Ambient Air Pollution Associated with Suppressed Serologic Responses to Pneumocystis jirovecii in a Prospective Cohort of HIV-Infected Patients with Pneumocystis Pneumonia

Background

Ambient air pollution (AAP) may be associated with increased risk for Pneumocystis pneumonia (PCP). The mechanisms underlying this association remain uncertain.

Objectives

To determine if real-life exposures to AAP are associated with suppressed IgM antibody responses to P. jirovecii in HIV-infected (HIV+) patients with active PCP, and to determine if AAP, mediated by suppressed serologic responses to Pneumocystis, is associated with adverse clinical outcomes.

Methods

We conducted a prospective cohort study in HIV+ patients residing in San Francisco and admitted to San Francisco General Hospital with microscopically confirmed PCP. Our AAP predictors were ambient air concentrations of particulate matter of < 10 µm in diameter (PM₁₀) and < 2.5 µm in diameter (PM_2.5), nitrogen dioxide (NO₂), ozone (O₃), and sulfur dioxide (SO₂) measured immediately prior to hospital admission and 2 weeks prior to admission. Our primary outcomes were the IgM serologic responses to four recombinant P. jirovecii major surface glycoprotein (Msg) constructs: MsgC1, MsgC3, MsgC8, and MsgC9.

Results

Elevated PM₁₀ and NO₂ exposures immediately prior to and two weeks prior to hospital admission were associated with decreased IgM antibody responses to P. jirovecii Msg. For exposures immediately prior to admission, every 10 µg/m³ increase in PM₁₀ was associated with a 25 to 35% decrease in IgM responses to Msg (statistically significant for all the Msg constructs), and every 10 ppb increase in NO₂ was associated with a 19-45% decrease in IgM responses to Msg (statistically significant for MsgC8 and MsgC9). Similar findings were seen with exposures two weeks prior to admission, but for fewer of the Msg constructs.

Conclusions

Real life exposures to PM₁₀ and NO₂ were associated with suppressed IgM responses to P. jirovecii Msg in HIV+ patients admitted with PCP, suggesting a mechanism of immunotoxicity by which AAP increases host susceptibility to pulmonary infection.     

Long-Term Exposure to Primary Traffic Pollutants and Lung Function in Children: Cross-Sectional Study and Meta-Analysis

Background

There is widespread concern about the possible health effects of traffic-related air pollution. Nitrogen dioxide (NO₂) is a convenient marker of primary pollution. We investigated the associations between lung function and current residential exposure to a range of air pollutants (particularly NO₂, NO, NOx and particulate matter) in London children. Moreover, we placed the results for NO₂ in context with a meta-analysis of published estimates of the association.

Methods and Findings

Associations between primary traffic pollutants and lung function were investigated in 4884 children aged 9–10 years who participated in the Child Heart and Health Study in England (CHASE). A systematic literature search identified 13 studies eligible for inclusion in a meta-analysis. We combined results from the meta-analysis with the distribution of the values of FEV₁ in CHASE to estimate the prevalence of children with abnormal lung function (FEV₁<80% of predicted value) expected under different scenarios of NO₂ exposure. In CHASE, there were non-significant inverse associations between all pollutants except ozone and both FEV1 and FVC. In the meta-analysis, a 10 μg/m³ increase in NO₂ was associated with an 8 ml lower FEV₁ (95% CI: -14 to -1 ml; p: 0.016). The observed effect was not modified by a reported asthma diagnosis. On the basis of these results, a 10 μg/m³ increase in NO₂ level would translate into a 7% (95% CI: 4% to 12%) increase of the prevalence of children with abnormal lung function.

Conclusions

Exposure to traffic pollution may cause a small overall reduction in lung function and increase the prevalence of children with clinically relevant declines in lung function.     

