Immune cell counts and risks of respiratory infections among infants exposed pre- and postnatally to organochlorine compounds: a prospective study

<p>Abstract</p> <p>Background</p> <p>Early-life chemical exposure may influence immune system development, subsequently affecting child health. We investigated immunomodulatory potentials of polychlorinated biphenyls (PCBs) and <it>p,p'</it>-DDE in infants.</p> <p>Methods</p> <p>Prenatal exposure to PCBs and <it>p,p'</it>-DDE was estimated from maternal serum concentrations during pregnancy. Postnatal exposure was calculated from concentrations of the compounds in mother's milk, total number of nursing days, and percentage of full nursing each week during the 3 month nursing period. Number and types of infections among infants were registered by the mothers (N = 190). White blood cell counts (N = 86) and lymphocyte subsets (N = 52) were analyzed in a subgroup of infants at 3 months of age.</p> <p>Results</p> <p>Infants with the highest prenatal exposure to PCB congeners CB-28, CB-52 and CB-101 had an increased risk of respiratory infection during the study period. In contrast, the infection odds ratios (ORs) were highest among infants with the lowest prenatal mono-<it>ortho </it>PCB (CB-105, CB-118, CB-156, CB-167) and di-<it>ortho </it>PCB (CB-138, CB-153, CB-180) exposure, and postnatal mono- and di-<it>ortho </it>PCB, and <it>p,p'</it>-DDE exposure. Similar results were found for pre- and postnatal CB-153 exposure, a good marker for total PCB exposure. Altogether, a negative relationship was indicated between infections and total organochlorine compound exposure during the whole pre- and postnatal period. Prenatal exposure to CB-28, CB-52 and CB-101 was positively associated with numbers of lymphocytes and monocytes in infants 3 months after delivery. Prenatal exposure to <it>p,p'</it>-DDE was negatively associated with the percentage of eosinophils. No significant associations were found between PCB and <it>p,p'</it>-DDE exposure and numbers/percentages of lymphocyte subsets, after adjustment for potential confounders.</p> <p>Conclusion</p> <p>This hypothesis generating study suggests that background exposure to PCBs and <it>p,p'</it>-DDE early in life modulate immune system development. Strong correlations between mono- and di-<it>ortho </it>PCBs, and <it>p,p'</it>-DDE exposures make it difficult to identify the most important contributor to the suggested immunomodulation, and to separate effects due to pre- and postnatal exposure. The suggested PCB and <it>p,p'</it>-DDE modulation of infection risks may have consequences for the health development during childhood, since respiratory infections early in life may be risk factors for asthma and middle ear infections.</p

Controlling Viral Immuno-Inflammatory Lesions by Modulating Aryl Hydrocarbon Receptor Signaling

Ocular herpes simplex virus infection can cause a blinding CD4+ T cell orchestrated immuno-inflammatory lesion in the cornea called Stromal Keratitis (SK). A key to controlling the severity of SK lesions is to suppress the activity of T cells that orchestrate lesions and enhance the representation of regulatory cells that inhibit effector cell function. In this report we show that a single administration of TCDD (2, 3, 7, 8- Tetrachlorodibenzo-p-dioxin), a non-physiological ligand for the AhR receptor, was an effective means of reducing the severity of SK lesions. It acted by causing apoptosis of Foxp3- CD4+ T cells but had no effect on Foxp3+ CD4+ Tregs. TCDD also decreased the proliferation of Foxp3- CD4+ T cells. The consequence was an increase in the ratio of Tregs to T effectors which likely accounted for the reduced inflammatory responses. In addition, in vitro studies revealed that TCDD addition to anti-CD3/CD28 stimulated naïve CD4+ T cells caused a significant induction of Tregs, but inhibited the differentiation of Th1 and Th17 cells. Since a single TCDD administration given after the disease process had been initiated generated long lasting anti-inflammatory effects, the approach holds promise as a therapeutic means of controlling virus induced inflammatory lesions

Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials

Background Patients with chronic obstructive pulmonary disease (COPD) have few options for treatment. The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD, but not in those concomitantly treated with longacting inhaled bronchodilators. The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium was investigated. Methods In two double-blind, multicentre studies done in an outpatient setting, after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 mu g or placebo once a day for 24 weeks, in addition to salmeterol (M2-127 study) or tiotropium (M2-128 study). The primary endpoint was change in prebronchodilator forced expiratory volume in 1s (FEV(1)). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128. Findings In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV(1) by 49 mL (p<0.0001) in patients treated with salmeterol, and 80 mL (p<0.0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV(1) was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal. Interpretation Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients

Protection against Lethal Challenge with Streptococcus pneumoniae Is Conferred by Aryl Hydrocarbon Receptor Activation but Is Not Associated with an Enhanced Inflammatory Response

