bluuebunny/crossref_metadata_2025 huggingface dataset:
Silence and Emptiness in the Service of Healing: Lessons from Meditation
Authors: Del Monte Michael
Published: June 2007

This article gives a brief historical introduction to meditation in the Christian and other religious traditions, relating it to concepts of Freud and Bion. Following a description of the technique of meditation, its essence is then discussed ‐ especially in terms of its embeddedness in mystical traditions which hail from the old religions of the Orient. The main part of this paper concerns the work and teachings of John Main, the Benedictine monk who arguably did most to reintroduce the ancient discipline of Christian meditation to contemporary Western practitioners. Parallels are drawn between Main's view of silence in meditation and silence in psychoanalysis.

The article ends with some cautious notes on the possibility that meditation, as Main described it, may not be ideal for schizoid, dissociated, or overly narcissistic individuals. Those practitioners with good ego‐strengths are likely to benefit the most.
Being in the Know: Thoughts on Training, Prestige and Knowledge
Authors: Gardner Fiona
Published: June 2007

This paper aims to explore aspects of psychoanalytic psychotherapy training, with particular reference to the pressures and uncertainties experienced following graduation. The prestige of the professional position places expectations ‘to know’, so there is an ambivalence in remaining open to analytic knowledge as supposition. The effect of unconscious processes is examined alongside the influence of role responsiveness. The concept of ‘embodied knowledge’ is proposed as a possible synthesis of the experiential and learning processes, whilst still leaving us with an open rather than restricted perspective… and ‘to know’ Rather consists in opening out a way. (Browning)
Holmes on Bowlby and the Future of Psychotherapy: A Response
Authors: Ryle Anthony
Published: June 2007

Holmes’ discussion of the clinical implications of attachment theory is critically discussed. It is argued that the use of interpretation presented by Holmes to explain Bowlby's dispute with the psychoanalytic establishment is inappropriate and that the differences between psychoanalytic ideas and those proposed by Bowlby and arising from later observational studies of early development are substantial. Finally it is suggested that neither Bowlby nor psychoanalysis pay sufficient attention to the child's organisation of meaning in the early interaction with caretakers.
On Beginning Treatment
Authors: Rycroft Charles
Published: June 2007

In ‘On Beginning Treatment’ I compare and contrast the ‘correct’ procedure for beginning an analysis that I was taught in the 1940s with how I begin treatment now in the 1990s. I argue that my present method is less rigid, less authoritarian and more realistic than the ‘classical’ procedure I was taught 50 years ago. I end the paper with some reflections on training analyses and their economic and emotional significance for both training analyst and trainee analysand.
Cross‐Gender Identifications in Heterosexual Couples
Authors: Colman Warren
Published: June 2007

A well‐established sense of gender does not depend on sexual object choice but on a sense of security in belonging to the gender correlated to one's biological sex. Cross‐gender identifications are often found in heterosexual couples who show a marked reversal of conventional gender norms and whose typical interaction constitutes a shared defence against their mutual lack of gender security. Both partners are ‘possessed’ by the contrasexual archetype (anima and animus) and have been unable to integrate their contrasexual potential. Three aetiological factors seem to predispose both men and women towards cross‐gender identification: an over‐close relationship with the parent of the opposite sex, a negative identification with the parent of the same sex and inappropriate use by their mothers as substitute caretakers (‘narcissistic objects’). In both sexes masculinity is idealised while femininity is denigrated.
The Dream of Psychoanalysis: Irma's Dream, Some Commentaries, and a Contemplation of its Navel
Authors: Morgan Sian
Published: June 2007

Freud's dream of 1895, ‘Irma's Dream’, stands at the beginning of psychoanalytic theory, but Freud's analysis only glancingly refers to the ‘unknown’ elements that are found at ‘the navel of the dream’. The imagery of the dream suggests this phrasing is significant and that unconscious elements refer to the oracle at Delphi. At Delphi a chthonic goddess was supplanted by a patriarchy; the ‘unknown’ at the centre of the dream is the archaic mother, repressed by Freud and by the patriarchal character of early psychoanalytic theory.
Group Analysis, Transculturality and Ethics
Authors: Brown Dennis G.
Published: June 2007

The foundation matrix described by Foulkes embodies values, standards and myths of each culture as well as our common biological characteristics. The workshops of the European Association for Transcultural Group Analysis have revealed how much of this matrix is unconscious, taken for granted, until we are confronted by people of another culture or have to move from one culture to another. Such a move is often traumatic. The abuse of difference is integral to historical tragedy and trauma, but a move from paranoid destructiveness to depressive reparation is possible in favourable circumstances.