Effectiveness of Low Emission Zones: Large Scale Analysis of Changes in Environmental NO2, NO and NOx Concentrations in 17 German Cities

Background

Low Emission Zones (LEZs) are areas where the most polluting vehicles are restricted from entering. The effectiveness of LEZs to lower ambient exposures is under debate. This study focused on LEZs that restricted cars of Euro 1 standard without appropriate retrofitting systems from entering and estimated LEZ effects on NO₂, NO, and NO_x ( = NO₂+NO).

Methods

Continuous half-hour and diffuse sampler 4-week average NO₂, NO, and NO_x concentrations measured inside and outside LEZs in 17 German cities of 6 federal states (2005–2009) were analysed as matched quadruplets (two pairs of simultaneously measured index values inside LEZ and reference values outside LEZ, one pair measured before and one after introducing LEZs with time differences that equal multiples of 364 days) by multiple linear and log-linear fixed-effects regression modelling (covariables: e.g., wind velocity, amount of precipitation, height of inversion base, school holidays, truck-free periods). Additionally, the continuous half-hour data was collapsed into 4-week averages and pooled with the diffuse sampler data to perform joint analysis.

Results

More than 3,000,000 quadruplets of continuous measurements (half-hour averages) were identified at 38 index and 45 reference stations. Pooling with diffuse sampler data from 15 index and 10 reference stations lead to more than 4,000 quadruplets for joint analyses of 4-week averages. Mean LEZ effects on NO₂, NO, and NO_x concentrations (reductions) were estimated to be at most −2 µg/m³ (or −4%). The 4-week averages of NO₂ concentrations at index stations after LEZ introduction were 55 µg/m³ (median and mean values) or 82 µg/m³ (95th percentile).

Conclusions

This is the first study investigating comprehensively the effectiveness of LEZs to reduce NO₂, NO, and NO_x concentrations controlling for most relevant potential confounders. Our analyses indicate that there is a statistically significant, but rather small reduction of NO₂, NO, and NO_x concentrations associated with LEZs.     

Socioeconomic Position and Low Birth Weight among Mothers Exposed to Traffic-Related Air Pollution

Background

Atmospheric pollution is a major public health concern. It can affect placental function and restricts fetal growth. However, scientific knowledge remains too limited to make inferences regarding causal associations between maternal exposure to air pollution and adverse effects on pregnancy. This study evaluated the association between low birth weight (LBW) and maternal exposure during pregnancy to traffic related air pollutants (TRAP) in São Paulo, Brazil.

Methods and findings

Analysis included 5,772 cases of term-LBW (<2,500 g) and 5,814 controls matched by sex and month of birth selected from the birth registration system. Mothers’ addresses were geocoded to estimate exposure according to 3 indicators: distance from home to heavy traffic roads, distance-weighted traffic density (DWTD) and levels of particulate matter ≤10 µg/m³ estimated through land use regression (LUR-PM₁₀). Final models were evaluated using multiple logistic regression adjusting for birth, maternal and pregnancy characteristics. We found decreased odds in the risk of LBW associated with DWTD and LUR-PM₁₀ in the highest quartiles of exposure with a significant linear trend of decrease in risk. The analysis with distance from heavy traffic roads was less consistent. It was also observed that mothers with higher education and neighborhood-level income were potentially more exposed to TRAP.

Conclusions

This study found an unexpected decreased risk of LBW associated with traffic related air pollution. Mothers with advantaged socioeconomic position (SEP) although residing in areas of higher vehicular traffic might not in fact be more expose to air pollution. It can also be that the protection against LBW arising from a better SEP is stronger than the effect of exposure to air pollution, and this exposure may not be sufficient to increase the risk of LBW for these mothers.     

