A. M. Rodríguez

A Mechanistic Role for Type III IFN-λ1 in Asthma Exacerbations Mediated by Human Rhinoviruses

RATIONALE Human rhinoviruses (HRV) are the leading cause of upper respiratory infections and have been postulated to trigger asthma exacerbations. However, whether HRV are detected during crises because upper respiratory infections often accompany asthma attacks, or because they specifically elicit exacerbations, is unclear. Moreover, although several hypotheses have been advanced to explain virus-induced exacerbations, their mechanism remains unclear. OBJECTIVES To determine the role of HRV in pediatric asthma exacerbations and the mechanisms mediating wheezing. METHODS We prospectively studied 409 children with asthma presenting with upper respiratory infection in the presence or absence of wheezing. Candidate viral and immune mediators of illness were compared among children with asthma with different degrees of severity of acute asthma. MEASUREMENTS AND MAIN RESULTS HRV infections specifically associated with asthma exacerbations, even after adjusting for relevant demographic and clinical variables defined a priori (odds ratio, 1.90; 95% confidence interval, 1.21-2.99; P = 0.005). No difference in virus titers, HRV species, and inflammatory or allergic molecules was observed between wheezing and nonwheezing children infected with HRV. Type III IFN-λ(1) levels were higher in wheezing children infected with HRV compared with nonwheezing (P < 0.001) and increased with worsening symptoms (P < 0.001). Moreover, after adjusting for IFN-λ(1), children with asthma infected with HRV were no longer more likely to wheeze than those who were HRV-negative (odds ratio, 1.18; 95% confidence interval, 0.57-2.46; P = 0.66). CONCLUSIONS Our findings suggest that HRV infections in children with asthma are specifically associated with acute wheezing, and that type III IFN-λ(1) responses mediate exacerbations caused by HRV. Modulation of IFN- λ(1) should be studied as a therapeutic target for exacerbations caused by HRV.

TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization

While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.

Macronutrients during Pregnancy and Life-Threatening Respiratory Syncytial Virus Infections in Children

RATIONALE Respiratory syncytial virus (RSV) is an important cause of hospitalization and death in infants worldwide. Most RSV deaths occur in developing countries, where burden and risk factors for life-threatening illness are unclear. OBJECTIVES We defined the burden of life-threatening (O(2) saturation [O(2) sat] ≤ 87%) and fatal RSV infection, and characterized risk factors for life-threatening disease in hospitalized children. Special emphasis was placed on studying the impact of dietary habits during pregnancy. We hypothesized that dietary preferences, differing from those of our remote ancestors, would negatively impact childrens pulmonary health. For instance, a diet rich in carbohydrates is a signature of recent millennia and typical of low-income populations, heavily burdened by life-threatening RSV disease. METHODS Prospective study in a catchment population of 56,560 children under 2 years of age during the RSV season in Argentina. All children with respiratory signs and O(2) sat less than 93% on admission were included. MEASUREMENTS AND MAIN RESULTS Among 1,293 children with respiratory infections, 797(61.6%) were infected with RSV: 106 of these had life-threatening disease; 1.9 per 1,000 children (95% confidence interval [CI], 1.5-2.2/1,000) under 24 months. A total of 22 hospitalized children died (9 RSV(+)), 26 died at home due to acute respiratory infection (14 attributed to RSV); all were under 12 months old. The annual attributable mortality rate for RSV was 0.7 per 1,000 infants (95% CI, 0.4-1.1/1,000). Life-threatening disease was dose-dependently associated with carbohydrate ingestion during pregnancy (adjusted odds ratio from 3.29 [95% CI, 1.15-9.44] to 7.36 [95% CI, 2.41-22.5] versus the lowest quartile). CONCLUSIONS Life-threatening and fatal RSV infections are a heavy burden on infants in the developing world. Diets rich in carbohydrates during pregnancy are associated with these severe outcomes.

Time‐differential perturbed angular correlations investigation of the (NH4)2ZrF6 thermal decomposition

Via the TDPAC technique and complementary x‐ray diffraction analysis, the thermal decomposition of (NH4)2ZrF6 has been observed to occur in the range 400–800 K according to the thermolysis scheme (NH4)2ZrF6→485 KNH4ZrF5→560 KNH4Zr2F9 →620 KZrF4→760 KZrO2. Assuming that the first transformation takes place through the simple chemical reaction (NH4)2ZrF6→NH4ZrF5+NH4F, the corresponding activation energy has been determined to be Ea=(82±6) kJ/mol. The hyperfine parameters of the NH4Zr2F9 decomposition product have been determined between 14 and 560 K. A complete analogy with the isomorphous compound NH4Hf2F9 was observed.

