The development and impact of nationalisation in Britain

The relationship between Government and economy, the best obtainable pattern of public and private sectors in market economies, is an issue of constant interest for economists and politicians of the Western world. Can nationalisation of industries, i.e. the alteration or termination of control or ownership of private property by the state, improve the economic situation of a country and its workers and consumers? Here is a survey on the more than thirty years’ development and impact of nationalisation in Great Britain

Measurement of the B→J/ψXB \to J/\psi X inclusive cross-section at the collider detector at Fermilab

The Collider Detector at Fermilab (CDF) is a multi-purpose detector designed to study proton-antiproton collisions at center-of-mass energies of 1.96 TeV/c{sup 2}. One of the most importatn components of CDF is the silicon tracking detector. A detailed description of the testing and construction of the CDF silicon tracker is presented. Measurements of the tracking efficiency of the completed detector are also provided. Using 36 pb{sup -1} of the J/{psi} data sample collected by CDF between February and October 2002, the inclusive B {yields} J/{psi} X cross-section is measured in p{bar p} interactions at {radical}s = 1.96 TeV/c{sup 2}. The fraction of J/{psi} events arising from the decay of b hadrons is extracted using an unbinned maximum likelihood fit to the decay length of the J/{psi} candidates. The p{sub T} dependent differential cross section for inclusive B {yields} J/{psi} X events with rapidity |y| < 0.6 is obtained by combining the B-fraction result with a measurement of the J/{psi} differential cross-section. For 2.0 < p{sub T}(J/{psi}) < 17.0 GeV/c, the integrated B {yields} J/{psi} X cross-section is measured to be {sigma}(J/{psi}, B) {center_dot} {Beta}(J/{psi} {yields} {mu}{mu}) = 16.02 {+-} 0.24(stat){sub -2.20}{sup +2.26}(syst) nb

Autoantibody-Specific Signalling in Pemphigus

Pemphigus is a severe autoimmune disease impairing barrier functions of epidermis and mucosa. Autoantibodies primarily target the desmosomal adhesion molecules desmoglein (Dsg) 1 and Dsg 3 and induce loss of desmosomal adhesion. Strikingly, autoantibody profiles in pemphigus correlate with clinical phenotypes. Mucosal-dominant pemphigus vulgaris (PV) is characterised by autoantibodies (PV-IgG) against Dsg3 whereas epidermal blistering in PV and pemphigus foliaceus (PF) is associated with autoantibodies against Dsg1. Therapy in pemphigus is evolving towards specific suppression of autoantibody formation and autoantibody depletion. Nevertheless, during the acute phase and relapses of the disease additional treatment options to stabilise desmosomes and thereby rescue keratinocyte adhesion would be beneficial. Therefore, the mechanisms by which autoantibodies interfere with adhesion of desmosomes need to be characterised in detail. Besides direct inhibition of Dsg adhesion, autoantibodies engage signalling pathways interfering with different steps of desmosome turn-over. With this respect, recent data indicate that autoantibodies induce separate signalling responses in keratinocytes via specific signalling complexes organised by Dsg1 and Dsg3 which transfer the signal of autoantibody binding into the cell. This hypothesis may also explain the different clinical pemphigus phenotypes

Desmoglein 2 is less important than desmoglein 3 for keratinocyte cohesion.

Desmosomes provide intercellular adhesive strength required for integrity of epithelial and some non-epithelial tissues. Within the epidermis, the cadherin-type adhesion molecules desmoglein (Dsg) 1-4 and desmocollin (Dsc) 1-3 build the adhesive core of desmosomes. In keratinocytes, several isoforms of these proteins are co-expressed. However, the contribution of specific isoforms to overall cell cohesion is unclear. Therefore, in this study we investigated the roles of Dsg2 and Dsg3, the latter of which is known to be essential for keratinocyte adhesion based on its autoantibody-induced loss of function in the autoimmune blistering skin disease pemphigus vulgaris (PV). The pathogenic PV antibody AK23, targeting the Dsg3 adhesive domain, led to profound loss of cell cohesion in human keratinocytes as revealed by the dispase-based dissociation assays. In contrast, an antibody against Dsg2 had no effect on cell cohesion although the Dsg2 antibody was demonstrated to interfere with Dsg2 transinteraction by single molecule atomic force microscopy and was effective to reduce cell cohesion in intestinal epithelial Caco-2 cells which express Dsg2 as the only Dsg isoform. To substantiate these findings, siRNA-mediated silencing of Dsg2 or Dsg3 was performed in keratinocytes. In contrast to Dsg3-depleted cells, Dsg2 knockdown reduced cell cohesion only under conditions of increased shear. These experiments indicate that specific desmosomal cadherins contribute differently to keratinocyte cohesion and that Dsg2 compared to Dsg3 is less important in this context

Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus

Pemphigus vulgaris (PV) is a severe autoimmune disease in which autoantibodies against the desmosomal cell adhesion molecules desmoglein (Dsg) 1 and Dsg3 cause intraepidermal blister formation. Mechanistically, the fundamental question is still unresolved whether loss of cell cohesion is a result of (1) direct inhibition of Dsg interaction by autoantibodies or (2) intracellular signaling events, which are altered in response to antibody binding and finally cause desmosome destabilization. We used atomic force microscopy (AFM) to perform Dsg3 adhesion measurements on living keratinocytes to investigate the contributions of direct inhibition and signaling to loss of cell cohesion after autoantibody treatment. Dsg3 binding was rapidly blocked following antibody exposure under conditions where no depletion of surface Dsg3 was detectable, demonstrating direct inhibition of Dsg3 interaction. Inhibition of p38MAPK, a central signaling molecule in PV pathogenesis, abrogated loss of cell cohesion, but had a minor effect on loss of Dsg3 binding. Similarly, the cholesterol-depleting agent methyl-β-cyclodextrin (β-MCD) fully blocked cell dissociation, but did not restore Dsg3 interactions or prevent the activation of p38MAPK. These results demonstrate that inhibition of Dsg3 binding is not sufficient to cause loss of cell cohesion, but rather alters signaling events which, in lipid raft-dependent manner, induce cell dissociation

Adducin Is Involved in Endothelial Barrier Stabilization

Adducins tightly regulate actin dynamics which is critical for endothelial barrier function. Adducins were reported to regulate epithelial junctional remodeling by controlling the assembly of actin filaments at areas of cell-cell contact. Here, we investigated the role of alpha-adducin for endothelial barrier regulation by using microvascular human dermal and myocardial murine endothelial cells. Parallel transendothelial electrical resistance (TER) measurements and immunofluorescence analysis revealed that siRNA-mediated adducin depletion impaired endothelial barrier formation and led to severe fragmentation of VE-cadherin immunostaining at cell-cell borders. To further test whether the peripheral localization of alpha-adducin is functionally linked with the integrity of endothelial adherens junctions, junctional remodeling was induced by a Ca2+-switch assay. Ca2+-depletion disturbed both linear vascular endothelial (VE)-cadherin and adducin location along cell junctions, whereas their localization was restored following Ca2+-repletion. Similar results were obtained for alpha-adducin phosphorylated at a site typical for PKA (pSer481). To verify that endothelial barrier properties and junction reorganization can be effectively modulated by altering Ca2+-concentration, TER measurements were performed. Thus, Ca2+-depletion drastically reduced TER, whereas Ca2+-repletion led to recovery of endothelial barrier properties resulting in increased TER. Interestingly, the Ca2+-dependent increase in TER was also significantly reduced after efficient alpha-adducin downregulation. Finally, we report that inflammatory mediator-induced endothelial barrier breakdown is associated with loss of alpha-adducin from the cell membrane. Taken together, our results indicate that alpha-adducin is involved in remodeling of endothelial adhesion junctions and thereby contributes to endothelial barrier regulation

Role of PKC and ERK Signaling in Epidermal Blistering and Desmosome Regulation in Pemphigus

Desmosomes reinforce cohesion of epithelial cells at the interface between adjacent cells. They include the cadherin-type adhesion molecules desmoglein 1 (Dsg1) and Dsg3. Pemphigus vulgaris (PV) is an autoimmune disease in which circulating autoantibodies (PV-IgG) targeting Dsg1 and 3 cause characteristic epidermal blister formation. It has been shown that PV-IgG binding induced activation of kinases such as ERK and PKC, and inhibition of these signaling pathways prevented loss of cell cohesion in cell cultures. However, the role of Erk and PKC in blister formation and regulation of desmosome ultrastructure in human skin are unknown. Accordingly, we assessed the role of PKC and ERK signaling pathways in blister formation and regulation of desmosome ultrastructure in human epidermis. Here we performed electron microscopy analyses using human skin explants injected with PV-IgG together with inhibitors for PKC or ERK signaling. Inhibition of PKC was not effective to prevent suprabasal blister formation or ultrastructural alterations of desmosomes. In contrast, inhibition of ERK signaling significantly ameliorated blister formation and decrease in the number of desmosomes whereas shortening and splitting of desmosomes and keratin filament insertion were not different from samples treated with PV-IgG alone. However, apical desmosomes between basal and suprabasal cells remained unaltered when ERK signaling was inhibited. Therefore, our results show that inhibition of ERK but not PKC signaling appears to be effective to ameliorate blistering and alterations of desmosome ultrastructure triggered by PV-IgG in human skin

Mechanisms Causing Acantholysis in Pemphigus-Lessons from Human Skin

Pemphigus vulgaris (PV) is an autoimmune bullous skin disease caused primarily by autoantibodies (PV-IgG) against the desmosomal adhesion proteins desmoglein (Dsg)1 and Dsg3. PV patient lesions are characterized by flaccid blisters and ultrastructurally by defined hallmarks including a reduction in desmosome number and size, formation of split desmosomes, as well as uncoupling of keratin filaments from desmosomes. The pathophysiology underlying the disease is known to involve several intracellular signaling pathways downstream of PV-IgG binding. Here, we summarize our studies in which we used transmission electron microscopy to characterize the roles of signaling pathways in the pathogenic effects of PV-IgG on desmosome ultrastructure in a human ex vivo skin model. Blister scores revealed inhibition of p38MAPK, ERK and PLC/Ca2+ to be protective in human epidermis. In contrast, inhibition of Src and PKC, which were shown to be protective in cell cultures and murine models, was not effective for human skin explants. The ultrastructural analysis revealed that for preventing skin blistering at least desmosome number (as modulated by ERK) or keratin filament insertion (as modulated by PLC/Ca2+) need to be ameliorated. Other pathways such as p38MAPK regulate desmosome number, size, and keratin insertion indicating that they control desmosome assembly and disassembly on different levels. Taken together, studies in human skin delineate target mechanisms for the treatment of pemphigus patients. In addition, ultrastructural analysis supports defining the specific role of a given signaling molecule in desmosome turnover at ultrastructural level

