Human PapillomaVirus vaccination in gay and bi men: Predictors, dynamic norms, and connectedness to the LGBT+ community.

OBJECTIVES: This study tested social cognitive predictors of vaccination and a dynamic norms intervention for increasing HPV vaccination intentions in gay, bisexual, and other men who have sex with men (gbMSM). DESIGN: The study employed an experiment embedded in a cross-sectional survey. METHODS: Participants (N = 217; gbMSM aged 18-45 in Ireland) provided cross-sectional data on sociodemographic constructs and constructs from the Theory of Planned Behaviour and the Health Belief Model. Unvaccinated participants (n = 94) were randomised to one of three experimental conditions (no norms, static norms, dynamic norms) and presented with information on HPV vaccine uptake in gbMSM in Ireland before reporting vaccination intentions. RESULTS: In an adjusted logistic regression, significant predictors of vaccination included being in a relationship (OR = 8.69 [1.09, 38.91]), perceived susceptibility (OR = 1.11 [1.04, 1.19]), healthcare provider recommendation (OR = 107.24 [26.87, 427.99]), and perceived barriers (OR = 0.83 [.7, 0.98]). Adjusted linear regression models showed no significant differences in HPV vaccination intentions between no norms and static norms (B = -1.24 [-4.6, 2.12]), dynamic norms and static norms (B = -0.62 [-3.86, 2.63]), and dynamic norms and no norms (B = 0.62 [-2.74, 3.98]). Connectedness to the LGBT+ community did not moderate these differences. CONCLUSIONS: The need for greater awareness of susceptibility, the impact of barriers, and the strong influence of a recommendation from a healthcare provider in predicting HPV vaccination among gbMSM are critical considerations for policymakers. Dynamic norm messaging may be less effective for vaccination than other behaviours more easily influenced by social norms. Efforts to implement dynamic norm-based interventions in gbMSM should consider the limited evidence of efficacy.

The Preventative Effect of Hydrocolloid Dressings on Nasal Bridge Pressure Ulceration in Acute Non-Invasive Ventilation.

BACKGROUND: Non-invasive ventilation (NIV) is a valuable treatment in the management of acute hypercapnic respiratory failure. NIV is not without risks. One such adverse effect is the development of pressure ulcers over the nasal bridge which have an incidence of up to 20% of patients requiring NIV in this setting. The role of medical devices in the development of hospital acquired pressure ulcers has been increasingly recognised with 10-35% of all hospital acquired ulcers attributed to medical devices. Guidelines on acute NIV use suggest good skin care strategies. However, data on the magnitude of the problem of nasal bridge pressure ulceration and the effect of proactive preventative steps remains scant. METHOD: A quality improvement project was designed to reduce the incidence of nasal bridge pressure ulcers during acute NIV. Hydrocolloid dressings were placed over the nasal bridge in all patients requiring NIV between 30th October 2015 and the 29th October 2016. Tissue viability was assessed daily with new pressure ulceration defined as grade 2 or above. Rates of nasal bridge pressure ulcers were compared to all patients requiring NIV in the 12-month period prior to intervention. RESULTS: In Group 1, there were 161 admissions and 9 grade 2 pressure ulcers from 666 NIV bed-days. In Group 2 there were 134 admissions and 0 pressure ulcers from 718 NIV bed-days. There was a statistically significant reduction in grade 2 pressure ulceration rates (p= 0.0013) in Group 2 compared to Group 1. CONCLUSION: Application of an early prophylactic pressure-relieving hydrocolloid nasal dressing reduces the risk of developing grade 2 pressure ulcers in patients in patients requiring acute NIV.

Bronchial epithelial cell lines and primary nasal epithelial cells from cystic fibrosis respond differently to cigarette smoke exposure.

The effects of cigarette smoke extract (CSE) on airway epithelial cells (AECs) from cystic fibrosis (CF) and non-cystic fibrosis (non-CF) individuals are not fully understood. It has been suggested that CSE modulates inflammatory cytokine release from AECs by modulating the epidermal growth factor receptor (EGFR) pathway; these pathways could reveal novel therapeutic targets. We compared the effect of CSE pre-incubation on IL-8 release from CF and non-CF bronchial epithelial cell lines, and separately, with primary nasal epithelial cells (NECs) retrieved from CF and non-CF individuals. We also determined if the EGFR pathway regulates IL-8 release by LPS or cytomix in non-CF and CF AECs at baseline and following CSE exposure. CF and non-CF cell lines, NECs derived from both CF patients (R117H heterozygous and F508del homozygous), and from healthy subjects, were cultured in the presence or absence of CSE, and subsequently exposed to inflammatory stimuli. In cell lines CSE significantly reduced IL-8 release following inflammatory challenge. Conversely, CSE pre-treatment was pro-inflammatory in primary NECs. In NECs from control subjects, CSE increased cytomix and LPS induced IL-8 release, and for the R117H heterozygous NEC cultures, CSE enhanced basal IL-8 release. Cytomix and LPS induced IL-8 release from F508del homozygous NEC cultures was further heightened following CSE pre-treatment. EGFR inhibition mitigated IL-8 release from immortalised and primary non-CF and CF AECs, suggesting that constitutive and CSE elicited IL-8 release from AECs is partly regulated via the EGFR pathway. This study demonstrates the importance of the EGFR cascade in the regulation of constitutive and CSE induced inflammatory mediator release from immortalised and primary AECs. Moreover, it clearly highlights the significance of using primary cells to confirm results obtained from immortalised cell studies, as these model systems may respond very differently to the stimuli under investigation.

