Effects of prescribed aerobic exercise volume on physical activity and sedentary time in postmenopausal women: a randomized controlled trial.

BACKGROUND: Physical activity has emerged as an important lifestyle factor for primary prevention of numerous diseases, including postmenopausal breast cancer. No study to date has assessed the acute and long-term effects of year-long aerobic exercise programs differing in prescribed exercise volume on physical activity and sedentary time in postmenopausal women. Therefore, we aimed to examine the effects of two moderate-vigorous intensity exercise doses on total, light and moderate-vigorous intensity physical activity times, and sedentary time in postmenopausal women during the year-long intervention and one year later. METHODS: The Breast Cancer and Exercise Trial in Alberta (BETA) was a two-center, two-arm, 12-month randomized controlled trial that included 400 previously inactive postmenopausal women randomized to either 150 (MODERATE) or 300 (HIGH) minutes/week of aerobic exercise. Physical activity and sedentary time were assessed at baseline, 6- (intervention mid-point), 12- (prior to end of intervention) and 24-months (follow-up) with waist-mounted accelerometers (Actigraph GTX3®). Self-reported activity and sedentary time at baseline, 12- and 24-months was also assessed (Past Year Total Physical Activity Questionnaire and SIT-Q). Intention-to-treat analyses were conducted using linear mixed models and adjusted for baseline variables. RESULTS: Both physical activity interventions led to increases in objective and subjective measures of total and moderate-vigorous intensity/recreational physical activity time, coupled with decreases in sedentary time, at 6- and 12-months compared to baseline. Additionally, greater increases in accelerometry-derived total physical activity time at 6- and 12-months, and self-reported recreational activity time at 12-months, compared to baseline were noted in the HIGH versus MODERATE groups. Decreases in total, light and moderate-vigorous intensity physical activity time, and an increase in sedentary time, in both groups were noted at 24-months compared to 12-months. A decrease in light intensity physical activity time in both groups at 24-months compared to baseline was also noted. CONCLUSION: These findings have important health implications, suggesting that total physical activity time can be increased with greater volumes of prescribed exercise, but that additional support and resources could be used to promote the maintenance of these high levels of aerobic exercise participation following study completion. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01435005 (BETA Trial). Registred September 15th 2011 (retrospectively registered).

CHADS2 Score Predicts Postoperative Atrial Fibrillation in Patients Undergoing Elective Pulmonary Lobectomy.

BACKGROUND: Postoperative atrial fibrillation (PAF) affects 12% to 17% of patients undergoing lobectomy and is associated with increased morbidity. CHADS2 (congestive heart failure history, hypertension history, age ≥75 years, diabetes mellitus history, and stroke or transient ischemic attack symptoms previously) is used to predict stroke risk in patients with existing AF. It also has been shown also to predict new-onset PAF. Our objective was to determine whether CHADS2 can predict PAF in patients undergoing lobectomy. METHODS: A prospective thoracic surgery clinical database was reviewed to identify adult patients, without prior AF, who underwent elective lobectomy between January 1, 2005, and June 30, 2014. Nonelective and combined operations were excluded. Two groups (PAF and no PAF) were analyzed. RESULTS: PAF developed in 113 of 933 patients with overall incidence of 12% for the entire group. Age (≥75 years) and coronary artery disease were the only significant preoperative characteristics between the two groups. Intensive care unit readmission, new neurologic events, length of stay, 30-day survival, and hospital mortality were significantly higher in the PAF group as were mean CHADS2 scores (1.4 and 1.1 respectively, p = 0.0014). Incidence of PAF ranged from 7.9% in low-risk groups to 11% in moderate-risk and 17.7% in high-risk groups, which was also significant, p < 0.0002. Similar findings were noted for CHA2DS2-VASc (age in years, sex, history of congestive heart failure, history of hypertension, history of stroke/transient ischemic symptoms/thromboembolic events, history of vascular disease, history of diabetes mellitus). CONCLUSIONS: Although multiple risk factors for PAF have been described, no easily applicable clinical model exists. Observed rate of PAF was significantly lower then the previously described 12% when CHADS2 was 0. CHADS2 can predict PAF in patients undergoing elective lobectomy and can identify patients to selectively institute prophylactic measures in patients at the greatest risk, such as patients with score of 2 or greater. Further validation of this model is warranted in a larger group.