Altered Colonic Mucosal Polyunsaturated Fatty Acid (PUFA) Derived Lipid Mediators in Ulcerative Colitis: New Insight into Relationship with Disease Activity and Pathophysiology

Objectives

Ulcerative colitis (UC) is a relapsing inflammatory disorder of unconfirmed aetiology, variable severity and clinical course, characterised by progressive histological inflammation and with elevation of eicosanoids which have a known pathophysiological role in inflammation. Therapeutic interventions targetting eicosanoids (5-aminosalicylates (ASA)) are effective first line and adjunctive treatments in mild-moderate UC for achieving and sustaining clinical remission. However, the variable clinical response to 5-ASA and frequent deterioration in response to cyclo-oxygenase (COX) inhibitors, has prompted an in depth simultaneous evaluation of multiple lipid mediators (including eicosanoids) within the inflammatory milieu in UC. We hypothesised that severity of inflammation is associated with alteration of lipid mediators, in relapsing UC.

Design

Study was case-control design. Mucosal lipid mediators were determined by LC-MS/MS lipidomics analysis on mucosal biopsies taken from patients attending outpatients with relapsing UC. Univariate and multivariate statistical analyses were used to investigate the association of mucosal lipid mediators, with the disease state and severity graded histologically.

Results

Levels of PGE₂, PGD₂, TXB₂, 5-HETE, 11-HETE, 12-HETE and 15-HETE are significantly elevated in inflamed mucosa and correlate with severity of inflammation, determined using validated histological scoring systems.

Conclusions

Our approach of capturing inflammatory mediator signature at different stages of UC by combining comprehensive lipidomics analysis and computational modelling could be used to classify and predict mild-moderate inflammation; however, predictive index is diminished in severe inflammation. This new technical approach could be developed to tailor drug treatments to patients with active UC, based on the mucosal lipid mediator profile.     

The Immune System in Children with Malnutrition—A Systematic Review

Background

Malnourished children have increased risk of dying, with most deaths caused by infectious diseases. One mechanism behind this may be impaired immune function. However, this immune deficiency of malnutrition has not previously been systematically reviewed.

Objectives

To review the scientific literature about immune function in children with malnutrition.

Methods

A systematic literature search was done in PubMed, and additional articles identified in reference lists and by correspondence with experts in the field. The inclusion criteria were studies investigating immune parameters in children aged 1–60 months, in relation to malnutrition, defined as wasting, underweight, stunting, or oedematous malnutrition.

Results

The literature search yielded 3402 articles, of which 245 met the inclusion criteria. Most were published between 1970 and 1990, and only 33 after 2003. Malnutrition is associated with impaired gut-barrier function, reduced exocrine secretion of protective substances, and low levels of plasma complement. Lymphatic tissue, particularly the thymus, undergoes atrophy, and delayed-type hypersensitivity responses are reduced. Levels of antibodies produced after vaccination are reduced in severely malnourished children, but intact in moderate malnutrition. Cytokine patterns are skewed towards a Th2-response. Other immune parameters seem intact or elevated: leukocyte and lymphocyte counts are unaffected, and levels of immunoglobulins, particularly immunoglobulin A, are high. The acute phase response appears intact, and sometimes present in the absence of clinical infection. Limitations to the studies include their observational and often cross-sectional design and frequent confounding by infections in the children studied.

Conclusion

The immunological alterations associated with malnutrition in children may contribute to increased mortality. However, the underlying mechanisms are still inadequately understood, as well as why different types of malnutrition are associated with different immunological alterations. Better designed prospective studies are needed, based on current understanding of immunology and with state-of-the-art methods.     

Intracellular Conversion of Environmental Nitrate and Nitrite to Nitric Oxide with Resulting Developmental Toxicity to the Crustacean Daphnia magna

Background

Nitrate and nitrite (jointly referred to herein as NO_x) are ubiquitous environmental contaminants to which aquatic organisms are at particularly high risk of exposure. We tested the hypothesis that NO_x undergo intracellular conversion to the potent signaling molecule nitric oxide resulting in the disruption of endocrine-regulated processes.

