Chitosan IFN-γ-pDNA Nanoparticle (CIN) Therapy for Allergic Asthma

BACKGROUND: Allergic subjects produce relatively low amounts of IFN-γ, a pleiotropic Th-1 cytokine that downregulates Th2-associated airway inflammation and hyperresponsiveness (AHR), the hallmarks of allergic asthma. Adenovirus-mediated IFN-γ gene transfer reduces AHR, Th2 cytokine levels and lung inflammation in mice, but its use would be limited by the frequency of gene delivery required; therefore, we tested chitosan/IFN-γ pDNA nanoparticles (CIN) for in situ production of IFN-γ and its in vivo effects. METHODS: CIN were administered to OVA-sensitized mice to investigate the possibility of using gene transfer to modulate ovalbumin (OVA)-induced inflammation and AHR. RESULTS: Mice treated with CIN exhibit significantly lower AHR to methacholine challenge and less lung histopathology. Production of IFN-γ is increased after CIN treatment while the Th2-cytokines, IL-4 and IL-5, and OVA-specific serum IgE are reduced compared to control mice. AHR and eosinophilia are also significantly reduced by CIN therapy administered therapeutically in mice with established asthma. CIN was found to inhibit epithelial inflammation within 6 hours of delivery by inducing apoptosis of goblet cells. Experiments performed on STAT4-defective mice do not show reduction in AHR with CIN treatment, thus implicating STAT4 signaling in the mechanism of CIN action. CONCLUSION: These results demonstrate that mucosal CIN therapy can effectively reduce established allergen-induced airway inflammation and AHR

Combined fluticasone propionate and salmeterol reduces RSV infection more effectively than either of them alone in allergen-sensitized mice

BACKGROUND: Respiratory syncytial virus (RSV) infection is the major cause of bronchiolitis in infants and is a risk factor for the development of asthma. Allergic asthmatics are more susceptible to RSV infection and viral exacerbation. METHODS: Since the effectiveness of corticosteroids in treating RSV infection has been controversial, we tested fluticasone propionate (FP) and salmeterol (Sal) alone versus FP plus Sal (FPS) on RSV-induced airway inflammation. Mice were sensitized and challenged with ovalbumin (OVA) and infected with RSV. Following infection they were treated with FP, Sal, or FPS intranasally and airway hyperreactivity (AHR), inflammation and RSV titers were examined. RESULTS: The group treated with FPS showed significantly lower AHR compared to the group treated with FP or Sal alone. The group treated with FP alone showed slightly decreased (non-significant) AHR compared to controls. Treatment with FPS resulted in significant decreases in the percentage of eosinophils and neutrophils in bronchoalveolar lavage fluid and in lung pathology compared to FP or Sal. FP alone decreased eosinophils but not neutrophils or lymphocytes, while Sal alone decreased eosinophils and neutrophils but not lymphocytes. FPS treatment of mice infected with RSV in the absence of allergen sensitization resulted in a 50% decrease of RSV titer in the lung and a reduction in neutrophils compared to FP or Sal. CONCLUSION: Together, these results indicate that fluticasone in combination with salmeterol is a more effective treatment for decreasing airway hyperreactivity and inflammation than either of them alone in allergen-sensitized, RSV-infected mice

Blended learning for accredited life support courses - A systematic review.

Aim To evaluate the effectiveness on educational and resource outcomes of blended compared to non-blended learning approaches for participants undertaking accredited life support courses. Methods This review was conducted in adherence with PRISMA standards. We searched EMBASE.com (including all journals listed in Medline), CINAHL and Cochrane from 1 January 2000 to 6 August 2021. Randomised and non-randomised studies were eligible for inclusion. Study screening, data extraction, risk of bias assessment (using RoB2 and ROBINS-I tools), and certainty of evidence evaluation (using GRADE) were all independently performed in duplicate. The systematic review was registered with PROSPERO (CRD42022274392). Results From 2,420 studies, we included data from 23 studies covering fourteen basic life support (BLS) with 2,745 participants, eight advanced cardiac life support (ALS) with 33,579 participants, and one Advanced Trauma Life Support (ATLS) with 92 participants. Blended learning is at least as effective as non-blended learning for participant satisfaction, knowledge, skills, and attitudes. There is potential for cost reduction and eventual net profit in using blended learning despite high set up costs. The certainty of evidence was very low due to a high risk of bias and inconsistency. Heterogeneity across studies precluded any meta-analysis. Conclusion Blended learning is at least as effective as non-blended learning for accredited BLS, ALS, and ATLS courses. Blended learning is associated with significant long term cost savings and thus provides a more efficient method of teaching. Further research is needed to investigate specific delivery methods and the effect of blended learning on other accredited life support courses

Practical psychosocial care for providers of pre-hospital care: a summary of the report 'valuing staff, valuing patients'.

