A calorimetric, volumetric and combined SANS and SAXS study of hybrid siloxane phosphocholine bilayers.

Siloxanes are molecules used extensively in commercial, industrial, and biomedical applications. The inclusion of short siloxane chains into phospholipids results in interesting physical properties, including the ability to form low polydispersity unilamellar vesicles. As such, hybrid siloxane phosphocholines (SiPCs) have been examined as a potential platform for the delivery of therapeutic agents. Using small angle X-ray and neutron scattering, vibrating tube densitometry, and differential scanning calorimetry, we studied four hybrid SiPCs bilayers. Lipid volume measurements for the different SiPCs compared well with those previously determined for polyunsaturated PCs. Furthermore, the different SiPC's membrane thicknesses increased monotonically with temperature and, for the most part, consistent with the behavior observed in unsaturated lipids such as, 1-palmitoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine and 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine, and the branched lipid 1,2-diphytanoyl-sn-glyerco-3-phosphocholine (DPhyPC).

Do Ambient Ozone or Other Pollutants Modify Effects of Controlled Ozone Exposure on Pulmonary Function?

Rationale: In a previous trial (MOSES [Multicenter Ozone Study of oldEr Subjects]), 3 hours of controlled ozone (O3) exposure caused concentration-related reductions in lung function with evidence of airway inflammation and injury, but without convincing evidence of effects on cardiovascular function. However, the subjects' exposures to indoor and outdoor air pollution in the hours and days before each controlled O3 exposure may have modified biomarker responses to the controlled O3 exposures.Objectives: We sought to determine whether personal measures of nitrogen dioxide (NO2) and O3, or ambient concentrations of O3, particulate matter ≤2.5 µm in aerodynamic diameter, NO2, carbon monoxide (CO), and sulfur dioxide (SO2) in the 72 and 96 hours before the exposure visit modified biomarker responses to controlled O3 exposure.Methods: MOSES subjects were exposed for 3 hours in random order to clean air containing 0 ppb O3, 70 ppb O3, or 120 ppm O3, alternating 15 minutes of moderate exercise with 15 minutes of rest. Cardiovascular and pulmonary endpoints (biomarkers of autonomic function, repolarization, ST segment change, arrhythmia, prothrombotic vascular status, systemic inflammation, vascular function, pulmonary function, oxidative stress, and lung injury) were measured on the day before, the day of, and up to 22 hours after each exposure. We evaluated whether ambient pollutant concentrations in the 96 hours before the pre-exposure visit modified pre- to post-exposure lung function biomarker responses to the controlled O3 exposures, using tertiles of passive personal exposure samplers (PES) of O3 and NO2, ambient air pollutant concentrations, and mixed effects linear regression. We also similarly explored the effect modification of controlled O3 effects on biomarkers of other MOSES outcome groups in the same way. Although we used P < 0.01 to define statistical significance, we did not formally correct for multiple comparisons.Results: The effects of MOSES controlled O3 exposures on forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were modified by ambient NO2 and CO, and PES NO2. Reductions in FEV1 and FVC were observed only when these concentrations were in the "medium" or "high" tertile in the 72 hours before the pre-exposure visit. There was no such modification of the effect of controlled O3 exposure on any other cardiopulmonary outcome group.Conclusions: Reductions in markers of lung function, but not other pathways, by the MOSES controlled O3 exposure were modified by ambient NO2 and CO, and PES NO2, and these reductions were observed only when these pollutant concentrations were elevated in the hours and days before the pre-exposure visit.Clinical trial registered with ClinicalTrials.gov (NCT01487005).

Ozone effects on blood biomarkers of systemic inflammation, oxidative stress, endothelial function, and thrombosis: The Multicenter Ozone Study in oldEr Subjects (MOSES).