Video-Assisted Thoracic Surgery in Patients With Previous Sternotomy and Cardiac Surgery.

OBJECTIVE: Although video-assisted thoracic surgery (VATS) lobectomy has become a standard approach for early-stage 1 lung cancer, concerns exist regarding potential damage to the heart or bypass grafts when VATS is performed after cardiac surgery via median sternotomy. We could find only case reports regarding VATS lobectomy after sternotomy for cardiac surgery. Therefore, we reviewed our series of patients who underwent VATS anatomic resections after sternotomy for cardiac surgery. METHODS: Between 1996 and 2010, there were 87 patients who underwent 88 pulmonary resections after sternotomy for coronary artery bypass grafting (64), valve replacement or repair (12), coronary artery bypass graft and valve replacement (6), and transplant (5). There were 10 women (11.5%) and 77 men (88.5%) with a mean age of 76.2 years. Diagnoses included lung cancer (83), pulmonary metastases (4), and benign disease (1). RESULTS: Dense adhesions between the lung and the mediastinum sometimes occur after cardiac surgery. Compared with the total series of 2684 VATS lobectomies, operations after sternotomy are associated with greater mortality (12, 0.4% vs 5, 5.7%), myocardial infarction (13, 0.5% vs 2, 2.3%), transfusion (45, 1.7% vs 12, 13.6), conversion to thoracotomy (188, 7% vs 14, 15.9%). Injury occurred to the left main pulmonary artery (1, 1%) and internal mammary artery graft (1, 1%). There were no intraoperative deaths. CONCLUSIONS: Previous sternotomy for cardiac surgery does increase the risk for VATS lobectomy. Conversion to thoracotomy should be considered if dense adhesions are found. Techniques to reduce the risk for the heart are discussed.

Validating the use of short interfering RNA as a novel technique for cell-specific target gene knockdown in lung ischemia-reperfusion injury.

OBJECTIVE: Short interfering RNA is an effective method for target gene knockdown. However, concerns surround the design, administration, efficacy, specificity, and immunostimulatory potential. Although uptake by alveolar macrophages has been demonstrated, studies have not examined its use in lung ischemia-reperfusion injury. We describe the validation of short interference RNA as a novel technique for cell-specific target gene knockdown in our model of lung ischemia-reperfusion injury. METHODS: Dose-response experiments were performed, and 3 distinct sequences of toll-like receptor-4, toll-like receptor-2, and myeloid differentiation factor-88 short interference RNA were tested for efficacy of knockdown. Saline, lipid vector, and noncoding short interference RNA controls were used. Similar experiments were performed in primary cultures of resident pulmonary cells. Target protein knockdown was assessed by Western blot. Rat serum and cell culture media were assessed for interferon and cytokine production. Biotin labeling was used to assess short interference RNA uptake. RESULTS: Target protein expression was significantly reduced using short interference RNA. However, toll-like receptor-4 knockdown was isolated to alveolar macrophages, and biotin labeling confirmed toll-like receptor-4 short interference RNA localization to alveolar macrophages. There was significant knockdown of toll-like receptor-4 expression in cultured cells treated with toll-like receptor-4 short interference RNA. There was no significant change in interferon production after short interference RNA treatment. There was effective target protein knockdown with each sequence used. CONCLUSIONS: Short interference RNA is a valid method for achieving target protein knockdown in alveolar macrophages and is an important tool in the evaluation of its role in the development of lung ischemia-reperfusion injury.

Video-Assisted Thoracic Surgery After Median Sternotomy for Cardiac Surgery.

Video-assisted thoracic surgery (VATS) lobectomy has become a standard approach for early stage 1 lung cancer. However, concerns still remain regarding certain clinical situations, such as potential damage to the heart or bypass grafts when VATS is performed after median sternotomy for cardiac surgery. In this article, techniques are described to minimize risk to an internal mammary artery graft during a VATS anatomic pulmonary resection in this group of patients. The article reviews data on VATS after median sternotomy for cardiac surgery and describes techniques to prevent, treat, and mitigate problems in this group of patients. Management of intraoperative crises is also discussed.