BACKGROUND: Caring for people who are ill or injured in pre-hospital environments is emotionally draining and physically demanding. This article focuses on the Psychosocial and Mental Health Programme commissioned by the Faculty of Pre-Hospital Care (FPHC) at the Royal College of Surgeons of Edinburgh (RCSEd) in 2018 to investigate the experiences and needs of responders to pre-hospital emergencies and make recommendations. It summarises the report to FPHC published in 2022, and adds material from research published subsequently. METHOD: FPHC appointed a team to undertake the work. Team members conducted a literature review, and a systematic review of the literature concerning the impacts on the mental health of pre-hospital practitioners. They conducted fieldwork, participated in training and had conversations with trainees and established practitioners, and took evidence from the Pre-hospital Emergency Medicine Trainees Association (PHEMTA). RESULTS: The Results summarise the evidence-based theoretical background derived from the programme and practical guidance for practitioners, professional organisations, and employers who deliver pre-hospital care on the implications of, preventing and intervening with pre-hospital providers who experience psychosocial and mental health problems. CONCLUSION: This paper summarises the outputs from a multidisciplinary programme of scholarship, research, and fieldwork. The authors condense the findings and the guidance developed by the Programme Team to provide a summary of the report and guidance on implementation. They believe that the recommendations are applicable to all healthcare organisations and particularly those that employ responders to emergencies and provide pre-hospital care

Evidence of reproductive endocrine effects in women with occupational fuel and solvent exposures.

Hydrocarbons (HCs) found in fuels and solvents are ubiquitous in the environment, yet we know little about their effects on the endocrine system. The objective of this study was to assess the potential reproductive endocrine effects of low-dose HCs encountered by female U.S. Air Force personnel with fuel (primarily JP-8 jet fuel) and solvent exposures (n = 63). We estimated the internal dose of HCs in fuels and solvents by measuring their levels in exhaled breath, including the sum of aliphatic HCs (C6H14-C16H34) and the sum of aromatic HCs (benzene, ethylbenzene, toluene, and m,p,o-xylenes). Adverse outcome measures included urinary endocrine markers that have been associated with nonconceptive (vs. conceptive) menstrual cycles in ovulatory women: lower preovulatory luteinizing hormone (LH) and mid-luteal phase pregnanediol 3-glucuronide (Pd3G) and estrone 3-glucuronide, and higher follicle phase Pd3G. We also obtained reproductive and exposure information from baseline questionnaires and daily diaries. Toluene was the most frequently found analyte in the breath, with values up to 52.0 ppb, and benzene breath levels were up to 97.5 ppb. Regression analysis revealed that preovulatory LH levels were significantly lower (p = 0.007) among women whose total aliphatic HC levels were above the median. The relationship between elevated aliphatic HC exposure and lowered preovulatory LH levels in the present study suggests that compounds in fuels and some solvents may act as reproductive endocrine disruptors. Confirmation of these findings is needed, not only to determine if fuel and solvent exposure may impact other LH-dependent physiologic functions but also to examine effects of fuels and solvents on conception

Chitosan Interferon-γ Nanogene Therapy for Lung Disease: Modulation of T-Cell and Dendritic Cell Immune Responses

