IL-10 is necessary for the expression of airway hyperresponsiveness but not pulmonary inflammation after allergic sensitization

Cytokines play an important role in modulating inflammatory responses and, as a result, airway tone. IL-10 is a regulatory cytokine that has been suggested for treatment of asthma because of its immunosuppressive and anti-inflammatory properties. In contrast to these suggestions, we demonstrate in a model of allergic sensitization that mice deficient in IL-10 (IL-10-/-) develop a pulmonary inflammatory response but fail to exhibit airway hyperresponsiveness in both in vitro and in vivo assessments of lung function. Reconstitution of these deficient mice with the IL-10 gene fully restores development of airway hyperresponsiveness comparable to control mice. These results identify an important role of IL-10, downstream of the inflammatory cascade, in regulating the tone of the airways after allergic sensitization and challenge.     

Precancerous conditions in gastric cancer (II): relationship between atrophic gastritis-intestinal metaplasia-gastric dysplasia-gastric carcinoma

We studied a group of gastric precancerous lesions in order to analyze their mutual relationship as well as and their association with the development of gastric carcinoma of the intestinal type. This study was performed on 850 gastric biopsy specimens. Our results demonstrate the strong association of atrophic gastritis, intestinal metaplasia and gastric dysplasia (p less than 0.001) which should be considered as precursor lesions of gastric cancer. Moreover, the relations between these lesions and the intestinal type of gastric carcinoma suggest their active participation in the genesis of this type of malignancy. Our results also suggest that chronic atrophic gastritis and intestinal metaplasia evolve to the dysplasia stage before developing gastric cancer.     

Murine models of asthma.

In vivo animal models can offer valuable information on several aspects of asthma pathogenesis and treatment. The mouse is increasingly used in these models, mainly because this species allows for the application in vivo of a broad range of immunological tools, including gene deletion technology. Mice, therefore, seem particularly useful to further elucidate factors influencing the response to inhaled allergens. Examples include: the role of immunoregulatory mechanisms that protect against T-helper cell type 2 cell development; the trafficking of T-cells; and the contribution of the innate immunity. However, as for other animal species, murine models also have limitations. Mice do not spontaneously develop asthma and no model mimics the entire asthma phenotype. Instead, mice should be used to model specific traits of the human disease. The present task force report draws attention to specific aspects of lung structure and function that need to be borne in mind when developing such models and interpreting the results. In particular, efforts should be made to develop models that mimic the lung function changes characteristic of asthma as closely as possible. A large section of this report is therefore devoted to an overview of airway function and its measurement in mice.     

Course and Predictors of Posttraumatic Stress Disorder in the Canadian Armed Forces: A Nationally Representative, 16-Year Follow-up Study: Cours et prédicteurs du trouble de stress post-traumatique dans les Forces armées canadiennes: une étude de suivi de 16 ans nationalement représentative

Objective:This study examined baseline risk and protective predictors and interim correlates of the persistence/recurrence, remission, and onset of posttraumatic stress disorder (PTSD) in a 16-year prospective, nationally representative sample of Canadian Forces members and veterans.Methods:The 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey is a prospective study of 2,941 regular force service members and veterans who participated in the 2002 Canadian Community Health Survey on Mental Health and Wellbeing: Canadian Forces Supplement (n = 5,155; ages 15 to 64 years; response rate 68%). PTSD diagnoses in 2002 and 2018 were used to create 4 groups: (1) no lifetime, (2) remitted, (3) new onset, and (4) persistent/recurrent PTSD. Multinomial regressions were conducted to identify predictors of PTSD courses.Results:Female sex, being a junior noncommissioned member (vs. officer), and land (vs. air) operations in 2002 were associated with all PTSD courses relative to no lifetime PTSD (relative risk ratio [RRR] range: 1.28 to 3.65). After adjusting for sociodemographic variables, baseline predictors of all PTSD courses included lifetime mental disorder, history of mental health care utilization, all trauma type categories (deployment-associated, sexual, “other”), and the number of lifetime traumatic events (RRR range: 1.14 to 8.95). New (“since 2002”) traumas, transitioning to veteran status, and alcohol dependence were mostly associated with the new onset and persistent/recurrent PTSD courses (RRR range: 1.79 to 4.31), while mental health care utilization and greater avoidance coping were associated with all PTSD courses (RRR range: 1.10 to 17.87). Protective factors for several PTSD courses at one or both time points included social support, social network size, and problem-focused coping (RRR range: 0.71 to 0.98).Conclusions:This is the first population-based survey to examine the longitudinal course of PTSD in Canadian Forces members. Prevention and intervention programs focused on bolstering social support and active coping strategies as possible protective factors/correlates may help mitigate the development and persistence of PTSD.     

A randomized controlled trial on the effect of inhaled corticosteroids on airways inflammation in adult cigarette smokers.

STUDY OBJECTIVE: To determine whether inhaled corticosteroid treatment can reduce airways inflammation in adult cigarette smokers. DESIGN: This was a randomized, placebo-controlled, double-blinded clinical trial. SETTING: The subjects were recruited from the community by advertising. PARTICIPANTS: Seventy-one adults with a > or = 5 pack-year history who were current smokers, had a normal FEV1, and produced sputum daily. INTERVENTION: Sixty subjects were randomized to receive four puffs of placebo or beclomethasone dipropionate ([BDP]; total dosage, 1,000 microg/d) using a metered-dose aerosol inhaler with a valved holding chamber (AeroChamber; Trudell Medical; London, Ontario, Canada) for 28 days. MEASUREMENTS AND RESULTS: Eleven subjects were not randomized because of poor compliance. The primary outcome was fractional airway neutrophilia, as assessed by a differential cell count of sputum. Additional outcome measures were spirometry, measurement of airway responsiveness by methacholine challenge, and lung epithelial permeability measured by the clearance of radiolabeled diethylenetriamine pentaacetic acid. There were no significant differences between the two groups in any outcome measurement after 4 weeks of treatment. CONCLUSIONS: With normal spirometry, we found no benefit of treatment with inhaled BDP, 1,000 microg/d, on noninvasive measures of airways inflammation in adult smokers. This indicates that cigarette smoke-induced inflammation in its early stages (before a demonstrable airflow obstruction) is not steroid sensitive. This may occur because the site of involvement is not accessible to inhaled medications or because the inflammatory process is resistant to moderate doses of inhaled corticosteroids.     

