Secretory leucoprotease inhibitor (SLPI) is a nonglycosylated protein produced by epithelial cells. In addition to its antiprotease activity, SLPI has been shown to exhibit antiinflammatory properties, including down-regulation of tumor necrosis factor α expression by lipopolysaccharide (LPS) in macrophages and inhibition of nuclear factor (NF)-κB activation in a rat model of acute lung injury. We have previously shown that SLPI can inhibit LPS-induced NF-κB activation in monocytic cells by inhibiting degradation of IκBα without affecting the LPS-induced phosphorylation and ubiquitination of IκBα. Here, we present evidence to show that upon incubation with peripheral blood monocytes (PBMs) and the U937 monocytic cell line, SLPI enters the cells, becoming rapidly localized to the cytoplasm and nucleus, and affects NF-κB activation by binding directly to NF-κB binding sites in a site-specific manner. SLPI can also prevent p65 interaction with the NF-κB consensus region at concentrations commensurate with the physiological nuclear levels of SLPI and p65. We also demonstrate the presence of SLPI in nuclear fractions of PBMs and alveolar macrophages from individuals with cystic fibrosis and community-acquired pneumonia. Therefore, SLPI inhibition of NF-κB activation is mediated, in part, by competitive binding to the NF-κB consensus-binding site.

Aims  Adverse drug reactions (ADRs) account for 3.2–7% of acute hospital admissions. The aim of this study was to assess prospectively knowledge of ADRs in patients admitted through the emergency department of a teaching hospital. Methods  Three hundred and ninety‐nine patients were admitted on acute medical call during study periods in September 2002 and May 2003. One hundred gave their perception of the risk of ADRs using visual analogue scales, where 0 indicates minimum and 10 maximum risk. The medications studied were warfarin, proton pump inhibitors (PPIs), corticosteroids, nonsteroidal anti‐inflammatory drugs (NSAIDs) and aspirin. Responses are compared against a medical control group. Results  Corticosteroids were ranked most dangerous by patients (median score, 25th–75th centiles: 5.4, 2.9–8.7). Medical staff ranked NSAIDs as highest risk (6.2, 4.0–7.5). Patients identified NSAIDs as low risk (2.1, 0.7–4.9), perceiving the risk of cardiac arrhythmias and disturbance in liver biochemistry to be equivalent to risk of upper gastrointestinal ulceration and bleeding. Risk of haemorrhage was ranked as the most common ADR for warfarin by patients (8.6, 3.3–9.5) and medical staff (8.8, 7.6–9.3). Conclusions  Patients underrate the risk of ADRs of their medications. While there is a good level of knowledge of ADRs amongst warfarin and aspirin users, there is a clear lack of knowledge regarding the risk of upper GI bleeding in NSAID users. Increased education may reduce the incidence of ADRs but it is more likely that it will serve to meet increasing patient expectations.

Background: Cystic fibrosis (CF) is a lethal hereditary disease characterised

AAT deficiency is an autosomal co-dominantly inherited disease which affects the lungs and liver predominantly. The clinical manifestations, prevalence, genetics, molecular pathophysiology, screening and treatment recommendations are summarised in this review.

Z ␣ 1 -antitrypsin (ZAAT) deficiency is a disease associated with emphysematous lung disease and also with liver disease. The liver disease of AAT deficiency is associated with endoplasmic reticulum (ER) stress. SEPS1 is a selenoprotein that, through a chaperone activity, decreases ER stress. To determine the effect of SEPS1 on ER stress in ZAAT deficiency, we measured activity of the grp78 promoter and levels of active ATF6 as markers of the unfolded protein response in HepG2 cells transfected with the mutant form of AAT, a ZAAT transgene. We evaluated levels of NFB activity as a marker of the ER overload response. To determine the effect of selenium supplementation on the function of SEPS1, we investigated glutathione peroxidase activity, grp78 promoter activity, and NFB activity in the presence or absence of selenium. SEPS1 reduced levels of active ATF6. Overexpression of SEPS1 also inhibited grp78 promoter and NFB activity, and this effect was enhanced in the presence of selenium supplementation. This finding demonstrates a role for SEPS1 in ZAAT deficiency and suggests a possible therapeutic potential for selenium supplementation.

Age does not diminish the severity of illness scores in patients with CAP. There was no blunting of the systemic cytokine response with advanced age in this study.

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