<p/> <p>The use of chitosan nanoparticles as carriers for expression plasmids represents a major improvement in gene expression technology. We demonstrated previously that treatment with chitosan interferon-γ (IFN-γ) plasmid deoxyribonucleic acid (DNA) nanoparticles (chitosan interferon-γ nanogene [CIN]) led to in situ production of IFN-γ and a reduction in inflammation and airway reactivity in mice, but the mechanism underlying the immunomodulatory effects of CIN remains unclear. In this report, the effect of CIN treatment on the immune responses of CD8⁺T cells and dendritic cells was examined in a BALB/c mouse model of ovalbumin (OVA)-induced allergic asthma. OT1 mice (OVA-T cell receptor [TCR] transgenic) were also used to test the effects of CIN on OVA-specific CD8⁺T cells. CIN treatment caused a reduction in IFN-γ production in a subpopulation of OVA-specific CD8⁺T cells cultured in vitro in the presence of OVA. CIN also reduced apoptosis of the CD8⁺T cells. Examination of dendritic cells from lung and lymph nodes indicated that CIN treatment decreased their antigen-presenting activity, as evident from the reduction in CD80 and CD86 expression. Furthermore, CIN treatment significantly decreased the number of CD11c⁺b⁺dendritic cells in lymph nodes, suggesting that endogenous IFN-γ expression may immunomodulate dendritic cell migration and activation. CIN therapy results in a reduction in proinflammatory CD8⁺T cells and decreases the number and antigen-presenting activity of dendritic cells.</p

An immunocompromised BALB/c mouse model for respiratory syncytial virus infection

BACKGROUND: Respiratory syncytial virus (RSV) infection causes bronchiolitis in infants and children, which can be fatal, especially in immunocompromised patients. The BALB/c mouse, currently used as a model for studying RSV immunopathology, is semi-permissive to the virus. A mouse model that more closely mimics human RSV infection is needed. Since immunocompromised conditions increase risk of RSV infection, the possibility of enhancing RSV infection in the BALB/c mouse by pretreatment with cyclophosphamide was examined in this study. BALB/c mice were treated with cyclophosphamide (CYP) and five days later, they were infected with RSV intranasally. Pulmonary RSV titers, inflammation and airway hyperresponsiveness were measured five days after infection. RESULTS: CYP-treated mice show higher RSV titers in their lungs of than the untreated mice. Also, a decreased percentage of macrophages and an increased number of lymphocytes and neutrophils were present in the BAL of CYP-treated mice compared to controls. The CYP-treated group also exhibited augmented bronchoalveolar and interstitial pulmonary inflammation. The increased RSV infection in CYP-treated mice was accompanied by elevated expression of IL-10, IL-12 and IFN-γ mRNAs and proteins compared to controls. Examination of CYP-treated mice before RSV infection showed that CYP treatment significantly decreased both IFN-γ and IL-12 expression. CONCLUSIONS: These results demonstrate that CYP-treated BALB/c mice provide a better model for studying RSV immunopathology and that decreased production of IL-12 and IFN-γ are important determinants of susceptibility to RSV infection

Nested Case–Control Study of Autoimmune Disease in an Asbestos-Exposed Population

OBJECTIVE: To explore the potential association between asbestos exposure and risk of autoimmune disease, we conducted a case–control study among a cohort of 7,307 current and former residents of Libby, Montana, a community with historical occupational and environmental exposure to asbestos-contaminated vermiculite. METHODS: Cases were defined as those who reported having one of three systemic autoimmune diseases (SAIDs): systemic lupus erythematosus, scleroderma, or rheumatoid arthritis (RA). Controls were randomly selected at a 3:1 ratio from among the remaining 6,813 screening participants using frequency-matched age and sex groupings. RESULTS: The odds ratios (ORs) and 95% confidence intervals (CIs) for SAIDs among those ≥ 65 years of age who had worked for the vermiculite mining company were 2.14 (95% CI, 0.90–5.10) for all SAIDs and 3.23 (95% CI, 1.31–7.96) for RA. In this age group, exposure to asbestos while in the military was also an independent risk factor, resulting in a tripling in risk. Other measures of occupational exposure to vermiculite indicated 54% and 65% increased risk for SAIDs and RA, respectively. Those who had reported frequent contact with vermiculite through various exposure pathways also demonstrated elevated risk for SAIDs and RA. We found increasing risk estimates for SAIDs with increasing numbers of reported vermiculite exposure pathways (p < 0.001). CONCLUSION: These preliminary findings support the hypothesis that asbestos exposure is associated with autoimmune disease. Refined measurements of asbestos exposure and SAID status among this cohort will help to further clarify the relationship between these variables