Primitive morality is contrasted with more mature ethics. In the microsphere the basis of a sense of justice and fairness is traced to the nursing couple and the early family. In the macrosphere its socio‐cultural base is seen to be manifested in family rules and laws of inheritance. Maturity involves the appreciation of and transcending of differences and different interests. It is proposed that the psychoanalytic concept of ‘genitality’ offers a paradigm for transculturality.
What Do We Mean by ‘Psychodynamic’? A Contribution to the Development of a Model
Authors: Lidmila Alan
Published: June 2007

I hope to make a preliminary contribution to the development of a model that more clearly reformulates the practices of psychoanalytic psychotherapy in a way that recognizes a diversity of analytic practice that I think has been misdescribed ‐ technically and politically ‐ as ‘psychodynamic’. The paper firstly considers the question of definition and suggests four identifiable meanings of the term’ psychodynamic’. The discussion then reviews a number of core and inextricably connected questions of theory and practice under the following headings: setting and regression, time and frequency, countertransference, creativity and the real relationship, interpretation and pure technique, and the problem of eclecticism. The paper concludes by briefly exploring the parameters of psychodynamic practice in relation to eclecticism in psychotherapy, and makes a plea for a model that is consistent, authentic and ecumenical.
An Attachment‐Based Approach to Working with Clients Affected by HIV and AIDS
Authors: Purnell Chris
Published: June 2007

This paper examines the relevance of attachment theory in the provision of psychological support to people who are affected by HIV. It highlights the themes of change, loss and vulnerability as central to the issues which confront members of this client group. Indications are provided of a range of attachment‐related behavioural responses which can be activated by these conditions, and illustrations are provided of how the activation of attachment behaviour can destabilize the relationships of some clients who are anxiously attached. The concept of a secure base, a term first coined by Mary Ainsworth and developed as a theme by the originator of attachment theory, John Bowlby, is presented as being a central provision by the therapist in work with clients who are affected by HIV, and illustrations are given of how the therapist might begin to help build a secure base for clients who have anxious, internal working models of attachment. The paper concludes with an indication of how an attachment‐based approach might be used in working with clients in the terminal stages of HIV‐related illness.
LOVE IN THE TIME OF PSYCHOTHERAPY
Authors: Gerrard Jackie
Published: June 2007

This paper examines the hypothesis that patients need to arouse the loving feelings of their psychotherapists in order to reach a sense of their own lovableness and capacities for loving. The history of love in the countertransference is reviewed and two kinds of love are described, leading to the idea that secondary love arises out of primary love. Examples of work with three patients demonstrate clinically various ways in which the therapist's loving feelings are reached.
PSYCHOTHERAPY AND MEMORY – AN ATTACHMENT PERSPECTIVE
Authors: Holmes Jeremy
Published: June 2007

Early Freudian concepts of memory are contrasted with those of contemporary psychoanalysis. Freud and Breuer's project to ‘remove the amnesias’ has been replaced with a more subtle, context‐bound view of memory, in which it is not only facts but their associated affects that need to be retrieved. The attachment‐based typology of insecure attachment patterns provides a framework for thinking about memories in psychotherapy, which may be suppressed, overwhelming or unintegrated. Memories are constructions and are therefore inherently unreliable. ‘Normal’ and traumatic memories are processed, stored and retrieved in different ways. The controversy over recovered memories and the false memory syndrome are reviewed in the light of this argument. Therapeutic implications are discussed.
Development of a New Simulation Technique Based on the Modal Approximation for Fluid Transients in Complex Pipeline Systems With Time-Variant Nonlinear Boundary Conditions
Authors: Kojima E. , Yamazaki T. , Shinada M.
Published: June 2007

A new simulation technique called the system modal approximation method (SMA) for fluid transients in complex pipeline systems has been proposed. The superiority of this technique compared to other existing methods has been verified. Thus far, however, detailed considerations have been limited to pipelines having elementary boundary conditions. In the present paper, for the generalization of the SMA method, calculation methods are newly proposed for the case in which the boundary conditions are given by the time-variant nonlinear relationship between pressure and flow rate, such as the conditions in a safety valve, and its usefulness is verified by comparison to experimental measurements.
Multifrequency Instability of Cavitating Inducers
Authors: Brennen Christopher E.
Published: June 2007

Recent testing of high-speed cavitating turbopump inducers has revealed the existence of more complex instabilities than the previously recognized cavitating surge and rotating cavitation. This paper explores one such instability that is uncovered by considering the effect of a downstream asymmetry, such as a volute on a rotating disturbance similar to (but not identical to) that which occurs in rotating cavitation. The analysis uncovers a new instability that may be of particular concern because it occurs at cavitation numbers well above those at which conventional surge and rotating cavitation occur. This means that it will not necessarily be avoided by the conventional strategy of maintaining a cavitation number well above the performance degradation level. The analysis considers a general surge component at an arbitrary frequency ω present in a pump rotating at frequency Ω and shows that the existence of a discharge asymmetry gives rise not only to beat components at frequencies, Ω−ω and Ω+ω (as well as higher harmonics), but also to rotating as well as surge components at all these frequencies. In addition, these interactions between the frequencies and the surge and rotating modes lead to “coupling impedances” that effect the dynamics of each of the basic frequencies. We evaluate these coupling impedances and show not only that they can be negative (and thus promote instability) but also are most negative for surge frequencies just a little below Ω. This implies potential for an instability involving the coupling of a surge mode with a frequency around 0.9Ω and a low-frequency rotating mode about 0.1Ω. We also examine how such an instability would be manifest in unsteady pressure measurements at the inlet to and discharge from a cavitating pump and establish a “footprint” for the recognition of such an instability.
Bicuspid aortic valve in competitive athletes
Authors: Stefani L , Galanti G , Toncelli L , Manetti P , Vono M C , Rizzo M , Maffulli N
Published: June 2007

Aim:

Bicuspid aortic valve (BAV) is a common congenital cardiac condition. The presence of BAV in non-elite athletes has been poorly investigated; it is usually asymptomatic until valvular stenosis, regurgitation or other vascular alterations are evident.