Differential toll-like receptor activation in lung ischemia reperfusion injury.

OBJECTIVE: The requirement for toll-like receptors (TLRs) in lung ischemia reperfusion injury (LIRI) has been demonstrated but not fully characterized. Previously, we reported that TLR-4 is required by alveolar macrophages but not pulmonary endothelial or epithelial cells for development of LIRI. Additionally, we demonstrated differential patterns of mitogen-activated protein kinase (MAPK) activation and cytokine release in these cell types during LIRI. Here, we sought to determine whether these differences in activation responses are related to cell-specific TLR activation requirements. METHODS: Primary cultures of alveolar macrophages, pulmonary endothelial, and immortalized epithelial cells were pretreated with TLR-2 or TLR-4 short interference RNA (ribonucleic acid) before hypoxia and reoxygenation. Cell lysates and media were analyzed for receptor knockdown, MAPK activation, and cytokine production. Rats were pretreated with TLR-2 or TLR-4 short interference RNA before lung ischemia reperfusion and changes in lung vascular permeability were assessed. RESULTS: Knockdown of TLR-2 in alveolar macrophages did not affect MAPK phosphorylation or cytokine secretion. Conversely, TLR-2 knockdown in pulmonary endothelial and epithelial cells demonstrated significant reductions in extracellular signal-regulated kinase 1/2 activation and cytokine secretion. The lung permeability index in LIRI was decreased by TLR-4 but not TLR-2. CONCLUSIONS: Differential TLR signaling and MAPK activation in response to LIRI seem to be cell specific. Short interference RNA provides an outstanding tool for examination of the underlying mechanism.

Role of toll-like receptor-4 in lung ischemia-reperfusion injury.

BACKGROUND: Toll-like receptor-4 has been implicated in modulating ischemia-reperfusion injury in cardiac, hepatic, renal, and cerebral models. However, its role in lung ischemia-reperfusion injury is unknown. We hypothesize that toll-like receptor-4 has a key role in initiating the inflammatory cascade in lung ischemia-reperfusion injury. METHODS: We used toll-like receptor-4 specific short interference RNA to achieve toll-like receptor-4 knockdown in rats prior to undergoing ischemia and reperfusion. Lungs were explanted and studied for protein expression and markers of lung injury. Additional animals were evaluated for cellular uptake of toll-like receptor-4 short interference RNA. Toll-like receptor-4 short interference RNA localized to the alveolar macrophage. RESULTS: In animals pretreated with toll-like receptor-4 short interference RNA, toll-like receptor-4 expression and mitogen-activated protein kinase phosphorylation were suppressed. Markers of lung injury including permeability index, myeloperoxidase content, and bronchoalveolar lavage inflammatory cell counts were all reduced with toll-like receptor-4 knockdown. CONCLUSIONS: Toll-like receptor-4 is critical in the development of lung ischemia-reperfusion injury and its activation in the alveolar macrophage may be the initiating step.

Functional roles of tumor necrosis factor-alpha and interleukin 1-Beta in hypoxia and reoxygenation.

BACKGROUND: Intercellular signaling plays an important role in the development of lung ischemia-reperfusion injury. However, the role of specific mediators remains poorly characterized. Alveolar macrophages (AM) produce soluble mediators early in reperfusion, which modulate the responses of endothelial and epithelial cells to oxidative stress. There is a burst of proinflammatory cytokine production in a variety of cells; however, interleukin 1-beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) localize to the AM. We hypothesized that these cytokines account for the costimulatory effects that AM exert on endothelial and epithelial cells. METHODS: Activated AM media was placed on cultured rat type 2 pneumocytes and pulmonary artery endothelial cells, which were then subjected to hypoxia and reoxygenation. To assess the contributions of IL-1ß and TNF-α, the cells were treated with control media or media that had been depleted of IL-1ß or TNF-α. To deplete specific cytokines, activated media was passed through a column with immobilized IL-1ß or TNF-α antibodies. Nuclear translocation of transcription factors, mitogen-activated protein kinase activation, and cytokine and chemokine production were assessed. RESULTS: Depletion of IL-1ß or TNF-α effectively eliminated the ability of AM media to enhance the response of endothelial and epithelial cells to oxidative stress. There were significant reductions in monocyte chemotactic protein 1 and cytokine-induced neutrophil chemoattractant (CINC) production (p < 0.05) at 4 hours of reperfusion. Additionally there was decreased nuclear translocation of nuclear factor-kappa B, and extracellular signal-regulated kinase phosphorylation. CONCLUSIONS: Interleukin 1-beta and TNF-α are critical mediators in the intercellular communication pathways that allow the AM to enhance the response of surrounding cells to oxidative stress.

