has proved successful in treatment of this subgroup. Nevertheless, resistance to this drug may be acquired by patients after a period of treatment, which indicates that other molecular mechanisms might influence success of this therapy. Dimerization between members of the HER family may contribute to resistance against treatments due to different combinations that trigger different downstream pathways. This is promoted by ligands, which are expressed as transmembrane precursor protein molecules and have a conserved epidermal growth factor‐like domain. Through resistance to trastuzumab, other drugs are being developed to interact in different domains of HER2 protein. It might be a good strategy to apply new drugs simultaneously to trastuzumab due to act in different domains of HER2. The study of interaction between receptors/ligands will characterize specifically their signalling pathway and understand which strategy to acquire.
High level of apoptosis and low AKT activation in mass screening as opposed to standard neuroblastoma
Authors: Sartelet Hervé , Ohta Shigeru , Barrette Stephane , Rougemont Anne‐Laure , Brevet Marie , Regairaz Marie , Harvey Isabelle , Bernard Chantal , Fabre Monique , Gaboury Louis , Oligny Luc L , Bosq Jacques , Valteau‐Couanet Dominique , Vassal Gilles
Published: March 2010

Sartelet H, Ohta S, Barrette S, Rougemont A‐Laure, Brevet M, Regairaz M, Harvey I, Bernard C, Fabre M, Gaboury L, Oligny L L, Bosq J, Valteau‐Couanet D & Vassal G (2010) Histopathology56, 607–616

High level of apoptosis and low AKT activation in mass screening as opposed to standard neuroblastoma

Aims:  Neuroblastoma is a paediatric solid tumour with a poor outcome except in children <1 year old. Based on catecholamine urinary excretion, mass screening (MS) programmes have been organized but failed to decrease the mortality of this tumour. To test the hypotheses of a spontaneous maturation/differentiation or regression, the levels of poly (ADP‐ribose) polymerase (PARP)‐1, an early apoptosis marker, of PhosphoAKT, a major apoptosis inhibitor, and of maturation/differentiation were compared in standard and in MS neuroblastomas.

Methods and results:  We performed a case–control study of 55 primary tumours and 21 metastases of MS neuroblastomas. Matched controls were standard unscreened neuroblastomas and were paired according to age, stage, and MYCN amplification. The tumours were included in tissue microarrays. Immunohistochemical staining was performed using antibodies against, AKT, phosphoAKT, TRKB and PARP‐1. The expression of PARP‐1 and that of phosphoAKT were significantly higher in standard than in MS neuroblastomas independently of age and stage of the tumour. PhosphoAKT and PARP‐1 expression was significantly correlated in both tumours.

Conclusions:  These data suggest that the better prognosis of patients with MS neuroblastomas compared with classical neuroblastomas was secondary to spontaneous tumour regression mediated by higher levels of apoptosis associated with low activation of AKT.
Correlation of hypoxic signalling to histological grade and outcome in cartilage tumours
Authors: Boeuf Stephane , Bovée Judith V M G , Lehner Burkhard , Hogendoorn Pancras C W , Richter Wiltrud
Published: March 2010

Boeuf S, Bovée J V M G, Lehner B, Hogendoorn P C W & Richter W (2010) Histopathology56, 641–651

Correlation of hypoxic signalling to histological grade and outcome in cartilage tumours

Aims:  The molecular mechanisms underlying the progression of central chondrosarcoma are so far poorly understood. The aim of this study was to identify genes involved in the progression of these tumours by comparison of gene expression and correlation of expression profiles to histological grade and clinical outcome.

Methods and results:  Array‐based gene expression profiling of 19 chondrosarcoma samples was performed. Beside differences in the expression of cartilage matrix molecules, high‐grade chondrosarcoma showed enhanced expression of the matrix metalloproteinase MMP‐2 and of the hypoxia‐inducible molecule galectin 1. Immunohistochemical analysis of galectin 1 and of further hypoxia‐associated proteins was performed on 68 central and peripheral tumour samples. Hypoxia‐inducible factor 1α (HIF‐1α) activation was significantly elevated in high‐grade central chondrosarcoma. A negative correlation of carbonic anhydrase IX expression to metastasis‐free survival was independent of histological grade.

Conclusions:  The expression patterns identified in this study point towards a substantial role for angiogenic and hypoxic signalling in chondrosarcoma progression. The constitutive activation of the transcription factor HIF‐1α in high‐grade chondrosarcoma could play a central role in the regulation of cell metabolism and vascularization in these tumours and may, for this reason, represent a potential target for chondrosarcoma therapy.
The role of topography in structuring the demographic history of the pine processionary moth, Thaumetopoea pityocampa (Lepidoptera: Notodontidae)
Authors: Rousselet Jérôme , Zhao Ruixing , Argal Dallal , Simonato Mauro , Battisti Andrea , Roques Alain , Kerdelhué Carole
Published: March 2010

Aim  We investigated the Quaternary history of the pine processionary moth, Thaumetopoea pityocampa, an oligophagous insect currently expanding its range. We tested the potential role played by mountain ranges during the post‐glacial recolonization of western Europe.

Location  Western Europe, with a focus on the Pyrenees, Massif Central and western Alps.

