High molecular weight kininogen regulates platelet-leukocyte interactions by bridging Mac-1 and glycoprotein Ib

Leukocyte-platelet interaction is important in mediating leukocyte adhesion to a thrombus and leukocyte recruitment to a site of vascular injury. This interaction is mediated at least in part by the beta2-integrin Mac-1 (CD11b/CD18) and its counter-receptor on platelets, glycoprotein Ibalpha (GPIbalpha). High molecular weight kininogen (HK) was previously shown to interact with both GPIbalpha and Mac-1 through its domains 3 and 5, respectively. In this study we investigated the ability of HK to interfere with the leukocyte-platelet interaction. In a purified system, HK binding to GPIbalpha was inhibited by HK domain 3 and the monoclonal antibody (mAb) SZ2, directed against the epitope 269-282 of GPIbalpha, whereas mAb AP1, directed to the region 201-268 of GPIbalpha had no effect. In contrast, mAb AP1 inhibited the Mac-1-GPIbalpha interaction. Binding of GPIbalpha to Mac-1 was enhanced 2-fold by HK. This effect of HK was abrogated in the presence of HK domains 3 or 5 or peptides from the 475-497 region of the carboxyl terminus of domain 5 as well as in the presence of mAb SZ2 but not mAb AP1. Whereas no difference in the affinity of the Mac-1-GPIbalpha interaction was observed in the absence or presence of HK, maximal binding of GPIbalpha to Mac-1 doubled in the presence of HK. Moreover, HK/HKa increased the Mac-1-dependent adhesion of myelomonocytic U937 cells and K562 cells transfected with Mac-1 to immobilized GPIbalpha or to GPIbalpha-transfected Chinese hamster ovary cells. Finally, Mac-1-dependent adhesion of neutrophils to surface-adherent platelets was enhanced by HK. Thus, HK can bridge leukocytes with platelets by interacting via its domain 3 with GPIbalpha and via its domain 5 with Mac-1 thereby augmenting the Mac-1-GPIbalpha interaction. These distinct molecular interactions of HK with leukocytes and platelets contribute to the regulation of the adhesive behavior of vascular cells and provide novel molecular targets for reducing atherothrombotic pathologies.

Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma

BACKGROUND: The aim of this multicenter trial was to prospectively evaluate neo-adjuvant chemotherapy followed by extrapleural pneumonectomy (EPP) and radiotherapy, including quality of life as outcome. PATIENTS AND METHODS: Eligible patients had malignant pleural mesothelioma of all histological types, World Health Organization performance status of zero to two and clinical stage T1-T3, N0-2, M0 disease considered completely resectable. Neo-adjuvant chemotherapy consisted of three cycles of cisplatin and gemcitabine followed by EPP. Postoperative radiotherapy was considered for all patients. RESULTS: In all, 58 of 61 patients completed three cycles of neo-adjuvant chemotherapy. Forty-five patients (74%) underwent EPP and in 37 patients (61%) the resection was complete. Postoperative radiotherapy was initiated in 36 patients. The median survival of all patients was 19.8 months [95% confidence interval (CI) 14.6-24.5]. For the 45 patients undergoing EPP, the median survival was 23 months (95% CI 16.6-32.9). Psychological distress showed minor variations over time with distress above the cut-off score indicating no morbidity with 82% (N = 36) at baseline and 76% (N = 26) at 3 months after surgery (P = 0.5). CONCLUSIONS: The observed rate of operability is promising. A median survival of 23 months for patients undergoing EPP compares favourably with the survival reported from single center studies of upfront surgery. This approach was not associated with an increase in psychological distress.

Detection of apoptosis in vivo using antibodies against caspase-induced neo-epitopes

Cell death induction by apoptosis is an important process in the maintenance of tissue homeostasis as well as tissue destruction during various pathological processes. Consequently, detection of apoptotic cells in situ represents an important technique to assess the extent and impact of cell death in the respective tissue. While scoring of apoptosis by histological assessment of apoptotic cells is still a widely used method, it is likely biased by sensitivity problems and observed-based variations. The availability of caspase-mediated neo-epitope-specific antibodies offers new tools for the detection of apoptosis in situ. Here, we discuss the use of immunohistochemical detection of cleaved caspase 3 and lamin A for the assessment of apoptotic cells in paraffin-embedded liver tissue. Furthermore, we evaluate the effect of tissue pretreatment and antigen retrieval on the sensitivity of apoptosis detection, background staining and maintenance of tissue morphology.

The Diverse Impacts of the Neo-liberal Social Policies on Children’s Welfare and Social Work with Young People: The Finnish Perspective

This article discusses the impacts of globalization, neo-liberal social policies and the Finnish economic recession of the 1990s on children's and young people's welfare. It summarises some of the impacts of Finnish social policies on the everyday lives of families with children and highlights some of the features of the recent and current debates surrounding youth delinquency and the societal reactions to young generations. All this contributes to a contradictory and conflicting societal context which challenges experts in the field of child welfare social work experts to operate - as expected - at the right moment, legally and effectively. Instead of being overly-defensive for the ‘good old’ ways of practicing social work with children, the authors invite social work scholars and practitioners to reconceptualise both the concept of children's citizenship and its position both in child welfare theory and practice in the context of children's global rights.