Streptococcus pneumoniae is a common respiratory pathogen and a major cause of morbidity and mortality in humans, particularly in the elderly and young children. The pulmonary immune response to S. pneumoniae is initiated very rapidly, and, ideally, innate immune responses are able to contain bacterial colonization. In the studies presented here, we sought to determine whether activation of the aryl hydrocarbon receptor (AhR) would protect mice from an otherwise lethal infection with S. pneumoniae. The rationale for this hypothesis is that, although most AhR agonists are potent immunosuppressants, AhR activation enhances the inflammatory response to pathogenic and nonpathogenic stimuli. Specifically, neutrophil numbers and levels of inflammatory cytokines are often increased in mice treated with the potent AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). To test the hypothesis, vehicle control- or TCDD-treated mice were intranasally infected with S. pneumoniae. Mortality, pulmonary bacterial burden, cytokine/chemokine levels, and influx of immune cells to the lung were analyzed at various times postinfection. As predicted, survival was substantially improved in the mice treated with TCDD, and the pulmonary bacterial burden was decreased. Surprisingly, however, there was no evidence suggesting that protection resulted from an enhanced inflammatory response. In fact, neutrophil numbers and inflammatory chemokines and cytokines were all decreased in the TCDD-treated mice relative to vehicle control-treated mice. This suggests that the protective effect of AhR activation is not the result of altered immune function but instead may reflect a direct effect on the response of lung cells to infection

Divergent Selection for Heat Loss in Mice: II. Correlated Responses in Feed Intake, Body Mass, Body Composition, and Number Born Through Fifteen Generations

Divergent selection for heat loss (kcal•kg-.75•d-1) , measured in 9- to 11-wk-old male mice, was conducted for 15 generations. Selection for high (MH) and low (ML) heat loss and unselected control (MC) occurred in each of three replicates for a total of nine unique lines. Feed intake in males was measured during Generations 9 through 15. Body mass at commencement of mating in females and at time of measurement of heat loss in males was recorded. Body fat percentage at 12 wk for animals of Generations 6, 10, and 14 was predicted as a function of electrical conductivity and body mass. Litter size was recorded for all generations, and components of litter size were evaluated at Generation 11 in one replicate and Generation 12 in the other two replicates. Feed intake changed in the same direction as heat loss for the MH and ML selections; at Generation 15, the difference between MH and ML ( P \u3c .002) was 20.6% of the MC mean. Body mass did not change with selection for heat loss. Differences in body fat percentage were not significant in earlier generations, but at Generation 14, MH and ML were significantly ( P \u3c .01) different with MH mice having the lowest fat percentage; MC was intermediate. Selection had a significant (MH vs ML; P \u3c .01) effect on litter size, causing an increase in MH and a decrease in ML. This difference was explained by a difference (P \u3c .01) in ovulation rate. There was no asymmetry of response in feed intake, fatness, litter size, or number of ovulations

Supplementary Material for: Place of Residence and Cognitive Function among the Adult Population in India

<b><i>Background:</i></b> The place of residence has been linked to cognitive function among adults in developed countries. This study examined how urban and rural residence was associated with cognitive function among adults in India. <b><i>Methods:</i></b> The World Health Organization Study on Global AGEing and Adult Health data was used to examine cognition among 6,244 community-residing adults age 50+ in 6 states in India. Residential status was categorized as urban, rural, urban-to-urban, rural-to-urban, rural-to-rural, and urban-to-rural. Cognition was assessed by immediate and delayed recall tests, digit span test, and verbal fluency test. Multilevel models were used to account for state-level differences and adjusted for individual-level sociodemographic, psychosocial, and health-related factors. <b><i>Results:</i></b> Urban residents and urban-to-urban migrants had the highest levels of cognition, whereas rural residents and those who migrated to (or within) rural areas had the lowest cognition. The differences largely persisted after adjustment for multiple covariates; however, rural-to-urban migrants had no difference in cognition from urban residents once socioeconomic factors were taken into account. <b><i>Conclusion:</i></b> Cognition among adults in India differed significantly according to their current and past place of residence. Socioeconomic factors played an important role in the cognitive function of adults in urban areas

Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound

VAF347 is a low-molecular-weight compound that inhibits allergic lung inflammation in vivo. This effect is likely the result of a block of dendritic cell (DC) function to generate proinflammatory T-helper (Th) cells because VAF347 inhibits interleukin (IL)–6, CD86, and human leukocyte antigen (HLA)–DR expression by human monocyte-derived DC, 3 relevant molecules for Th-cell generation. Here we demonstrate that VAF347 interacts with the aryl hydrocarbon receptor (AhR) protein, resulting in activation of the AhR signaling pathway. Functional AhR is responsible for the biologic activity of VAF347 because (1) other AhR agonists display an identical activity profile in vitro, (2) gene silencing of wild-type AhR expression or forced overexpression of a trans-dominant negative AhR ablates VAF347 activity to inhibit cytokine induced IL-6 expression in a human monocytic cell line, and (3) AhR-deficient mice are resistant to the compound's ability to block allergic lung inflammation in vivo. These data identify the AhR protein as key molecular target of VAF347 and its essential role for mediating the anti-inflammatory effects of the compound in vitro and in vivo