Neutrophil Elastase Increases Airway Epithelial Nonheme Iron Levels

Alpha-1-antitrypsin (A1AT) deficiency is characterized by increased neutrophil elastase (NE) activity and oxidative stress in the lung. We hypothesized that NE exposure generates reactive oxygen species by increasing lung nonheme iron. To test this hypothesis, we measured bronchoalveolar lavage (BAL) iron and ferritin levels, using inductively coupled plasma (ICP) optical emission spectroscopy and an ELISA, respectively, in A1AT-deficient patients and healthy subjects. To confirm the role of NE in regulating lung iron homeostasis, we administered intratracheally NE or control buffer to rats and measured BAL and lung iron and ferritin. Our results demonstrated that A1AT-deficient patients and rats postelastase exposure have elevated levels of iron and ferritin in the BAL. To investigate the mechanism of NE-induced increased iron levels, we exposed normal human airway epithelial cells to either NE or control vehicle in the presence or absence of ferritin, and quantified intracellular iron uptake using calcein fluorescence and ICP mass spectroscopy. We also tested whether NE degraded ferritin in vitro using ELISA and western analysis. We demonstrated in vitro that NE increased intracellular nonheme iron levels and degraded ferritin. Our results suggest that NE digests ferritin increasing the extracellular iron pool available for cellular uptake.

Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription

Background: Glycogen synthase kinase-3 (GSK-8) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3.

Crossing borders through cyberspace: a discussion of a social work education electronic exchange pilot project across the Atlantic

This article discusses a trial electronic exchange project developed between social work education departments in the Republic of Ireland and the USA. It outlines the contemporary significance and challenges of integrating global content into national social work curricula, which are often strongly tied to statutory or accreditation requirements. The mechanics of the exchange are explained and critiqued in detail. An illustrative example of how the transnational students discussed two questions is analyzed. The article finds that an international electronic exchange has great potential to make global social work real to students by allowing them to cross borders through cyberspace, however it requires careful planning and attention to cultural and educational system differences.

Peadiatric social admission

The phenomenon of paediatric social admission describes the hospitalisation of children for medicallynon- urgent and/or social reasons. Much of the research in this field has been in relation to avoidable admissions which have been identified, studied and condoned based on strict medical criteria. Such research has tended to mask the significance of social factors and the commonplace practice of Paediatric Social Admission. This paper examines decision making from the perspective of the health professionals at the clinical coal face. It explores how health professionals are influenced by social, organisational and subjective factors which determine their decision to admit or not to admit a child to hospital. The paper reports findings from interviews with 27 health professionals involved in PSA and a document audit of 21 specific cases. In doing so it begins to address the inherent paradox of responding to a child and families social needs in a medical context.

A case study in group learning and supervision

Student units or the group-based field education and supervision of social work students offer many advantages as an efficient field placement model as well as opportunities for students to learn from each other through sharing knowledge, working collaboratively, hearing different perspectives and discussing issues. Despite the enormous potential of student units, they are a largely uncharted territory. There is a scarcity of literature on the topic and very few guidelines as to the provision of student units. The term student unit covers a broad range of student group learning opportunities and activities. This study explores this model of social work field education and its implications for student field work learning in a group context. The discussion is based on a review of the experiences, opinions and impressions of participants of an actual university based social work student unit.

The paradox of peadiatric social admission

The paradox of paediatric social admission involves the hospitalisation of children for medically non- urgent and/or social reasons. Much of the research in this field has been in relation to avoidable admissions which have been identified, studied and condoned based on strict medical criteria. Such research has tended to mask the significance of social influences and the reasons why health professionals make such decisions. This paper explores social, organisational and subjective influences on medical decision making and is based on study involving interviews with 27 health professionals directly involved in paediatric social admissions (PSA). The findings highlight inherent paradoxes as a consequence of responding to social concerns in a medical context.

Glucocorticoid receptor β and histone deacetylase 1 and 2 expression in the airways of severe asthma.