The evidence that exposure to ozone air pollution causes acute cardiovascular effects is mixed. We postulated that exposure to ambient levels of ozone would increase blood markers of systemic inflammation, prothrombotic state, oxidative stress, and vascular dysfunction in healthy older subjects, and that absence of the glutathione S-transferase Mu 1 (GSTM1) gene would confer increased susceptibility. This double-blind, randomized, crossover study of 87 healthy volunteers 55-70 years of age was conducted at three sites using a common protocol. Subjects were exposed for 3 h in random order to 0 parts per billion (ppb) (filtered air), 70 ppb, and 120 ppb ozone, alternating 15 min of moderate exercise and rest. Blood was obtained the day before, approximately 4 h after, and approximately 22 h after each exposure. Linear mixed effect and logistic regression models evaluated the impact of exposure to ozone on pre-specified primary and secondary outcomes. The definition of statistical significance was p<0.01. There were no effects of ozone on the three primary markers of systemic inflammation and a prothrombotic state: C-reactive protein, monocyte-platelet conjugates, and microparticle-associated tissue factor activity. However, among the secondary endpoints, endothelin-1, a potent vasoconstrictor, increased from pre- to post-exposure with ozone concentration (120 vs 0 ppb: 0.07 pg/mL, 95% confidence interval [CI] 0.01, 0.14; 70 vs 0 ppb: -0.03 pg/mL, CI -0.09, 0.04; p = 0.008). Nitrotyrosine, a marker of oxidative and nitrosative stress, decreased with increasing ozone concentrations, with marginal significance (120 vs 0 ppb: -41.5, CI -70.1, -12.8; 70 vs 0 ppb: -14.2, CI -42.7, 14.2; p = 0.017). GSTM1 status did not modify the effect of ozone exposure on any of the outcomes. These findings from healthy older adults fail to identify any mechanistic basis for the epidemiologically described cardiovascular effects of exposure to ozone. The findings, however, may not be applicable to adults with cardiovascular disease.

Ambient and controlled exposures to particulate air pollution and acute changes in heart rate variability and repolarization.

Previous studies have reported increased risks of myocardial infarction in association with elevated ambient particulate matter (PM) in the previous hour(s). However, whether PM can trigger mechanisms that act on this time scale is still unclear. We hypothesized that increases in PM are associated with rapid changes in measures of heart rate variability and repolarization. We used data from panel studies in Augsburg, Germany, and Rochester, New York, USA, and two controlled human exposure studies in Rochester. Data included ECG recordings from all four studies, controlled exposures to (concentrated) ultrafine particles (UFP; particles with an aerodynamic diameter <100 nm) and ambient concentrations of UFP and fine PM (PM2.5, aerodynamic diameter <2.5 µm). Factor analysis identified three representative ECG parameters: standard deviation of NN-intervals (SDNN), root mean square of successive differences (RMSSD), and T-wave complexity. Associations between air pollutants and ECG parameters in the concurrent and previous six hours were estimated using additive mixed models adjusting for long- and short-term time trends, meteorology, and study visit number. We found decreases in SDNN in relation to increased exposures to UFP in the previous five hours in both of the panel studies (e.g. Augsburg study, lag 3 hours: -2.26%, 95% confidence interval [CI]: -3.98% to -0.53%; Rochester panel study, lag 1 hour: -2.69%; 95% CI: -5.13% to -0.26%) and one of the two controlled human exposure studies (1-hour lag: -13.22%; 95% CI: -24.11% to -2.33%). Similarly, we observed consistent decreases in SDNN and RMSSD in association with elevated PM2.5 concentrations in the preceding six hours in both panel studies. We did not find consistent associations between particle metrics and T-wave complexity. This study provided consistent evidence that recent exposures to UFP and PM2.5 can induce acute pathophysiological responses.

Influenza Virus Infection of Human Lymphocytes Occurs in the Immune Cell Cluster of the Developing Antiviral Response.

Monocytes-macrophages and lymphocytes are recruited to the respiratory tract in response to influenza virus challenge and are exposed to the virus during the establishment of immune defenses. The susceptibility of human lymphocytes to infection was assessed. The presence of monocytes-macrophages was required to attain infection of both resting and proliferating lymphocytes. Lymphocyte infection occurred in the context of immune cell clusters and was blocked by the addition of anti-intercellular adhesion molecule-1 (ICAM-1) antibody to prevent cell clustering. Both peripheral blood-derived and bronchoalveolar lymphocytes were susceptible to infection. Both CD4⁺ and CD8⁺ T lymphocytes were susceptible to influenza virus infection, and the infected CD4⁺ and CD8⁺ lymphocytes served as infectious foci for other nonpermissive or even virus-permissive cells. These data show that monocytes-macrophages and both CD4⁺ and CD8⁺ lymphocytes can become infected during the course of an immune response to influenza virus challenge. The described leukocyte interactions during infection may play an important role in the development of effective anti-influenza responses.

Characterization of self-assembled hybrid siloxane-phosphocholine bilayers.