Methods  Maternal genetic structure was investigated using a fragment of the mitochondrial cytochrome c oxidase subunit I (COI) gene. We analysed 412 individuals from 61 locations and performed maximum likelihood and maximum parsimony phylogenetic analyses and hierarchical analysis of molecular variance, and we investigated signs of past expansion.

Results  A strong phylogeographic pattern was found, with two deeply divergent clades. Surprisingly, these clades were not separated by the Pyrenees but rather were distributed from western to central Iberia and from eastern Iberia to the Italian Peninsula, respectively. This latter group consisted of three shallowly divergent lineages that exhibited strong geographic structure and independent population expansions. The three identified lineages occurred: (1) on both sides of the Pyrenean range, with more genetically diverse populations in the east, (2) from eastern Iberia to western France, with a higher genetic diversity in the south, and (3) from the western Massif Central to Italy. Admixture areas were found at the foot of the Pyrenees and Massif Central.

Main conclusions  The identified genetic lineages were geographically structured, but surprisingly the unsuitable high‐elevation areas of the main mountainous ranges were not responsible for the spatial separation of genetic groups. Rather than acting as barriers to dispersal, mountains appear to have served as refugia during the Pleistocene glaciations, and current distributions largely reflect expansion from these bottlenecked refugial populations. The western and central Iberian clade did not contribute to the northward post‐glacial recolonization of Europe, yet its northern limit does not correspond to the Pyrenees. The different contributions of the identified refugia to post‐glacial expansion might be explained by differences in host plant species richness. For example, the Pyrenean lineage could have been trapped elevationally by tracking montane pines, while the eastern Iberian lineage could have expanded latitudinally by tracking thermophilic lowland pine species.
Epistemology and ethics of evidence‐based medicine: putting goal‐setting in the right place
Authors: Sestini Piersante
Published: March 2010

While evidence‐based medicine (EBM) is often accused on relying on a paradigm of ‘absolute truth’, it is in fact highly consistent with Karl Popper's criterion of demarcation through falsification. Even more relevant, the first three steps of the EBM process are closely patterned on Popper's evolutionary approach of objective knowledge: (1) recognition of a problem; (2) generation of solutions; and (3) selection of the best solution. This places the step 1 of the EBM process (building an answerable question) in a pivotal position for the understanding of the whole process, and underscores a few aspects which are often overlooked in EBM courses. First in this step internal evidence (including personal expertise) must be appraised and integrated in the problem. Second, issues of applicability of the possible solution should be anticipated. Third, and possibly more important, the goal of the intervention should be set at this stage (typically by choosing the outcome in a PICO question). Depending whether or not goals depend on the goals of others, and whether they concern others' voluntary behaviour, goals may be classified as self‐serving, moral, altruistic or moralistic. Thus, delicate ethical questions must be addressed at this stage, which means that patient preferences and values must be carefully sought, so that empathy, counselling and narrative medicine must be mastered to be able to formulate correctly an answerable question. The need to modify the current description of the EBM process to increase the recognition of implicit assumptions and increase the consistency of this model is discussed.
The limitations of randomized controlled trials in predicting effectiveness
Authors: Cartwright Nancy , Munro Eileen
Published: March 2010

What kinds of evidence reliably support predictions of effectiveness for health and social care interventions? There is increasing reliance, not only for health care policy and practice but also for more general social and economic policy deliberation, on evidence that comes from studies whose basic logic is that of JS Mill's method of difference. These include randomized controlled trials, case–control studies, cohort studies, and some uses of causal Bayes nets and counterfactual‐licensing models like ones commonly developed in econometrics. The topic of this paper is the ‘external validity’ of causal conclusions from these kinds of studies. We shall argue two claims. Claim, negative: external validity is the wrong idea; claim, positive: ‘capacities’ are almost always the right idea, if there is a right idea to be had. If we are right about these claims, it makes big problems for policy decisions. Many advice guides for grading policy predictions give top grades to a proposed policy if it has two good Mill's‐method‐of difference studies that support it. But if capacities are to serve as the conduit for support from a method‐of‐difference study to an effectiveness prediction, much more evidence, and much different in kind, is required. We will illustrate the complexities involved with the case of multisystemic therapy, an internationally adopted intervention to try to diminish antisocial behaviour in young people.
Evidence and simplicity: why we should reject homeopathy
Authors: Sehon Scott , Stanley Donald
Published: March 2010

Homeopathic medications are used by millions, and hundreds of millions of dollars are spent on these remedies in the USA alone. In the UK, the NHS covers homeopathic treatments. Nonetheless, homeopathy is held in considerable disrepute by much of the medical and scientific community. Many proponents of homeopathy are well aware of these criticisms but remain unimpressed. The differences of opinion run deep, and the debate seems deadlocked. We aim to shed some light on this situation. We briefly recap some of the major arguments on each side, but we try to go further by making explicit an underlying philosophical presupposition. In particular, we will claim that there is an important principle, which has ancient roots going back at least to Occam, some version of which constrains all empirical reasoning. We call this constraint the simplicity principle. We argue that this is not something specific to a scientific paradigm, but that, all of us, including proponents of homeopathy, are themselves deeply committed to the simplicity principle. However, once the simplicity principle is made explicit and applied to homeopathy, allegiance to homeopathy is clearly seen as irrational. The point is not merely the lack of clinical trials supporting homeopathy; rather, belief in the efficacy of homeopathy leaves a mountain of unexplained mysteries, and thereby flies in the face of the simplicity rule that guides the homeopaths' own reasoning and arguments. If nothing else, we hope that defenders of homeopathy will gain a greater understanding of why critics are so deeply reluctant to accept the efficacy of homeopathic interventions – and that this reluctance is not mere stubbornness or artificial allegiance to western medicine. Finally, we also hope thereby to illustrate the usefulness of philosophy in unearthing presuppositions in seemingly deadlocked debates.
Clinical judgement, expertise and skilled coping
Authors: Thornton Tim
Published: March 2010

