Second-hand Smoke Increases Nitric Oxide and Alters the IgE Response in a Murine Model of Allergic Aspergillosis

This study was performed to determine the effects of environmental tobacco smoke (ETS) on nitric oxide (NO) and immunoglobulin (Ig) production in a murine model of allergic bronchopulmonary aspergillosis (ABPA). Adult BALB/c mice were exposed to aged and diluted sidestream cigarette smoke from day 0 through day 43 to simulate “second-hand smoke”. During exposure, mice were sensitized to soluble Aspergillus fumigatus (Af) antigen intranasally between day 14 and 24. All Af sensitized mice in ambient air (Af + AIR) made elevated levels of IgE, IgG1, IgM, IgG2a and IgA. Af sensitized mice housed in ETS (Af + ETS) made similar levels of immunoglobulins except for IgE that was significantly reduced in the serum and bronchoalveolar lavage (BAL). However, immunohistochemical evaluation of the lung revealed a marked accumulation of IgE positive cells in the lung parenchyma of these Af + ETS mice. LPS stimulation of BAL cells revealed elevated levels of NO in the Af + AIR group, which was further enhanced in the Af+ETS group. In vitro restimulation of the BAL cells on day 45 showed a TH0 response with elevated levels of IL3, 4, 5, 10 and IFN-γ. However, by day 28 the response shifted such that TH2 cytokines increased while IFN-γ decreased. The Af + ETS group showed markedly reduced levels in all cytokines tested, including the inflammatory cytokine IL6, when compared to the Af+AIR group. These results demonstrate that ETS affects ABPA by further enhancing the NO production and reduces the TH2 and the inflammatory cytokines while altering the pattern of IgE responses

Gender Differences in the Allergic Response of Mice Neonatally Exposed to Environmental Tobacco Smoke

Exposure to environmental tobacco smoke (ETS) has been shown to increase allergic sensitization and reactivity and there has been some suggestion that the influence of ETS on the allergic response is dissimilar in males and females. It is to be determined whether gender differences exist in the IgE response to ovalbumin (OVA) sensitization following ETS exposure from the neonatal period through adulthood. To address this thesis, we examined gender differences in OVA sensitization of BALB/c mice housed from birth through adulthood under smoking and nonsmoking conditions. At 6 weeks of age (day 0) all mice were injected i.p. with OVA in aluminum hydroxide adjuvant followed by three 20 min exposures to 1% aerosolized OVA between day 14 and 80. There were significantly (p<0.05) more total and OVA specific IgE and IgG1 in the serum of females compared to males. Moreover, these sex responses, along with eosinophilia, were further enhanced in mice exposed to ETS. There were also significantly more IgE positive cells in the lungs of female, but not male, mice exposed to ETS compared with ambient air (p<0.05). There was also an elevation of Th2 cytokines (IL4, IL5, IL10, and IL13) after re-stimulation of lung homogenates following ETS exposure. These data demonstrate that female animals are significantly more susceptible than males to the influence of ETS on the allergic response

Second-Hand Smoke Increases Bronchial Hyperreactivity and Eosinophilia in a Murine Model of Allergic Aspergillosis

Involuntary inhalation of tobacco smoke has been shown to aggravate the allergic response. Antibodies to fungal antigens such as Aspergillus fumigatus (Af) cause an allergic lung disease in humans. This study was carried out to determine the effect of environmental tobacco smoke (ETS) on a murine model of allergic bronchopulmonary aspergillosis (ABPA). BALB/c mice were exposed to aged and diluted sidestream cigarette smoke to simulate 'second-hand smoke'. The concentration was consistent with that achieved in enclosed public areas or households where multiple people smoke. During exposure, mice were sensitized to Af antigen intranasally. Mice that were sensitized to Af antigen and exposed to ETS developed significantly greater airway hyperreactivity than did mice similarly sensitized to Af but housed in ambient air. The effective concentration of aerosolized acetylcholine needed to double pulmonary flow resistance was significantly lower in Af + ETS mice compared to the Af + AIR mice. Immunological data that supports this exacerbation of airway hyperresponsiveness being mediated by an enhanced type 1 hypersensitivity response include: eosinophilia in peripheral blood and lung sections. All Af sensitized mice produced elevated levels of IL4, IL5 and IL10 but no IFN-γ indicating a polarized Th2 response. Thus, ETS can cause exacerbation of asthma in ABPA as demonstrated by functional airway hyperresponsiveness and elevated levels of blood eosinophilia

Signal Transmission in the Auditory System

Contains table of contents for Section 3, an introduction and reports on six research projects.National Institutes of Health Grant RO1-DC-00194-11National Institutes of Health Grant PO1-DC00119 Sub-Project 1National Institutes of Health Grant F32-DC00073-3National Institutes of Health Contract P01-DC00119National Institutes of Health Grant R01 DC00238National Institutes of Health Grant P01-DC00119National Institutes of Health Grant T32-DC00038National Institutes of Health Contract P01-DC00361National Institutes of Health Grant R01-DC00235National Institutes of Health Contract NO1-DC2240

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Second-hand smoke increases nitric oxide and alters the IgE response in a murine model of allergic aspergillosis

