Hyaluronidase recruits mesenchymal-like cells to the lung and ameliorates fibrosis

Hyaluronidases (HYALs) comprise a group of enzymes that degrade hyaluronic acid (HA). In this report, we reveal that a single intranasal inoculation of HYAL induces an increase in mononuclear cells within the bronchoalveolar space demonstrating a mesenchymal-like phenotype, expressing stem cell antigen-1 (SCA-1), CD44 and CD73 but not CD34, CD45, CD3, CD4, CD8 or CD19. This influx of mesenchymal stem cell (MSC)-like cells was dependent on leukotriene production within the lung parenchyma. These findings prompted experiments demonstrating that HYAL treatment potently blocked bleomycin-induced lung injury and fibrosis while decreasing transforming growth factor (TGF)-β production and collagen deposition. These data suggest that HYAL is a novel and promising tool to use autologous MSC-like cells in the treatment of pulmonary fibrosis

Partial motivation, multiple motivation: the role of output schemas in morphology

Theoretical and Experimental Linguistic

Formulacija i evaluacija monolitnih matriksnih polimernih filmova za transdermalnu isporuku nitrendipina

The objective of the present work was to develop a suitable transdermal drug delivery system for nitrendipine. Polymeric films of nitrendipine were prepared by the film casting technique (glass ring) on mercury substrate. They were evaluated for physicochemical parameters, in vitro release and ex vivo permeation (heat separated human epidermis). Release of the drug from the films followed anomalous transport (0.5 < n < 1). Polymeric combination containing Eudragit RL 100:PVP K 30 in 4:6 ratio showed the best results. Maximum drug release and skin permeability coefficient in 48 h were 85.8 % and 0.0142 cm h-1, respectively, in formulation C3 (Eudragit RL 100: Plasdone S 630; 4:6) and 88.0 % and 0.0155 cm h-1, respectively, in formulation D3 (Eudragit RL 100: PVP K 30; 4:6). FTIR and TLC studies indicated no drug and polymer interaction.Cilj rada bio je razvoj transdermalnog sustava nitrendipina. Polimerni filmovi nitrendipina pripravljeni su metodom lijevanja (stakleni prsten) na podlozi od žive. Ispitivani su fizičkokemijski parametri, in vitro oslobađanje i ex vivo permeacija (toplinom odvojena humana epiderma). Oslobađanje lijeka iz filmova slijedilo je anomalni transport (0,5 < n < 1). Najbolji rezultati postignuti su kombinacijom polimera Eudragit RL 100 i PVP K 30 u omjeru 4:6. Maksimalno oslobađanje ljekovite tvari i najbolji koeficijent permeacije kroz kožu tijekom 48 h bio je 85,8 %, odnosno 0,0142 cm h1 za formulaciju C3 (Eudragit RL 100 : Plasdone S 630; 4:6) i 88,0 %, odnosno 0,0155 cm h1 za formulaciju D3 (Eudragit RL 100 : PVP K 30; 4:6). FTIR i TLC ukazuju na to da nema interakcije između ljekovite tvari i polimera

Post-operative Aspergillus mediastinitis in a man who was immunocompetent: a case report

<p>Abstract</p> <p>Introduction</p> <p><it>Aspergillus </it>spp. infections mainly affect patients who are immunocompromised, and are extremely rare in immunocompetent individuals.</p> <p>Case presentation</p> <p><it>Aspergillus </it>post-operative mediastinitis is considered to be a devastating infection, usually affecting patients undergoing cardiothoracic surgery with specific predisposing factors. We describe the case of an immunocompetent 68-year-old Caucasian man with severe chronic thromboembolic pulmonary hypertension, who underwent pulmonary thromboendarterectomy and developed post-operative mediastinitis due to <it>Aspergillus flavus</it>. The environmental control did not reveal the source of <it>A. flavus </it>infection and, despite combined antifungal therapy, our patient died as a result of septic shock and multiple organ failure.</p> <p>Conclusion</p> <p><it>Aspergillus </it>mediastinitis mainly affects patients after cardiosurgery operations with predisposing factors, and it is unusual in patients who are immunocompetent. The identification of the <it>Aspergillus </it>spp. source is often difficult, and there are no guidelines for the administration of pre-emptive therapy in this population of at-risk patients.</p