Medicine involves specific practical expertise as well as more general context‐independent medical knowledge. This raises the question, what is the nature of the expertise involved? Is there a model of clinical judgement or understanding that can accommodate both elements? This paper begins with a summary of a published account of the kinds of situation‐specific skill found in anaesthesia. It authors claim that such skills are often neglected because of a prejudice in favour of the ‘technical rationality’ exemplified in evidence‐based medicine but they do not themselves offer a general account of the relation of practical expertise and general medical knowledge. The philosopher Hubert Dreyfus provides one model of the relation of general knowledge to situation‐specific skilled coping. He claims that the former logically depends on the latter and provides two arguments, which I articulate in the second section, for this. But he mars those arguments by building in the further assumption that such situation‐specific responses must be understood as concept‐free and thus mindless. That assumption is held in place by three arguments all of which I criticize in the next section to give a unified account of clinical judgement as both practical and conceptually structured and thus justified in the face of a prejudice in favour of ‘technical rationality’.
Polanyi's tacit knowing and the relevance of epistemology to clinical medicine
Authors: Henry Stephen G.
Published: March 2010

Most clinicians take for granted a simple, reductionist understanding of medical knowledge that is at odds with how they actually practice medicine; routine medical decisions incorporate more complicated kinds of information than most standard accounts of medical reasoning suggest. A better understanding of the structure and function of knowledge in medicine can lead to practical improvements in clinical medicine. This understanding requires some familiarity with epistemology, the study of knowledge and its structure, in medicine. Michael Polanyi's theory of tacit knowing is advanced as the basis for developing a more accurate understanding of medical knowledge. Tacit knowing, which explores the taken‐for‐granted background knowledge that underlies all human knowing, is explained in detail with a focus on its relevance for clinical medicine. The implications of recognizing tacit knowing in medicine and medical decisions are discussed. These include the ability to explain the importance of the clinical encounter in medical practice, mechanisms for analysing patient and doctor as persons, and the need for humility given the uncertainty that the tacit dimension injects into all medical decisions. This more robust medical epistemology allows clinicians to better articulate the nature and importance of patient‐centred care, to avoid pitfalls inherent in reductionist approaches to medical knowledge, and to think more clearly about the relationships between medicine and health care at the individual and population levels.
Whatever suits you: unpicking personalization for the NHS
Authors: Cribb Alan , Owens John
Published: March 2010

In this paper we argue that policy calls for personalization or ‘tailored’ services derive a large part of their appeal from the way they ‘fudge together’ different things. Using the recent policy discourses surrounding personalization in the UK NHS as a case study we illustrate the policy ‘work’ that is accomplished by this vagueness and focus in on one important fudge – that between a health service tailored to people's medically defined needs and one tailored to people's wants. Our analysis highlights some of the fundamental philosophical and political questions that need to be addressed before personalization can take shape as a coherent policy option. We also highlight the potential scale of the implications personalization has for the welfare state and argue that such implications warrant greater discussion than is currently being afforded to them. We conclude that philosophical analysis is crucial for guiding the redirection of services implied by personalization discourses. The process of selecting and justifying the way in which the personalization agenda is advanced requires both an analysis of the relationships between needs and wants in human flourishing and an explicit reconsideration of the purpose of the welfare state.
Narrative evidence and evidence‐based medicine
Authors: Misak Cheryl J.
Published: March 2010

I argue that evidence‐based medicine (EBM) imposes methodological limits that constrain the practice and study of medicine in unfortunate ways. EBM attempts to rid the study of medicine of the subjectivity of individual judgements, while in fact, any use of any kind of evidence requires judgement. On this basis, I argue that there are compelling reasons to broaden the range of evidence employed in EBM, and in particular, to include both straightforward and evaluative narratives. This would mark a shift from the current focus of EBM on purely quantitative data to the inclusion of qualitative data as well. I conclude by emphasizing that objectivity in medicine must come not from the exclusion of wide swaths of potentially valuable evidence, but from the careful application of our critical practices.
Redox sensing by a Rex‐family repressor is involved in the regulation of anaerobic gene expression in Staphylococcus aureus
Authors: Pagels Martin , Fuchs Stephan , Pané‐Farré Jan , Kohler Christian , Menschner Leonhard , Hecker Michael , McNamarra Peter J. , Bauer Mikael C. , Von Wachenfeldt Claes , Liebeke Manuel , Lalk Michael , Sander Gunnar , Von Eiff Christof , Proctor Richard A. , Engelmann Susanne
Published: March 2010