Design:

Over a three-year period, 2273 competitive athletes were consecutively investigated with transthoracic echocardiography. The traditional parameters, the aortic root dimensions at four levels and the systolic and diastolic flow of aortic valve, were studied with continuous Doppler according to the echo guidelines.

Setting:

The study protocol included all the non-elite athletes investigated for the first evaluation to obtain eligibility.

Patients:

2273 competitive athletes aged 8–60 years from several sports and regularly trained were evaluated with anamnesis, clinical check-up and echocardiography in order to exclude subjects with systemic or congenital heart disease.

Results:

BAV was diagnosed in 58 athletes (2.5%). Of these, nine had normal valvular function, 47 had abnormal valvular function with mild–moderate aortic regurgitation, and two had moderate stenosis. Aortic root dimensions at all levels were significantly greater in athletes with BAV than in athletes with a normal tricuspid valve. No relation was found with age, body surface area, aortic regurgitation or years of training.

Conclusions:

BAV is a relatively common congenital cardiac disease in athletes and commonly asymptomatic for a long time. This study suggests the usefulness of evaluating young athletes using echocardiography at least once when they start their sporting activity.
RESEARCH LABORATORIES CONFORMING TO ISO/IEC 17025
Authors: NARA YOSHIHIRO
Published: June 2007

Many countries have promoted the multilateral commerce in the global market according to the WTO/TBT (Agreement of Technical Barrier to Trade). One of the most important factors to implement this agreement is that the trade goods should be evaluated once in the export or import country. Therefore the test laboratories for product assessment should construct the new management systems to get the same results of tests anywhere in the world. Even the research laboratories are in the same situation as well as the test laboratories because they must compare their data with others for joint study. They should be encouraged to apply the requirements of ISO/IEC 17025 to their systems.
ORIGINAL METHODS OF QUANTITATIVE ANALYSIS DEVELOPED FOR DIVERSE SAMPLES IN VARIOUS RESEARCH FIELDS — QUANTITATIVE ANALYSIS AT NMCC
Authors: SERA KOICHIRO
Published: June 2007

Nishina Memorial Cyclotron Center (NMCC) has been opened for nationwide-common utilization of positron nuclear medicine (PET) and PIXE since April 1993. At the present time, nearly 40 subjects of PIXE in various research fields are pursued here, and more than 50,000 samples have been analyzed up to the present. In order to perform quantitative analyses of diverse samples, technical developments in sample preparation, measurement and data analysis have been continuously carried out. Especially, a "standard-free method for quantitative analysis" made it possible to perform analysis of infinitesimal samples, powdered samples and untreated bio samples, which could not be well analyzed quantitatively in the past. The "standard-free method" and a "powdered internal standard method" made the process for target preparation quite easier. It has been confirmed that results obtained by these methods show satisfactory accuracy and reproducibility preventing any ambiguity coming from complicated target preparation processes.
PIXE QUANTITATIVE ANALYSIS AT NMCC
Authors: FUTATSUGAWA S. , HATAKEYAMA S. , SAITOH Y. , SERA K.
Published: June 2007

The facilities of the NMCC have been opened to other scientists and researchers of universities and institutes in Japan for their academic contribution since 1993. A lot of study subjects of PIXE are accepted every year. We tried to confirm that elemental concentrations in a sample were determined exactly at the quantitative analysis using PIXE facilities at NMCC. The known quantity of a standard liquid sample was dropped and dried on a polycarbonate membrane filter that was used ordinarily as a backing film for an aerosol sample collection. The determined values of elements in targets agree with the values evaluated from the added quantities of the standard liquid samples.
CHARACTERIZATION OF ATMOSPHERIC TOTAL SUSPENDED PARTICULATE (TSP) IN A MIDSIZE CITY IN NORTHERN JAPAN: NON-SNOW-CLAD PERIOD TO SNOW-CLAD PERIOD COMPARISON
Authors: SAITOH KATSUMI , IWATA YOSHIHIRO , SERA KOICHIRO , HIRANO KOICHIRO
Published: June 2007

Total suspended particulate (TSP) samples were collected from three areas (commercial, residential and agricultural) in and near Akita City in northern Japan, from May – June 1996 (non-snow-clad period) and January – February 1997 (snow-clad period), over three days with a one-hour sampling interval for each area. The elemental composition and particle shape of TSP samples were determined and/or observed by Particle Induced X-ray Emission (PIXE) and a Scanning Electron Microscope (SEM) combined with Energy Dispersive X-ray (EDX) analysis. In the hourly TSP samples collected during the non-snow-clad period, 23 elements were determined for each area, and Na , Mg , Al , Si , S , Cl , K , Ca and Fe were the major components. On the other hand, 25 elements, excluding As and Rb , were found in the snow-clad period samples, and P , Ga , Nb and Mo were only found in the snow-clad-period samples. Dominant elements, i.e., major components, of the snow-clad period were the same as the non-snow-clad period. Comparing the arithmetic means of elemental concentrations in TSP for the non-snow-clad and snow-clad periods, in the commercial area the elemental concentrations in the snow-clad period were the same or lower than those in the non-snow-clad period, with the concentrations of Na , Mg , Al , Si , S , K , Ca , Ti and Fe in particular being markedly lower. In the residential area the concentrations of Na , Mg and Cl were markedly higher in the snow-clad period than in the non-snow-clad period, while the concentrations of the other elements were the same or only slightly lower. In the agricultural area, the concentrations of Na and Cl were markedly higher in the snow-clad period relative to the non-snow-clad period, and the concentrations of the other elements, except for P , were low. The concentrations of the major elements and Pb were particularly low. Thus, in the residential and agricultural areas the effect of northwesterly winter wind on TSP can be observed by Cl , and it is conjectured that soil particles rising up into the air is inhibited by snow accumulation. Soil particles rising up into the air seems to be inhibited by snow accumulation in the commercial area as well. With the aid of SEM and EDX analysis, aggregates of diesel exhaust particles (DEP), soil particles and small silicon-rich spherical particles were observed in the non-snow-clad and snow-clad period samples for each area. In addition, small aluminum-rich and iron-rich spheres were observed during the non-snow-clad period in the commercial area. Zinc-rich fiber was observed during the non-snow-clad period in the residential area.
Equipment-independent reference values for dopamine transporter imaging with 123I-FP-CIT
Authors: Hornung J. , Hamann C. , Pöpperl G. , Tatsch K. , Koch W.
Published: June 2007