We have synthesized six new hybrid siloxane phosphocholines (SiPCs) and examined their self-assembly behaviour in aqueous dispersions. Employing small angle X-ray scattering we have characterized SiPC bilayers. SiPCs exhibit differential self-assembly behaviour that results from the interplay between the siloxane fatty acid in the sn-2 position and the differing chain length fatty acids in the sn-1 position. SiPCs that possess a fatty acid chain of a C8-C14 chain length in the sn-1 position form unilamellar vesicles. Extending the fatty acid chain length to C16 and C18 allows for the formation of both unilamellar and multilamellar vesicles. We propose that the preferential formation of unilamellar vesicles is the result of an enhanced hydrophobic effect imparted by siloxane chains at the termini of lipid tails.

Cardiovascular function and ozone exposure: The Multicenter Ozone Study in oldEr Subjects (MOSES).

BACKGROUND: To date, there have been relatively few studies of acute cardiovascular responses to controlled ozone inhalation, although a number of observational studies have reported significant positive associations between both ambient ozone levels and acute cardiovascular events and long-term ozone exposure and cardiovascular mortality. OBJECTIVES: We hypothesized that short-term controlled exposure to low levels of ozone in filtered air would induce autonomic imbalance, repolarization abnormalities, arrhythmia, and vascular dysfunction. METHODS: This randomized crossover study of 87 healthy volunteers 55-70 years of age was conducted at three sites using a common protocol, from June 2012 to April 2015. Subjects were exposed for 3 h in random order to 0 ppb (filtered air), 70 ppb ozone, and 120 ppb ozone, alternating 15 min of moderate exercise with 15 min of rest. A suite of cardiovascular endpoints was measured the day before, the day of, and up to 22 h after each exposure. Mixed effect linear and logit models evaluated the impact of exposure to ozone on pre-specified primary and secondary outcomes. Site and time were included in the models. RESULTS: We found no significant effects of ozone exposure on any of the primary or secondary measures of autonomic function, repolarization, ST segment change, arrhythmia, or vascular function (systolic blood pressure and flow-mediated dilation). CONCLUSIONS: In this multicenter study of older healthy women and men, there was no convincing evidence for acute effects of 3-h, relatively low-level ozone exposures on cardiovascular function. However, we cannot exclude the possibility of effects with higher ozone concentrations, more prolonged exposure, or in subjects with underlying cardiovascular disease. Further, we cannot exclude the possibility that exposure to ambient ozone and other pollutants in the days before the experimental exposures obscured or blunted cardiovascular biomarker response to the controlled ozone exposures.

Respiratory Responses to Ozone Exposure. MOSES (The Multicenter Ozone Study in Older Subjects).

RATIONALE: Acute respiratory effects of low-level ozone exposure are not well defined in older adults. OBJECTIVES: MOSES (The Multicenter Ozone Study in Older Subjects), although primarily focused on acute cardiovascular effects, provided an opportunity to assess respiratory responses to low concentrations of ozone in older healthy adults. METHODS: We performed a randomized crossover, controlled exposure study of 87 healthy adults (59.9 ± 4.5 yr old; 60% female) to 0, 70, and 120 ppb ozone for 3 hours with intermittent exercise. Outcome measures included spirometry, sputum markers of airway inflammation, and plasma club cell protein-16 (CC16), a marker of airway epithelial injury. The effects of ozone exposure on these outcomes were evaluated with mixed-effect linear models. A P value less than 0.01 was chosen a priori to define statistical significance. MEASUREMENTS AND MAIN RESULTS: The mean (95% confidence interval) FEV1 and FVC increased from preexposure values by 2.7% (2.0-3.4) and 2.1% (1.3-2.9), respectively, 15 minutes after exposure to filtered air (0 ppb). Exposure to ozone reduced these increases in a concentration-dependent manner. After 120-ppb exposure, FEV1 and FVC decreased by 1.7% (1.1-2.3) and 0.8% (0.3-1.3), respectively. A similar concentration-dependent pattern was still discernible 22 hours after exposure. At 4 hours after exposure, plasma CC16 increased from preexposure levels in an ozone concentration-dependent manner. Sputum neutrophils obtained 22 hours after exposure showed a marginally significant increase in a concentration-dependent manner (P = 0.012), but proinflammatory cytokines (IL-6, IL-8, and tumor necrosis factor-α) were not significantly affected. CONCLUSIONS: Exposure to ozone at near ambient levels induced lung function effects, airway injury, and airway inflammation in older healthy adults. Clinical trial registered with www.clinicaltrials.gov (NCT01487005).