Therapieerfolg, Rezidivrate und Komplikationen der hyperthermen, isolierten Extremitätenperfusion (HILP) beim Malignen Melanom ermittelt am Erlanger Patientenkollektiv

Background and objective: The “hyperthermic isolated limb perfusion ” is a method of local chemotherapy which is used as treatment of primary tumors as well as locoregionally metastasised melanoma relapses of the extremities. This therapy is an alter-native to the amputation of the particular extremity which would otherwise be inevitable. In the following the results of our patient population shall be analysed particularly with regard to response rate, local recurrences and complication rate. Patients and methods: In the course of a retrospective analysis between 1992 and 2007, 152 patients (101 females, 51 males) with an average age of 62 years and locoregionally metastasised malignant melanoma underwent HILP using Melphalan and Dactinomycin. At the time of the perfusion 51 patients presented stage IIIA according to M.D. Anderson’s classification, 43 patients stage IIIAB and 58 patients stage IV. If indicated, lymph node dissection was performed prior to perfusion of the extremity. The data, which was collected from archival patient files and questionnaires filled in by the doctors responsible for aftercare, was statistically evaluated by means of the software SPSS (Version 16.0.© SPSS Inc.). Results: Complete remission was observed in 91 (62.7%) of 145 patients, partial remission in 26 (18%) patients. 28 (19%) patients showed no response. The overall response rate was 80.7% (117 of 145 patients). The average recur-rence-free survival was 17 months. Severe complications (Wieberdink IV/V) were seen in 8 cases. The median survival was 39 months; the five-year overall survival rate was 38%. The overall survival rate was significantly influenced by the stage of the disease. Conclusion: HILP is an efficient therapy for multiple or recurrent intransit metastases of malignant melanoma of the lower extremities. The efficiency could be increased by improving the technique of the perfusion. Long term survival can be observed in patients without regional lymph node metastases or distant metastases.Hintergrund und Ziele: Die hypertherme isolierte Extremitätenperfusion (HILP) ist eine Methode der regionalen Chemotherapie, die sowohl bei Primärtumoren als auch bei lokoregionären Melanomrezidiven der Extremitäten zum Einsatz kommt. Diese Therapie ist die Alternative zu einer sonst notwendigen Amputation der jeweiligen Gliedmaße. Im Folgenden sollen die Ergebnisse unseres Patientenkollektivs vor allem im Hinblick auf Ansprechrate, Rezidivquote und Komplikationsrate untersucht werden. Patienten und Methoden: Im Rahmen einer retrospektiven Analyse wurde in einem Zeitraum von 1992 bis 2007 bei 152 Patienten (101 Frauen und 51 Männer) mit einem Altersdurchschnitt von 62 Jahren eine HILP mit Melphalan und Dactinomycin bei lokoregionär metastasierten Malignen Melanomen angewandt. Zum Zeitpunkt der Perfusion befanden sich 51 Patienten im Stadium IIIA nach M.D. Anderson, 43 Patienten im Stadium IIIAB und 58 Patienten im Stadium IV. Falls notwendig, erfolgte im Rahmen der Extremitätenperfusion eine Lymphknotendissektion. Die Daten wurden mittels Patientenakten aus dem Archiv und Fragebögen an die jeweiligen nachsorgenden Ärzte ermittelt und mithilfe der Software SPSS (Version.16.0.©SPSS Inc.) statistisch ausgewertet. Ergebnisse: Bei 91 (62,7%) von 145 Patienten war eine komplette Remission und bei 26 (18%) Patienten eine partielle Remission feststellbar. 28 (19%) Erkrankte zeigten kein Ansprechen. Die Gesamtansprechrate lag bei 80,7% (117 von 145 Patienten). Das mittlere rezidivfreie Intervall beläuft sich auf 17 Monate. Schwere Komplikationen (Wieberdink IV/V) wurden bei 8 Patienten beobachtet. Die mediane Gesamtüberlebensrate betrug 39 Monate mit einer 5-JÜR von 38%. Die Überlebensrate war signifikant abhängig vom Stadium der Erkrankung. Fazit: Die hypertherme isolierte Extremitätenperfusion ist eine effektive Therapie beim lokoregionär metastasierten Malignen Melanom. Die Wirksamkeit konnte durch Verbesserung des Perfusionsregims gesteigert werden. Ein Langzeitüberleben kann bei Patienten ohne regionäre Lymphknotenmetastasen und Fernmetastasen erreicht werden