Aim: Reliable reference values are helpful to interpret and compare the results of dopamine transporter imaging with SPECT. Since semi-quantitative reference values cannot be easily transferred between imaging equipments, this study aimed to establish equipment independent normal values for the true striatal binding of 123I-FP-CIT. Patients, methods: Specific striatal FP-CIT binding of 6 healthy volunteers and 26 patients with essential tremor were used to generate a reference range by applying an equipment specific resolution dependent factor to compensate for recovery effects. This factor has been determined previously by a series of standardized phantom measurements of an anthropomorphic basal ganglia phantom. Herewith, the resulting DAT binding values represent the expected true specific binding in the striatum. Results: On average, true specific striatal binding was 5.83 ± 0.96 in healthy controls, 5.25 ± 0.67 in patients with essential tremor and 5.36 ± 0.75 in the entire study cohort. Conclusion: These preliminary results may serve as a basis for the generation of a generally accepted equipment independent reference range for dopamine transporter imaging with 123I-FP-CIT. By a simple phantom measurement that can be accomplished within one day factors related to specific imaging equipment and processing can be corrected for, resulting in specific binding values which may enable a more standardized interpretation of dopamine transporter scans.
Acute tissue-type plasminogen activator release in human microvascular endothelial cells: The roles of Gαq, PLC-β, IP3 and 5,6-epoxyeicosatrienoic acid
Authors: Muldowney III James , Painter Corrie , Sanders-Bush Elaine , Brown Nancy , Vaughan Douglas
Published: June 2007

The acute physiologic release of tissue-type plasminogen activator (t-PA) from the endothelium is critical for vascular homeostasis. This process is prostacyclin- and nitric oxide (NO)-independent in humans. It has been suggested that calcium signaling and endothelial-derived hyperpolarizing factors (EDHF) may play a role in t-PA release. G-protein-coupled receptor-dependent calcium signaling is typically Gαq -dependent. EDHFs have been functionally defined and in various tissues are believed to be various regioisomers of the epoxyeicosatrienoic acids (EETs). We tested the hypothesis in vitrothat thrombin-stimulated t-PA release from human microvascular endothelial cells (HMECs) is both Gαq - and EDHF-dependent. Conditioned media was harvested following thrombin stimulation, and t-PA antigen was measured by ELISA. Thrombin-induced t-PA release was limited by a membrane-permeable Gαq inhibitory peptide, the PLC-β antagonist U73122, and the IP3 receptor antagonist 2-aminoethoxyphenylborane, while the Gαq agonist Pasteurellatoxin modestly induced t-PA release. The cytochrome P450 (CYP450) inhibitor, miconazole, and the arachidonic acid epoxygenase inhibitor MS-PPOH inhibited thrombin-stimulated t-PA release, while 5,6-EET-methyl ester stimulated t-PA release. The 5,6- and 14,15-EET antagonist, 14,15-epoxyeicosa-5(Z)- enoic acid, inhibited t-PA release at the 100 µM concentration. However, thrombin-stimulated t-PA release was unaffected by the prostacyclin and NO inhibitors ASA and L-NAME, as well as the potassium channel inhibitors TEA, apamin and charybdotoxin. These studies suggest that thrombin-stimulated t-PA release is Gαq-, PLC-β -, IP3 -, and 5,6-EET-dependent while being prostacyclin-, NO- and K + channel-independent in HMECs.
Inhibition of clot formation process by treatment with the lowmolecular-weight heparin nadroparin in patients with carotid artery disease undergoing angioplasty and stenting - A thromboelastography study on whole blood
Authors: Konstantinidis Konstantinos , Gerasimidis Thomas , Verdy Elisabeth , Elalamy Ismail , Samama Michel M. , Gerotziafas Grigoris T.
Published: June 2007

