Cigarette Smoke Constituents and Nicotine Differentially Affect Cytokine Production by Human Macrophages Stimulated by TLR Ligands In Vitro: Considerations for a Standardised Protocol.

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition associated with cigarette (tobacco) smoking. Numerous in vivo animal studies have been conducted to investigate the links between cigarette smoke, nicotine and infection in lung pathology. As an alternative to animal experiments, we used an in vitro system to investigate the effects of cigarette smoke extract (CSE) or nicotine on TNF-α and IL-10 production by monocyte-derived human macrophages. The macrophages were simultaneously stimulated with either poly-IC (as a chemical surrogate for viral infection) or lipopolysaccharide (as a chemical surrogate for Gram-negative bacterial infection). CSE enhanced TNF-α production, whereas nicotine inhibited IL-10 production by the macrophages, particularly when co-stimulated with the microbial chemical surrogates. A system of this type may help to further our understanding of the immunological and inflammatory effects of smoking, without recourse to in vivo studies. Requirements for the optimisation and standardisation of such an in vitro system are also discussed.

Mutations in the binding site of TNFR1 PLAD reduce homologous interactions but can enhance antagonism of wild-type TNFR1 activity.

The tumour necrosis factor receptor superfamily (TNFRSF) members contain cysteine-rich domains (CRD) in their extracellular regions, and the membrane-distal CRD1 forms homologous interactions in the absence of ligand. The CRD1 is therefore termed a pre-ligand assembly domain (PLAD). The role of PLAD-PLAD interactions in the induction of signalling as a consequence of TNF-TNFR binding led to the development of soluble PLAD domains as antagonists of TNFR activation. In the present study, we generated recombinant wild-type (WT) PLAD of TNFR1 and mutant forms with single alanine substitutions of amino acid residues thought to be critical for the formation of homologous dimers and/or trimers of PLAD (K19A, T31A, D49A and D52A). These mutated PLADs were compared with WT PLAD as antagonists of TNF-induced apoptosis or the activation of inflammatory signalling pathways. Unlike WT PLAD, the mutated PLADs showed little or no homologous interactions, confirming the importance of particular amino acids as contact residues in the PLAD binding region. However, as with WT PLAD, the mutated PLADs functioned as antagonists of TNF-induced TNFR1 activity leading to induction of cell death or NF-κB signalling. Indeed, some of the mutant PLADs, and K19A PLAD in particular, showed enhanced antagonistic activity compared with WT PLAD. This is consistent with the reduced formation of homologous multimers by these PLAD mutants effectively increasing the concentration of PLAD available to bind and antagonize WT TNFR1 when compared to WT PLAD acting as an antagonist. This may have implications for the development of antagonistic PLADs as therapeutic agents.

Prediction of marine mammal auditory-impact risk from Acoustic Deterrent Devices used in Scottish aquaculture.

Acoustic Deterrent Devices (ADDs) are used worldwide to deter pinnipeds from predating fish-aquaculture facilities. Desk-based noise-propagation modelling of six commercial ADD models, and a 'fictional' ADD was performed, the latter involving alternating source level, frequency, duty cycle, noise-exposure duration, and number of ADDs active simultaneously. Potential auditory impacts on marine mammals were explored using the Southall et al. (2019) criteria. Depending on operational characteristics, real ADDs were predicted to cause Temporary Threshold Shift (TTS) to Very High Frequency (VHF) cetaceans at ranges of 4-31 km, and a single fictional device operating at the highest outputs tested was predicted to cause TTS to VHF cetaceans at up to 32 km. Cumulative effects of 23 real fish-farm ADDs produced noise across large swathes of the Inner-Hebrides. The single variable causing greatest reduction in potential impact to marine mammals from fictional ADDs was SL.

Array-based measurements of aero-allergen-specific IgE correlate with skin-prick test reactivity in asthma regardless of specific IgG4 or total IgE measurements.