Methodology/Principal Findings

These experiments were performed with insect cells (Drosophila S2) and whole organisms Daphnia magna. We first evaluated the ability of cells to convert nitrate (NO₃ ⁻) and nitrite (NO₂ ⁻) to nitric oxide using amperometric real-time nitric oxide detection. Both NO₃ ⁻ and NO₂ ⁻ were converted to nitric oxide in a substrate concentration-dependent manner. Further, nitric oxide trapping and fluorescent visualization studies revealed that perinatal daphnids readily convert NO₂ ⁻ to nitric oxide. Next, daphnids were continuously exposed to concentrations of the nitric oxide-donor sodium nitroprusside (positive control) and to concentrations of NO₃ ⁻ and NO₂ ⁻. All three compounds interfered with normal embryo development and reduced daphnid fecundity. Developmental abnormalities were characteristic of those elicited by compounds that interfere with ecdysteroid signaling. However, no compelling evidence was generated to indicate that nitric oxide reduced ecdysteroid titers.

Conclusions/Significance

Results demonstrate that nitrite elicits developmental and reproductive toxicity at environmentally relevant concentrations due likely to its intracellular conversion to nitric oxide.     

Immune Surveillance by Rhinovirus-Specific Circulating CD4+ and CD8+ T Lymphocytes

Background

It is difficult to experimentally infect volunteers with RV strains to which the subject demonstrates serological immunity. However, in RV challenges, viral clearance begins before de novo adaptive immune responses would develop. We speculated that adaptive immunity to RV reflects heterologous immunity by effector memory cells.

Methods

DCs were generated from monocytes using GM-CSF and IL-4 and RV39 loading accomplished with a dose of ∼350 TCID₅₀/10⁵ cells. RV-induced maturation was established as modulation of MHC class II, CD80, CD83, and CD86. Circulating RV targeting CD4 and CD8 T cells were investigated as induction of RV-specific proliferation (CFSE-dilution).

Results

Maturation of DC by RV was confirmed as upregulation of MHC Class II (83.3±5.0% to 87.8±4.1%), CD80 (39.4±7.2% to 47.6±7.7%) and CD86 (78.4±4.7% to 84.1±3.4%). Both CD4 and CD8 memory T cells were recognized in the circulation of healthy subjects.

Conclusions

RV drives DC maturation and results in their ability to present RV antigens to both T helper and cytotoxic lymphocytes. Both CD4 and CD8 cells capable of recognizing RV-associated antigens are present in the circulation of healthy subjects where they are presumably involved in immune surveillance and explain the rapid recruitment of an adaptive immune response during RV infection.     

Analysis of Serum Inflammatory Mediators Identifies Unique Dynamic Networks Associated with Death and Spontaneous Survival in Pediatric Acute Liver Failure

Background

Tools to predict death or spontaneous survival are necessary to inform liver transplantation (LTx) decisions in pediatric acute liver failure (PALF), but such tools are not available. Recent data suggest that immune/inflammatory dysregulation occurs in the setting of acute liver failure. We hypothesized that specific, dynamic, and measurable patterns of immune/inflammatory dysregulation will correlate with outcomes in PALF.

Methods

We assayed 26 inflammatory mediators on stored serum samples obtained from a convenience sample of 49 children in the PALF study group (PALFSG) collected within 7 days after enrollment. Outcomes were assessed within 21 days of enrollment consisting of spontaneous survivors, non-survivors, and LTx recipients. Data were subjected to statistical analysis, patient-specific Principal Component Analysis (PCA), and Dynamic Bayesian Network (DBN) inference.

Findings

Raw inflammatory mediator levels assessed over time did not distinguish among PALF outcomes. However, DBN analysis did reveal distinct interferon-gamma-related networks that distinguished spontaneous survivors from those who died. The network identified in LTx patients pre-transplant was more like that seen in spontaneous survivors than in those who died, a finding supported by PCA.

Interpretation

The application of DBN analysis of inflammatory mediators in this small patient sample appears to differentiate survivors from non-survivors in PALF. Patterns associated with LTx pre-transplant were more like those seen in spontaneous survivors than in those who died. DBN-based analyses might lead to a better prediction of outcome in PALF, and could also have more general utility in other complex diseases with an inflammatory etiology.     