Low-molecular-weight heparins (LMWHs) have become the corner stone of antithrombotic treatment but their administration protocol needs to be optimized for certain groups of patients. In this paper, we studied the influence of nadroparin treatment on clot formation process assessed by thromboelastography in patients with carotid artery disease undergoing angioplasty and stenting. Standard thromboelastography assays (in-TEM® and ex-TEM® ) and minimal TF-triggered thromboelastography assay in citrated whole blood were performed in normal volunteers (n=20), in patients with carotid artery disease receiving only antiplatelet treatment (n=30), and in patients undergoing angioplasty receiving nadroparin 5750 anti-Xa IU s.c. twice daily (n=60). Blood samples were collected four hours after a second injection of nadroparin. In a subgroup of LMWH-patients (n=18) blood samples were also obtained prior to first injection of LMWH. Antiplatelet treatment had no effect on any parameter of the thromboelastographic pattern. Nadroparin treatment resulted in significant prolongation of clotting time (CT) and clot formation time (CFT) and significantly reduced α-angle in minimal TF-triggered thromboelastography and 30–38% of nadroparin treated patients had thromboelastographic parameters beyond the normal maximum limit. In-TEM test revealed a significant prolongation of clotting time while ex-TEM was not modified, and 20 to 30% of the patients had thromboelastographic parameters beyond the normal maximum limit. Anti factor-Xa activity in platelet-poor plasma (PPP) was also measured, and statistical analysis showed that prolongation of CFT of minimal TF-triggered TEM was significantly correlated to the levels of anti-Xa activity in patients’ plasma (p=0.04; r2 =0.7). There was no statistical correlation for any other parameter in all tests. In conclusion, the present study shows that nadroparin treatment in patients with carotid artery disease undergoing endovascular procedures induces significant modification of the thrombus kinetics assessed by minimal TF-triggered whole blood thromboelastography. The clinical relevance of these findings has to be evaluated in future studies.
Performance evaluation of the new CoaguChek XS system compared with the established CoaguChek system by patients experienced in INR-self management
Authors: Watzke Herbert , Hasenkam Michael , Schwab Michael , Wolf Tanja , Dovifat Clemens , Völler Heinz , Braun Siegmund
Published: June 2007

The aim of the study was to analyze the concordance of INR values obtained by educated lay users with those obtained by professionals and to determine the imprecision of the new system. The new CoaguChek® XS system was tested in a user study over six weeks at four study centres in Austria, Denmark and Germany. Seventy-five patients receiving oral anticoagulant therapy were enrolled in the study. The INR results in capillary whole blood taken by professionals and by patients using the Coagu- Chek XS system were similar, and the mean relative bias was < 1%. The imprecision of the CoaguChek XS system calculated from duplicate testing is low (<6%) and slightly better than for the established CoaguChek S system. The INR results measured during the home testing phase correlated quite well between the established CoaguChek S system and the new CoaguChek XS system with a mean bias of 0.14 INR. This is a remarkably low bias taking into consideration that more than 30 different test strip lots were applied. A questionnaire was filled out by all patients to assess their personal impression. It revealed that patients were very satisfied with the new system and found it easy to operate. The results demonstrate that the agreement between professional and patient INR results for the new Coagu- Chek XS system was excellent and that INR values can be determined by lay users as well as by professionals. The instrument is very well accepted by the patients and their satisfaction even increased after four weeks practice at home.
Design and characterization of dipetacompinR10H, a dipetalogastin II-derived, classical competitive thrombin inhibitor
Authors: López Mercedes , Nowak Goetz , Bitter Thomas
Published: June 2007

The design of small chimeric thrombin inhibitors based on the structure of dipetalogastin II has been previously described. These proteins are effective inhibitors of thrombin showing slow binding or slow, tight-binding kinetics. We report here about dipetacompinR10H, a new dipetalogastin II-derived chimeric thrombin inhibitor, which exhibits classical competitive kinetics. The dissociation constant Ki of dipetacompinR10H was determined to be 17.1 ± 0.8 pM. In various coagulation assays it showed a comparable anticoagulant activity like r-hirudin and r-dipetalogastin II. DipetacompinR10H’s inhibition of thrombin was specific, since no inhibition of other serine proteases like factor Xa, plasmin, trypsin or chymotrypsin has been observed.
Aspirin-triggered lipoxin A4 blocks reactive oxygen species generation in endothelial cells: A novel antioxidative mechanism
Authors: Nascimento-Silva Vany , Arruda Maria Augusta , Barja-Fidalgo Christina , Fierro Iolanda M.
Published: June 2007

Lipoxins and their aspirin-triggered carbon-15 epimers have emerged as mediators of key events in endogenous anti-inflammation and resolution. However, the implication of these novel lipid mediators on cardiovascular diseases such as hypertension, atherosclerosis, and heart failure has not been investigated. One of the major features shared by these pathological conditions is the increased production of reactive oxygen species (ROS) generated by vascular NAD(P)H oxidase activation. In this study, we have examined whether an aspirin-triggered lipoxin A4 analog (ATL-1) modulates ROS generation in endothelial cells (EC). Pre-treatment of EC with ATL-1 (1–100 nM) completely blocked ROS production triggered by different agents, as assessed by dihydrorhodamine 123 and hydroethidine. Furthermore, ATL-1 inhibited the phosphorylation and translocation of the cytosplamic NAD(P)H oxidase subunit p47phox to the cell membrane as well as NAD(P)H oxidase activity. Western blot and immunofluorescence microscopy analyses showed that ATL-1 (100 nM) impaired the redox-sensitive activation of the transcriptional factor NF-κB, a critical step in several events associated to vascular pathologies. These results demonstrate that ATL-1 suppresses NAD(P)H oxidase-mediated ROS generation in EC, strongly indicating that lipoxins may play a protective role against the development and progression of cardiovascular diseases.
Immunization of LDL receptor-deficient mice with β2-glycoprotein 1 or human serum albumin induces a more inflammatory phenotype in atherosclerotic plaques
Authors: Dunoyer-Geindre Sylvie , Kwak Brenda R. , Pelli Graziano , Roth Isabelle , Satta Nathalie , Fish Richard J. , Reber Guido , Mach François , Kruithof Egbert K. O. , de Moerloose Philippe
Published: June 2007