Skin prick testing (SPT) and measurement of serum allergen-specific IgE (sIgE) are used to investigate asthma and other allergic conditions. Measurement of serum total IgE (tIgE) and allergen-specific IgG4 (sIgG4) may also be useful. The aim was to ascertain the correlation between these serological parameters and SPT. Sera from 60 suspected asthmatic patients and 18 healthy controls were assayed for sIgE and sIgG4 reactivity against a panel of 70 SPT allergen preparations, and for tIgE. The patients were also assessed by skin prick tests for reactivity to cat, dog, house dust mite and grass allergens. Over 50% of the patients had tIgE levels above the 75th percentile of the controls. 58% of patients and 39% of controls showed sIgE reactivity to ≥1 allergen. The mean number of allergens detected by sIgE was 3.1 in suspected asthma patients and 0.9 in controls. 58% of patients and 50% of controls showed sIgG4 reactivity to ≥1 allergen. The mean number of allergens detected by sIgG4 was 2.5 in patients and 1.7 in controls. For the patients, a strong correlation was observed between clinical SPT reactivity and serum sIgE levels to cat, dog, house dust mite (HDM) and grass allergens. SPT correlations using sIgE/sIgG4 or sIgE/tIgE ratios were not markedly higher. The measurement of serum sIgE by microarray using SPT allergen preparations showed good correlation with clinical SPT reactivity to cat, dog, HDM and grass allergens. This concordance was not improved by measuring tIgE or sIgG4.

The role of CD8 + T lymphocytes in chronic obstructive pulmonary disease: a systematic review.

OBJECTIVE AND DESIGN: This systematic review aims to establish the role of CD8 + T lymphocytes in COPD. METHODS: Forty-eight papers published in the last 15 years were identified for inclusion. RESULTS: CD8 + T-cells are increased in the lungs of patients with COPD (17 studies, 16 positive) whereas in the circulation, findings were inconclusive. Activation of CD8 + T-cells was enhanced in lungs (four studies, three positive) but cell phenotype was unclear. There was substantial evidence of a higher proportion of type 1 CD8 + (Tc1) cells in COPD (11 studies, 9 positive), though the population of type 2 (Tc2) cells was also increased (5 studies, 4 positive). CD8 + T-cells in COPD exhibited greater expression of cytotoxic proteins (five studies, five positive). Studies assessed a variety of questions so evidence was insufficient to draw firm conclusions. The role of CD8 + T-cells at acute exacerbation of COPD and also their contribution to alveolar destruction can only be hypothesised at this stage. CONCLUSIONS: Not only is the number of CD8 + T-cells increased in COPD, these cells have increased capacity to exert effector functions and are likely to contribute to disease pathogenesis. Several mechanisms highlighted show promise for future investigation to consolidate current knowledge.

Proximate underwater soundscape of a North Sea offshore petroleum exploration jack-up drilling rig in the Dogger Bank.

Little is known about localized, near-field soundscapes during offshore hydrocarbon drilling campaigns. In the Dogger Bank, North Sea, underwater noise recordings were made 41-60 m from the drill stem of the Noble Kolskaya jack-up exploration drilling rig. The aims were to document noise received levels (RLs) and frequency characteristics of rig-associated near-field noise. The rig produced sound pressure levels (SPLs) of 120 dB re 1 µPa in the frequency range of 2-1400 Hz. Over transient periods, RLs varied by 15-20 dB between softest (holding) and noisiest (drilling) operations. Tonal components at different frequencies varied with depth. Support vessel noise was significantly louder than the jack-up rig at frequencies <1 kHz, even in its noisiest "boulder-drilling" phase, though radiated noise levels were higher above 2 kHz. Rig SPLs fell rapidly above 8 kHz. Marine mammals, such as harbor porpoise (Phocoena phocoena) forage regularly near offshore oil and gas rigs and platforms, and it is predicted that animals experience different noise regimes while traversing the water column and can potentially detect the higher-frequency components of drilling noise to a distance of 70 m from the source; however, while levels were unlikely to cause auditory injury, effects on echolocation behavior are still unknown.

Differences in the prescribing of potentially inappropriate medicines in older Australians: comparison of community dwelling and residential aged care residents.

Potentially inappropriate medications (PIMs) can contribute to morbidity through exacerbations or progression of existing conditions among older people. In order to characterize the prevalence of PIMs according to the Beers Criteria in older Australians, three hundred and eleven participants were recruited from three residential aged care facilities (RACFs) and two hundred and twenty participants from three community pharmacies in South Australia for a retrospective audit of medication administration charts and community pharmacy dispensing histories. Although a similar number of participants were prescribed at least one PIM (P = 0.09), the average number of PIMs was significantly greater in the RACF cohort (1.96 vs 1.26, P < 0.05). Additionally, PIMs prescribed as pro re nata (PRN) in the RACF cohort had a significantly low administration rate compared to prescription rate (19.7% vs 40.7%). The mean number of PIMs within each cohort was statistically significant (RACF = 1.93 vs CDOA = 1.26, P < 0.05). RACF residents were at a slightly greater risk of being prescribed more than one PIM compared to those within the community. Routine medication reviews by pharmacists embedded in RACFs and within the community could be utilised to detect PIMs before such harm occurs.