Epidermal Growth Factor Removal or Tyrphostin AG1478 Treatment Reduces Goblet Cells & Mucus Secretion of Epithelial Cells from Asthmatic Children Using the Air-Liquid Interface Model.

RATIONALE: Epithelial remodelling in asthma is characterised by goblet cell hyperplasia and mucus hypersecretion for which no therapies exist. Differentiated bronchial air-liquid interface cultures from asthmatic children display high goblet cell numbers. Epidermal growth factor and its receptor have been implicated in goblet cell hyperplasia. OBJECTIVES: We hypothesised that EGF removal or tyrphostin AG1478 treatment of differentiating air-liquid interface cultures from asthmatic children would result in a reduction of epithelial goblet cells and mucus secretion. METHODS: In Aim 1 primary bronchial epithelial cells from non-asthmatic (n = 5) and asthmatic (n = 5) children were differentiated under EGF-positive (10 ng/ml EGF) and EGF-negative culture conditions for 28 days. In Aim 2, cultures from a further group of asthmatic children (n = 5) were grown under tyrphostin AG1478, a tyrosine kinase inhibitor, conditions. All cultures were analysed for epithelial resistance, markers of differentiation using immunocytochemistry, ELISA for MUC5AC mucin secretion and qPCR for MUC5AC mRNA. RESULTS: In cultures from asthmatic children the goblet cell number was reduced in the EGF negative group (p = 0.01). Tyrphostin AG1478 treatment of cultures from asthmatic children had significant reductions in goblet cells at 0.2 µg/ml (p = 0.03) and 2 µg/ml (p = 0.003) as well as mucus secretion at 2 µg/ml (p = 0.04). CONCLUSIONS: We have shown in this preliminary study that through EGF removal and tyrphostin AG1478 treatment the goblet cell number and mucus hypersecretion in differentiating air-liquid interface cultures from asthmatic children is significantly reduced. This further highlights the epidermal growth factor receptor as a potential therapeutic target to inhibit goblet cell hyperplasia and mucus hypersecretion in asthma.

The histamine H4 receptor is a potent inhibitor of adhesion-dependent degranulation in human neutrophils.

The histamine H4 receptor regulates the inflammatory response. However, it is not known whether this receptor has a functional role in human neutrophils. We found that fMLP (1 µM), but not histamine (0.1-1 µM), induced Mac-1-dependent adhesion, polarization, and degranulation (release of lactoferrin). A pretreatment of neutrophils with histamine (0.001-1 µM) or JNJ 28610244 (0.1-10 µM), a specific H4 receptor agonist, led to inhibition of degranulation. Total inhibition of degranulation was obtained with 0.1 µM histamine and 10 µM JNJ 28610244. Furthermore, such inhibition by histamine of degranulation was reversed by JNJ 7777120 and JNJ 28307474, two selective H4 receptor antagonists. However, neither histamine nor the H4 receptor agonist JNJ 28610244 prevented fMLP-induced, Mac-1-dependent adhesion, indicating that the H4 receptor may block signals emanating from Mac-1-controlling degranulation. Likewise, engagement of the H4 receptor by the selective agonist JNJ 28610244 blocked Mac-1-dependent activation of p38 MAPK, the kinase that controls neutrophil degranulation. We also show expression of the H4 receptor at the mRNA level in ultrapure human neutrophils and myeloid leukemia PLB-985 cells. We concluded that engagement of this receptor by selective H4 receptor agonists may represent a good, therapeutic approach to accelerate resolution of inflammation.

Inflammatory and cytotoxic effects of acrolein, nicotine, acetylaldehyde and cigarette smoke extract on human nasal epithelial cells.

BACKGROUND: Cigarette smoke induces a pro-inflammatory response in airway epithelial cells but it is not clear which of the various chemicals contained within cigarette smoke (CS) should be regarded as predominantly responsible for these effects. We hypothesised that acrolein, nicotine and acetylaldehyde, important chemicals contained within volatile cigarette smoke in terms of inducing inflammation and causing addiction, have immunomodulatory effects in primary nasal epithelial cell cultures (PNECs). METHODS: PNECs from 19 healthy subjects were grown in submerged cultures and were incubated with acrolein, nicotine or acetylaldehyde prior to stimulation with Pseudomonas aeruginosa lipopolysaccharide (PA LPS). Experiments were repeated using cigarette smoke extract (CSE) for comparison. IL-8 was measured by ELISA, activation of NF-κB by ELISA and Western blotting, and caspase-3 activity by Western blotting. Apoptosis was evaluated using Annexin-V staining and the terminal transferase-mediated dUTP nick end-labeling (TUNEL) method. RESULTS: CSE was pro-inflammatory after a 24 h exposure and 42% of cells were apoptotic or necrotic after this exposure time. Acrolein was pro-inflammatory for the PNEC cultures (30 µM exposure for 4 h inducing a 2.0 fold increase in IL-8 release) and also increased IL-8 release after stimulation with PA LPS. In contrast, nicotine had anti-inflammatory properties (0.6 fold IL-8 release after 50 µM exposure to nicotine for 24 h), and acetylaldehyde was without effect. Acrolein and nicotine had cellular stimulatory and anti-inflammatory effects respectively, as determined by NF-κB activation. Both chemicals increased levels of cleaved caspase 3 and induced cell death. CONCLUSIONS: Acrolein is pro-inflammatory and nicotine anti-inflammatory in PNEC cultures. CSE induces cell death predominantly by apoptotic mechanisms.