Testosterone,Sex Hormone-Binding Globulin and the Metabolic Syndrome in Men: An Individual Participant Data Meta-Analysis of Observational Studies

Background

Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably.

Objectives

We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components.

Data sources

Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE.

Study Eligibility Criteria

Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men.

Methods

We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied.

Results

Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension.

Conclusions

Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk.     

A Low-Dose β1-Blocker in Combination with Milrinone Improves Intracellular Ca2+ Handling in Failing Cardiomyocytes by Inhibition of Milrinone-Induced Diastolic Ca2+ Leakage from the Sarcoplasmic Reticulum

Objectives

The purpose of this study was to investigate whether adding a low-dose β1-blocker to milrinone improves cardiac function in failing cardiomyocytes and the underlying cardioprotective mechanism.

Background

The molecular mechanism underlying how the combination of low-dose β1-blocker and milrinone affects intracellular Ca²⁺ handling in heart failure remains unclear.

Methods

We investigated the effect of milrinone plus landiolol on intracellular Ca²⁺ transient (CaT), cell shortening (CS), the frequency of diastolic Ca²⁺ sparks (CaSF), and sarcoplasmic reticulum Ca²⁺ concentration ({Ca²⁺}_SR) in normal and failing canine cardiomyocytes and used immunoblotting to determine the phosphorylation level of ryanodine receptor (RyR2) and phospholamban (PLB).

Results

In failing cardiomyocytes, CaSF significantly increased, and peak CaT and CS markedly decreased compared with normal myocytes. Administration of milrinone alone slightly increased peak CaT and CS, while CaSF greatly increased with a slight increase in {Ca²⁺}_SR. Co-administration of β1-blocker landiolol to failing cardiomyocytes at a dose that does not inhibit cardiomyocyte function significantly decreased CaSF with a further increase in {Ca²⁺}_SR, and peak CaT and CS improved compared with milrinone alone. Landiolol suppressed the hyperphosphorylation of RyR2 (Ser2808) in failing cardiomyocytes but had no effect on levels of phosphorylated PLB (Ser16 and Thr17). Low-dose landiolol significantly inhibited the alternans of CaT and CS under a fixed pacing rate (0.5 Hz) in failing cardiomyocytes.

Conclusion

A low-dose β1-blocker in combination with milrinone improved cardiac function in failing cardiomyocytes, apparently by inhibiting the phosphorylation of RyR2, not PLB, and subsequent diastolic Ca²⁺ leak.     

Diabetes,Glucose Metabolism,and Glaucoma: The 2005–2008 National Health and Nutrition Examination Survey

Background

Diabetes may affect vascular autoregulation of the retina and optic nerve and may be associated with an increased risk of glaucoma,but the association of prediabetes, insulin resistance, markers of glucose metabolismwith glaucoma has not beenevaluated in general population samples.

Objective

To examine the relation between diabetes, pre-diabetes, metabolic syndrome and its components and the levels of fasting glucose, HbA1c and HOMA-IR with the prevalence of glaucoma in the general U.S. population.

Methods

Cross-sectional study of 3,299 adult men and women from the 2005–2008 National Health and NutritionExamination Survey (NHANES). The presence of diabetes, prediabetes, the metabolic syndrome and its individual components and biomarkers of glucose metabolisms were based on standardized questionnaire and physical exam data and laboratory tests. The history of glaucoma was assessed through questionnaire during the home interview.

Results

Diabetes was strongly associated with prevalent glaucoma.In fully adjusted models, the odds ratiofor glaucoma comparing participants with diabetes with participants in the reference group with neither pre-diabetes nor diabetes was 2.12 (95% CI: 1.23, 3.67). The corresponding odd ratio comparing participants with pre-diabetes to those in the reference group was 1.01 (95% CI: 0.57, 1.82). Patients with 5 or more years of diabetes duration hadan OR for glaucoma of 3.90 (95% CI: 1.63, 9.32) compared with patients with <5 years of diabetes duration. We also found a hockey-stick shaped associations between biomarkers of glucose metabolisms and the prevalence of glaucoma.