Analysis of Trisiloxane Phosphocholine Bilayers.

We have synthesized unique siloxane phosphocholines and characterized their aggregates in aqueous solution. The siloxane phosphocholines form nearly monodisperse vesicles in aqueous solution without the need for secondary extrusion processes. The area/lipid, lipid volume, and bilayer thickness were determined from small-angle X-ray scattering experiments. The impetus for the spontaneous formation of unilamellar vesicles by these compounds is discussed.

Biocatalysis in Silicon Chemistry.

The application of biocatalytic or chemoenzymatic techniques in silicon chemistry serves two roles: it provides a greater understanding of the processing of silicon species by natural systems, such as plants, diatoms, and sponges, as well opening up avenues to green methodologies in the field. In the latter case, biocatalytic approaches have been applied to the synthesis of small-molecule systems and polymeric materials. Often these biocatalytic approaches allow access to molecular structures under mild conditions and, in some cases, molecular structures that are not accessible through traditional chemical methodologies. A review of recent advances in the applications of biocatalysis in silicon chemistry is presented.

A joint ERS/ATS policy statement: what constitutes an adverse health effect of air pollution? An analytical framework.

The American Thoracic Society has previously published statements on what constitutes an adverse effect on health of air pollution in 1985 and 2000. We set out to update and broaden these past statements that focused primarily on effects on the respiratory system. Since then, many studies have documented effects of air pollution on other organ systems, such as on the cardiovascular and central nervous systems. In addition, many new biomarkers of effects have been developed and applied in air pollution studies.This current report seeks to integrate the latest science into a general framework for interpreting the adversity of the human health effects of air pollution. Rather than trying to provide a catalogue of what is and what is not an adverse effect of air pollution, we propose a set of considerations that can be applied in forming judgments of the adversity of not only currently documented, but also emerging and future effects of air pollution on human health. These considerations are illustrated by the inclusion of examples for different types of health effects of air pollution.

Human Alveolar Macrophages May Not Be Susceptible to Direct Infection by a Human Influenza Virus.

The current studies were undertaken to determine the susceptibility of human alveolar macrophages (AMs) to influenza A virus (IAV) infection in comparison with autologous peripheral blood-derived monocytes-macrophages (PBMs). AMs and PBMs were exposed to IAV in vitro and examined for their ability to bind and internalize IAV, and synthesize viral proteins and RNA. PBMs but not AMs demonstrated binding and internalization of the virus, synthesizing viral proteins and RNA. Exposure of AMs in the presence of a sialidase inhibitor or anti-IAV antibody resulted in viral protein synthesis by the cells. Exposure of AMs to fluorescein isothiocyanate-labeled IAV in the presence of anti-fluorescein isothiocyanate antibody also resulted in viral protein synthesis. Thus, human AMs are apparently not susceptible to direct infection by a human IAV but are likely to be infected indirectly in the setting of exposure in the presence of antibody that binds the challenging strain of IAV.

Does total antioxidant capacity modify adverse cardiac responses associated with ambient ultrafine, accumulation mode, and fine particles in patients undergoing cardiac rehabilitation?