Synergistic protection in lung ischemia-reperfusion injury with calcineurin and thrombin inhibition.

BACKGROUND: Ischemia-reperfusion injury impairs lung transplant outcomes. The transcription factors, activator protein-1, and nuclear factor kappa B, are activated early in reperfusion and drive the development of injury. Thrombin inhibition with hirudin, and calcineurin inhibition with tacrolimus have independently been shown to ameliorate lung ischemia-reperfusion injury by reducing activator protein-1 and nuclear factor kappa B activation, respectively. However, high doses were required to achieve protection using individual agents, raising concerns about potential toxicities. We sought to determine if low-dose combination therapy reduced injury through synergistic inhibition of pretranscriptional signaling events. METHODS: Rats were pretreated with either intravenous hirudin or tacrolimus at low doses or high doses, or both at low doses, prior to undergoing left lung ischemia and reperfusion. Lungs were assessed for markers of lung injury, including bronchoalveolar lavage cytokine-chemokine content and transcription factor transactivation of activator protein-1 and nuclear factor kappa B. RESULTS: High-dose monotherapy with hirudin or tacrolimus reduced lung injury and transactivation of activator protein-1 and nuclear factor kappa B activation, respectively, whereas low-dose monotherapy with either agent did not alter transcription factor activation or lung injury compared with positive controls. Low-dose combination therapy was more protective than high-dose monotherapy with either drug, and correlated with a reduction in activation of both transcription factors and their associated cytokines. CONCLUSIONS: The significant decrease in lung injury severity and transcription factor activation with combined pathway inhibition suggests pretranscriptional signaling redundancy between the calcineurin and thrombin dependent pathways in lung reperfusion injury.

Lipopolysaccharide pre-conditioning is protective in lung ischemia-reperfusion injury.

BACKGROUND: The availability of suitable lung donors has remained a significant barrier to lung transplantation. The clinical relevance of an isolated positive Gram stain in potential donor lungs, which occurs in >80%, is unclear. Low doses of lipopolysaccharide (LPS) have been protective in several models of ischemia-reperfusion injury through a pre-conditioning response. We sought to demonstrate that low-dose LPS is protective against subsequent lung ischemia-reperfusion injury. METHODS: Pathogen-free Long-Evans rats were pre-treated with vehicle or LPS 24 hours before 90 minutes of ischemia and up to 4 hours of reperfusion. Lungs were assessed for vascular permeability, myeloperoxidase content, bronchoalveolar lavage inflammatory cell and cytokine/chemokine content, as well as nuclear translocation of nuclear factor kappaB (NFkappaB) and activator protein-1 (AP-1), and interleukin-1 receptor-associated kinase-1 (IRAK-1) and stress-activated protein kinase (SAPK) activation. RESULTS: Compared with positive controls, LPS pre-treatment resulted in reductions in vascular permeability (70%, p < 0.001), myeloperoxidase content (93%, p < 0.001), bronchoalveolar lavage inflammatory cells (91%, p < 0.001), and inflammatory cytokine/chemokine content (cytokine-induced neutrophil chemoattractant, 99%, p = 0.003; interleukin-1beta, 72%, p < 0.0001; tumor necrosis factor-alpha, 76%, p < 0.0001), NFkappaB (86%, p < 0.001) and AP-1 (97%, p < 0.001) nuclear translocation, and IRAK-1 (87%, p < 0.001) and SAPK (80%, p < 0.001) phosphorylation. CONCLUSIONS: Lipopolysaccharide pre-treatment reduced lung injury and inflammatory mediator production after subsequent exposure to ischemia-reperfusion. Understanding the clinical significance of lipopolysaccharide in donor lungs has the potential to expand and clarify donor inclusion criteria.