Conclusions

Diabetes was associated with higher risk of glaucoma. Participants without diabetes but at the higher levels of fasting glucose, fasting insulin, HbA1c and HOMA-IR spectrum may also be at greater risk of glaucoma.     

Preserved Antigen-Specific Immune Response in Patients with Multiple Sclerosis Responding to IFNβ-Therapy

Background

Interferon-beta (IFNβ) regulates the expression of a complex set of pro- as well as anti-inflammatory genes. In cohorts of MS patients unstratified for therapeutic response to IFNβ, normal vaccine-specific immune responses have been observed. Data capturing antigen-specific immune responses in cohorts of subjects defined by response to IFNβ-therapy are not available.

Objective

To assess antigen-specific immune responses in a cohort of MS patients responding clinically and radiologically to IFNβ.

Methods

In 26 MS patients, clinical and MRI disease activity were assessed before and under treatment with IFNβ. Humoral and cellular immune response to influenza vaccine was prospectively characterized in these individuals, and 33 healthy controls by influenza-specific Enzyme-Linked Immunosorbent Assay (ELISA) and Enzyme Linked Immuno Spot Technique (ELISPOT).

Results

Related to pre-treatment disease activity, IFNβ reduced clinical and radiological MS disease-activity. Following influenza vaccination, frequencies of influenza-specific T cells and concentrations of anti-influenza A and B IgM and IgG increased comparably in MS-patients and in healthy controls.

Conclusions

By showing in a cohort of MS-patients responding to IFNβ vaccine-specific immune responses comparable to controls, this study indicates that antigen-specific immune responses can be preserved under successful IFNβ-therapy.     

MiR-17-5p Impairs Trafficking of H-ERG K+ Channel Protein by Targeting Multiple ER Stress-Related Chaperones during Chronic Oxidative Stress

Background

To investigate if microRNAs (miRNAs) play a role in regulating h-ERG trafficking in the setting of chronic oxidative stress as a common deleterious factor for many cardiac disorders.

Methods

We treated neonatal rat ventricular myocytes and HEK293 cells with stable expression of h-ERG with H₂O₂ for 12 h and 48 h. Expression of miR-17-5p seed miRNAs was quantified by real-time RT-PCR. Protein levels of chaperones and h-ERG trafficking were measured by Western blot analysis. Luciferase reporter gene assay was used to study miRNA and target interactions. Whole-cell patch-clamp techniques were employed to record h-ERG K⁺ current.

Results

H-ERG trafficking was impaired by H₂O₂ after 48 h treatment, accompanied by reciprocal changes of expression between miR-17-5p seed miRNAs and several chaperones (Hsp70, Hsc70, CANX, and Golga2), with the former upregulated and the latter downregulated. We established these chaperones as targets for miR-17-5p. Application miR-17-5p inhibitor rescued H₂O₂-induced impairment of h-ERG trafficking. Upregulation of endogenous by H₂O₂ or forced miR-17-5p expression either reduced h-ERG current. Sequestration of AP1 by its decoy molecule eliminated the upregulation of miR-17-5p, and ameliorated impairment of h-ERG trafficking.

Conclusions

Collectively, deregulation of the miR-17-5p seed family miRNAs can cause severe impairment of h-ERG trafficking through targeting multiple ER stress-related chaperones, and activation of AP1 likely accounts for the deleterious upregulation of these miRNAs, in the setting of prolonged duration of oxidative stress. These findings revealed the role of miRNAs in h-ERG trafficking, which may contribute to the cardiac electrical disturbances associated with oxidative stress.     