BACKGROUND: Previous studies suggest that pathways reducing oxidative stress may have a protective effect against adverse cardiac responses associated with ambient PM. However, few studies have directly assessed total antioxidant capacity (TAC) as a potential effect modifier of cardiac responses to increased ambient PM. OBJECTIVES: We examined if TAC modifies the association between ambient PM and markers of heart rate variability (HRV), repolarization, systemic inflammation, and systolic blood pressure (SBP) in post-infarction patients. METHODS: We recruited 76 patients with a recent coronary event (myocardial infarction or unstable angina) who participated in a cardiac rehabilitation program from June 2006 to November 2009 in Rochester, New York. Ambient fine particle (PM2.5,≤2.5µm in aerodynamic diameter), accumulation mode particle (AMP, 100-500nm) and ultrafine particle (UFP, 10-100nm) concentrations were measured continuously by fixed-site monitors. Markers of HRV and repolarization were measured by continuous Holter electrocardiogram (ECG) recordings before and during exercise sessions of the rehabilitation program. Blood pressure was measured and venous blood samples were collected before exercise to measure TAC and inflammation markers. We applied linear mixed models to assess changes in markers of HRV, repolarization, systemic inflammation, and SBP associated with increased PM concentrations in the low, medium and high TAC tertile groups, after adjusting for covariates including temperature, calendar time since the beginning of the study, visit number, month of year, and hour of day. RESULTS: Based on subject-visits with available TAC, we observed increases in SBP, C-reactive protein, and fibrinogen, and decreases in rMSSD (square root of the mean of the sum of the squared differences between adjacent normal to normal intervals) and SDNN (standard deviation of normal to normal beat intervals) associated with increased PM2.5, AMP and UFP in the previous 6-120h (e.g. change in SBP associated with each interquartile range (IQR) increase in PM2.5 lagged 0-5h was 1.27mmHg [95%CI: 0.09, 2.46mmHg]). However, we did not observe a consistent pattern of effect measure modification by TAC for any combination of pollutant and outcome (e.g. changes in SBP associated with each IQR increase in PM2.5 lagged 0-5h for the low, medium and high TAC tertile groups were 1.93mmHg [95%CI: 0.23, 3.63 mmHg], -0.31 mmHg [95%CI: -2.62, 2.01 mmHg], and 1.29mmHg [95%CI: -0.64, 3.21 mmHg], respectively. P for interaction=0.28). CONCLUSIONS: In a post-infarction population, total antioxidant capacity does not appear to modify the association between biomarkers of heart rate variability, repolarization, systemic inflammation, and systolic blood pressure and ambient PM concentrations in the previous 6-120h.

Increases in ambient particulate matter air pollution, acute changes in platelet function, and effect modification by aspirin and omega-3 fatty acids: A panel study.

Increased particulate matter (PM) air pollutant concentrations have been associated with platelet activation. It was postulated that elevated air pollutant concentrations would be associated with increases in measures of platelet function and that responses would be blunted when taking aspirin and/or fish oil. Data from a sequential therapy trial (30 subjects with type 2 diabetes mellitus), with 4 clinic visits (first: no supplements, second: aspirin, third: omega-3 fatty acid supplements, fourth: aspirin and omega-3 fatty acids) per subject, were utilized. Using linear mixed models, adjusted for relative humidity, temperature, visit number, and season, changes in three platelet function measures including (1) aggregation induced by adenosine diphosphate (ADP), (2) aggregation induced by collagen, and (3) thromboxane B2 production were associated with interquartile range (IQR) increases in mean concentrations of ambient PM2.5, black carbon, ultrafine particles (UFP; 10-100 nm), and accumulation mode particles (AMP; 100-500 nm) in the previous 1-96 h. IQR increases in mean UFP and AMP concentrations were associated with significant decreases in platelet response, with the largest being a -0.43 log(pg/ml) decrease in log(thromboxane B2) (95% CI = -0.8, -0.1) associated with each 582-particles/cm(3) increase in AMP, and a -1.7 ohm reduction in collagen-induced aggregation (95% CI = -3.1, -0.3) associated with each 2097-particles/cm(3) increase in UFP in the previous 72 h. This UFP effect on thromboxane B2 was significantly muted in diabetic subjects taking aspirin (-0.01 log[pg/ml]; 95% CI = -0.4, 0.3). The reason for this finding remains unknown, and needs to be investigated in future studies.

Ambient and Controlled Particle Exposures as Triggers for Acute ECG Changes.

