Multicenter Ozone Study in oldEr Subjects (MOSES): Part 1. Effects of Exposure to Low Concentrations of Ozone on Respiratory and Cardiovascular Outcomes.

INTRODUCTION: Exposure to air pollution is a well-established risk factor for cardiovascular morbidity and mortality. Most of the evidence supporting an association between air pollution and adverse cardiovascular effects involves exposure to particulate matter (PM). To date, little attention has been paid to acute cardiovascular responses to ozone, in part due to the notion that ozone causes primarily local effects on lung function, which are the basis for the current ozone National Ambient Air Quality Standards (NAAQS). There is evidence from a few epidemiological studies of adverse health effects of chronic exposure to ambient ozone, including increased risk of mortality from cardiovascular disease. However, in contrast to the well-established association between ambient ozone and various nonfatal adverse respiratory effects, the observational evidence for impacts of acute (previous few days) increases in ambient ozone levels on total cardiovascular mortality and morbidity is mixed.Ozone is a prototypic oxidant gas that reacts with constituents of the respiratory tract lining fluid to generate reactive oxygen species (ROS) that can overwhelm antioxidant defenses and cause local oxidative stress. Pathways by which ozone could cause cardiovascular dysfunction include alterations in autonomic balance, systemic inflammation, and oxidative stress. These initial responses could lead ultimately to arrhythmias, endothelial dysfunction, acute arterial vasoconstriction, and procoagulant activity. Individuals with impaired antioxidant defenses, such as those with the null variant of glutathione S-transferase mu 1 (GSTM1), may be at increased risk for acute health effects.The Multicenter Ozone Study in oldEr Subjects (MOSES) was a controlled human exposure study designed to evaluate whether short-term exposure of older, healthy individuals to ambient levels of ozone induces acute cardiovascular responses. The study was designed to test the a priori hypothesis that short-term exposure to ambient levels of ozone would induce acute cardiovascular responses through the following mechanisms: autonomic imbalance, systemic inflammation, and development of a prothrombotic vascular state. We also postulated a priori the confirmatory hypothesis that exposure to ozone would induce airway inflammation, lung injury, and lung function decrements. Finally, we postulated the secondary hypotheses that ozone-induced acute cardiovascular responses would be associated with: (a) increased systemic oxidative stress and lung effects, and (b) the GSTM1-null genotype. METHODS: The study was conducted at three clinical centers with a separate Data Coordinating and Analysis Center (DCAC) using a common protocol. All procedures were approved by the institutional review boards (IRBs) of the participating centers. Healthy volunteers 55 to 70 years of age were recruited. Consented participants who successfully completed the screening and training sessions were enrolled in the study. All three clinical centers adhered to common standard operating procedures (SOPs) and used common tracking and data forms. Each subject was scheduled to participate in a total of 11 visits: screening visit, training visit, and three sets of exposure visits, each consisting of the pre-exposure day, the exposure day, and the post-exposure day. The subjects spent the night in a nearby hotel the night of the pre-exposure day.On exposure days, the subjects were exposed for three hours in random order to 0 ppb ozone (clean air), 70 ppb ozone, and 120 ppm ozone, alternating 15 minutes of moderate exercise with 15 minutes of rest. A suite of cardiovascular and pulmonary endpoints was measured on the day before, the day of, and up to 22 hours after, each exposure. The endpoints included: (1) electrocardiographic changes (continuous Holter monitoring: heart rate variability [HRV], repolarization, and arrhythmia); (2) markers of inflammation and oxidative stress (C-reactive protein [CRP], interleukin-6 [IL-6], 8-isoprostane, nitrotyrosine, and P-selectin); (3) vascular function measures (blood pressure [BP], flow-mediated dilatation [FMD] of the brachial artery, and endothelin-1 [ET-1]; (4) venous blood markers of platelet activation, thrombosis, and microparticle-associated tissue factor activity (MP-TFA); (5) pulmonary function (spirometry); (6) markers of airway epithelial cell injury (increases in plasma club cell protein 16 [CC16] and sputum total protein); and (7) markers of lung inflammation in sputum (polymorphonuclear leukocytes [PMN], IL-6, interleukin-8 [IL-8], and tumor necrosis factor-alpha [TNF-α]). Sputum was collected only at 22 hours after exposure.The analyses of