CLINICAL EVALUATION OF NOVEL METHODS FOR EXTENDING MICRONEEDLE PORE LIFETIME

Microneedles are a minimally invasive method for delivering drugs through the impermeable skin layers, and have been used to deliver a variety of compounds including macromolecules, vaccines, and naltrexone. Microneedles can be applied to the skin once, creating micropores that allow for drug delivery into the underlying circulation from a drug formulation. The utility of this technique, however, is blunted by rapid micropore closure. This research project sought to: 1) characterize micropore lifetime and re-sealing kinetics, and 2) prolong micropore lifetime via inhibition of the skin’s barrier restoration processes. Impedance spectroscopy was used as a surrogate technique in animals and humans to measure micropore formation and lifetime. A proof of concept study in humans, using impedance spectroscopy, demonstrated that diclofenac (a topical anti-inflammatory) applied to microporated skin resulted in slower re-sealing kinetics compared to placebo, in agreement with previous animal studies. The clinical feasibility of prolonging micropore lifetime with diclofenac was confirmed via 7-day delivery of naltrexone through microneedle treated skin in humans (compared to 72 hour delivery with placebo). Lastly, naltrexone gels with calcium salts were applied to microneedle treated skin (hairless guinea pigs) to restore the altered epidermal calcium gradient; this method did not significantly extend micropore lifetime

Sigurðar saga fóts (The Saga of Sigurðr Foot): A Translation

This is the first English translation of the short Icelandic romance Sigurðar saga fóts, with an introduction presenting the evidence for its dating and immediate literary context. Like most Icelandic romances, Sigurðar saga is a bridal-quest story; the support of a foster-brother is key to the hero winning the bride; and the foster-brothers start out as opponents before recognising their mutual excellence and swearing foster-brotherhood. Uniquely, however, the men who become foster-brothers begin by competing for the same bride (Signý): the eponymous Sigurðr fótr wins Signý only because Ásmundr gives her to him in exchange for foster-brotherhood. Ásmundr’s decision can be read as demonstrating with unusual starkness the superior importance in much Icelandic romance of homosocial relationships over heterosexual ones, giving the saga a certain paradigmatic status. Translating the saga in an open-access forum and reconstructing its literary context will, we hope, encourage further analyses

Sigurðar saga fóts (The Saga of Sigurðr Foot): A Translation

This is the first English translation of the short Icelandic romance Sigurðar saga fóts, with an introduction presenting the evidence for its dating and immediate literary context. Like most Icelandic romances, Sigurðar saga is a bridal-quest story; the support of a foster-brother is key to the hero winning the bride; and the foster-brothers start out as opponents before recognising their mutual excellence and swearing foster-brotherhood. Uniquely, however, the men who become foster-brothers begin by competing for the same bride (Signý): the eponymous Sigurðr fótr wins Signý only because Ásmundr gives her to him in exchange for foster-brotherhood. Ásmundr’s decision can be read as demonstrating with unusual starkness the superior importance in much Icelandic romance of homosocial relationships over heterosexual ones, giving the saga a certain paradigmatic status. Translating the saga in an open-access forum and reconstructing its literary context will, we hope, encourage further analyses

The Common European Framework of Reference (CEFR) in Canada: A Research Agenda

This article proposes a research agenda for future inquiry into the use of the Common European Framework of Reference (CEFR) in the plurilingual Canadian context. Drawing on data collected from a research forum hosted by the Canadian Association of Second Language Teachers in 2014, as well as a detailed analysis of Canadian empirical studies and practice-based projects to date, the authors examine three areas of emphasis related to CEFR use: (a) K-12 education, including uses with learners; (b) initial teacher education, where additional language teacher candidates are situated as both learners and future teachers; and (c) postsecondary language learning contexts. Future research directions are proposed in consideration of how policymaking, language teaching and language learning are articulated across each of these three contexts. To conclude, a call is made for ongoing conversations encouraging stakeholders to consider how they might take up pan-Canadian interests when introducing various aspects of the CEFR and its related tools

The Effects of Danofloxacin and Tilmicosin on Neutrophil Function and Lung Consolidation in Beef Heifer Calves with Induced Pasteurella (Mannheimia) haemolytica Pneumonia

Pneumonia caused by Pasteurella (Mannheimia) haemolytica was induced in weaned beef heifer calves, approximately 6 months of age. Calves were treated at 20 h after challenge with therapeutic doses of danofloxacin or tilmicosin. Peripheral blood neutrophils were collected at 3, 24 and 48 h after treatment. The ex vivo effects on neutrophil function, neutrophil apoptosis, and hematological parameters were examined, as was the effect on percentage lung consolidation. Neutrophil function assays included random migration under agarose, cytochrome C reduction, iodination, Staphylococcus aureus ingestion, chemotaxis, and antibody-dependent and antibody-independent cell-mediated cytotoxicity. Apoptosis was determined using a cell death detection kit. Killing was performed at 72 h after treatment. Statistical comparisons were made among the three groups of challenged–treated animals: saline, danofloxacin, and tilmicosin. Comparisons were also made between nonchallenged nontreated animals (NCH) and challenged saline-treated animals. There were no significant differences for any of the neutrophil function assays or neutrophil apoptosis among the challenged–treated groups. This suggests that danofloxacin and tilmicosin have no clinically significant effects on neutrophil function or apoptosis. There were also no significant differences in percentage lung consolidation among the challenged–treated groups. Significant differences were found between the NCH calves and the challenged saline-treated calves in several neutrophil assays, which were attributed to effects of P. haemolyticainfectio