An alignment of upstream regions of anaerobically induced genes in Staphylococcus aureus revealed the presence of an inverted repeat, corresponding to Rex binding sites in Streptomyces coelicolor. Gel shift experiments of selected upstream regions demonstrated that the redox‐sensing regulator Rex of S. aureus binds to this inverted repeat. The binding sequence – TTGTGAAW4TTCACAA – is highly conserved in S. aureus. Rex binding to this sequence leads to the repression of genes located downstream. The binding activity of Rex is enhanced by NAD+ while NADH, which competes with NAD+ for Rex binding, decreases the activity of Rex. The impact of Rex on global protein synthesis and on the activity of fermentation pathways under aerobic and anaerobic conditions was analysed by using a rex‐deficient strain. A direct regulatory effect of Rex on the expression of pathways that lead to anaerobic NAD+ regeneration, such as lactate, formate and ethanol formation, nitrate respiration, and ATP synthesis, is verified. Rex can be considered a central regulator of anaerobic metabolism in S. aureus. Since the activity of lactate dehydrogenase enables S. aureus to resist NO stress and thus the innate immune response, our data suggest that deactivation of Rex is a prerequisite for this phenomenon.
Human allergy to environmental pet danders: a public health perspective
Authors: Morris Daniel O.
Published: March 2010

The prevalence of human allergy to pet danders has increased rapidly over the past six decades, as a consequence of lifestyle changes that have enhanced ambient exposure to pet allergens. This is a problem of global public health importance, as the morbidity associated with allergic diseases disproportionately affects socio‐economically disadvantaged populations, particularly children. Although the public often seeks advice from veterinary health‐care professionals regarding healthy pet ownership practices, including strategies for reducing residential pet dander exposure, many misconceptions persist in the public domain regarding pet dander allergy, such as the belief that certain dog and cat breeds are ‘hypoallergenic’ due to their hair/coat type. This review considers the epidemiology of human exposure to the major cat and dog dander allergens, Fel d 1 and Can f 1 respectively, and the sensitization mechanisms to them, including the hygiene hypothesis and the putative role of bacterial endotoxin. The literature regarding primary and secondary exposures in different ambient environments is explored including threshold effects that influence allergen sensitization and elicitation of symptoms, and environmental intervention strategies that seek to reduce allergen exposure. Pet‐specific factors, including the aetiopathogenesis of the several cat and dog allergens that have been characterized to the molecular level, individual animal characteristics that influence Fel d 1 and Can f 1 shedding, and pet‐directed interventions intended to reduce allergen dispersal, are discussed.
Stratum corneum TARC level is a new indicator of lesional skin inflammation in atopic dermatitis
Authors: Morita E. , Takahashi H. , Niihara H. , Dekio I. , Sumikawa Y. , Murakami Y. , Matsunaka H.
Published: March 2010

To cite this article: Morita E, Takahashi H, Niihara H, Dekio I, Sumikawa Y, Murakami Y, Matsunaka H. Stratum corneum TARC level is a new indicator of lesional skin inflammation in atopic dermatitis. Allergy 2010; 65: 1166–1172.

Background:  Management of atopic dermatitis (AD) requires judging the symptoms of local skin lesions and prescribing a suitable treatment. However, no method has been established in which objective measures can be used to evaluate the severity of local symptoms. We established a method for measuring thymus and activation‐regulated chemokine (TARC) levels in the stratum corneum (scTARC), and examined whether the scTARC can be used as an indicator of the severity of local skin lesions in patients with AD.

Methods:  Stratum corneum was obtained from patients with AD by tape‐stripping, and scTARC was evaluated using a TARC‐specific antibody followed by image analysis. The scTARC was examined to determine correlation with the severity of local skin lesions (the severity of erythema, edema/papule, oozing/crusts, excoriations, lichenification, and xerosis) as well as with the severity scoring of atopic dermatitis (SCORAD) index, serum TARC level, serum IgE level, serum lactate dehydrogenase (LDH) level, interleukin (IL)‐4‐producing T cell ratio (Th2 cell ratio), and blood eosinophil count.

Results:  The scTARC was correlated with the severity of local skin lesions, especially with the erythema, edema/papule, and oozing/crusts score. The scTARC in the most severe lesions was also correlated with the SCORAD index, serum TARC level, serum IgE level, and blood eosinophil count. The scTARC was not, however, correlated with the serum LDH level and Th2 cell ratio.

Conclusion:  An immunofluorescent technique combined with tape‐stripping was used to measure scTARC. The scTARC can be used as an indicator of the severity of local acute inflammation in patients with AD.
Exposure to cadmium‐contaminated soils increases allergenicity of Poa annua L. pollen
Authors: Aina R. , Asero R. , Ghiani A. , Marconi G. , Albertini E. , Citterio S.
Published: March 2010

To cite this article: Aina R, Asero R, Ghiani A, Marconi G, Albertini E, Citterio S. Exposure to cadmium‐contaminated soils increases allergenicity of Poa annua L. pollen. Allergy 2010; 65: 1313–1321.

Background:  Pollution is considered as one main cause for the increase of allergic diseases. Air pollutants may cause and worsen airway diseases and are probably able to make pollen allergens more aggressive. Previous studies looked at traffic‐related air pollution, but no data about the effects of polluted soils on pollen allergens are available. We aimed to assess the effects of plant exposure to cadmium‐contaminated soil on allergenicity of the annual blue grass, Poa annua L, pollen.