Electronic cigarette vapour moderately stimulates pro-inflammatory signalling pathways and interleukin-6 production by human monocyte-derived dendritic cells.

Dendritic cells (DCs) are professional antigen presenting cells that play a critical role in bridging innate and adaptive immunity. Numerous studies have shown that tobacco constituents present in conventional cigarettes affect the phenotype and function of DCs; however, no studies have examined the effects of vapour from E-cigarettes on human DCs. Here, the effects of E-cigarette vapour extract (ECVE) on the phenotype and function of DCs were investigated by creating an in vitro cell culture model using human monocyte-derived DCs (MoDCs). Immature DCs were generated from peripheral blood monocytes and mature DCs were then produced by treatment with LPS or Poly I:C for 24 h. For LPS-matured DCs, 3% ECVE treatment slightly suppressed HLA-DR and CD86 expression, whereas 1% ECVE treatment enhanced IL-6 production. The overall expression of 29 signalling molecules and other cytoplasmic proteins (mainly associated with DC activation) was significantly upregulated in immature DCs by 1% ECVE, and in LPS-treated DCs by 3% ECVE. In particular, the condition that induced IL-6 production also upregulated MAPK pathway activation. These findings indicate that E-cigarette vapour moderately affects human DCs, but the effects are less pronounced than those reported for tobacco smoke.

Correction to: Atopic dermatitis and autoimmunity: the occurrence of autoantibodies and their association with disease severity.

Two of the references included in this review concern antigens derived from the fungus Malassezia globosa that have also been found in human sweat.

Extracellular vesicles and asthma: A review of the literature.

Asthma is a chronic, recurrent and incurable allergy-related respiratory disease characterized by inflammation, bronchial hyperresponsiveness and narrowing of the airways. Extracellular vesicles (EVs) are a universal feature of cellular function and can be detected in different bodily fluids. Recent evidence has shown the possibility of using EVs in understanding the pathogenesis of asthma, including their potential as diagnostic and therapeutic tools. Studies have reported that EVs released from key cells involved in asthma can induce priming and activation of other asthma-associated cells. A literature review was conducted on all current research regarding the role and function of EVs in the pathogenesis of asthma via the PRISMA statement method. An electronic search was performed using EMBASE and PubMed through to November 2018. The EMBASE search returned 76 papers, while the PubMed search returned 211 papers. Following duplicate removal, titles and abstracts were screened for eligibility with a total of 34 studies included in the final qualitative analysis. The review found evidence of association between the presence of EVs and physiological changes characteristic of asthma, suggesting that EVs are involved in the pathogenesis, with the weight of evidence presently favouring deleterious effects of EVs in asthma. Numerous studies highlighted differences in exosomal contents between EVs of healthy and asthmatic individuals, which could be employed as potential diagnostic markers. In some circumstances, EVs were also found to be suppressive to disease, but more often promote inflammation and airway remodelling. In conclusion, EVs hold immense potential in understanding the pathophysiology of asthma, and as diagnostic and therapeutic markers. While more research is needed for definitive conclusions and their application in medical practice, the literature presented in this review should encourage further research and discovery within the field of EVs and asthma.

Life-threatening hypersensitivity pneumonitis secondary to e-cigarettes.

We report a case of hypersensitivity pneumonitis (HP) in a young person secondary to vaping. He presented with a putative diagnosis of asthma and required extracorporeal membrane oxygenationbecause of intractable respiratory failure. He developed a critical illness and steroid myopathy and required prolonged rehabilitation. Our patient fulfils diagnostic criteria for HP secondary to e-cigarettes with a positive exposure history, deterioration after skin prick testing, specific serum IgM antibodies against the implicated liquid raising the possibility that the relevant antigen was present in that liquid and radiological and histopathological features compatible with acute HP. There are two learning points. The first is always to consider a reaction to e-cigarettes in someone presenting with an atypical respiratory illness. The second is that we consider e-cigarettes as 'much safer than tobacco' at our peril.

Autoantibodies in chronic obstructive pulmonary disease: A systematic review.