the continuous electrocardiographic monitoring, the brachial artery ultrasound (BAU) images, and the blood and sputum samples were carried out by core laboratories. The results of all analyses were submitted directly to the DCAC.The variables analyzed in the statistical models were represented as changes from pre-exposure to post-exposure (post-exposure minus pre-exposure). Mixed-effect linear models were used to evaluate the impact of exposure to ozone on the prespecified primary and secondary continuous outcomes. Site and time (when multiple measurements were taken) were controlled for in the models. Three separate interaction models were constructed for each outcome: ozone concentration by subject sex; ozone concentration by subject age; and ozone concentration by subject GSTM1 status (null or sufficient). Because of the issue of multiple comparisons, the statistical significance threshold was set a priori at P < 0.01. RESULTS: Subject recruitment started in June 2012, and the first subject was randomized on July 25, 2012. Subject recruitment ended on December 31, 2014, and testing of all subjects was completed by April 30, 2015. A total of 87 subjects completed all three exposures. The mean age was 59.9 ± 4.5 years, 60% of the subjects were female, 88% were white, and 57% were GSTM1 null. Mean baseline body mass index (BMI), BP, cholesterol (total and low-density lipoprotein), and lung function were all within the normal range.We found no significant effects of ozone exposure on any of the primary or secondary endpoints for autonomic function, repolarization, ST segment change, or arrhythmia. Ozone exposure also did not cause significant changes in the primary endpoints for systemic inflammation (CRP) and vascular function (systolic blood pressure [SBP] and FMD) or secondary endpoints for systemic inflammation and oxidative stress (IL-6, P-selectin, and 8-isoprostane). Ozone did cause changes in two secondary endpoints: a significant increase in plasma ET-1 (P = 0.008) and a marginally significant decrease in nitrotyrosine (P = 0.017). Lastly, ozone exposure did not affect the primary prothrombotic endpoints (MP-TFA and monocyte-platelet conjugate count) or any secondary markers of prothrombotic vascular status (platelet activation, circulating microparticles [MPs], von Willebrand factor [vWF], or fibrinogen.).Although our hypothesis focused on possible acute cardiovascular effects of exposure to low levels of ozone, we recognized that the initial effects of inhaled ozone involve the lower airways. Therefore, we looked for: (a) changes in lung function, which are known to occur during exposure to ozone and are maximal at the end of exposure; and (b) markers of airway injury and inflammation. We found an increase in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) after exposure to 0 ppb ozone, likely due to the effects of exercise. The FEV1 increased significantly 15 minutes after 0 ppb exposure (85 mL; 95% confidence interval [CI], 64 to 106; P < 0.001), and remained significantly increased from pre-exposure at 22 hours (45 mL; 95% CI, 26 to 64; P < 0.001). The increase in FVC followed a similar pattern. The increase in FEV1 and FVC were attenuated in a dose-response manner by exposure to 70 and 120 ppb ozone. We also observed a significant ozone-induced increase in the percentage of sputum PMN 22 hours after exposure at 120 ppb compared to 0 ppb exposure (P = 0.003). Plasma CC16 also increased significantly after exposure to 120 ppb (P < 0.001). Sputum IL-6, IL-8, and TNF-α concentrations were not significantly different after ozone exposure. We found no significant interactions with sex, age, or GSTM1 status regarding the effect of ozone on lung function, percentage of sputum PMN, or plasma CC16. CONCLUSIONS: In this multicenter clinical study of older healthy subjects, ozone exposure caused concentration-related reductions in lung function and presented evidence for airway inflammation and injury. However, there was no convincing evidence for effects on cardiovascular function. Blood levels of the potent vasoconstrictor, ET-1, increased with ozone exposure (with marginal statistical significance), but there were no effects on BP, FMD, or other markers of vascular function. Blood levels of nitrotyrosine decreased with ozone exposure, the opposite of our hypothesis. Our study does not support acute cardiovascular effects of low-level ozone exposure in healthy older subjects. Inclusion of only healthy older individuals is a major limitation, which may affect the generalizability of our findings. We cannot exclude the possibility of effects with higher ozone exposure concentrations or more prolonged exposure, or the possibility that subjects with underlying vascular disease, such as hypertension or diabetes, would show effects under these conditions.