Alveolar macrophage secretory products effect type 2 pneumocytes undergoing hypoxia-reoxygenation.

BACKGROUND: Activation of the alveolar macrophage is centrally important to the development of lung ischemia reperfusion injury. Alveolar macrophages and type 2 pneumocytes secrete a variety of proinflammatory mediators in response to oxidative stress. The manner in which they interact and how the macrophage may influence pneumocyte responses in lung ischemia reperfusion injury is unknown. Utilizing an in vitro model of hypoxia and reoxygenation, we sought to determine if the proinflammatory response of type 2 pneumocytes to oxidative stress would be amplified by alveolar macrophage secretory products. METHODS: Cultured pneumocytes were exposed to control media or media from cultured macrophages exposed to hypoxia and reoxygenation. Pneumocytes were subsequently subjected to hypoxia and reoxygenation and assessed for both nuclear translocation of nuclear factor kappa B and inflammatory cytokine and chemokine secretion. To examine for any reciprocal interactions, we reversed the experiment, exposing macrophages to conditioned pneumocyte media. RESULTS: In the presence of media from stimulated macrophages, production of proinflammatory mediators by type 2 pneumocytes was dramatically enhanced. In contrast, exposure of the macrophage to conditioned pneumocyte media had an inhibitory effect on macrophage responses subsequently exposed to hypoxia and reoxygenation. CONCLUSIONS: The alveolar macrophage drives the development of lung reperfusion injury in part through amplification of the inflammatory response of type 2 pneumocytes subjected to hypoxia and reoxygenation.

Stress-activated protein kinase inhibition to ameliorate lung ischemia reperfusion injury.

OBJECTIVE: Inhibition of cytokines offers modest protection from injury in animal models of lung ischemia-reperfusion. Improved strategies would selectively inhibit the transcriptional activation response to oxidative stress. Mitogen-activated protein kinases (p38, c-jun N-terminal kinase, extracellular signal-regulated kinase) have been shown to be activated after oxidative stress and in animal models of acute inflammatory lung injury. We hypothesized that mitogen-activated protein kinase inhibition would block downstream transcriptional activation, providing robust protection from lung ischemia-reperfusion injury. METHODS: Experimental rats received inhibitors of p38, c-jun kinase, or extracellular signal-regulated kinase before in situ left lung ischemia-reperfusion. Immunohistochemistry localized cellular sites of mitogen-activated protein kinase activation. Several markers of lung injury were assessed. Enzyme-linked immunosorbent assay measured soluble cytokine and chemokine contents. Western blotting assessed mitogen-activated protein kinase phosphorylation. Electromobility shift assays measured transcription factor nuclear translocation. RESULTS: Immunohistochemistry localized p38 and c-jun kinase activations in positive controls to alveolar macrophages. Extracellular signal-regulated kinase was activated in endothelial and epithelial cells. Animals treated with p38 or c-jun kinase inhibitor demonstrated significant reductions in transcription factor activation and markers of lung injury. Extracellular signal-regulated kinase inhibition was not protective. Western blotting confirmed inhibitor specificity. CONCLUSION: Inhibition of p38 and c-jun kinase provided significant protection from injury. The alveolar macrophage appears to be the key coordinator of injury in response to oxidative stress. Therapeutically targeting specific cell population (macrophage) responses to oxidative stress has the potential benefit of reducing lung reperfusion injury severity while leaving host immune responses intact.

Alveolar macrophage secretory products augment the response of rat pulmonary artery endothelial cells to hypoxia and reoxygenation.