Methods:  Poa plants were grown in soil contaminated or not contaminated (control) with cadmium. At flowering, mature pollen was analyzed by microscopy, to calculate the percentage of pollen grains releasing cytoplasmic granules, and by proteomic techniques to analyze allergen proteins. Allergens were identified by sera from grass pollen–allergic patients and by mass spectrometry.

Results:  Pollen from Cd‐exposed plants released a higher amount of allergenic proteins than control plants. Moreover, Cd‐exposed pollen released allergens‐containing cytoplasmic grains much more promptly than control pollen. Group 1 and 5 allergens, the major grass pollen allergens, were detected both in control and Cd‐exposed extracts. These were the only allergens reacting with patient’s sera in control pollen, whereas additional proteins strengthening the signal in the gel region reacting with patient’s sera were present in Cd‐exposed pollen. These included a pectinesterase, a lipase, a nuclease, and a secretory peroxydase. Moreover, a PR3 class I chitinase‐like protein was also immunodetected in exposed plants.

Conclusion:  Pollen content of plants grown in Cd‐contaminated soils is more easily released in the environment and also shows an increased propensity to bind specific IgE.
Safety and cardiovascular behavior during pulmonary function in patients with Marfan syndrome
Authors: Cipriano GFB , Peres PAT , Cipriano G , Arena R , Carvalho AC
Published: March 2010

Cipriano GFB, Peres PAT, Cipriano G Jr, Arena R, Carvalho AC. Safety and cardiovascular behavior during pulmonary function in patients with Marfan syndrome.

Marfan syndrome (MS) is a dominant autosomal connective tissue disease that impacts multiple systems, such as the cardiovascular system, tissue viscoelastic properties, bone calcification matrix and, most specific to the present investigation, pulmonary parenchyma. The aim of the present study was to evaluate pulmonary function (PF) in patients with MS and relate it to thoracic cage abnormalities (TCA) and the occurrence of cardiac arrhythmias during the spirometric exam (SE). A sample of 75 subjects (46 with MS) underwent clinical, anthropometric, echocardiographic, radiographic and PF evaluation; 51 subjects (33 with MS) had their electrocardiogram (ECG) information evaluated during PF. These individuals were matched and compared with a healthy control group (CG). Forced vital capacity (FVC) and forced expiratory volume (FEV) in the first second (FEV1) in the patients with MS were significantly lower in comparison with the CG (p = 0.012 and 0.0006) and predicted values (p = 0.04 and 0.003). Subgroup analysis based on TCA revealed differences between patients with MS with two combined abnormalities (scoliosis + pectus) in comparison with both the CG (p = 0.012 and 0.002) and patients without abnormalities (p = 0.05 and 0.006). There were no differences regarding the occurrence of arrhythmia during exertion on the SE. There was a correlation between clinical history, cardiovascular behavior and PF. PF is reduced in patients with MS, and deformities in the thoracic cage appear to contribute to this reduction. Despite the apparent structural alterations in the cardiovascular system in this population, exertion during the SE appears to be safe.
Cryptic speciation in Hymenoscyphus albidus
Authors: Queloz V. , Grünig C. R. , Berndt R. , Kowalski T. , Sieber T. N. , Holdenrieder O.
Published: March 2010

Ash dieback caused by the mitosporic ascomycete Chalara fraxinea is a novel disease of major concern affecting Fraxinus excelsior and Fraxinus angustifolia in large parts of Europe. Recently, its teleomorph was detected and assigned to Hymenoscyphus albidus, which has been known from Europe since 1851. In this study, we present molecular evidence for the existence of two morphologically very similar taxa, H. albidus, which is lectotypified and Hymenoscyphus pseudoalbidus sp. nov. Differences were found between the species in the loci calmodulin, translation elongation factor 1‐α and the internal transcribed spacers of the rDNA genes, and strong differentiation was obtained with ISSR markers. It is likely that H. albidus is a non‐pathogenic species, whereas H. pseudoalbidus is a virulent species causing ash dieback. Genotyping herbarium specimens showed that H. pseudoalbidus has been present in Switzerland for at least 30 years prior to the outbreak of the epidemic.
Different pharmacological properties of the optical isomers of MN9202, a novel 1,4‐dihydropyridine Ca2+ channel modulator, in rat ventricular myocytes
Authors: Li Xiao‐Qiang , Cao Wei , Zeng Ai‐Guo , Yang Zhi‐Fu , Xing Bin , Dong Ling , Zhang Hai‐Feng , Mei Qi‐Bing
Published: March 2010

1. We have shown previously that 1,4‐dihydro‐2,6‐dimethyl‐4‐(3‐nitrophenyl)‐3,5‐pyridinedicarboxylic acid pentyl methyl ester (MN9202), a new 1,4‐dihydropyridine Ca2+ channel modulator, has significant hypotensive effects and favourable pharmacokinetic characteristics. As a chiral molecule, MN9202 has two optical isomers. The aim of the present study was to evaluate the pharmacological properties of the two enantiomers.