Socioeconomic status and lifestyle behaviours in cancer survivors: smoking and physical activity.

PURPOSE: Smoking cessation and increased physical activity (pa) have been linked to better outcomes in cancer survivors. We assessed whether socioeconomic factors influence changes in those behaviours after a cancer diagnosis. METHODS: As part of a cross-sectional study, a diverse group of cancer survivors at the Princess Margaret Cancer Centre (Toronto, ON), completed a questionnaire about past and current lifestyle behaviours and perceptions about the importance of those behaviours with respect to their health. The influence of socioeconomic indicators on smoking status and physical inactivity at 1 year before and after diagnosis were assessed using multivariable logistic regression with adjustment for clinico-demographic factors. RESULTS: Of 1222 participants, 1192 completed the smoking component. Of those respondents, 15% smoked before diagnosis, and 43% of those smokers continued to smoke after. The proportion of survivors who continued to smoke increased with lower education level (p = 0.03). Of the 1106 participants answering pa questions, 39% reported being physically inactive before diagnosis, of whom 82% remained inactive afterward. Survivors with a lower education level were most likely to remain inactive after diagnosis (p = 0.003). Lower education level, household income, and occupation were associated with the perception that pa had no effect or could worsen fatigue and quality of life (p ≤ 0.0001). CONCLUSIONS: In cancer survivors, education level was a major modifier of smoking and pa behaviours. Lower socioeconomic status was associated with incorrect perceptions about pa. Targeting at-risk survivors by education level should be evaluated as a strategy in cancer survivorship programs.

Patient preference: a comparison of electronic patient-completed questionnaires with paper among cancer patients.

In this study, we compared cancer patients preference for computerised (tablet/web-based) surveys versus paper. We also assessed whether the understanding of a cancer-related topic, pharmacogenomics is affected by the survey format, and examined differences in demographic and medical characteristics which may affect patient preference and understanding. Three hundred and four cancer patients completed a tablet-administered survey and another 153 patients completed a paper-based survey. Patients who participated in the tablet survey were questioned regarding their preference for survey format administration (paper, tablet and web-based). Understanding was assessed with a 'direct' method, by asking patients to assess their understanding of genetic testing, and with a 'composite' score. Patients preferred administration with tablet (71%) compared with web-based (12%) and paper (17%). Patients <65 years old, non-Caucasians and white-collar professionals significantly preferred the computerised format following multivariate analysis. There was no significant difference in understanding between the paper and tablet survey with direct questioning or composite score. Age (<65 years) and white-collar professionals were associated with increased understanding (both P = 0.03). There was no significant difference in understanding between the tablet and print survey in a multivariate analysis. Patients overwhelmingly preferred computerised surveys and understanding of pharmacogenomics was not affected by survey format.

Rac1 is required for Prkar1a-mediated Nf2 suppression in Schwann cell tumors.

Schwannomas are peripheral nerve sheath tumors that often occur in the setting of an inherited tumor predisposition syndrome, including neurofibromatosis types 1 (NF1) and 2 (NF2), familial schwannomatosis and Carney complex. Loss of the NF2 tumor suppressor (encoding NF2, or Merlin) is associated with upregulation of the Rac1 small GTPase, which is thought to have a key role in mediating tumor formation. In prior studies, we generated a mouse model of schwannomas by performing tissue-specific knockout (KO) of the Carney complex gene Prkar1a, which encodes the type 1A regulatory subunit of protein kinase A. These tumors exhibited down-regulation of Nf2 protein and an increase in activated Rac1. To assess the requirement for Rac1 in schwannoma formation, we generated a double KO (DKO) of Prkar1a and Rac1 in Schwann cells and monitored tumor formation. Loss of Rac1 reduced tumor formation by reducing proliferation and enhancing apoptosis. Surprisingly, the reduction of tumor formation was accompanied by re-expression of the Nf2 protein. Furthermore, activated Rac1 was able to downregulate Nf2 in vitro in a Pak-dependent manner. These in vivo data indicate that activation of Rac1 is responsible for suppression of Nf2 protein production; deficiency of Nf2 in Schwann cells leads to loss of cellular growth control and tumor formation. Further, PKA activation through mutation in Prkar1a is sufficient to initiate Rac1 signaling, with subsequent reduction of Nf2 and schwannomagenesis. Although in vitro evidence has shown that loss of Nf2 activates Rac1, our data indicate that signaling between Nf2 and Rac1 occurs in a bidirectional fashion, and these interactions are modulated by PKA.