Mortality due to Respiratory Syncytial Virus. Burden and Risk Factors.

Rationale: Respiratory syncytial virus (RSV) is the most frequent cause of hospitalization and an important cause of death in infants in the developing world. The relative contribution of social, biologic, and clinical risk factors to RSV mortality in low‐income regions is unclear. Objectives: To determine the burden and risk factors for mortality due to RSV in a low‐income population of 84,840 infants. Methods: This was a prospective, population‐based, cross‐sectional, multicenter study conducted between 2011 and 2013. Hospitalizations and deaths due to severe lower respiratory tract illness (LRTI) were recorded during the RSV season. All‐cause hospital deaths and community deaths were monitored. Risk factors for respiratory failure (RF) and mortality due to RSV were assessed using a hierarchical, logistic regression model. Measurements and Main Results: A total of 2,588 (65.5%) infants with severe LRTI were infected with RSV. A total of 157 infants (148 postneonatal) experienced RF or died with RSV. RSV LRTI accounted for 57% fatal LRTI tested for the virus. A diagnosis of sepsis (odds ratio [OR], 17.03; 95% confidence interval [CI], 13.14‐21.16 for RF) (OR, 119.39; 95% CI, 50.98‐273.34 for death) and pneumothorax (OR, 17.15; 95% CI, 13.07‐21.01 for RF) (OR, 65.49; 95% CI, 28.90‐139.17 for death) were the main determinants of poor outcomes. Conclusions: RSV was the most frequent cause of mortality in low‐income postneonatal infants. RF and death due to RSV LRTI, almost exclusively associated with prematurity and cardiopulmonary diseases in industrialized countries, primarily affect term infants in a developing world environment. Poor outcomes at hospitals are frequent and associated with the cooccurrence of bacterial sepsis and clinically significant pneumothoraxes.

On the kinetics of chemical reactions in hafnium tetrafluorides using time differential-perturbed angular correlations

Abstract Quadrupole hyperfine interactions in HfF 4 and HfF 4 ·3H 2 O determined by time differential-perturbed angular correlations technique are reported. Changes in the hyperfine interactions of HfF 4 ·3H 2 O with temperature are interpreted in terms of a dehydration process. The reversal process is studied at room temperature as a function of time. Assuming that the hydration obeys a first-order rate law, a rate constant k = 0.49 ± 0.10 d −1 is obtained.

High-resolution TDPAC measurement in K2ZrF6

A time resolution of 2τ=0.75 ns, achieved with a conventional TDPAC setup with FCs detectors, allowed a determination of the very high electric field gradient at Hf impurity sites in K2ZrF6.Simple theoretical calculations seem to indicate that nearest neighbours are responsible for the interaction observed.

TDPAC investigation on NH4Hf2F9

Time-differential perturbed angular correlation (TDPAC) measurements in NH4Hf2F9 were performed between 15 and 580 K. The compound was found to be stable in the whole temperature range and no phase transitions were observed. Experimental results could be explained assuming two equally populated quadrupole interactions which suggest a neat inequivalence between the two sites occupied by the hafnium atoms in the molecule.

The thermal behaviour of the quadrupole hyperfine interaction in (NH4)2HfF6

A TDPAC investigation has been accomplished on (NH4)2 HfF6 between 14 and 620 K. A phase transition was observed below 390 K. The low temperature phase is characterized by two non-equivalent sites for hafnium atoms in a 1∶1 ratio. The high temperature phase, on the other hand, is depicted by a unique quadrupole interaction. Above 400 K, the compound decomposes successively to NH4 HfF5, NH4 Hf2F9 and HfF4. An enthalpy of 76±4 kJ/mol could be determined for the (NH4)2 HfF6→NH4 HfF5+NH4F chemical reaction. The hyperfine interaction and thermal evolution of (NH4)2 HfF6 was found to be quite similar to that of (NH4)2 ZrF6.

Temperature defendence of the hyperfine interaction in (NH4)2ZrF6

The thermal evolution of the hyperfine quadrupole interaction in (NH4)2ZrF6 has been investigated via TDPAC from 14 to 400 K. A phase transition is detected near 370 K. The low-temperature phase exhibits two sites equally populated for181Ta probes. The associated electric field gradients are described by both high asymmetry parameters and high interaction frequencies. On the other hand, the high-temperature phase corresponds to an unique axially symmetric and more intense electric field gradient.