Physical Activity versus Sedentary Behavior: Associations with Lipoprotein Particle Subclass Concentrations in Healthy Adults

Background

Physical activity (PA) and sedentary behavior (SED) may have independent effects on health and disease. This might be due to PA and SED having distinct effects on lipoprotein metabolism. The aim of this study was to determine associations between lipoprotein subclass particle concentrations (-P) and accelerometer-measured SED and moderate-to-vigorous PA (MVPA) in a sample of healthy adult subjects.

Methods

Lipoprotein subclass particle concentrations were determined by proton nuclear magnetic resonance spectroscopy, whereas SED and MVPA were measured using Agtigraph GT1M and GT3X+ accelerometers. We obtained valid data in 73 subjects (30 men and 43 women, age 40.5 ± 10.6 years; body mass index 24.0 ± 2.8). Multiple regression analysis was used to determine associations (partial correlations) with lipoproteins.

Results

Positive associations were detected between SED and small VLDL-P, large LDL-P and TG (partial r = 0.24 to 0.25, p < .047). Corresponding associations were non-significant for MVPA (partial r = -0.12 to 0.04, p > .355). On the contrary, MVPA was positively associated with large HDL-P, average HDL size, Apo A1 and HDL-cholesterol (partial r = 0.28 to 0.50, p < .027), whereas SED was not (partial r = -0.06 to 0.07, p > .607).

Conclusion

There might be a specific effect of SED versus MVPA on lipoprotein metabolism. However, our results must be interpreted carefully due to possible effect-modification by gender and a low sample size. Thus, our findings should be viewed as preliminary.     

The K+ Channel KCa3.1 as a Novel Target for Idiopathic Pulmonary Fibrosis

Background

Idiopathic pulmonary fibrosis (IPF) is a common, progressive and invariably lethal interstitial lung disease with no effective therapy. We hypothesised that K_Ca3.1 K⁺ channel-dependent cell processes contribute to IPF pathophysiology.

Methods

K_Ca3.1 expression in primary human lung myofibroblasts was examined using RT-PCR, western blot, immunofluorescence and patch-clamp electrophysiology. The role of K_Ca3.1 channels in myofibroblast proliferation, wound healing, collagen secretion and contraction was examined using two specific and distinct K_Ca3.1 blockers (TRAM-34 and ICA-17043 [Senicapoc]).

Results

Both healthy non fibrotic control and IPF-derived human lung myofibroblasts expressed K_Ca3.1 channel mRNA and protein. K_Ca3.1 ion currents were elicited more frequently and were larger in IPF-derived myofibroblasts compared to controls. K_Ca3.1 currents were increased in myofibroblasts by TGFβ1 and basic FGF. K_Ca3.1 was expressed strongly in IPF tissue. K_Ca3.1 pharmacological blockade attenuated human myofibroblast proliferation, wound healing, collagen secretion and contractility in vitro, and this was associated with inhibition of TGFβ1-dependent increases in intracellular free Ca²⁺.

Conclusions

K_Ca3.1 activity promotes pro-fibrotic human lung myofibroblast function. Blocking K_Ca3.1 may offer a novel approach to treating IPF with the potential for rapid translation to the clinic.     

Association between Air Pollution and General Outpatient Clinic Consultations for Upper Respiratory Tract Infections in Hong Kong

Background and Objectives

Many studies have shown the adverse effects of air pollution on respiratory health, but few have examined the effects of air pollution on service utilisation in the primary care setting. The aim of this study was to examine the association between air pollution and the daily number of consultations due to upper respiratory tract infections (URTIs) in general outpatient clinics (GOPCs) in Hong Kong.

Methods

Daily data on the numbers of consultations due to URTIs in GOPCs, the concentrations of major air pollutants, and the mean values of metrological variables were retrospectively collected over a 3-year period (2008–2010, inclusive). Generalised additive models were constructed to examine the association between air pollution and the daily number of consultations, and to derive the relative risks and 95% confidence intervals (95% CI) of GOPC consultations for a unit increase in the concentrations of air pollutants.