Chronic Obstructive Pulmonary Disease (COPD) is a major cause of death worldwide in which the involvement of autoimmunity has been widely investigated and debated. The role of autoantibodies in COPD has been extensively researched in recent years. The aim of this systematic review is to assess the association between autoantibodies and COPD and analyse whether autoantibody levels correlate with disease severity and/or phenotype. PubMed, Embase, OpenGrey and the reference lists of articles were searched. The strongest evidence for an association between autoantibodies and COPD lies with anti-endothelial/epithelial cell autoantibodies (7 studies, all positive), rheumatoid factor autoantibodies (4 studies, all positive), anti-cytokeratin autoantibodies (3 studies, all positive), anti-nuclear autoantibodies (8 studies, 7 positive) and anti-collagen autoantibodies (10 studies, 6 positive). This review also identifies several other autoantibodies which had both positive and negative associations with COPD, however the evidence for these was not as strong and/or the number of studies is low, and further research is required. In particular, a clear case can be made for the potential importance of autoantibodies to carbonylated proteins. The relationship between autoantibody levels and disease severity requires further research with only 17/43 studies investigating this; however, 12 of the studies did show a positive association, making it a promising area for future research. There was also not enough evidence available on the relationship between autoantibody levels and disease phenotype to draw any conclusions, with only 2 studies investigating it (1 positive and 1 negative). This review has shown very promising evidence for the association of several autoantibodies in COPD and has identified those autoantibodies which require further research.

Cigarette smoking differentially affects immunoglobulin class levels in serum and saliva: An investigation and review.

The aim of the present study was to compare concentrations of IgG, IgA, IgM and IgD in both serum and saliva samples from smoking and non-smoking individuals using a protein microarray assay. The findings were also compared to previous studies. Serum and saliva were collected from 48 smoking male individuals and 48 age-matched never-smoker male individuals. The protein microarray assays for detection of human IgG, IgM, IgA and IgD were established and optimized using Ig class-specific affinity-purified goat anti-human Ig-Fc capture antibodies and horseradish peroxidase (HRP)-conjugated goat anti-human Ig-Fc detection antibodies. The Ig class specificity of the microarray assays was verified, and the optimal dilutions of serum and saliva samples were determined for quantification of Ig levels against standard curves. We found that smoking is associated with reduced IgG concentrations and enhanced IgA concentrations in both serum and saliva. By contrast, smoking differentially affected IgM concentrations-causing increased concentrations in serum, but decreased concentrations in saliva. Smoking was associated with decreased IgD concentrations in serum and did not have a significant effect on the very low IgD concentrations in saliva. Thus, cigarette smoking differentially affects the levels of Ig classes systemically and in the oral mucosa. Although there is variation between the results of different published studies, there is a consensus that smokers have significantly reduced levels of IgG in both serum and saliva. A functional antibody deficiency associated with smoking may compromise the body's response to infection and result in a predisposition to the development of autoimmunity.

Immunological and pathological effects of electronic cigarettes.

Electronic cigarettes (E-cigarettes) are considered a preferable alternative to conventional cigarettes due to the lack of combustion and the absence of tobacco-specific toxicants. E-cigarettes have rapidly gained in popularity in recent years amongst both existing smokers and previous non-smokers. However, a growing literature demonstrates that E-cigarettes are not as safe as generally believed. Here, we discuss the immunological, and other, deleterious effects of E-cigarettes on a variety of cell types and host defence mechanisms in humans and in murine models. We review not only the effects of complete E-cigarette liquids, but also each of the main components-nicotine, humectants and flavourings. This MiniReview thus highlights the possible role of E-cigarettes in the pathogenesis of disease and raises awareness of the potential harm that E-cigarettes may cause.

Atopic dermatitis and autoimmunity: the occurrence of autoantibodies and their association with disease severity.

Atopic dermatitis (AD) is a widespread condition that appears to be increasing in prevalence and severity worldwide, yet the underlying mechanisms are not well understood. Recent research has identified various similarities between AD and autoimmune conditions, as well as indicating that there may be an association between AD and autoimmunity. This systematic review evaluates the association between AD and autoimmunity, as well as between severity of disease in AD and autoimmunity, with an emphasis on the associations with autoantibodies. MEDLINE (1946 to December 2017) and Embase (1974 to December 2017) databases were searched. Further relevant articles were retrieved from reference lists. Only studies measuring direct indicators of autoimmunity, in humans, were included. Qualitative analysis was carried out for all studies. In addition, quantitative analysis was used to evaluate prevalence of IgE autoantibodies and anti-nuclear antibodies (ANAs) in AD patients and control subjects. The Mantel-Haenszel method was used with a random-effects model. 28 studies assessed the occurrence of autoantibodies in AD patients and 16 studies were used to evaluate association between disease severity and autoantibodies. Pooled analysis from 14 studies, involving 986 AD patients and 441 control subjects, showed that IgE autoantibodies were significantly more prevalent in patients with AD (P < 0.00001) than control subjects. Similar analysis was carried out for ANAs, with eight studies that involved 1045 AD patients and 1273 control subjects. ANAs were significantly more prevalent in patients with AD (P = 0.003). This quantitative analysis supported an association between AD and IgE autoantibodies, as well as between AD and ANAs. There was insufficient data to make similar conclusions for other indicators of autoimmunity. The weight of evidence also suggests an association between IgE autoantibodies and disease severity. There was insufficient evidence to make this link for other indicators of autoimmunity.