Transient Increase in Cyclic AMP Localized to Macrophage Phagosomes

Cyclic AMP (cAMP) regulates many biological processes and cellular functions. The importance of spatially localized intracellular gradients of cAMP is increasingly appreciated. Previous work in macrophages has shown that cAMP is produced during phagocytosis and that elevated cAMP levels suppress host defense functions, including generation of proinflammatory mediators, phagocytosis and killing. However, the spatial and kinetic characteristics of cAMP generation in phagocytosing macrophages have yet to be examined. Using a Förster resonance energy transfer (FRET)-based cAMP biosensor, we measured the generation of cAMP in live macrophages. We detected no difference in bulk intracellular cAMP levels between resting cells and cells actively phagocytosing IgG-opsonized particles. However, analysis with the biosensor revealed a rapid decrease in FRET signal corresponding to a transient burst of cAMP production localized to the forming phagosome. cAMP levels returned to baseline after the particle was internalized. These studies indicate that localized increases in cAMP accompany phagosome formation and provide a framework for a more complete understanding of how cAMP regulates macrophage host defense functions

The role of the humoral immune response to Clostridium difficile toxins A and B in susceptibility to C. difficile infection: a case-control study

Antibody levels to Clostridium difficile toxin A (TcdA), but not toxin B (TcdB), have been found to determine risk of C. difficile infection (CDI). Historically, TcdA was thought to be the key virulence factor; however the importance of TcdB in disease is now established. We re-evaluated the role of antibodies to TcdA and TcdB in determining patient susceptibility to CDI in two separate patient cohorts. In contrast to earlier studies, we find that CDI patients have lower pre-existing IgA titres to TcdB, but not TcdA, when compared to control patients. Our findings suggest that mucosal immunity to TcdB may be important in the early stages of infection and identifies a possible target for preventing CDI progression

Impaired neonatal macrophage phagocytosis is not explained by overproduction of prostaglandin E2

<p>Abstract</p> <p>Background</p> <p>Neonates and young infants manifest increased susceptibility to bacterial, viral and fungal lung infections. Previous work has identified a role for eicosanoids in mediating host defense functions of macrophages. This study examines the relationship between alveolar macrophage (AM) host defense and production of lipid mediators during the neonatal period compared to adult AMs.</p> <p>Methods</p> <p>AMs were harvested from young (day 7 and day 14) and adult (~10 week) rats. The functionality of these cells was assessed by examining their ability to phagocytose opsonized targets, produce cytokines, eicosanoids and intracellular cAMP measured by enzyme immunoassays, and gene expression of proteins, enzymes and receptors essential for eicosanoid generation and phagocytosis measured by real time RT-PCR.</p> <p>Results</p> <p>AMs from young animals (day 7 and 14) were defective in their ability to phagocytose opsonized targets and produce tumor necrosis factor (TNF)- α. In addition, young AMs produce more prostaglandin (PG) E₂, a suppressor of host defense, and less leukotriene (LT) B₄, a promoter of host defense. Young AMs express higher levels of enzymes responsible for the production of PGE₂and LTB₄; however, there was no change in the expression of E prostanoid (EP) receptors or LT receptors. Despite the similar EP profiles, young AMs are more responsive to PGE₂as evidenced by their increased production of the important second messenger, cyclic AMP. In addition, young AMs express higher levels of PDE3B and lower levels of PDE4C compared to adult AMs. However, even though the young AMs produced a skewed eicosanoid profile, neither the inhibition of PGE₂by aspirin nor the addition of exogenous LTB₄rescued the defective opsonized phagocytosis. Examination of a receptor responsible for mediating opsonized phagocytosis showed a significant decrease in the gene expression levels of the Fcgamma receptor in young (day 7) AMs compared to adult AMs.</p> <p>Conclusion</p> <p>These results suggest that elevated production of PGE₂and decreased production of LTB₄do not contribute to impaired opsonized macrophage phagocytosis and highlight an important difference between young and adult AMs.</p