Antiphospholipid antibodies are a risk factor for venous and arterial thrombosis and may contribute to the development of atherosclerosis. The aim of this study was to investigate whether antibodies to human β2-glycoprotein 1 (β2 GP1), as a model of antiphospholipid antibodies, modify the phenotype of atherosclerotic lesions. LDL receptor-deficient mice were immunized with human β2 GP1, human serum albumin (HSA), or not immunized, and fed a high-cholesterol diet for 14 weeks. Some mice also received pravastatin. Immunization with human β2 GP1 or HSA resulted in formation of autoantibodies recognizing murine β2 GP1 or murine albumin, respectively. We quantified atherosclerotic lesion development and mRNA levels of inflammationassociated proteins in the thoraco-abdominal aorta as well as lesion development, cellular composition and collagen content in the aortic roots. Immunization with β2 GP1 or HSA had no effect on lesion size, but modified the expression in plaque areas of several inflammation-associated proteins. Expression of matrix metalloproteinase-9, tissue factor, interferon-gamma and CD25 was highest in the thoraco-abdominal aorta of β2 GP1-immunized mice, lowest in non-immunized mice and intermediate in HSA-immunized animals. Immunization with β2 GP1, but not HSA, resulted in a lower smooth muscle cell and collagen content of lesions in aortic roots. Statin treatment partially reversed the effects of β2 GP1 immunization. We conclude that immunization with β2 GP1, and to a lesser extent with HSA, leads to modifications in the cellular and protein composition of atherosclerotic plaques, which are associated with a more inflammatory phenotype. Statin treatment partially prevents these changes.
Therapeutic action of tranexamic acid in hereditary haemorrhagic telangiectasia (HHT): Regulation of ALK-1/endoglin pathway in endothelial cells
Authors: Fernandez-L Africa , Garrido-Martin Eva , Sanz-Rodriguez Francisco , Ramirez Jose-Ramon , Morales-Angulo Carmelo , Zarrabeitia Roberto , Perez-Molino Alfonso , Bernabéu Carmelo , Botella Luisa-María
Published: June 2007

Recurrent epistaxis is the most frequent clinical manifestation of hereditary haemorrhagic telangiectasia (HHT). Its treatment is difficult. Our objective was to assess the use of tranexamic acid (TA), an antifibrinolytic drug, for the treatment of epistaxis in HHT patients and to investigate in vitro the effects of TA over endoglin and ALK-1 expression and activity in endothelial cells. A prospective study was carried out on patients with epistaxis treated with oral TA in the HHT Unit of Sierrallana Hospital (Cantabria, Spain). Primary cultures of endothelial cells were treated with TA to measure the levels of endoglin and ALK-1 at the cell surface by flow cytometry. RNA levels were also measured by real-time PCR, and the transcriptional effects ofTA on reporters for endoglin, ALK-1 and the endoglin/ALK-1 TGF-beta pathway were assessed. The results showed that the fourteen HHT patients treated orally withTA improved, and the frequency and severity of their epistaxis were decreased. No complications derived from the treatment were observed. Cultured endothelial cells incubated with TA exhibited increased levels of endoglin and ALK-1 at the protein and mRNA levels, enhanced TGF-β signaling, and improved endothelial cell functions like tubulogenesis and migration. In summary, oral administration of TA proved beneficial for epistaxis treatment in selected patients with HHT. In addition to its already reported antifibrinolytic effects, TA stimulates the expression ofALK-1 and endoglin,as well as the activity of the ALK-1/endoglin pathway.
Clot structure modification by fondaparinux and consequence on fibrinolysis: A new mechanism of antithrombotic activity
Authors: Varin Rémi , Mirshahi Shahsultan , Mirshahi Pezhman , Kierzek Gerald , Sebaoun David , Mishal Zohar , Vannier Jean-Pierre , Borg Jeanne Yvonne , Simoneau Guy , Soria Claudine , Soria Jeannette
Published: June 2007

Fondaparinux is a synthetic pentasaccharide consisting of the minimal sequence of heparin which interacts with antithrombin (AT). It represents a new class of selective factor Xa inhibitors without any antithrombin activity. It has been shown to exhibit potent antithrombotic properties in clinical studies. However, the mechanism of its antithrombotic action has not yet been fully established. In the present study it was shown that fondaparinux, used at pharmacological concentration (500 ng/ml), rendered the clot more susceptible to fibrinolysis induced by t-PA: plasma fibrin clots formed in the presence of fondaparinux and perfused with t-PA were degraded at a faster rate than those formed in the absence of fondaparinux. This fibrinolytic activity of fondaparinux is mainly due to a modification of clot structure characterized by a loose fibrin conformation with less branched fibers and the presence of large pores in comparison to control clots which present a tighter conformation. The difference in fibrin structure was responsible for an increase in clot porosity leading to a better availability of t-PA to the fibrin network. It is related to the decrease in thrombin generation, in an AT-dependent pathway. It was also demonstrated that in the presence of exogenous thrombomodulin, the inhibition of TAFI activation by fondaparinux could contribute, to a lesser extent, to the increased thrombus lysis. The increase in t-PA induced thrombus lysis could contribute to the antithrombotic activity of fondaparinux.
Effect of staphylokinase-derived nonadecapeptide on the activation of plasminogen
Authors: Okada Kiyotaka , Ueshima Shigeru , Matsuno Hiroyuki , Kawao Naoyuki , Okamoto Chikako , Tanaka Masaki , Matsuo Osamu
Published: June 2007