Airway epithelial cell apoptosis and inflammation in COPD, smokers and nonsmokers.

We hypothesised that primary bronchial epithelial cells (PBECs) from subjects with chronic obstructive pulmonary disease (COPD) respond differently to Pseudomonas aeruginosa lipopolysaccharide (LPS) after cigarette smoke extract (CSE) exposure than PBECs obtained from smokers without airflow obstruction and nonsmokers. PBECs from 16 COPD subjects, 10 smokers without airflow obstruction and nine nonsmokers were cultured at air-liquid interface. Cultures were incubated with CSE prior to stimulation with P. aeruginosa LPS. Interleukin (IL)-6 and IL-8 were measured by ELISA and Toll-like receptor (TLR)-4 expression by fluorescence-activated cell sorter. Activation of nuclear factor (NF)-κB was determined by Western blotting and ELISA, and MAPK and caspase-3 activity by Western blotting. Apoptosis was evaluated using Annexin-V staining and the terminal transferase-mediated dUTP nick end-labelling methods. Constitutive release of IL-8 and IL-6 was greatest from the COPD cultures. However, CSE pretreatment followed by P. aeruginosa LPS stimulation reduced IL-8 release from COPD PBECs, but increased it from cells of smokers without airflow obstruction and nonsmokers. TLR-4 expression, MAPK and NF-κB activation in COPD cultures were reduced after CSE treatment, but not in the smokers without airflow obstruction or nonsmoker groups, which was associated with increased apoptosis. CSE attenuates inflammatory responses to LPS in cells from people with COPD but not those from nonsmoking individuals and those who smoke without airflow obstruction.

Comparison of nasal and bronchial epithelial cells obtained from patients with COPD.

For in vitro studies of airway pathophysiology, primary epithelial cells have many advantages over immortalised cell lines. Nasal epithelial cells are easier to obtain than bronchial epithelial cells and can be used as an alternative for in vitro studies. Our objective was to compare nasal and bronchial epithelial cells from subjects with COPD to establish if these cells respond similarly to pro-inflammatory stimuli. Cell cultures from paired nasal and bronchial brushings (21 subjects) were incubated with cigarette smoke extract (CSE) prior to stimulation with Pseudomonas aeruginosa lipopolysaccharide. IL-6 and IL-8 were measured by ELISA and Toll-like receptor 4 (TLR-4) message and expression by RT-PCR and FACS respectively. IL-8 release correlated significantly between the two cell types. IL-6 secretion was significantly less from bronchial compared to nasal epithelial cells and secreted concentrations did not correlate. A 4 h CSE incubation was immunosuppressive for both nasal and bronchial cells, however prolonged incubation for 24 h was pro-inflammatory solely for the nasal cells. CSE reduced TLR-4 expression in bronchial cells only after 24 h, and was without effect on mRNA expression. In subjects with COPD, nasal epithelial cells cannot substitute for in vitro bronchial epithelial cells in airway inflammation studies.

Successful Endobronchial stenting for bronchial compression from a massive thoracic aortic aneurysm.

A case of bronchial occlusion caused by a thoracic aortic aneurysm and the relief of this obstruction by the implantation of expandable metallic stents is described. Stent deployment provided an immediate improvement in lung ventilation and chest radiograph appearances. Stent insertion was uncomplicated, but weaning from mechanical ventilation was unsuccessful and the patient died from a ventilator-associated pneumonia, unrelated to the procedure. Endobronchial stenting should be considered as a non-invasive therapy for the treatment of bronchial obstruction, with respiratory compromise, caused by a thoracic aortic aneurysm when vascular surgery is not an option. The medium to long term survival of this patient group is poor. This can be attributed to complications related to the stent and also to the poor performance status of these patients.

A diagnostic dilemma: a case report.

BACKGROUND: A seventy nine year old lady presented with acute bilateral foot drop and paraesthesia of her lower limbs as a presenting feature of Wegener's Granulomatosis (WG). CASE PRESENTATION: There was no evidence of pulmonary involvement and her renal function was normal. WG can masquerade as very diverse pathology. It is recognised that neuropathy can occur early and often in the absence of more classical pulmonary and renal findings, often resulting in a delay in diagnosis. CONCLUSION: Anti-neutrophil cytoplasmic antibody (ANCA) testing was particularly useful in this case permitting early diagnosis.