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

Outcrop conservation : Promoting accessibility, inclusivity, and reproducibility through digital preservation

We thank Georgina Heldreich for providing useful comments on an early draft of the manuscript. We gratefully acknowledge the detailed and constructive reviews by Kim Senger and two anonymous reviewers, all of which greatly improved the manuscript.Peer reviewedPublisher PD

Stereotactic body radiation therapy for melanoma and renal cell carcinoma: impact of single fraction equivalent dose on local control

<p>Abstract</p> <p>Background</p> <p>Melanoma and renal cell carcinoma (RCC) are traditionally considered less radioresponsive than other histologies. Whereas stereotactic body radiation therapy (SBRT) involves radiation dose intensification via escalation, we hypothesize SBRT might result in similar high local control rates as previously published on metastases of varying histologies.</p> <p>Methods</p> <p>The records of patients with metastatic melanoma (n = 17 patients, 28 lesions) or RCC (n = 13 patients, 25 lesions) treated with SBRT were reviewed. Local control (LC) was defined pathologically by negative biopsy or radiographically by lack of tumor enlargement on CT or stable/declining standardized uptake value (SUV) on PET scan. The SBRT dose regimen was converted to the single fraction equivalent dose (SFED) to characterize the dose-control relationship using a logistic tumor control probability (TCP) model. Additionally, the kinetics of decline in maximum SUV (SUV_max) were analyzed.</p> <p>Results</p> <p>The SBRT regimen was 40-50 Gy/5 fractions (n = 23) or 42-60 Gy/3 fractions (n = 30) delivered to lung (n = 39), liver (n = 11) and bone (n = 3) metastases. Median follow-up for patients alive at the time of analysis was 28.0 months (range, 4-68). The actuarial LC was 88% at 18 months. On univariate analysis, higher dose per fraction (p < 0.01) and higher SFED (p = 0.06) were correlated with better LC, as was the biologic effective dose (BED, p < 0.05). The actuarial rate of LC at 24 months was 100% for SFED ≥45 Gy v 54% for SFED <45 Gy. TCP modeling indicated that to achieve ≥90% 2 yr LC in a 3 fraction regimen, a prescription dose of at least 48 Gy is required. In 9 patients followed with PET scans, the mean pre-SBRT SUV_maxwas 7.9 and declined with an estimated half-life of 3.8 months to a post-treatment plateau of approximately 3.</p> <p>Conclusions</p> <p>An aggressive SBRT regimen with SFED ≥ 45 Gy is effective for controlling metastatic melanoma and RCC. The SFED metric appeared to be as robust as the BED in characterizing dose-response, though additional studies are needed. The LC rates achieved are comparable to those obtained with SBRT for other histologies, suggesting a dominant mechanism of in vivo tumor ablation that overrides intrinsic differences in cellular radiosensitivity between histologic subtypes.</p

Aquilegia, Vol. 31 No. 6, Winter 2007, Newsletter of the Colorado Native Plant Society

