Protease inhibitors prevent plasminogen-mediated, but not pemphigus vulgaris-induced, acantholysis in human epidermis

Pemphigus is an autoimmune blistering disease of the skin and mucous membranes. It is caused by autoantibodies directed against desmosomes, which are the principal adhesion structures between epidermal keratinocytes. Binding of autoantibodies leads to the destruction of desmosomes resulting in the loss of cell-cell adhesion (acantholysis) and epidermal blisters. The plasminogen activator system has been implicated as a proteolytic effector in pemphigus. We have tested inhibitors of the plasminogen activator system with regard to their potential to prevent pemphigus-induced cutaneous pathology. In a human split skin culture system, IgG preparations of sera from pemphigus vulgaris patients caused histopathologic changes (acantholysis) similar to those observed in the original pemphigus disease. All inhibitors that were tested (active site inhibitors directed against uPA, tPA, and/or plasmin; antibodies neutralizing the enzymatic activity of uPA or tPA; substances interfering with the binding of uPA to its specific cell surface receptor uPAR) failed to prevent pemphigus vulgaris IgG-mediated acantholysis. Plasminogen-mediated acantholysis, however, was effectively antagonized by the synthetic active site serine protease inhibitor WX-UK1 or by p-aminomethylbenzoic acid. Our data argue against applying anti-plasminogen activator/anti-plasmin strategies in the management of pemphigus

Toxic Epidermal Necrolysis after Pemetrexed and Cisplatin for Non-Small Cell Lung Cancer in a Patient with Sharp Syndrome

Background: Pemetrexed is an antifolate drug approved for maintenance and second-line therapy, and, in combination with cisplatin, for first-line treatment of advanced nonsquamous non-small cell lung cancer. The side-effect profile includes fatigue, hematological and gastrointestinal toxicity, an increase in hepatic enzymes, sensory neuropathy, and pulmonary and cutaneous toxicity in various degrees. Case Report: We present the case of a 58-year-old woman with history of Sharp's syndrome and adenocarcinoma of the lung, who developed toxic epidermal necrolysis after the first cycle of pemetrexed, including erythema, bullae, extensive skin denudation, subsequent systemic inflammation and severe deterioration in general condition. The generalized skin lesions occurred primarily in the previous radiation field and responded to immunosuppressive treatment with prednisone. Conclusion: Although skin toxicity is a well-known side effect of pemetrexed, severe skin reactions after pemetrexed administration are rare. Caution should be applied in cases in which pemetrexed is given subsequent to radiation therapy, especially in patients with pre-existing skin diseases

ifo Konjunkturprognose 2007/2008: Aufschwung mit niedrigerem Tempo

Die Weltwirtschaft befindet sich im vierten Jahr eines konjunkturellen Aufschwungs und expandierte auch im Frühjahr 2007 kräftig. Das Bruttoinlandsprodukt legte infolge der günstigen Ertragslage der Unternehmen, höherer Aktienkurse und der zwar zuletzt gestiegenen, aber immer noch vergleichsweise niedrigen langfristigen Zinsen dynamisch zu. Und auch im Prognosezeitraum wird die Expansion der Weltwirtschaft schwungvoll bleiben, sich jedoch etwas abflachen. In der Eurozone setzt sich der Aufschwung zunächst schwungvoll fort, verliert aber im nächsten Jahr etwas an Dynamik. In den Industrieländern wird das Bruttoinlandsprodukt im Jahr 2007 um 2,5% und im Jahr 2008 um 2,8% zunehmen. Der Welthandel wird in diesem Jahr um 7,5% und im nächsten Jahr um 8,0% expandieren. In Deutschland hat sich der Aufschwung nach der Jahreswende trotz der Erhöhung der Mehrwertsteuer fortgesetzt. Saisonbereinigt ist die gesamtwirtschaftliche Produktion im ersten Quartal mit einer laufenden Jahresrate von 2,1% gestiegen, zuvor hatte das Expansionstempo allerdings noch bei 4,0% gelegen. Im Prognosezeitraum dürfte sich der konjunkturelle Aufschwung fortsetzen, dabei aber nicht mehr die hohe Dynamik des vergangenen Jahres erreichen. Die gesamtwirtschaftliche Produktion wird im laufenden Jahr um 2,6% expandieren; arbeitstäglich bereinigt um 2,8%. Im Jahr 2008 tritt der konjunkturelle Aufschwung in seine Spätphase ein.Weltkonjunktur, Konjunkturprognose, Wirtschaftslage, Wirtschaftswachstum, Deutschland, Welt

