Cellular uptake and localization of inhaled gold nanoparticles in lungs of mice with chronic obstructive pulmonary disease

Background: Inhalative nanocarriers for local or systemic therapy are promising. Gold nanoparticles (AuNP) have been widely considered as candidate material. Knowledge about their interaction with the lungs is required, foremost their uptake by surface macrophages and epithelial cells. Diseased lungs are of specific interest, since these are the main recipients of inhalation therapy. We, therefore, used Scnn1b-transgenic (Tg) mice as a model of chronic obstructive pulmonary disease (COPD) and compared uptake and localization of inhaled AuNP in surface macrophages and lung tissue to wild-type (Wt) mice. Methods: Scnn1b-Tg and Wt mice inhaled a 21-nm AuNP aerosol for 2 h. Immediately (0 h) or 24 h thereafter, bronchoalveolar lavage (BAL) macrophages and whole lungs were prepared for stereological analysis of AuNP by electron microscopy. Results: AuNP were mainly found as singlets or small agglomerates of ≤ 100 nm diameter, at the epithelial surface and within lung-surface structures. Macrophages contained also large AuNP agglomerates (> 100 nm). At 0 h after aerosol inhalation, 69.2±4.9% AuNP were luminal, i.e. attached to the epithelial surface and 24.0±5.9% in macrophages in Scnn1b-Tg mice. In Wt mice, 35.3±32.2% AuNP were on the epithelium and 58.3±41.4% in macrophages. The percentage of luminal AuNP decreased from 0 h to 24 h in both groups. At 24 h, 15.5±4.8% AuNP were luminal, 21.4±14.2% within epithelial cells and 63.0±18.9% in macrophages in Scnn1b-Tg mice. In Wt mice, 9.5±5.0% AuNP were luminal, 2.2±1.6% within epithelial cells and 82.8±0.2% in macrophages. BAL-macrophage analysis revealed enhanced AuNP uptake in Wt animals at 0 h and in Scnn1b-Tg mice at 24 h, confirming less efficient macrophage uptake and delayed clearance of AuNP in Scnn1b-Tg mice. Conclusions: Inhaled AuNP rapidly bound to the alveolar epithelium in both Wt and Scnn1b-Tg mice. Scnn1b-Tg mice showed less efficient AuNP uptake by surface macrophages and concomitant higher particle internalization by alveolar type I epithelial cells compared to Wt mice. This likely promotes AuNP depth translocation in Scnn1b-Tg mice, including enhanced epithelial targeting. These results suggest AuNP nanocarrier delivery as successful strategy for therapeutic targeting of alveolar epithelial cells and macrophages in COPD

The dramatic illusion in the theory and later plays of Friedrich Schiller

Statements in Schiller's early essays seem to suggest that he adhered to the view of the dramatic illusion as a temporary escape from reality, an experience in which the spectator is encouraged to forget that he is in the theatre and be caught up in a deceptive and convincing illusion. Analysis of Schiller's dramatic and aesthetic theory and of his correspondence from 1790 onwards, however, shows that the ideas of moral freedom, aesthetic harmony and of the autonomy of art led Schiller to reject the ideal of convincing illusion which was current and popular in his time. In its place he wished to encourage awareness of the illusory nature of the stage action and drama which was obviously different from everyday reality in its subject matter and style. Analysis of Schiller's plays from Wallenstein to Wilhelm Tell shows that Schiller aimed at illusion of this type in his own practice. With reference to the dramatic illusion, Schiller's views actually come close to those of Brecht, in spite of statements to the contrary in Brecht's Kleines Organon für das Theater. The detailed analysis of Schiller's theory and of his later plays is preceded firstly by a chapter on problems associated with the topic of the dramatic illusion. Secondly, a background chapter considers influential developments in drama, dramatic theory and in aesthetics from the origins of western drama in Greek classical tragedy to the theatre of Schiller's time, to establish possible influences on Schiller or similarities between his views and existing traditions, and to suggest Schiller's position with regard to his contemporaries and to the historical development of the dramatic illusion