Effects of modified electrical stimulation-induced leg cycle ergometer training for individuals with spinal cord injury.

Computer-controlled electrical stimulation (ES)-induced leg cycle ergometer (ES-LCE) exercise can be beneficial for individuals with spinal cord injury (SCI), but exercise performance is often insufficient for eliciting continuous gains in cardiopulmonary training adaptations. The first purpose of this study was to determine whether a modified ES-LCE improved exercise performance and responses compared with the standard ES-LCE. Modifications to the ES-LCE included increased ES current amplitude (140-300 mA), added shank muscle activation, and increased ES firing angle ranges (+55 degrees). The second purpose was to evaluate the effects of a 6-week interval training program (ITP) with this modified methodology on ES-LCE exercise performance, peak metabolic and cardiorespiratory responses, and muscle strength in experienced and novice riders. No significantly different peak values for power output and stroke volume were found for the two systems, but the modified ES-LCE elicited significantly higher peak values for oxygen uptake (+22%), carbon dioxide production (+51%), pulmonary ventilation (+37%), cardiac output (+32%), heart rate (+19%), and blood lactate concentration (+50%). Power output, metabolic rate, and lower-limb muscle strength increased significantly following training. This study showed that an ITP with the modified ES-LCE can elicit marked improvements in ES-LCE performance (peak power output), peak metabolic and cardiorespiratory responses, and muscle strength in men with SCI, even in those subjects whose performance has plateaued during training on the standard ES-LCE.

The Self-Injury Questionnaire: evaluation of the psychometric properties in a clinical population.

This paper presents the findings, from a clinical study, on the reliability and validity of a new measure for intentions in self-harm behaviour, the Self-Injury Questionnaire (SIQ). Eighty-three patients, who had presented to an emergency department with an episode of self-harm/suicidal behaviour, were given the SIQ as part of a battery of measures to evaluate differentiation in self-harm intentions based upon a history of childhood physical and/or sexual abuse. The internal consistency for the total scale was strong (alpha = 0.83). Construct validity demonstrated significant correlations with standardized measures. A principle component analysis of responses yielded a five-factor solution with 'affect regulation' items loading on the first factor. Cronbach's alphas were adequate for each subscale (alpha = 0.72-0.77). These preliminary findings indicate that the SIQ is a valid and reliable measure for research in an acute self-harming population.

Dementia caregiving: the role of the primary care physician.

BACKGROUND: Family and friends play an important role in caring for individuals with dementia living in the community. In preparation for the Canadian Consensus Conference on Dementia held in Montreal, Canada in February 1998, the subject of dementia caregiving was reviewed in order to provide primary care physicians with some guidelines for their practice. The review was updated in June 2000 in preparation for this article. METHOD: Pertinent English-language publications and resources from the Alzheimer Society of Canada were reviewed from 1985 onwards. Findings related to the consequences of caregiving, services for caregivers and recommendations regarding the role of the primary care physician were reviewed. FINDINGS: Dementia caregivers experience many positive and negative consequences of caregiving. Some comprehensive services for caregivers have been shown to delay institutionalization and reduce negative consequences of caregiving. The primary care physician has a role to play in working with families and should address the following issues: 1) education about dementia; 2) psychological support for caregivers; 3) assistance mobilizing caregiver social support networks. CONCLUSION: Primary care physicians have an important role to play in acknowledging and supporting the caregiving provided by family and friends to individuals with dementia.

Successful treatment of severe atenolol overdose with calcium chloride.

Atenolol, a selective beta(1)-adrenergic antagonist, is commonly used to treat hypertension, ischemic heart disease and cardiac dysrhythmias. Few cases of severe atenolol intoxication have been described, and only one of these reports discussed the use of calcium chloride as a treatment. We present a case of atenolol overdose associated with shock and first-degree heart block, in which administration of calcium chloride led to dramatic improvement after failure of conventional treatment. In addition, we discuss the pharmacokinetics, toxicology and management of beta-blocker overdose, focusing on the possible role of calcium chloride.

Effects of an abilities-focused program of morning care on residents who have dementia and on caregivers.