INTRODUCTION: Previous studies have examined changes in heart rate variability (HRV*) and repolarization associated with increased particulate matter (PM) concentrations on the same and previous few days. However, few studies have examined whether these health responses to PM occur within a few hours or even less. Moreover, it is not clear whether exposure of subjects to ambient or-controlled PM concentrations both lead to similar health effects or whether any of the subjects' individual characteristics modify any of their responses to PM. The aims of the cur- rent study were to investigate whether exposure to PM was associated with rapid changes (< 60 minutes or con- current hour up to a delay of 6 hours) in markers of car- diac rhythni or changes in total antioxidant capacity (a marker of protection against oxidative stress) and whether any PM effects on cardiac rhythm markers were modified by total antioxidant capacity, age, obesity, smoking, hypertension, exertion, prior myocardial infarction (MI), or medication. METHODS: We obtained data from a completed study in Augsburg, Germany (a panel study in N= 109 subjects, including a group with type 2 diabetes or impaired glucose tolerance [IGT; also known as prediabetes]) and a group of other- wise healthy subjects with a potential genetic susceptibil- ity to detoxifying and inflammatory pathways (Hampel et al. 2012b), as well as three completed studies in Rochester, New York (the REHAB panel study of N= 76 postinfarction patients in a cardiac rehabilitation pro- gram [Rich et al. 2012b]; the UPDIABETES study of con- trolled exposure to ultrafine particles [UFPs, particles with an aerodynamic diameter < 100 nm] of N = 19 patients with type 2 diabetes [Stewart et al. 2010; Vora et al. 2014j; and the UPCON controlled-exposure study of concentrated UFP exposure in N = 20 young, healthy, life- time nonsmokers). Data included 5-minute and 1-hour values for HRV and repolarization parameters from elec- trocardiogram (ECG) recordings and total antioxidant capacity measured in stored blood samples. Ambient con- centrations of UFPs, accumulation-mode particles (AMP, particles with an aerodynamic diameter of 100-500 nm), fine PM (PM2.5, particles with an aerodynamic diameter 2.5 pm), and black carbon (BC) were also available. We first conducted factor analyses in each study to find subgroups of correlated ECG outcomes and to reduce the number of outcomes examined in our statistical models. We then restricted the statistical analyses to the factors and representative.outcomes that were common to all four studies, including total HRV (measured as the standard deviation of normal-to-normal [NN] beat intervals [SDNNj), parasympathetic modulation (measured as the root mean square of the successive differences [RMSSD between adjacent NN beat intervals), and T-wave morphol- ogy (measured as T-wave complexity). Next, we used addi- tive mixed models to estimate the change in each outcome associated with increased pollutant concentrations in the . concurrent and previous 6 hours and with 5-minute inter- vals up to the previous 60 minutes, accounting for the correlation of repeated outcome measures for each subject and adjusting for time trend, hour of the day, temperature, relative humidity, day of the week, month, and visit number. Because multiple comparisons were an issue in our. analyses, we used a discovery-and-replication approach to draw conclusions across studies for each research question. RESULTS: In the Augsburg study, interquartile range (IQR) increases in UFP concentrations lagged 2 to 5 hours were associated with 1%-3% decreases in SDNN (e.g., lagged 3 hours in the group with a genetic susceptibility: -2.26%; 95% confidence interval [CI], -3.98% to -0.53%). In the REHAB study, similarly, IQR increases in UFP concentra- tions in the previous 5 hours were associated with < 3% decreases in SDNN (e.g., lagged 1 hour: -2.69%; 95% CI, -5.13% to -0.26%). We also found decreases in SDNN associated with IQR increases in total particle count-(a surrogate for UFP) in the UPDIABETES study (lagged 1 hour: -13.22%; 95% CI, -24.11% to -2.33%) but not in the UPCON study. In the Augsburg study, IQR increases in PM2.5 concen- trations in the concurrent hour and lagged 1-5 hours, AMP concentrations lagged 1 and 3 hours, and BC con- centrations lagged 1-5 hours were associated with -1%-5% decreases in SDNN (e.g., PM2.5 lagged 2 hours in the group with diabetes or IGT: -4.59%; 95% CI, -7.44% to -1.75%). In the REHAB study, IQR increases in PM2.5 concentrations lagged 5 and 6 hours and AMP concentra- tions in the concurrent hour and lagged up to 5 hours were associated with 1%-2% decreases in SDNN (e.g., PM2.5 lagged 4 hours: -2.13%; 95% CI, -3.91% to -0.35%). In the Augsburg study, IQR increases in PM2.5 concen- trations in the concurrent hour and BC lagged 1 and 6 hours were associated with 3%-7% decreases in RMSSD (e.g., PM2.5 concurrent hour in the group with diabetes or IGT: -7.20%; 95% CI, -12.11% to -2.02%). In the REHAB study, similarly, increases in PM2.5 concen- trations lagged 4 to 6 hours-though not AMP or BC con- centrations at any lag hour-were associated with -2.5%-3.5% decreases in RMSSD (e.g., PM2.5 lagged 5 hours: -3.49%; 95% CI, -6.13% to -0.84%). We did not find consistent evidence of any pollutant effects on T-wave complexity in 1-hour recordings. For 5-minute record- ings, there was no consistent evidence of UFP effects on SDNN, RMSSD, or T-wave complexity at any 5-minute interval within 60 minutes. We further concluded that these replicated hourly effects of UFP and PM2.5 on short-term measures of SDNN and RMSSD generally did not differ between the groups in the studies (i.e., type 2 diabetes, pre-diabetes/IGT, post- infarction, and healthy subjects). Last, we found no con- sistent evidence of effects of any pollutant on total anti- oxidant capacity and no consistent evidence of modification of our PM2.5-outcome associations by any of the potential effect modifiers. ONCLUSIONS: Increased UFP concentrations were associated with decreased SDNN in both of the panel studies and one of the two controlled-exposure studies. We also found that decreased SDNN was associated with both increased PM2.5 and AMP concentrations in the previous 6 hours in the panel studies and that decreased RMSSD was associ- ated with increased PM2.5 concentrations in the previous 6 hours in the panel studies. We therefore concluded that the research questions were replicated. Our findings suggest that both UFPs and PM2.5 are associated with autonomic dysfunction within hours of exposure, which may in part. explain the previously reported risk of acute cardiovascular events associated with increased PM in the previous few hours. Despite the heterogeneity of the study populations,and protocols, our findings provided consistent evidence for the induction of rapid pathophysiological responses by UFPs and PM2.5- The absence of consistent associations between UFPs, PM2.5, and these outcomes when examining shorter time intervals indicates that the 5- to 60-minute responses may be less pronounced than the responses occurring within hours. However, the findings from the 5-minute intervals may have been affected by the variety of proto- cols and conditions from study to study as well as by the potential effects of underlying diseases (e.g., healthy indi- viduals versus individuals with diabetes or a recent cor- onary artery. event), physical activity, circadian rhythms, stress, and/or medications.