Staphylokinase (SAK) expresses plasminogen activator (PA) activity by forming a complex with plasmin. The interaction between the plasmin-SAK complex and plasminogen was investigated using synthesized peptides, which were constructed according to the amino acid sequence of the SAK molecule.A synthetic nonadecapeptide (SAK22–40) corresponding to Glu22-Leu40 by the SAK molecule enhanced the activation of Glu-plasminogen by the plasmin-SAK complex.Analysis of IAsys resonant mirror biosensor showed that SAK22–40 bound to Glu-plasminogen.This binding was completely inhibited by IgG against the B-chain in the plasminogen molecule. But, this binding was not inhibited by IgG against lysine-binding sites (LBS) of the A-chain in the plasminogen molecule. The substitution of Lys35 with Ala in SAK22–40 did not enhance the activation of Glu-plasminogen by the plasmin-SAK complex. When SAK22–40 was administrated in a mouse thrombosis model, earlier recanalization was observed than in mice with vehicle administration. Thus, a newly synthesized peptide, SAK22–40 enhanced Glu-plasminogen activation and induced effective thrombolysis.
Thalidomide and thrombosis
Authors: El Accaoui Ramzi , Shamseddeen Wael , Taher Ali
Published: June 2007

With the increase in the number of reports and trials on the use of thalidomide as a part of the treatment of different medical conditions, particularly multiple myeloma (MM), it was observed that this drug might be associated with an increase in the risk of venous thromboembolic (VTE) events. It was the objective of this study to assess this risk, to check whether it might be affected by the concomitant administration of other medications, specifically dexamethasone, and to study the effect of anticoagulation and anti-platelet medications. A literature search for articles describing the use of thalidomide and the resultant VTE events was performed, and 50 articles were reviewed. A sample consisting of 3,322 patients resembling the above-mentioned studies was designed, and multivariate logistic regression was conducted.While thalidomide, dexamethasone and their combination were found to significantly increase the risk of VTE events among MM patients by 2.6, 2.8 and eight times, respectively, “adequate” anticoagulation significantly reduced the risk. In conclusion, patients receiving thalidomide should be carefully monitored for thromboembolic events,and those receiving concomitantly dexamethasone or other chemotherapy should be followed even more closely. Administering prophylactic doses of low-molecular-weight heparin or warfarin with therapeutic International Normalized Ratio reduces the risk of thromboembolic events among MM patients.
Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia
Authors: von Auer Charis , Huber Christoph , Scharrer Inge , Heidel Florian , Lipka Daniel , Hess Georg
Published: June 2007

Treatment of relapsed or refractory autoimmune mediated haemolytic syndromes, such as autoimmune haemolytic anaemia (AIHA) and thrombotic thrombocytopenic purpura (TTP), represents a therapeutic challenge. Here we report on our experience with the monoclonal anti-CD20 antibody rituximab (R) compared to standard treatment in these diseases. Patients with non-familialTTP orAIHA and no underlying malignancy were included in our analysis. Safety and efficacy of R-treatment were compared to results obtained in standard treatment approaches. Altogether, 27 patients were analyzed, comprising 15 patients withTTP and 12 patients with AIHA. The patients’ average age at the time of diagnosis was 54 years. Eleven patients received antibody treatment (8 TTP, 3 AIHA). No acute or late WHO grade III/IV toxicity associated with rituximab was noted. With standard therapy, the overall response rate (ORR) was 66.7% for AIHA and 65.8% for TTP, respectively. For the R-containing regimens the ORR was 100%. In patients with TTP, median progression free survival (PFS) with R-treatment was 3.8 years, as compared to 0.1 years in the standard-treatment group. In patients with AIHA median PFS was not reached for R-containing treatment; all patients are in sustained remissions with a median follow up of 12.5 months. In the absence of prospective trials, our data underline the safety and efficacy of rituximab in relapsed and refractory autoimmune anaemias with favourable response rates and promising long-term progressionfree survival. Therefore, prospective clinical trials evaluating rituximab as salvage- and first-line-therapy are clearly warranted.
Alternatively spliced human tissue factor (asHTF) is not pro-coagulant
Authors: Censarek Petra , Bobbe Anett , Grandoch Maria , Schrör Karsten , Weber Artur-Aron
Published: June 2007

It has been proposed that alternatively-spliced human tissue factor (asHTF) is pro-coagulant. We have evaluated the function of asHTF in a mammalian expression system. Full-length human tissue factor (HTF) and asHTF were cloned from smooth muscle cells and over-expressed in HEK293 cells. As expected, a marked pro-coagulant activity (FX activation, thrombin generation) was observed on the surface, in lysates, and on microparticles from HTF transfected cells. In contrast, no pro-coagulant activity of as HTF was observed.
A novel inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) – Part I: Pharmacological characterization
Authors: Zhao Lei , Nagashima Mariko , Vincelette Jon , Sukovich Drew , Li Weiwei , Subramanyam Babu , Yuan Shendong , Emayan Kumar , Islam Imadul , Hrvatin Paul , Bryant Judi , Light David R. , Vergona Ronald , Morser John , Buckman Brad O. , Wang Yi-Xin
Published: June 2007