2. The two enantiomers, S‐(−)‐ and R‐(+)‐MN9202, were obtained by HPLC. At 1 μmol/L, both racemic MN9202 and S‐(−)‐MN9202 decreased the contractility of rat ventricular myocytes by 54.0 and 64.4%, respectively, compared with control, whereas R‐(+)‐MN9202 enhanced cell shortening by 10.1%. At 1 μmol/L, racemic MN9202 markedly reduced calcium transient (CaT) and L‐type Ca2+ channel current (ICa,L) by 60.0 and 50.7%, respectively, whereas the reductions in CaT and ICa,L produced by 1 μmol/L S‐(−)‐MN9202 were greater still (62.2 and 65.7%, respectively). In contrast, 1 μmol/L R‐(+)‐MN9202 increased CaT and ICa,L by 11.4 and 10.6%, respectively. Furthermore, findings from kinetics studies of ICa,L revealed that the steady state inactivation curve of ICa,L was shifted towards a hyperpolarizing potential by S‐(−)‐MN9202, but towards a depolarizing potential by R‐(+)‐MN9202. These results demonstrate different effects of R‐(+)‐MN9202 and S‐(−)‐MN9202.

3. In conclusion, the findings of the present study suggest that the chirality of MN9202 results in opposing pharmacological properties of its two enantiomers: S‐(−)‐MN9202 may be responsible for the therapeutic effects of racemic MN9202, whereas R‐(+)‐MN9202 contributes to it unwanted effects. The findings of the present study also indicate that MN9202 may be used as a new probe with which to investigate the structure–function relationships of Ca2+ channels.
GSTA1, GSTO1 and GSTO2 gene polymorphisms in Italian asthma patients
Authors: Polimanti Renato , Piacentini Sara , Moscatelli Barbara , Pellicciotti Luisa , Manfellotto Dario , Fuciarelli Maria
Published: March 2010

1. Previous studies have established that genetic alterations in glutathione S‐transferase enzymes may change the ability of the airway to deal with toxic substances and increase the risk of asthma. The present study analysed the association between asthma and GSTA1, GSTO1 and GSTO2 gene polymorphisms.

2. The GSTA1*‐69C/T, GSTO1*A140D and GSTO2*N142D polymorphisms were detected by polymerase chain reaction–restriction fragment length polymorphism, whereas the GSTO1*E155del polymorphism was detected using the confronting two‐pair primer method.

3. Distribution of the GSTA1*‐69C/T genotype differed significantly between asthmatics and controls. Subjects with at least one allele ‐69T in the GSTA1 genotype have an increased risk of asthma (odds ratio (OR) 3.45; 95% confidence interval (CI) 1.80–6.62). The distribution of the GSTO1 genotype was nearly equal between the control group and asthmatics, however, the distribution of the GSTO2 gene differed significantly between asthmatics and controls (Chi‐squared test). Subjects who had the GSTO2 homozygous D142 genotype were found to have an increased risk of asthma (OR 5.91; 95% CI 1.80–19.42).

4. The results show a potential association between the GST genes and asthma. This is particularly significant given that, in the literature, there are no epidemiological studies on alpha and omega classes of glutathione transferases in asthma.
Rate‐limiting factors of cholesterol efflux in reverse cholesterol transport: Acceptors and donors
Authors: Fu Ying
Published: March 2010

1. Plasma levels of high‐density lipoprotein (HDL) are believed to be inversely related to coronary artery disease. High‐density lipoprotein plays a key role in the process of reverse cholesterol transport, by which HDL is able to extract excess cholesterol from peripheral tissues and transfer it to the liver for biliary excretion.

2. Efflux of lipids (cholesterol and phospholipids) is the first step in reverse cholesterol transport. Several cellular membrane transporters, including ABCA1 and ABCG1, as well as scavenger receptor (SR)‐BI receptor, are believed to facilitate the active efflux of cholesterol to lipid‐poor apolipoprotein A‐I and mature HDL, respectively. Furthermore, overexpression or deletion of one or more specific genes supports the view that HDL is involved in cholesterol efflux.

3. In conclusion, current evidence supports a critical role for HDL in atheroprotection via an active efflux pathway through reverse cholesterol transport, with the substantial support of appropriate functions of cell donors.
Anti‐atherogenic effects of high‐density lipoprotein on nitric oxide synthesis in the endothelium
Authors: Andrews Karen L , Moore Xiao L , Chin‐Dusting Jaye PF
Published: March 2010

1. The endothelium is critical in the control of vascular haemodynamics and haemostasis. Endothelial dysfunction, typically characterized by decreased nitric oxide bioavailability and response to endothelium‐dependent agonists, is well accepted as a defining characteristic of early atherosclerosis.

2. Numerous epidemiological studies have reported that increased levels of circulating HDL are vasculoprotective and reduce the incidence of adverse cardiovascular events. Traditionally, these effects have been attributed to the ability of HDL to remove cholesterol from cells via reverse cholesterol transport. However, there is increasing evidence that the beneficial effects on the endothelium by HDL encompass its anti‐inflammatory, antithrombotic and anti‐oxidative properties, which include the release of nitric oxide (NO).