BACKGROUND: Endothelial cell activation is an important response to ischemia and reperfusion in a variety of vascular beds. Endothelial cells secrete a multitude of proinflammatory mediators and express adhesion molecules that promote leukocyte recruitment into injured tissues. Pulmonary artery endothelial cell response to lung ischemia-reperfusion injury does not appear robust enough to drive the development of lung injury independently. Rather, the alveolar macrophage is the key cell in the development of ischemia-reperfusion injury of the lung. Macrophages are known to be a rich source of inflammatory mediators, but the precise mechanism whereby they amplify injury is unknown. The aim of this study was to determine whether alveolar macrophage secretory products amplify the response of the endothelial cell using an in vitro model of lung reperfusion injury. METHODS: Macrophages were exposed to hypoxia and reoxygenation and the media collected. Cultured endothelial cells were then exposed to macrophage media and maintained at normoxia or subjected to hypoxia and reoxygenation. To assess any reciprocal effects of endothelial cell products on macrophage activation, macrophages were likewise exposed to activated endothelial cell media. RESULTS: Exposure of endothelial cells to activated alveolar macrophage media enhanced chemokine secretion in response to hypoxia and reoxygenation. In the reciprocal experiment, activated endothelial cell media increased the production of macrophage inflammatory protein 1alpha from macrophages. CONCLUSIONS: Alveolar macrophages drive the development of lung reperfusion injury, by enhancing the production of proinflammatory chemokines from endothelial cells, which impart a degree of positive feedback on alveolar macrophages.

Poly (ADP) ribose synthetase inhibition in alveolar macrophages undergoing hypoxia and reoxygenation.

BACKGROUND: Inhibition of the nuclear enzyme poly ribose synthetase (PARS) protects against in vivo lung ischemia reperfusion injury (LIRI). The effectiveness of intratracheal treatment suggests that PARS inhibition may primarily modulate alveolar macrophage (AM) activation. These studies attempted to characterize the effects of PARS on AM activation in response to oxidative stress. METHODS: Primary cultures of AM were rendered hypoxic for 2 h and reoxygenated for up to 4 h. Cells were preincubated with INO-1001, a specific PARS inhibitor 1 h prior to hypoxia. Gel shift assays characterized nuclear factor kappa B (NFkappaB), and enzyme linked immunosorbent assay quantitated chemokine/cytokine protein secretion. RESULTS: Hypoxia and reoxygenation resulted in an increase in the early nuclear translocation of NFkappaB, and an increase in the secretion of the cytokine tumor necrosis factor-alpha (TNF-alpha), chemokines macrophage inflammatory protein (MIP-1alpha), monocyte chemoattractant protein one (MCP-1) and cytokine induced neutrophil chemoattractant (CINC). Pretreatment of AM with INO-1001 decreased both the early translocation of NFkappaB and the production of TNF-alpha (p<0.05) and MIP-1alpha p=0.02, but did not affect CINC or MCP-1 production. CONCLUSIONS: These findings indicate that PARS inhibition in the AM blunts their response to oxidative stress and may help explain the protective effects of intratracheal PARS inhibition in LIRI.

Is pre-transplant vascular disease a risk factor for mortality and morbidity after heart transplantation?

BACKGROUND: Severe vascular disease is a relative contraindication to heart transplantation (HTx). We addressed the effect of vascular disease on HTx outcomes. METHODS: This is a nonconcurrent cohort study of 402 patients who received HTx at our institution between 1985 and 2004. Pre-transplant vascular evaluation included carotid, lower extremity, and renal artery duplex studies, and CT angiogram when indicated. Patients with severe and nontreatable vascular disease were excluded. Patients were divided into Group 1: those with pre-transplant vasculopathy, and Group 2: those without pre-transplant vasculopathy. Group 1 had 24 patients with 25 vascular lesions: 1 aortic dissection, 2 abdominal aortic aneurysm (AAA)'s, 5 carotid artery stenoses, 1 renal artery stenosis, and 16 peripheral vascular lesions. Interventions were performed to 15 lesions prior to HTx and to 2 lesions after HTx. RESULTS: Median follow-up was 5.5 years. Group 1 had higher incidence of ischemic cardiomyopathy (p<0.001), hypertension (p=0.028), chronic obstructive pulmonary disease (COPD) (p=0.004), and smoking history (p<0.001). There were no differences in sex, hyperlipidemia, diabetes, stroke, or renal dysfunction. Multivariate analysis revealed odds of post-transplant death in Group 1 was 1.4 (95% CI: 0.48-4.1, p=0.54) times greater than that in Group 2. Cox proportional hazards model for survival showed a 50% increase in the hazard of death in patients with pre-transplant vasculopathy, but without statistical significance. Group 1 had higher incidence of post-transplant stroke (p=0.001) but no difference in allograft coronary atherosclerosis. CONCLUSIONS: Pre-transplant vascular disease seems to have negative effect on outcomes after HTx. Larger scale study is needed for further evaluation.