Rationale Upregulation of glucocorticoid receptor ß (GRß) has been implicated in steroid resistance in severe asthma, although previous studies are conflicting. GRß has been proposed as a dominant negative isoform of glucocorticoid receptor a (GRa) but it has also been suggested that GRß can cause steroid resistance via reduced expression of histone deacetylase 2 (HDAC2), a key regulator of steroid responsiveness in the airway.


Objectives To examine GRß, GRa, HDAC1 and HDAC2 expression at transcript and protein levels in bronchial biopsies from a large series of patients with severe asthma, and to compare the findings with those of patients with mild to moderate asthma and healthy volunteers.


Methods Bronchoscopic study in two UK centres with real-time PCR and immunohistochemistry performed on biopsies, western blotting of bronchial epithelial cells and immunoprecipitation with anti-GRß antibody.


Measurements and main results Protein and mRNA expression for GRa and HDAC2 did not differ between groups. GRß mRNA was detected in only 13 of 73 samples (seven patients with severe asthma), however immunohistochemistry showed widespread epithelial staining in all groups. Western blotting of bronchial epithelial cells with GRß antibody detected an additional ‘cross-reacting’ protein, identified as clathrin. HDAC1 expression was increased in patients with severe asthma compared with healthy volunteers.


Conclusions GRß mRNA is expressed at low levels in a minority of patients with severe asthma. HDAC1 and HDAC2 expression was not downregulated in severe asthma. These data do not support upregulated GRß and resultant reduced HDAC expression as the principal mechanism of steroid resistance in severe asthma. Conflicting GRß literature may be explained in part by clathrin cross-reactivity with commercial antibodies.

Strategies for critical reflection in international contexts for social work students

International contexts provide social work students with the opportunity to develop knowledge of international social work, global citizenship and cultural competency. While these contexts are powerful sites of learning, there is a need to ensure that this occurs within a critical framework. The paradigm of critical reflection is used to facilitate this and has been popular in international programs. In this article, we develop this further by describing critically-reflective techniques and providing examples used in a pilot exchange program between a social work school in the UK and in India. The potential implications of these strategies for social work education are discussed. © The Author(s) 2012

COLLISION PUMPED SOFT-X-RAY LASERS - PROGRESS AT RAL

Recent developments and progress on collision pumped soft X-ray lasers using the VULCAN glass laser at Rutherford-Appleton Laboratory are presented. This includes saturated output operation of a double target germanium system within a low Fresnel number half-cavity, measurement of the spatial coherence of the output beam in the above and other geometries, use of the beam to demonstrate almost-equal-to 0.15 mum spatial resolution in a full-field microscope and initial studies of other Ne-like and Ni-like systems. Future directions, in the light of new developments of VULCAN facilities, are outlined.

The cellular level of O-antigen polymerase Wzy determines chain length regulation by WzzB and WzzpHS-2 in Shigella flexneri 2a

The lipopolysaccharide O antigen of Shigella flexneri 2a has two preferred chain lengths, a short (S-OAg) composed of an average of 17 repeated units and a very long (VL-OAg) of about 90 repeated units. These chain length distributions are controlled by the chromosomally encoded WzzB and the plasmid-encoded Wzz(pHS-2) proteins, respectively. In this study, genes wzzB, wzz(pHS-2) and wzy (encoding the O-antigen polymerase) were cloned under the control of arabinose- and rhamnose-inducible promoters to investigate the effect of varying their relative expression levels on O antigen polysaccharide chain length distribution. Controlled expression of the chain length regulators wzzB and wzz(pHS-2) revealed a dose-dependent production of each modal length. Increase in one mode resulted in a parallel decrease in the other, indicating that chain length regulators compete to control the degree of O antigen polymerization. Also, when expression of the wzy gene is low, S-OAg but not VL-OAg is produced. Production of VL-OAg requires high induction levels of wzy. Thus, the level of expression of wzy is critical in determining O antigen modal distribution. Western blot analyses of membrane proteins showed comparable high levels of the WzzB and Wzz(pHS-2) proteins, but very low levels of Wzy. In vivo cross-linking experiments and immunoprecipitation of membrane proteins did not detect any direct interaction between Wzy and WzzB, suggesting the possibility that these two proteins may not interact physically but rather by other means such as via translocated O antigen precursors.