Oxidative Stress in Canine Histiocytic Sarcoma Cells Induced by an Infection with Canine Distemper Virus Led to a Dysregulation of HIF-1α Downstream Pathway Resulting in a Reduced Expression of VEGF-B in vitro

Histiocytic sarcomas represent malignant tumors which require new treatment strategies. Canine distemper virus (CDV) is a promising candidate due to its oncolytic features reported in a canine histiocytic sarcoma cell line (DH82 cells). Interestingly, the underlying mechanism might include a dysregulation of angiogenesis. Based on these findings, the aim of the present study was to investigate the impact of a persistent CDV-infection on oxidative stress mediated changes in the expression of hypoxia-inducible factor (HIF)-1\u3b1 and its angiogenic downstream pathway in DH82 cells in vitro. Microarray data analysis, immunofluorescence for 8-hydroxyguanosine, superoxide dismutase 2 and catalase, and flow cytometry for oxidative burst displayed an increased oxidative stress in persistently CDV-infected DH82 cells (DH82Ond pi) compared to controls. The HIF-1\u3b1 expression in DH82Ond pi increased, as demonstrated by Western blot, and showed an unexpected, often sub-membranous distribution, as shown by immunofluorescence and immunoelectron microscopy. Furthermore, microarray data analysis and immunofluorescence confirmed a reduced expression of VEGF-B in DH82Ond pi compared to controls. In summary, these results suggest a reduced activation of the HIF-1\u3b1 angiogenic downstream pathway in DH82Ond pi cells in vitro, most likely due to an excessive, unusually localized, and non-functional expression of HIF-1\u3b1 triggered by a CDV-induced increased oxidative stress

Effect of Stress on Viral–Bacterial Synergy in Bovine Respiratory Disease: Novel Mechanisms to Regulate Inflammation

The severity of bovine respiratory infections has been linked to a variety of factors, including environmental and nutritional changes, transportation, and social reorganization of weaned calves. Fatal respiratory infections, however, usually occur when a primary viral infection compromises host defences and enhances the severity of a secondary bacterial infection. This viral–bacterial synergy can occur by a number of different mechanisms and disease challenge models have been developed to analyse host responses during these respiratory infections. A primary bovine herpesvirus-1 (BHV-1) respiratory infection followed by a secondary challenge with Mannheimia haemolytica results in fatal bovine respiratory disease (BRD) and host responses to these two pathogens have been studied extensively. We used this disease model to demonstrate that stress significantly altered the viral–bacterial synergy resulting in fatal BRD. Functional genomic analysis revealed that BHV-1 infection enhanced toll-like receptors (TLR) expression and increased pro-inflammatory responses which contribute to the severity of a Mannheimia haemolytica infection. TLRs play a critical role in detecting bacterial infections and inducing pro-inflammatory responses. It is difficult to understand, however, how stress-induced corticosteroids could enhance this form of viral–bacterial synergy. Nuclear translocation of the glucocorticoid receptor activates cell signalling pathways which inhibit both TLR signalling and pro-inflammatory responses. The apparent conundrum between stress-induced corticosteroids and enhanced BRD susceptibility is discussed in terms of present data and previous investigations of stress and respiratory disease

Antimicrobial Peptides and Skin: A Paradigm of Translational Medicine

Antimicrobial peptides (AMPs) are small, cationic, amphiphilic peptides with broad-spectrum microbicidal activity against both bacteria and fungi. In mammals, AMPs form the first line of host defense against infections and generally play an important role as effector agents of the innate immune system. The AMP era was born more than 6 decades ago when the first cationic cyclic peptide antibiotics, namely polymyxins and tyrothricin, found their way into clinical use. Due to the good clinical experience in the treatment of, for example, infections of mucus membranes as well as the subsequent understanding of mode of action, AMPs are now considered for treatment of inflammatory skin diseases and for improving healing of infected wounds. Based on the preclinical findings, including pathobiochemistry and molecular medicine, targeted therapy strategies are developed and first results indicate that AMPs influence processes of diseased skin. Importantly, in contrast to other antibiotics, AMPs do not seem to propagate the development of antibiotic-resistant micro-organisms. Therefore, AMPs should be tested in clinical trials for their efficacy and tolerability in inflammatory skin diseases and chronic wounds. Apart from possible fields of application, these peptides appear suited as an example of the paradigm of translational medicine for skin diseases which is today seen as a `two-way road' - from bench to bedside and backwards from bedside to bench. Copyright (c) 2012 S. Karger AG, Base

Influence of smoking on gingival crevicular fluid cytokines in severe chronic periodontitis

The aim of this study was to compare the expression of 22 chemokines and cytokines in gingival crevicular fluid (GCF) from smokers and non-smokers with periodontitis and periodontally healthy control subjects