Interleukin-6 regulation of direct lung ischemia reperfusion injury.

BACKGROUND: Lung ischemia reperfusion injury continues to adversely affect patient and graft survival after transplantation. While the role of interleukin-6 has been studied in ischemia-reperfusion models of intestine, liver, and heart, its participation in lung reperfusion injury has not been characterized. METHODS: We administered recombinant interleukin-6 to rat lungs through the intratracheal route before inducing left lung ischemia and reperfusion. Multiple in-vivo indicators of left lung injury were studied, as were transactivation patterns for nuclear factor kappa B and signal transduction and activators of transcription-3. Downstream effects on the elaboration of proinflammatory chemokines and cytokines were also studied. RESULTS: Recombinant interleukin-6 reduced endothelial disruption and neutrophil sequestration in left lung and alveolar spaces, resulting in improved oxygenation after ischemia and 4 hours of reperfusion. This protection was associated with decreased nuclear factor kappa B and signal transduction and activators of transcription-3 nuclear translocation early in reperfusion, and diminished proinflammatory mediator secretion late in reperfusion. CONCLUSIONS: Further studies focusing on the effects of recombinant interleukin-6 in large animal models are warranted, as this may be a novel strategy to improve outcomes after lung transplantation. Intratracheal administration may focus its efficacy on the lung while reducing effects on other organ systems during organ procurement.

Rates of influenza vaccination in older adults and factors associated with vaccine use: a secondary analysis of the Canadian Study of Health and Aging.

BACKGROUND: Influenza vaccination has been shown to reduce morbidity and mortality in the older adult population. In Canada, vaccination rates remain suboptimal. We identified factors predictive of influenza vaccination, in order to determine which segments of the older adult population might be targeted to increase coverage in influenza vaccination programs. METHODS: The Canadian Study of Health and Aging (CSHA) is a population-based national cohort study of 10263 older adults (>/= 65) conducted in 1991. We used data from the 5007 community-dwelling participants in the CSHA without dementia for whom self-reported influenza vaccination status is known. RESULTS: Of 5007 respondents, 2763 (55.2%) reported having received an influenza vaccination within the previous 2 years. The largest predictive factors for flu vaccination included: being married (57.4 vs. 52.6%, p = 0.0007), having attained a higher education (11.0 vs. 10.3 years, p < 0.0001), smoking (57.1% vs. 52.9%, p = 0.0032), more alcohol use (57.9% of those who drank more vs. 53.2% of those who drank less, p = 0.001), poorer self-rated health (54.1% of those with good self-rated health vs. 60.6% of those with poor self-rated health, p = 0.0006), regular exercise (56.8% vs. 52.0%, p = 0.001), and urban living (55.8% vs. 51.0%, p = 0.03). While many other differences were statistically significant, most were small (e.g. mean age 75.1 vs. 74.6 years for immunized vs. unimmunized older adults, p = 0.006, higher Modified Mini Mental Status Examination score (89.9 vs. 89.1, p < 0.0001), higher comorbidity (2.7 vs. 2.3 comorbidities, p < 0.0001). Residents of Ontario were more likely (64.6%) to report vaccination (p < 0.0001), while those living in Quebec were less likely to do so (48.2%, p < 0.0001). Factors retaining significance in a multivariate analysis included older age, higher education, married status, drinking alcohol, smoking, engaging in regular exercise, and having higher comorbidity. CONCLUSIONS: The vaccination rate in this sample, in whom influenza vaccination is indicated, was low (55.2%). Even in a publicly administered health care setting, influenza vaccination did not reach an important proportion of the elderly population. Whether these differences reflect patient preference or access remains to be determined.