Macrocyclic Oligoesters Incorporating a Cyclotetrasiloxane Ring.

Macrocyclic oligoester structures based on a cyclotetrasiloxane core consisting of tricyclic (60+ atoms) and pentacycylic (130+ atoms) species were identified as the major components of a lipase-mediated transesterification reaction. Moderately hydrophobic solvents with log P values in the range of 2-3 were more suitable than those at lower or higher log P values. Temperature had little effect on total conversion and yield of the oligoester macrocycles, except when a reaction temperature of 100 °C was employed. At this temperature, the amount of the smaller macrocycle was greatly increased, but at the expense of the larger oligoester. For immobilized lipase B from Candida antarctica (N435), longer chain length esters and diols were more conducive to the synthesis of the macrocycles. Langmuir isotherms indicated that monolayers subjected to multiple compression/expansion cycles exhibited a reversible collapse mechanism different from that expected for linear polysiloxanes.

Cardiovascular effects of ozone in healthy subjects with and without deletion of glutathione-S-transferase M1.

CONTEXT: Exposure to ozone has acute respiratory effects, but few human clinical studies have evaluated cardiovascular effects. OBJECTIVE: We hypothesized that ozone exposure alters pulmonary and systemic vascular function, and cardiac function, with more pronounced effects in subjects with impaired antioxidant defense from deletion of the glutathione-S-transferase M1 gene (GSTM1 null). METHODS: Twenty-four young, healthy never-smoker subjects (12 GSTM1 null) inhaled filtered air, 100 ppb ozone and 200 ppb ozone for 3 h, with intermittent exercise, in a double-blind, randomized, crossover fashion. Exposures were separated by at least 2 weeks. Vital signs, spirometry, arterial and venous blood nitrite levels, impedance cardiography, peripheral arterial tonometry, estimation of pulmonary capillary blood volume (Vc), and blood microparticles and platelet activation were measured at baseline and during 4 h after each exposure. RESULTS: Ozone inhalation decreased lung function immediately after exposure (mean ± standard error change in FEV1, air: -0.03 ± 0.04 L; 200 ppb ozone: -0.30 ± 0.07 L; p < 0.001). The immediate post-exposure increase in blood pressure, caused by the final 15-min exercise period, was blunted by 200 ppb ozone exposure (mean ± standard error change for air: 16.7 ± 2.6 mmHg; 100 ppb ozone: 14.5 ± 2.4 mmHg; 200 ppb ozone: 8.5 ± 2.5 mmHg; p = 0.02). We found no consistent effects of ozone on any other measure of cardiac or vascular function. All results were independent of the GSTM1 genotype. CONCLUSIONS: We did not find convincing evidence for early acute adverse cardiovascular consequences of ozone exposure in young healthy adults. The ozone-associated blunting of the blood pressure response to exercise is of unclear clinical significance.