https://epublications.regis.edu/aquilegia/1122/thumbnail.jp

ifo Konjunkturprognose 2005/2006: Nur zögerliche Erholung

Die Weltwirtschaft hat im laufenden Jahr merklich an Dynamik eingebüßt, nachdem sie 2004 außerordentlich stark gewachsen war. In Deutschland fehlen die binnenwirtschaftlichen Auftriebskräfte immer noch fast vollständig. Die gesamtwirtschaftliche Produktion kommt sofort aus dem Tritt, sobald vom Ausland geringere Impulse ausgehen. Für die deutsche Wirtschaft ist eine fundamentale Wachstumsschwäche zu diagnostizieren; das Produktionspotential steigt derzeit nur um 1%, das ist halb so hoch wie im restlichen Euroraum. Die Entwicklung dieses und des kommenden Jahres wird ungefähr dem Trend folgen. Das reale Bruttoinlandsprodukt dürfte im Jahresdurchschnitt 2005 um 0,8% expandieren, nach 1,6% im Jahr 2004. Im nächsten Jahr dürfte sich das Expansionstempo der gesamtwirtschaftlichen Produktion parallel zur Besserung der Weltkonjunktur wieder leicht beschleunigen; die Zuwachsrate des realen Bruttoinlandsprodukts dürfte sich dann auf 1,2% belaufen. Damit wird die gesamtwirtschaftliche Auslastung der Produktionskapazitäten wieder zunehmen. Die Inflationsrate dürfte trotz des Ölpreisschubs im Durchschnitt des Prognosezeitraums unter der 2-Prozentmarke liegen. Auf dem deutschen Arbeitsmarkt ist bisher keine Wende eingetreten. Im Mai dieses Jahres gab es 4,81 Mill. registrierte Arbeitslose; das entspricht einem Anstieg von 510 000 gegenüber dem vergleichbaren Vorjahresmonat. Der überwiegende Teil dieser Zunahme (ca. 360 000) ist auf die im Zuge der Hartz-IV-Gesetzgebung erfolgte Zusammenlegung von Arbeitslosen- und Sozialhilfe zurückzuführen. Rechnet man dagegen, dass inzwischen rund 155 000 Zusatzjobs die Statistik entlasten, so dürfte die rein konjunkturelle Zunahme der Arbeitslosigkeit rund 300 000 betragen haben. Erst im nächsten Jahr ist eine leichte Besserung auf dem Arbeitsmarkt zu erwarten. Unter der Annahme, dass bis zum Jahresende 2006 etwa 300 000 Zusatzjobs geschaffen werden, dürfte sich die Zahl der registrierten Arbeitslosen in diesem Jahr auf 4,86 Millionen belaufeWeltkonjunktur, Konjunkturprognose, Wirtschafstwachstum, Konjunkturumfrage, Geschäftsklima, Deutschland, Welt

High probability of comorbidities in bronchial asthma in Germany

Clinical experience has shown that allergic and non-allergic respiratory, metabolic, mental, and cardiovascular disorders sometimes coexist with bronchial asthma. However, no study has been carried out that calculates the chance of manifestation of these disorders with bronchial asthma in Saarland and Rhineland-Palatinate, Germany. Using ICD10 diagnoses from health care institutions, the present study systematically analyzed the co-prevalence and odds ratios of comorbidities in the asthma population in Germany. The odds ratios were adjusted for age and sex for all comorbidities for patients with asthma vs. without asthma. Bronchial asthma was strongly associated with allergic and with a lesser extent to non-allergic comorbidities: OR 7.02 (95% CI:6.83–7.22) for allergic rhinitis; OR 4.98 (95%CI:4.67–5.32) allergic conjunctivitis; OR 2.41 (95%CI:2.33–2.52) atopic dermatitis; OR 2.47 (95%CI:2.16–2.82) food allergy, and OR 1.69 (95%CI:1.61–1.78) drug allergy. Interestingly, increased ORs were found for respiratory diseases: 2.06 (95%CI:1.64–2.58) vocal dysfunction; 1.83 (95%CI:1.74–1.92) pneumonia; 1.78 (95%CI:1.73–1.84) sinusitis; 1.71 (95%CI:1.65–1.78) rhinopharyngitis; 2.55 (95%CI:2.03–3.19) obstructive sleep apnea; 1.42 (95%CI:1.25–1.61) pulmonary embolism, and 3.75 (95%CI:1.64–8.53) bronchopulmonary aspergillosis. Asthmatics also suffer from psychiatric, metabolic, cardiac or other comorbidities. Myocardial infarction (OR 0.86, 95%CI:0.79–0.94) did not coexist with asthma. Based on the calculated chances of manifestation for these comorbidities, especially allergic and respiratory, to a lesser extent also metabolic, cardiovascular, and mental disorders should be taken into consideration in the diagnostic and treatment strategy of bronchial asthma

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

Cutaneous infection by Mycobacterium haemophilum and kansasii in an IgA-deficient man

<p>Abstract</p> <p>Background</p> <p>The prevalence of infections by nontuberculous mycobacteria (NTM) has steadily increased over the past decades, especially in immunocompromised patients.</p> <p>Case presentation</p> <p>We present a patient with IgA-deficiency and mixed cutaneous infection by two slowly growing mycobacteria, <it>Mycobacterium </it>(<it>M.</it>) <it>haemophilum </it>and <it>M. kansasii.</it></p> <p>Conclusions</p> <p>Cutaneous <it>M. haemophilum </it>infections most often result from HIV or transplantation-associated immunosuppression. Rarely, <it>M. haemophilum </it>may also infect healthy patients or iatrogenically immunosuppressed patients without transplantation. <it>M. kansasii </it>is one of the most frequent NTM and large awareness exists about its involvement in human diseases. Mycobacterial diagnosis of cutaneous infections should be considered in long-lasting skin lesions.</p