ifo Konjunkturprognose 2007: Konjunkturelle Auftriebskräfte bleiben stark

Am 14. Dezember 2006 stellte das ifo Institut im Rahmen seines vorweihnachtlichen Pressegesprächs seine Prognose für die Jahre 2007 und 2008 vor. Die deutsche Wirtschaft befindet sich zum Jahresende 2006 in einem kräftigen Aufschwung, der Anfang 2005 begonnen hat. Treibende Kraft des Booms ist weiterhin die Auslandsnachfrage, die trotz der diesjährigen kräftigen Aufwertung des Euro gegenüber dem US-Dollar erneut erheblich zugelegt hat. Die Exporte dürften im Jahresdurchschnitt 2006 um 10,5% gestiegen sein, das ist der größte Zuwachs seit dem Jahr 2000. Anders als im Jahr 2005 ist nunmehr aber auch die Binnenkonjunktur in Schwung gekommen. Die Investitionen in Bauten und Ausrüstungen wurden im laufenden Jahr recht zügig ausgeweitet. Der private Konsum, mit einem Anteil von 59% am nominalen BIP die gewichtigste Verwendungskomponente, vermochte im laufenden Jahr zum ersten Mal seit dem Jahr 2001 wieder etwas zuzulegen. Alles in allem dürfte die gesamtwirtschaftliche Produktion im Jahresdurchschnitt 2006 um 2,5% expandiert sein, nach 0,9% im Vorjahr. Nach Ausschaltung dieser Kalenderschwankung ist die Zuwachsrate der Produktion im laufenden Jahr sogar auf 2,7% zu veranschlagen. Der Aufschwung hat zugleich auch zu einem deutlichen Rückgang der Arbeitslosigkeit geführt. Im Jahresdurchschnitt 2006 dürfte die Zahl der Arbeitslosen um gut 360 000 gesunken sein. Im kommenden Jahr wird die Konjunktur durch die massive Erhöhung von Steuern und Abgaben zunächst erheblich gedämpft; gleichwohl wird sich dann aber der Aufschwung fortsetzen. Die Investitionsdynamik bei den Ausrüstungen und im Wirtschaftsbau wird 2007 recht kräftig bleiben. Alles in allem wird das reale Bruttoinlandsprodukt im Jahr 2007 um 1,9% expandieren, kalenderbereinigt um 2,0%. Bei alledem wird sich die Lage auf dem Arbeitsmarkt weiter bessern.Weltkonjunktur, Konjunkturprognose, Wirtschaftslage, Wirtschaftswachstum, Geschäftsklima, Deutschland, Welt

Divergent in situ expression of IL-31 and IL-31RA between bullous pemphigoid and pemphigus vulgaris

Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are two major autoimmune blistering skin diseases. Unlike PV, BP is accompanied by intense pruritus, suggesting possible involvement of the pruritogenic cytokine IL-31. However, the underlying mechanisms of the clinical difference between BP and PV in terms of pruritus are not fully understood. To compare the expression levels of IL-31 and its receptor IL-31RA in the lesional skin, including peripheral nerves in BP and PV patients, immunohistochemical staining for IL-31 and IL-31RA was performed in skin samples of BP and PV patients and healthy controls (HC). The IL-31RA-expressing area in epidermis and peripheral nerves was analysed using ImageJ and the percentage of positive cells for IL-31/IL-31RA in dermal infiltrating cells was manually quantified. Quantitative analyses revealed that IL-31/IL-31RA expressions in the epidermis and dermal infiltrate were significantly increased in BP compared to PV and HC. The difference between BP and PV became more obvious when advanced bullous lesions were compared. Peripheral nerves in BP lesions presented significantly higher IL-31RA expression compared to PV lesions. In conclusion, we found significantly augmented expressions of IL-31/IL-31RA in BP lesions, including peripheral nerves, in comparison to PV. These results suggest a possible contribution of IL-31/IL-31RA signalling to the difference between BP and PV in the facilitation of pruritus and local skin inflammation, raising the possibility of therapeutic targeting of the IL-31/IL-31RA pathway in BP patients

Ambient vibration tests of a cross-laminated timber building

Cross-laminated timber has, in the last 6 years, been used for the first time to form shear walls and cores in multi-storey buildings of seven storeys or more. Such buildings can have low mass in comparison to conventional structural forms. This low mass means that, as cross-laminated timber is used for taller buildings still, their dynamic movement under wind load is likely to be a key design parameter. An understanding of dynamic lateral stiffness and damping, which has so far been insufficiently researched, will be vital to the effective design for wind-induced vibration. In this study, an ambient vibration method is used to identify the dynamic properties of a seven-storey cross-laminated timber building in situ. The random decrement method is used, along with the Ibrahim time domain method, to extract the modal properties of the structure from the acceleration measured under ambient conditions. The results show that this output-only modal analysis method can be used to extract modal information from such a building, and that information is compared with a simple structural model. Measurements on two occasions during construction show the effect of non-structural elements on the modal properties of the structure

Increased survival with enzalutamide in prostate cancer after chemotherapy

Contains fulltext : 108324.pdf (publisher's version ) (Open Access)BACKGROUND: Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. METHODS: In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival. RESULTS: The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; P<0.001). The superiority of enzalutamide over placebo was shown with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%, P<0.001), the soft-tissue response rate (29% vs. 4%, P<0.001), the quality-of-life response rate (43% vs. 18%, P<0.001), the time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P<0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and the time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). Rates of fatigue, diarrhea, and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide. CONCLUSIONS: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy. (Funded by Medivation and Astellas Pharma Global Development; AFFIRM ClinicalTrials.gov number, NCT00974311.)

Epigenetic scores for the circulating proteome as tools for disease prediction

Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNA methylation (DNAm) signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample (Generation Scotland; n = 9537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore-disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors, and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification

Blood-based epigenome-wide analyses of cognitive abilities

BACKGROUND: Blood-based markers of cognitive functioning might provide an accessible way to track neurodegeneration years prior to clinical manifestation of cognitive impairment and dementia. RESULTS: Using blood-based epigenome-wide analyses of general cognitive function, we show that individual differences in DNA methylation (DNAm) explain 35.0% of the variance in general cognitive function (g). A DNAm predictor explains ~4% of the variance, independently of a polygenic score, in two external cohorts. It also associates with circulating levels of neurology- and inflammation-related proteins, global brain imaging metrics, and regional cortical volumes. CONCLUSIONS: As sample sizes increase, the ability to assess cognitive function from DNAm data may be informative in settings where cognitive testing is unreliable or unavailable. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-021-02596-5