Tobacco smoke and nicotine suppress expression of activating signaling molecules in human dendritic cells.

Cigarette smoke has significant toxic effects on the immune system, and increases the risk of developing autoimmune diseases; one immunosuppressive effect of cigarette smoke is that it inhibits the T cell-stimulating, immunogenic properties of myeloid dendritic cells (DCs). As the functions of DCs are regulated by intra-cellular signaling pathways, we investigated the effects of cigarette smoke extract (CSE) and nicotine on multiple signaling molecules and other regulatory proteins in human DCs to elucidate the molecular basis of the inhibition of DC maturation and function by CSE and nicotine. Maturation of monocyte-derived DCs was induced with the TLR3-agonist poly I:C or with the TLR4-agonist lipopolysaccharide, in the absence or presence of CSE or nicotine. Reverse-phase protein microarray was used to quantify multiple signaling molecules and other proteins in cell lysates. Particularly in poly I:C-matured DCs, cigarette smoke constituents and nicotine suppressed the expression of signaling molecules associated with DC maturation and T cell stimulation, cell survival and cell migration. In conclusion, constituents of tobacco smoke suppress the immunogenic potential of DCs at the signaling pathway level.

Assessment of patient understanding of their medicines: interviews with community dwelling older Australians.

OBJECTIVE: To identify patterns of medication load, client's care team, coordination of healthcare and clients' understanding of their medications. METHODS: Face-to-face interviews were conducted with community-dwelling older Australians between June and August 2017 in three community pharmacies in Adelaide, South Australia. KEY FINDINGS: Forty interviews were conducted. On average, participants were taking 7.53 medicines with 77.5% using five or more regularly. Lack of collaboration between healthcare professionals, need for increased communication between prescribers and increased patient education on medicines, were highlighted. This study demonstrates that polypharmacy and inappropriate prescribing are occurring within the community pharmacy setting, but shows insight into how these concerns can be overcome, by implementing pharmacist-led services such as non-dispensing pharmacists in community pharmacies. CONCLUSION: Careful consideration when prescribing and effective communication are required to minimise risks associated with polypharmacy in this population.

Prophylactic Antibiotic Use in COPD and the Potential Anti-Inflammatory Activities of Antibiotics.

Antibiotics have previously demonstrated anti-inflammatory properties, and they have been linked to therapeutic benefit in several pulmonary conditions that feature inflammation. Previous research suggests that these anti-inflammatory properties may be beneficial in the treatment of COPD. This review assesses the potential benefit of prophylactic, long-term, and low-dose antibiotic therapy in COPD, and whether any effects seen are anti-inflammatory in nature. Randomized, controlled trials comparing antibiotic therapy with placebo in subjects with stable COPD were evaluated. Twelve trials involving 3,784 participants and a range of antibiotics were included: azithromycin (6 studies, 1,972 participants), clarithromycin (1 study, 67 participants), erythromycin (3 studies, 254 participants), roxithromycin (1 study, 191 participants), and moxifloxacin (2 studies, 1,198 participants). In vitro, in vivo, and ex vivo experimental study designs exploring the mechanisms via which antibiotics may act in subjects with stable COPD were evaluated. Azithromycin and erythromycin showed the greatest effect in subjects with COPD, with evidence suggesting improvement in exacerbation-related outcomes and health status, as measured by the St George Respiratory Questionnaire. An increase in antibiotic resistance was reported in 2 studies. The macrolide class of antibiotics exhibited convincing anti-inflammatory properties with relevance to COPD, implicating several pathways as potential mechanisms of action. In conclusion, the therapeutic benefit of macrolide antibiotics in subjects with stable COPD is consistent with anti-inflammatory properties, and macrolides should be considered as a potential therapy in COPD. Safety concerns regarding antibiotic resistance need to be addressed before widespread use in clinical practice.