Results

The mean daily consultations due to URTIs in GOPCs ranged from 68.4 to 253.0 over the study period. The summary relative risks (and 95% CI) of daily consultations in all GOPCs for the air pollutants PM₁₀, NO₂, O₃, and SO₂ were 1.005 (1.002, 1.009), 1.010 (1.006, 1.013), 1.009 (1.006, 1.012), and 1.004 (1.000, 1.008) respectively, per 10 µg/m³ increase in the concentration of each pollutant.

Conclusion

Significant associations were found between the daily number of consultations due to URTIs in GOPCs and the concentrations of air pollutants, implying that air pollution incurs a substantial morbidity and increases the burden of primary health care services.     

Hemodynamic and Metabolic Correlates of Perinatal White Matter Injury Severity

Background and Purpose

Although the spectrum of perinatal white matter injury (WMI) in preterm infants is shifting from cystic encephalomalacia to milder forms of WMI, the factors that contribute to this changing spectrum are unclear. We hypothesized that the variability in WMI quantified by immunohistochemical markers of inflammation could be correlated with the severity of impaired blood oxygen, glucose and lactate.

Methods

We employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI. Since there is small but measurable residual brain blood flow during occlusion, we sought to determine if the metabolic state of the residual arterial blood was associated with severity of WMI. Near the conclusion of hypoxia-ischemia, we recorded cephalic arterial blood pressure, blood oxygen, glucose and lactate levels. To define the spectrum of WMI, an ordinal WMI rating scale was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microgliosis derived from the entire white matter.

Results

A spectrum of WMI was observed that ranged from diffuse non-necrotic lesions to more severe injury that comprised discrete foci of microscopic or macroscopic necrosis. Residual arterial pressure, oxygen content and blood glucose displayed a significant inverse association with WMI and lactate concentrations were directly related. Elevated glucose levels were the most significantly associated with less severe WMI.

Conclusions

Our results suggest that under conditions of hypoxemia and severe cephalic hypotension, WMI severity measured using unbiased immunohistochemical measurements correlated with several physiologic parameters, including glucose, which may be a useful marker of fetal response to hypoxia or provide protection against energy failure and more severe WMI.     

Risk of Narcolepsy Associated with Inactivated Adjuvanted (AS03) A/H1N1 (2009) Pandemic Influenza Vaccine in Quebec

Context

An association between an adjuvanted (AS03) A/H1N1 pandemic vaccine and narcolepsy has been reported in Europe.

Objective

To assess narcolepsy risk following administration of a similar vaccine in Quebec.

Design

Retrospective population-based study.

Setting

Neurologists and lung specialists in the province were invited to report narcolepsy cases to a single reference centre.

Population

Patients were interviewed by two sleep experts and standard diagnostic tests were performed. Immunization status was verified in the provincial pandemic influenza vaccination registry.

Main Outcome Measures

Confirmed narcolepsy with or without cataplexy with onset of excessive daytime sleepiness between January 1^st, 2009, and December 31^st, 2010. Relative risks (RRs) were calculated using a Poisson model in a cohort analysis, by a self-controlled case series (SCCS) and a case-control method.

Results

A total of 24 cases were included and overall incidence rate was 1.5 per million person-years. A cluster of 7 cases was observed among vaccinated persons in the winter 2009–2010. In the primary cohort analysis, 16-week post-vaccination RR was 4.32 (95% CI: 1.50–11.12). RR was 2.07 (0.70–6.17) in the SCCS, and 1.48 (0.37–7.03) using the case-control method. Estimates were lower when observation was restricted to the period of pandemic influenza circulation, and tended to be higher in persons <20 years old and for cataplexy cases.

Conclusions

Results are compatible with an excess risk of approximately one case per million vaccine doses, mainly in persons less than 20 years of age. However, a confounding effect of the influenza infection cannot be ruled out.