Abstract This study was performed to determine the effects of environmental tobacco smoke (ETS) on nitric oxide (NO) and immunoglobulin (Ig) production in a murine model of allergic bronchopulmonary aspergillosis (ABPA). Adult BALB/c mice were exposed to aged and diluted sidestream cigarette smoke from day 0 through day 43 to simulate &quot;second-hand smoke&quot;. During exposure, mice were sensitized to soluble Aspergillus fumigatus (Af) antigen intranasally between day 14 and 24. All Af sensitized mice in ambient air (Af þ AIR) made elevated levels of IgE, IgG1, IgM, IgG2a and IgA. Af sensitized mice housed in ETS (Af þ ETS) made similar levels of immunoglobulins except for IgE that was significantly reduced in the serum and bronchoalveolar lavage (BAL). However, immunohistochemical evaluation of the lung revealed a marked accumulation of IgE positive cells in the lung parenchyma of these Af þ ETS mice. LPS stimulation of BAL cells revealed elevated levels of NO in the Af þ AIR group, which was further enhanced in the Af þ ETS group. In vitro restimulation of the BAL cells on day 45 showed a TH0 response with elevated levels of IL3, 4, 5, 10 and IFN-g. However, by day 28 the response shifted such that TH2 cytokines increased while IFN-g decreased. The Af þ ETS group showed markedly reduced levels in all cytokines tested, including the inflammatory cytokine IL6, when compared to the Af þ AIR group. These results demonstrate that ETS affects ABPA by further enhancing the NO production and reduces the TH2 and the inflammatory cytokines while altering the pattern of IgE responses

Women in Intensive Care study: a preliminary assessment of international data on female representation in the ICU physician workforce, leadership and academic positions

Abstract Background Despite increasing female enrolment into medical schools, persistent gender gaps exist in the physician workforce. There are limited published data on female representation in the critical care medicine workforce. Methods To obtain a global perspective, societies (n = 84; 79,834 members (40,363 physicians, 39,471 non-physicians)) registered with the World Federation of Societies of Intensive and Critical Care Medicine were surveyed. Longitudinal data on female trainee and specialist positions between 2006-2017 were obtained from Australia and New Zealand. Data regarding leadership and academic faculty representation were also collected from national training bodies and other organisations of critical care medicine. Results Of the 84 societies, 23 had a registered membership of greater than 500 members. Responses were received from 27 societies (n = 55,996), mainly high-income countries, covering 70.1% of the membership. Amongst the physician workforce, the gender distribution was available from six (22%) participating societies—mean proportion of females 37 ± 11% (range 26–50%). Longitudinal data from Australia and New Zealand between 2006 and 2017 demonstrate rising proportions of female trainees and specialists. Female trainee and specialist numbers increased from 26 to 37% and from 13 to 22% respectively. Globally, female representation in leadership positions was presidencies of critical care organisations (0–41%), representation on critical care medicine boards and councils (8–50%) and faculty representation at symposia (7–34%). Significant gaps in knowledge exist: data from low and middle-income countries, the age distribution and the time taken to enter and complete training. Conclusions Despite limited information globally, available data suggest that females are under-represented in training programmes, specialist positions, academic faculty and leadership roles in intensive care. There are significant gaps in data on female participation in the critical care workforce. Further data from intensive care organisations worldwide are required to understand the demographics, challenges and barriers to their professional progress

Repeated Iron–Soot Exposure and Nose-to-brain Transport of Inhaled Ultrafine Particles

Particulate exposure has been implicated in the development of a number of neurological maladies such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, and idiopathic Parkinson's disease. Only a few studies have focused on the olfactory pathway as a portal through which combustion-generated particles may enter the brain. The primary objective of this study was to define the deposition, uptake, and transport of inhaled ultrafine iron-soot particles in the nasal cavities of mice to determine whether combustion-generated nanoparticles reach the olfactory bulb via the olfactory epithelium and nerve fascicles. Adult female C57B6 mice were exposed to iron-soot combustion particles at a concentration of 200 μg/m3, which included 40 μg/m3 of iron oxide nanoparticles. Mice were exposed for 6 hr/day, 5 days/week for 5 consecutive weeks (25 total exposure days). Our findings visually demonstrate that inhaled ultrafine iron-soot reached the brain via the olfactory nerves and was associated with indicators of neural inflammation

Pulmonary Effects of Silver Nanoparticle Size, Coating, and Dose over Time upon Intratracheal Instillation

Silver nanoparticles (Ag NPs) can be found in myriad consumer products, medical equipment/supplies, and public spaces. However, questions remain regarding the risks associated with Ag NP exposure. As part of a consortium-based effort to better understand these nanomaterials, this study examined how Ag NPs with varying sizes and coatings affect pulmonary responses at different time-points. Four types of Ag NPs were tested: 20 nm (C20) and 110 nm (C110) citrate-stabilized NPs, and 20 nm (P20) and 110 nm (P110) PVP-stabilized NPs. Male, Sprague Dawley rats were intratracheally instilled with Ag NPs (0, 0.1, 0.5, or 1.0 mg/kg bodyweight [BW]), and bronchoalveolar lavage fluid (BALF) and lung tissues were obtained at 1, 7, and 21 days post-exposure for analysis of BAL cells and histopathology. All Ag NP types produced significantly elevated polymorphonuclear cells (PMNs) in BALF on Days 1, 7, and/or 21 at the 0.5 and/or 1.0 mg/kg BW dose(s). Histology of animals exposed to 1.0 mg/kg BW Ag NPs showed patchy, focal, centriacinar inflammation for all time-points; though neutrophils, macrophages, and/or monocytes were also found in the airway submucosa and perivascular regions at Days 1 and 7. Confocal microscopy of ethidium homodimer-stained lungs at Day 1 showed dead/dying cells at branch points along the main airway. By Day 21, only animals exposed to the high dose of C110 or P110 exhibited significant BALF neutrophilia and marked cellular debris in alveolar airspaces. Findings suggest that 110 nm Ag NPs may produce lasting effects past Day 21 post instillation