OBJECTIVE: To conduct a controlled investigation to examine the effects of an abilities-focused program of morning care on the interaction behaviors and functioning of residents with dementia and on caregivers' interaction behaviors and perceptions of caregiving. DESIGN: A quasi-experimental, repeated measures design. SETTING: The study was conducted on four, nursing-home-level cognitive supports units in a geriatric care center. One of the units was randomly selected as the experimental unit; the other three served as controls. PARTICIPANTS: The final sample consisted of 40 residents (20 each in the experimental and three control groups) and 44 caregivers (16 on the experimental unit and 28 on the three control units). INTERVENTION: An educational program on delivering abilities-focused morning care, designed by the authors, was provided to caregivers on the experimental unit. MEASUREMENTS: Measures were taken at baseline and at 3 and 6 months postintervention with regard to residents' interaction behaviors, level of agitation, and level of function and to caregivers' interaction behaviors, perceived ease of caregiving, and level of stress. RESULTS: Repeated measures analysis of variance (RM-ANOVA) was used to compare the experimental and control groups in regard to changes in the outcomes over time. Results indicated that the abilities-focused program had statistically significant effects on (a) residents' personal attending and calm/functional behaviors, level of agitation, and levels of overall and social function, and (b) caregivers' verbal relevance and personal attending, relaxed, and social/flexible behaviors. CONCLUSIONS: The evidence suggests that both residents and caregivers benefit from morning care that is oriented toward the abilities of people with dementia.

The effects of perceived and preferred control on nurses' job satisfaction in long term care environments.

The purpose of this study is to explore how perceived and preferred clinical control and organizational control are associated with nurses' job satisfaction in long-term care settings. A sample of 113 nurses who work in long-term care units of a community hospital or a teaching hospital completed a questionnaire that included a job satisfaction scale, an organizational control scale, and a set of vignettes specific to long-term care developed to examine clinical control. There was a positive relationship between perceived organizational control and job satisfaction and a negative relationship between preferred clinical control and job satisfaction. Furthermore, as predicted, congruence between perceived and preferred control in the clinical and in the organizational domains were related to job satisfaction. Counter to prediction, organizational control explained more variance in job satisfaction than clinical control. The challenges of conceptualizing clinical control and its measurement are discussed.

Hypothesized foetal and early life influences on adult heart disease mortality: an ecological analysis of data for the Republic of Ireland.

Spatial disparities in the prevalence of heart disease are frequently explained in terms of adult lifestyle factors (e.g. diet, smoking, alcohol consumption, stress, exercise, etc.). However, research in recent years suggests an alternative explanation: namely, that the risk of heart disease in adult life may be influenced either by living conditions shortly after birth or by foetal development before birth. This paper outlines the evolution of this line of thought, and tests whether these hypotheses are consistent with ecological data for deaths from ischaemic heart disease between 1981 and 1990 and infant deaths between 1916 and 1935 in the Republic of Ireland. Support for the hypotheses is found to be ambiguous. Possible interpretations of these findings are discussed, paying particular attention to the anomalous nature of infant mortality in Ireland between 1916 and 1935.

Differences in conformational dynamics of ribonucleases A and S as observed by infrared spectroscopy and hydrogen-deuterium exchange.

Differences in conformational dynamics of bovine pancreatic RNase A and RNase S have been investigated using hydrogen-deuterium (H-D) exchange in conjunction with Fourier transform infrared spectroscopy. Deuteration-induced spectral changes in the amide I and II regions were monitored as a function of time. Second-derivative analysis revealed similar amide I spectral patterns for both proteins in H2O as well as fully deuterated in D2O. However, the rate of amide proton exchange of RNase S is much faster than that of RNase A at 25 degrees C as determined by changes in the intensity ratio of amide II/amide I bands and frequency red-shifts of amide I components. The frequency red-shifts of the amide I components ascribed to beta-sheet, alpha-helix, and beta-turns are continuous as a function of time, indicating that both proteins are too small to contain isolated secondary structural groups containing only exchanged or unexchanged amide protons in the partially deuterated intermediate states. Despite the dramatic difference in H-D exchange rate, the patterns of spectral changes in the conformation-sensitive amide I regions of RNase A and RNase S are very similar throughout the course of deuteration, indicating a similar pathway of amide proton exchange in both proteins.