Variations in case definition affect prevalence but not outcomes of mild cognitive impairment.

OBJECTIVE: To examine the prevalence estimates and 5-year outcomes of various case definitions of mild cognitive impairment (MCI). METHODS: The authors examined 1,790 adults 65 years of age or older who completed neuropsychological and clinical assessments in the Canadian Study of Health and Aging, a 5-year, representative, prospective cohort study. RESULTS: The most commonly used case definition of MCI yielded a population prevalence estimate of 1.03% (95% CI 0.66 to 1.40). Eliminating the requirements for subjective memory complaints and intact instrumental activities of daily living (IADL) increased the prevalence to 3.02% (CI 2.40 to 3.64). Five-year outcomes, including the risk of death, institutionalization, and dementia, were not distinctly different for various case definitions of MCI, but all were at increased risk of institutionalization (RR 2.3 to 5.2) and dementia (RR 9.3 to 19.7). Regardless of the case definition, most people with MCI developed dementia, chiefly Alzheimer disease (AD). Still, for each case definition, almost one third were considered to have no cognitive impairment after 5 years. CONCLUSIONS: Memory complaints and intact IADL may be unnecessary requirements for a case definition of MCI in population-based samples. The MCI criteria identify people at increased risk of AD, but the potential for improvement of a substantial proportion of those with MCI needs to be acknowledged.

Use of complementary and alternative medical therapies in patients with cardiovascular disease.

BACKGROUND: Complementary and alternative medical (CAM) therapies are becoming increasingly popular, yet little information is available about the prevalence and patterns of CAM therapy use by patients with cardiovascular disease (CVD). METHODS: Interviewers administered telephone questionnaires to 107 patients randomly selected from a stratified cohort of 2487 eligible patients participating in a registry of patients with CVD. RESULTS: The current use of CAM therapies was reported by 64% of the patients surveyed. Nutritional supplements (40%) and megadose vitamins (35%) were the most frequently used preparations. Most CAM therapy users (65%) cited their underlying cardiac condition as the reason for taking such therapy. The most common sources of information about CAM were a friend or relative (43%) or the respondent's usual physician. However, although 80% of respondents claimed that they had discussed their use of CAM therapies with their physician, 58% of respondents taking a potentially toxic cardiovascular medication (digoxin, warfarin, sotalol, or amiodarone) were simultaneously taking an oral supplement. CONCLUSION: The use of CAM therapies was high in the cohort of patients surveyed. Physicians caring for patients with CVD need to inquire about CAM therapy use. Further scientific study should be performed to evaluate the potential benefits and risks of CAM therapies in this patient population.

Five-year outcomes for dementia defined solely by neuropsychological test performance.

Cognitive impairment that does not meet criteria for dementia is common and progresses to dementia at a high rate. It is not clear how best to define this type of cognitive impairment. We assessed the predictive validity of different case definitions for cognitive impairment and dementia by comparing rates of adverse outcomes for individuals who did not meet dementia criteria but had neuropsychological test results indicating dementia (NPDementia), those who had traditional dementia diagnoses (mild and moderate-severe severity), those who had other cognitive impairment but no dementia (CIND), and those with no cognitive impairment (NCI). Our sample comprised 1,659 participants who had completed a neuropsychological assessment in the Canadian Study of Health and Aging, a prospective, cohort study of 10,263 randomly selected persons aged 65 years or older. Outcomes were determined after 5 years. Institutionalization and death rates for the NPDementia and CIND groups were higher than for the NCI group. Both groups had lower institutionalization rates than the two Dementia groups and lower death rates than the Moderate-Severe Dementia group. Rates of progression to dementia were increased in NPDementia and CIND groups, relative to the NCI group, and the NPDementia group was less likely than the CIND group to revert to a diagnosis of NCI at the 5-year follow-up. Thus, individuals with NPDementia and CIND have substantially worse outcomes over 5 years than those with NCI. The case definition of NPDementia identified individuals with cognitive impairment that is unlikely to resolve and likely to progress to dementia.