Social Work and a New Social Order - Challenging Neo-liberalism's Erosion of Solidarity

The world in which social work operates today is a very different world from that in which most of us took their social work training, and the changes we are facing are profound. This paper argues that these changes are not merely a regime change in social policy but that they are essentially about a re-ordering of social relationships and attempt to model them on neo-liberal ideas. In view of these pressures it is understandable that social workers often try to ignore those changes and withdraw into a private world of therapeutic relationships in which the methods they trained in are made to be still valid, or they simply go along with new service delivery designs without asking too many questions. Both reactions fail to question what the "social" can still mean in the light of these changes and how social workers can fulfil their mandate to be responsible for the social dimension of public life. Nothing less than a head-on challenge of the basic presuppositions of neo-liberalism (Willke 2003) and their manifold applications to social service delivery systems will thereby suffice.

Marked Silence, Neo-Feudalistic Reactions and the Stabilized Moral Regime – The Current De- and Reformation of „the Social“

The German chancellor and leader of the German conservative party, Angela Merkel, said in an interview a few weeks ago: “Nobody could have imagined a few months ago to what extent we would be pushed into state intervention programs. Of course, Merkel spoke on, this intervention is not easy for anybody. Therefore, she recommended turning back to the former course as soon as possible” (tagesschau.de, 11. März 2008, zit. nach Bildzeitungsinterview mit Angela Merkel, own translation). The worldwide celebrated new president of the United States, Barack Obama, said in an interview on CBS-News a few weeks before Merkel: “(...) there's no doubt that we have not been able yet to reset the confidence in the financial markets and in the consumer markets and among businesses that allow the economy to move forward in a strong way. And my job as president is gonna be to make sure that we restore that confidence“ (CBS News, 16. November 2008, Obama On Economic Crisis, Transition; http://www.cbsnews.com/stories/2008/11/16/60minutes/main4607893.shtml; Stand: 16. April 2009).

Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells

Notch is an intercellular signaling pathway related mainly to sprouting neo-angiogenesis. The objective of our study was to evaluate the angiogenic mechanisms involved in the vascular augmentation (sprouting/intussusception) after Notch inhibition within perfused vascular beds using the chick area vasculosa and MxCreNotch1(lox/lox) mice. In vivo monitoring combined with morphological investigations demonstrated that inhibition of Notch signaling within perfused vascular beds remarkably induced intussusceptive angiogenesis (IA) with resultant dense immature capillary plexuses. The latter were characterized by 40 % increase in vascular density, pericyte detachment, enhanced vessel permeability, as well as recruitment and extravasation of mononuclear cells into the incipient transluminal pillars (quintessence of IA). Combination of Notch inhibition with injection of bone marrow-derived mononuclear cells dramatically enhanced IA with 80 % increase in vascular density and pillar number augmentation by 420 %. Additionally, there was down-regulation of ephrinB2 mRNA levels consequent to Notch inhibition. Inhibition of ephrinB2 or EphB4 signaling induced some pericyte detachment and resulted in up-regulation of VEGFRs but with neither an angiogenic response nor recruitment of mononuclear cells. Notably, Tie-2 receptor was down-regulated, and the chemotactic factors SDF-1/CXCR4 were up-regulated only due to the Notch inhibition. Disruption of Notch signaling at the fronts of developing vessels generally results in massive sprouting. On the contrary, in the already existing vascular beds, down-regulation of Notch signaling triggered rapid augmentation of the vasculature predominantly by IA. Notch inhibition disturbed vessel stability and led to pericyte detachment followed by extravasation of mononuclear cells. The mononuclear cells contributed to formation of transluminal pillars with sustained IA resulting in a dense vascular plexus without concomitant vascular remodeling and maturation.

Beyond the tree of texts: Building an empirical model of scribal variation through graph analysis of texts and stemmata

Stemmatology, or the reconstruction of the transmission history of texts, is a field that stands particularly to gain from digital methods. Many scholars already take stemmatic approaches that rely heavily on computational analysis of the collated text (e.g. Robinson and O’Hara 1996; Salemans 2000; Heikkilä 2005; Windram et al. 2008 among many others). Although there is great value in computationally assisted stemmatology, providing as it does a reproducible result and allowing access to the relevant methodological process in related fields such as evolutionary biology, computational stemmatics is not without its critics. The current state-of-the-art effectively forces scholars to choose between a preconceived judgment of the significance of textual differences (the Lachmannian or neo-Lachmannian approach, and the weighted phylogenetic approach) or to make no judgment at all (the unweighted phylogenetic approach). Some basis for judgment of the significance of variation is sorely needed for medieval text criticism in particular. By this, we mean that there is a need for a statistical empirical profile of the text-genealogical significance of the different sorts of variation in different sorts of medieval texts. The rules that apply to copies of Greek and Latin classics may not apply to copies of medieval Dutch story collections; the practices of copying authoritative texts such as the Bible will most likely have been different from the practices of copying the Lives of local saints and other commonly adapted texts. It is nevertheless imperative that we have a consistent, flexible, and analytically tractable model for capturing these phenomena of transmission. In this article, we present a computational model that captures most of the phenomena of text variation, and a method for analysis of one or more stemma hypotheses against the variation model. We apply this method to three ‘artificial traditions’ (i.e. texts copied under laboratory conditions by scholars to study the properties of text variation) and four genuine medieval traditions whose transmission history is known or deduced in varying degrees. Although our findings are necessarily limited by the small number of texts at our disposal, we demonstrate here some of the wide variety of calculations that can be made using our model. Certain of our results call sharply into question the utility of excluding ‘trivial’ variation such as orthographic and spelling changes from stemmatic analysis.