3. This review highlights recent findings on the importance of HDL in reducing atherosclerotic risk. We focus on the beneficial effects of HDL‐induced NO release and how this relates to endothelial dysfunction and on the effect of HDL on vascular repair via endothelial progenitor cells.
The epidemiological association of altitude with chronic kidney disease: Evidence of protective effect
Authors: GHAHRAMANI NASROLLAH , AHMED FARIS , AL‐LAHAM AMMAR , LENGERICH EUGENE J.
Published: March 2010

Aims:  We sought to determine the association between living at high altitudes and the estimated glomerular filtration rate (eGFR) and also to determine the prevalence of end‐stage renal disease (ESRD) at various altitudes.

Methods:  In the first part of the study, we used data from the National Health and Nutrition Examination Survey III to examine the association between altitude of residence and eGFR. In the second part, we used the United States Renal Data System to study the association between altitude and prevalence of ESRD. The query revealed an ESRD prevalence of 485 012 for the year 2005. The prevalence rates were merged with the zip codes dataset.

Results:  The mean eGFR was significantly increased at higher altitudes (78.4 ± 21.6 vs 85.4 ± 26.8 mL/min for categories 1 and 5, respectively; P < 0.05). In the analysis of the United States Renal Data System data for prevalence of ESRD, we found a significantly lower prevalence at the altitude of 523 feet and higher.

Conclusion:  Using a population‐based approach, our study demonstrates an association between altitude and renal function. This association is independent of all factors studied and is reached at approximately 250 feet. There is also a negative association between the prevalence of ESRD and altitude of residence. Further studies are needed to elucidate the pathophysiological basis of these epidemiological findings.
Serum prostate‐specific antigen is better correlated to body surface area than body mass index in a population of healthy Korean men
Authors: Song Miho , Doo Seung Whan , Yang Won Jae , Song Yun Seob , Kim Yongbae
Published: March 2010

It has been suggested that the larger vascular volume among obese men causes a dilution effect, decreasing the concentration of serum prostate‐specific antigen (PSA). However, plasma volume is proportional to body surface area (BSA) rather than to body mass index (BMI). We determined whether serum PSA level is better correlated to BSA than BMI in a population of ostensibly healthy Korean men. Data from 2604 men who visited our health promotion center were evaluated. All men underwent anthropometric measurements, digital rectal examination, serum PSA determination, and transrectal ultrasound examination. The correlation between serum PSA and other parameters was statistically analyzed. The mean age was 49.9 years and the mean serum PSA level was 1.14ng/mL. The multivariate analysis revealed that the serum PSA was positively correlated with age, prostate volume, and negatively correlated with BSA only and not with BMI. In addition, BSA, rather than BMI, was the significant factor in predicting the prostate volume. Our results suggest that men with larger BSA (rather than BMI), have larger prostate volumes, and lower serum PSA.
Laparoscopic radical prostatectomy: Transfer validity
Authors: Erdogru Tibet , Yucel Selcuk , Frede Thomas , Baykara Mehmet , Rassweiler Jens , Teber Dogu
Published: March 2010

Objectives:  The impact of a formal fellowship training program on the independent practice of the trainees (i.e. transfer validity) has not been evaluated. We analyzed the transfer validity of a structured curriculum in an in‐door as well as an out‐door setting.

Methods:  After completing their training, two fourth generation laparoscopic surgeons who started at the same time compared operative parameters and oncological outcomes in their independent practice, prospectively analyzing the next 100 patients in each. One surgeon continued laparoscopic radical prostatectomy (LRP) in the same center of excellence (Group‐In), whereas the other implemented the procedure in a separate academic center (Group‐Out).

Results:  The demographics for both groups (Group‐In vs Group‐Out) were similar regarding age, prostate volume and preoperative prostate‐specific antigen levels. Mean operation times (214.8 vs 224.2 min; P = 0.494) and estimated blood loss (472.4 vs 402.6 mL; P = 0.109) did not differ significantly in both groups as well as complication rate (20 vs 24%), median catheter time (8 vs 8.5 days) and continence rates at 12 months (95 vs 95.5%). According to the pathological stages, the rates of positive surgical margins were similar for pT2 (3.2 vs 4.3%) and pT3 (42.8 vs 45.2%), respectively.

Conclusions:  With a well designed, long‐term preclinical and clinical fellowship training program, LRP techniques can be efficiently transferred from the center of excellence to other centers with no significant impact on surgical, functional and oncological outcomes.
Pseudomonas aeruginosa produces an extracellular deoxyribonuclease that is required for utilization of DNA as a nutrient source
Authors: Mulcahy Heidi , Charron‐Mazenod Laetitia , Lewenza Shawn
Published: March 2010

Pseudomonas aeruginosa is an opportunistic pathogen that occupies a wide variety of environmental niches. Extracellular DNA is ubiquitous in various environments and is a rich source of carbon, nitrogen and phosphate. Here we show that P. aeruginosa is capable of using DNA as a nutrient source. Under phosphate‐limiting conditions, or when DNA is supplied as a source of phosphate, expression of PA3909 is induced. PA3909 encodes an extracellular deoxyribonuclease (DNase), which is required for degradation of DNA and utilization of DNA as a source of carbon, nitrogen and phosphate. Stabilization of PA3909 by the addition of excess Mg2+ and Ca2+ was required for DNase activity in culture supernatants. Extracellular DNase activity was seen in multiple P. aeruginosa strains and isolates from cystic fibrosis patients. The primary Xcp type II secretion system but not the Hxc type II secretion system is required for DNase activity and the ability to use DNA as a source of nutrients. This study identifies an extracellular DNase produced by P. aeruginosa that enables degradation of extracellular DNA into an accessible source of carbon, nitrogen and phosphate. DNase production by P. aeruginosa also has important implications for virulence and biofilm formation.
Vibrio infections triggering mass mortality events in a warming Mediterranean Sea
Authors: Vezzulli Luigi , Previati Monica , Pruzzo Carla , Marchese Anna , Bourne David G , Cerrano Carlo ,   the VibrioSea Consortium
Published: March 2010