We have discovered a novel small-molecule (3-phosphinoylpropionic acid) inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa), BX 528, which had an IC50 of 2 nM in an enzymatic assay and 50 nM in an in-vitro clot lysis assay, with 3,500- to 35,000-fold selectivity against other carboxypeptidases, such as CPN, CPZ and CPD, and 5- and 12-fold selectivity against CPE (CPH) and CPB, respectively. At 10 µM, BX 528 had no significant activity (< 50% inhibition or antagonism) in a panel of 137 enzymes and receptors. It had no effects on blood coagulation and platelet aggregation up to 300 and 10 µM, respectively. The plasma half-life following intravenous administration was 0.85 hours in rats and 4.5 hours in dogs. No significant metabolism was detected in human, dog or rabbit hepatic microsomes, and no significant inhibition of cytochrome P450 3A4 and 2D6 up to 30 µM. No cytotoxic or cell proliferative effects were found in three hepatic and renal cell lines up to 300 µM and no mutagenic activity was seen in the Ames II screen. There were no significant hemodynamic effects in rats and dogs up to 100 and 30 mg/kg with peak plasma drug concentrations of ~1,000 and 300 µM, respectively. In an in-vivo complement activation model in guinea pigs, BX 528 showed minimal inhibition of plasma CPN activity up to 60 mg/kg with peak plasma concentrations up to 250 µM. Thus, these data demonstrate that BX 528 is a novel, potent, selective and safe TAFIa inhibitor.
Severe haemophilia B due to a 6 kb factor IX gene deletion including exon 4: Non-homologous recombination associated with a shortened transcript from whole blood
Authors: Hsu Ting-Chang , Nakaya Shelley , Thompson Arthur
Published: June 2007

In genotyping a severe hemophilia B subject, exons 1–3 and 5–8 were normal. Exon 4 did not amplify, suggesting a partial gene deletion. Previously, a French family with an exon 4 deletion had severe haemophilia B with a circulating, dysfunctional factor IX protein missing its first growth factor-like domain; breakpoints were not analyzed. Using a 5’ primer for exon 3 and a 3’ primer for exon 5 fragments, the subject’s factor IX gene amplified a 5 kb fragment whereas 11 kb was predicted, indicating a 6 kb deletion. Restriction endonucleases localized the 3’ intron 4 deletion breakpoint to 1.2 kb 5’ to exon 5. Sequencing through the breakpoints revealed a 5,969 bp deletion that included exon 4 and was accompanied by a 13 bp duplication inserted near the 3’ breakpoint site. Haemophilia was familial; on testing, his mother was confirmed as a heterozygous carrier, whereas his sister was homozygous for the normal, larger fragments. As exons 4 and 5 of the factor IX gene are in frame, this deletion should produce a shortened transcript, missing 114 bp (38 codons from the first growth factor-like domain). Reverse transcription of mRNA prepared from whole blood and PCR identified the shorter cDNA fragment. Western blotting demonstrated a smaller factor IX protein.
Biphasic effect of pioglitazone on isolated human endothelial progenitor cells: Involvement of peroxisome proliferator-activated receptor-γ and transforming growth factor-β1
Authors: Hristov Mihail , Gümbel Denis , Tejerina Teresa , Redondo Santiago , Weber Christian
Published: June 2007

Endothelial progenitor cells (EPCs) have been implicated in vascular repair and found to be functionally impaired in patients with diabetes. We evaluated the effects of the anti-diabetic drug pioglitazone on human EPC function and the involvement of PPAR-γ and TGF-β1. EPCs in culture were characterized at day 7 by the development of colony-forming units (CFUs) and flow cytometry assessment of differentiation marker (DiI-ac-LDL/lectin, KDR and CD31). Adhesion on fibronectin and fibrinogen in flow was analyzed as functional parameter. Treatment with pioglitazone for 72 hours increased the number of EPC-CFUs, DiI-ac-LDL+/lectin+, CD31+ and KDR+ EPCs at 1 μM but not at 10 μM. Since pioglitazone did not significantly alter proliferation and apoptosis in cultured EPCs, the increase in EPC number was most likely attributable to augmented adhesion and differentiation. Indeed, pioglitazone increased EPC adhesion in flow at 1 μM, an effect prevented by PPAR-γ and β2-integrin blockade. In contrast, pioglitazone did not promote EPC adhesion at 10 μM; however, increased adhesion became evident by co-incubation with a blocking TGF-β1 antibody. As determined by ELISA, pioglitazone induced a persistent increase in TGF-β1 secretion only at 10 μM when a significantly elevated expression of endoglin, the accessory receptor forTGF-β1, was also observed. Taken together, pioglitazone exerts biphasic effects on the function of isolated EPCs, causing a PPAR-γ-dependent stimulation at 1 μM and a TGF-β1-mediated suppression at 10 μM. These results may help to define optimal therapeutic doses of pioglitazone for improving endothelial dysfunction.