Differential Regulation of PDE5 Expression in Left and Right Ventricles of Feline Hypertrophy Models

Though long known to affect smooth muscle biology, recent studies indicate that phosphodiesterase 5 (PDE5) is also expressed in myocardium. Recognizing that the regulation of PDE5 in hypertrophy is not well understood, we assessed the response of PDE5 expression and the level of cGMP-dependent kinase I (cGKI) in the left and right ventricles of feline hypertrophy models.Using a cDNA library of feline aortic smooth muscle cells, we identified and cloned PDE5 cDNA for the first time in this species. The sequence shares 98% identity with its human orthologue at the amino acid level. E. coli expression of the cloned allele allowed selection of antibodies with appropriate specificity, facilitating the analysis of PDE5 expression in feline models created by selective proximal aortic (Ao) or pulmonary artery (PA) banding that resulted in hypertrophy of the left ventricle (LV) and right ventricle (RV), respectively. We demonstrated that PDE5 expression responded differentially with a decreased expression in the LV and an increased expression in the RV in the Ao-banded model. Similarly, in the PA-banded model, LV showed reduced expression while the RV expression was unaltered. In addition, the expression of cGKI was significantly decreased in the RV of Ao-banded group, correlating inversely with the increase in PDE5 expression.The differential regulation of PDE5 and cGKI expression suggests that the mechanisms involved in hypertrophy could be different in RV vs. LV. Reciprocal PDE5 and cGKI expression in the RV of Ao-banded model suggests functional significance for PDE5 up-regulation

PTSD in paramedics: history, conceptual issues and psychometric measures

Post-traumatic stress disorder (PTSD) is more common in paramedics than in the general population because of the stressful and distressing nature of their work. Forms of PTSD associated with chronic stress and repeated trauma are scarcely researched among paramedics. This is striking as this workforce is potentially more likely to be affected by these types of PTSD. Diagnostic processes are still largely based on acute rather than chronic psychological trauma. PTSD diagnosis has been influenced by sociological perceptions of mental illness and changes in diagnostic criteria. Criteria for the diagnosis of PTSD in the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases have changed in the past decade, which may facilitate more appropriate diagnoses of PTSD in paramedics. Paramedics often have a complex aetiology of PTSD resulting from experiences of both chronic and acute events. Questionnaires that cover exposure to both individual and repeated stressful events are required to enable further research in the area of PTSD in paramedics

De Novo

International audienceA proof-of-concept library of pyrrolodiazepinone small molecules was designed based on the Bip-Lys-Tyr motif found in a recently described modulator of the urotensinergic system. Solid-phase synthesis provided 13 analogues, which were tested for their ability to modulate selectively and differentially the potency (EC50) and efficacy (E(max)) of hUII and URP ex vivo in a rat aortic ring bioassay. Notably, at 14 μM, pyrrolodiazepinone R-4a inhibited completely hUII-induced contractions and increased URP-associated vasoconstriction. Pyrrolodiazepinone R-4a represents, to the best of our knowledge, a first-in-class small molecule that exerts a probe-dependent effect on hUII and URP biological activities and proves that UT modulators of the urotensin II receptor (UT) can be rationally designed. The importance of the UT system in the pathogenesis and progression of cardiovascular diseases highlights the utility of pyrrolodiazepinones such as R-4a, which exhibit promising potential as tools for differentiating the respective roles, signaling pathways, and phenotypic outcomes of UII and URP in the UT system

Measurement of the effects of lateral release

AbstractIn a prospective trial of 37 knees with anterior knee pain, 12 improved with conservative treatment. Twenty five knees in 23 patients required arthroscopy and lateral release. It was found that the clinical examination combined with skyline X-Rays gave a good assessment of these patients. The medial angle and the congruence angle were rarely abnormal but often showed improved centring after lateral release. It seems unlikely, however, that this is responsible for improved symptoms especially as the asymptomatic side frequently showed similar X-Ray changes.</jats:p