Replication-Defective Adenovirus Infection Reduces Helicobacter felis Colonization in the Mouse in a Gamma Interferon- and Interleukin-12-Dependent Manner

Helicobacter infection leads to chronic inflammation of the stomach. Although the infection persists in spite of an immune response, animal studies have shown that adjuvant-based oral vaccines can protect against infection and even eliminate established infection. These vaccines are thought to induce a Th2 immune response, counterbalancing the Th1 response seen with natural infections. As a prelude to using adenovirus vectors carrying cytokine genes to modulate the immune response to established Helicobacter felis infection, we first examined the effect of the replication-defective adenovirus (RDA) vector itself. C57BL/6 mice chronically infected with H. felis (8 to 10 weeks) received intramuscular injections of RDA. The effect of RDA on the severity of H. felis colonization and the degree of gastric inflammation was assessed 2 weeks later. RDA caused a significant decrease in H. felis colonization without significantly altering the associated inflammation. RDA did not alter the H. felis-specific immunoglobulin G1 (IgG1), IgG2a, and IgA responses in the serum but was associated with an increase in gamma interferon (IFN-gamma)-producing CD8(+) spleen cells. To determine if IFN-gamma or Th1 cytokines were involved in the response to RDA, we examined RDA treatment of H. felis infection in mice lacking either IFN-gamma or interleukin-12 (IL-12). RDA failed to alter H. felis colonization in either of these two mouse strains. Thus, viral infection of mice chronically infected with H. felis led to a significant decrease in H. felis colonization in an IFN-gamma- and IL-12-dependent manner. These results demonstrate that Th1 responses associated with systemic viral infection can influence an established H. felis infection.     

Sleep problems in young infants and maternal mental and physical health

AIM: Sleep problems in the second 6 months of life are common and associated with maternal depression. This paper extends previous research to (i) establish the prevalence of sleep problems in younger infants from a broader socio-economic spectrum, (ii) examine the relationship between infant sleep problems and maternal physical, as well as mental, health, and (iii) explore mothers' sleep quality as a potential mediator of this relationship. METHODS: Design: Cross-sectional, community survey in Melbourne, Australia. Sample: Mothers of 3- to 6-month-old infants (mean 4.6 months) recruited from well-child clinics in six sociodemographically diverse metropolitan local government areas. Outcome measures: Maternal mental and physical health; standardised questionnaire on infant sleep patterns; maternal report of an infant sleep problem (yes/no). RESULTS: The survey was completed by 692 mothers; 237 (34%) reported an infant sleep problem, of whom 73 (31%) rated the problem as severe. Sleep patterns characterising a problem included the infant waking seven nights per week, nursing the infant to sleep at the beginning of the night, the infant sleeping in the parent's room, and parental disagreement regarding managing infant sleep. There was no relationship between sleep problems and socio-economic levels. Mothers reporting infant sleep problems had poorer mental and physical health compared with those not reporting sleep problems. CONCLUSION: Sleep problems are common in early infancy across metropolitan socio-economic levels and are associated with poorer maternal health and well-being. Preventive strategies for infant sleep problems need to begin early in primary care to improve mothers' health.     

Promotion of eosinophil survival by human bronchial epithelial cells and its modulation by steroids

Accumulation of eosinophils in the bronchial tissue occurs in a variety of inflammatory disorders of the human airway. We asked whether airway epithelial cells released factors that could influence eosinophil survival and thus contribute to accumulation of these cells in the tissues. Using conditioned medium (CM) generated from cultured human bronchial epithelial cells (HBEC), we examined the in vitro survival of eosinophils isolated from human peripheral blood. When cultured in control medium, more than 90% of the eosinophils were dead by day 4. In contrast, culture in HBEC-CM resulted in dose-dependent survival at day 6 of 69 +/- 9.4%, 40.5 +/- 5.9%, and 25 +/- 2% viability with 2, 0.5, and 0.1% HBEC-CM, respectively (n = 4). Granulocyte/macrophage colony-stimulating factor (GM-CSF) was detected in the HBEC-CM by enzyme-linked immunosorbent assay at levels of 22 to 48 pg/ml. Furthermore, preincubation of the HBEC-CM with a neutralizing monoclonal antibody to human GM-CSF completely inhibited this increased survival of eosinophils. Because corticosteroids are potent eosinopenic agents, we also examined the effects of the synthetic steroid budesonide on this system. Budesonide inhibited both spontaneous and interleukin-1 (IL-1)-induced GM-CSF production by cultured HBEC. In addition, preincubation of eosinophils with budesonide caused marked abrogation of the survival induced subsequently with either HBEC-CM or recombinant human GM-CSF. In summary, HBEC can support eosinophil survival via the elaboration of GM-CSF and thus may contribute to the local control of inflammatory cell accumulation. Steroids may modulate this process both by inhibiting cytokine production from HBEC and by a direct effect on eosinophils, preventing their response to cytokines.