Mass mortality events of benthic invertebrates in the temperate north‐western (NW) Mediterranean Sea have been observed in recent seasons. A 16 month in situ study in the Ligurian Sea (NW Mediterranean Sea) demonstrated that the occurrence of Paramuricea clavata mortality episodes were concomitant to a condition of prolonged high sea surface temperatures, low chlorophyll concentrations and the presence of culturable Vibrio spp. in seawater. The occurrence of Vibrio spp. at the seasonal scale was correlated with temperature; with few vibrios retrieved on specific media when the temperature dropped below 18°C and a sharp increase of vibrios abundance (up to 3.4 × 104 MPN l−1) when the temperature was greater than or equal to 22°C. Phylogenetic and phenotypic analysis of Vibrio isolates associated with healthy and diseased P. clavata colonies collected during a mortality episode showed that these bacteria were significantly more abundant in diseased than in healthy corals and were related to the V. harveyi, V. splendidus and V. coralliilyticus groups, the latter only identified in diseased organisms. Inoculation of bacterial isolates from these groups onto healthy P. clavata in aquaria caused disease signs and death in a range of Vibrio concentrations, temperature values and trophic conditions consistent with those recorded in the field. It is concluded that Vibrio infections may act as an additional triggering mechanism of mass mortality events in the coastal Mediterranean Sea and that their occurrence is climate‐linked. Predicted global warming leading to long‐lasting hot summer periods together with stratification resulting in energetic constraints represent a major threat to the survival of benthic invertebrates in the temperate NW Mediterranean Sea due to potential disease outbreak associated with Vibrio pathogens.
Association of TCF7L2 gene variants with low GAD autoantibody titre in LADA subjects (NIRAD Study 5)
Authors: Zampetti S. , Spoletini M. , Petrone A. , Capizzi M. , Arpi M. L. , Tiberti C. , Di Pietro S. , Bosi E. , Pozzilli P. , Giorgino F. , Buzzetti for the NIRAD Study Group R.
Published: March 2010

Diabet. Med. 27, 701–704 (2010)

Aims  We previously demonstrated the presence of two different populations among adult‐onset autoimmune diabetes (latent autoimmume diabetes of adults; LADA) having high or low titre of antibodies to glutamic acid decarboxylase (GADA). The transcription factor 7‐like 2 (TCF7L2) gene has been recognized as the major gene associated with Type 2 diabetes. The aim of the present study was to evaluate whether the phenotypic heterogeneity of LADA based on GADA titre is associated with TCF7L2 polymorphisms.

Methods  Two hundred and fifty patients identified as LADA, divided into two subgroups with low (≤ 32 arbitrary units) or high (> 32 units) GADA titre, 620 subjects with Type 2 diabetes [from the Non‐Insulin Requiring Autoimmune Diabetes (NIRAD) study cohort of 5330 subjects] in addition to 551 consecutive cases of Type 1 diabetes and 545 normoglycaemic subjects were analysed for the rs12255372 and rs7903146 polymorphisms of the TCF7L2 gene using Taqman.

Results  The genotype and allele distributions of the two polymorphisms revealed similar frequencies in subjects with low GADA titre and Type 2 diabetes. High GADA titre, Type 1 diabetes and controls also showed comparable frequencies. A significant increase of GT/TT genotypes of the rs12255372 single‐nucleotide polymorphism (SNP) and CT/TT genotypes of the rs7903146 SNP was observed in low GADA titre and Type 2 diabetes compared with high GADA titre, Type 1 diabetes and controls (P ≤ 0.04 for both comparisons). The risk alleles of both variants were increased in low GADA titre and Type 2 diabetes compared with high GADA titre, Type 1 diabetes and control subjects (P < 0.02 for all comparisons).

Conclusions  TCF7L2 common genetic variants of susceptibility are associated only with low GADA antibody titre in LADA patients.
Middle Managers, Strategic Sensemaking, and Discursive Competence
Authors: Rouleau Linda , Balogun Julia
Published: March 2010

abstract

This paper seeks to better understand the way middle managers contribute strategically to the development of an organization by examining how they enact the strategic roles allocated to them, with particular reference to strategic change. Through vignettes drawn from the authors' current research, a framework is developed that shows two situated, but interlinked, discursive activities, ‘performing the conversation’ and ‘setting the scene’, to be critical to the accomplishment of middle manager sensemaking. Language use is key, but needs to be combined with an ability to devise a setting in which to perform the language. The paper shows how middle managers knowledgeably enact these two sets of discursive activities by drawing on contextually relevant verbal, symbolic, and sociocultural systems, to allow them to draw people from different organizational levels into the change as they go about their day‐to‐day work.