Janice Y. Bunn

Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation

BACKGROUND Asthma in obese subjects is poorly understood, and these patients are often refractory to standard therapy. OBJECTIVES We sought to gain insights into the pathogenesis and treatment of asthma in obese subjects by determining how obesity and bariatric surgery affect asthma control, airway hyperresponsiveness (AHR), and markers of asthmatic inflammation. METHODS We performed a prospective study of (1) asthmatic and nonasthmatic patients undergoing bariatric surgery compared at baseline and (2) asthmatic patients followed for 12 months after bariatric surgery. RESULTS We studied 23 asthmatic and 21 nonasthmatic patients undergoing bariatric surgery. At baseline, asthmatic patients had lower FEV(1) and forced vital capacity and lower numbers of lymphocytes in bronchoalveolar lavage fluid. After surgery, asthmatic participants experienced significant improvements in asthma control (asthma control score, 1.55 to 0.74; P < .0001) and asthma quality of life (4.87 to 5.87, P < .0001). Airways responsiveness to methacholine improved significantly (methacholine PC(20), 3.9 to 7.28, P = .03). There was a statistically significant interaction between IgE status and change in airways responsiveness (P for interaction = .01). The proportion of lymphocytes in bronchoalveolar lavage fluid and the production of cytokines from activated peripheral blood CD4(+) T cells increased significantly. CONCLUSIONS Bariatric surgery improves AHR in obese asthmatic patients with normal serum IgE levels. Weight loss has dichotomous effects on airway physiology and T-cell function typically involved in the pathogenesis of asthma, suggesting that obesity produces a unique phenotype of asthma that will require a distinct therapeutic approach.

Aerobic Capacity in Patients Entering Cardiac Rehabilitation

Background— Symptom-limited treadmill testing is commonly performed on entry to cardiac rehabilitation (CR) for its prognostic value and to design a safe and effective exercise program. Normative values for this evaluation are not available. The primary goals of this study were to establish normative values for peak aerobic capacity (peak &OV0312;o2) for patients entering CR and to create nomograms for conversion of peak &OV0312;o2 to a percentage of predicted exercise capacity, stratified by age, gender, and diagnosis. Methods and Results— Peak &OV0312;o2 was measured in 2896 patients entering CR from 1996 to 2004. Peak &OV0312;o2 was higher in men than in women: 19.3±6.1 mL · kg−1 · min−1 (range, 5.2 to 49.7 mL · kg−1 · min−1) versus 14.5±3.9 mL · kg−1 · min−1 (range, 3.8 to 29.8 mL · kg−1 · min−1) (P<0.0001). Peak &OV0312;o2 decreased steadily with age with a greater rate of decline in men than women (−0.242 versus −0.116 mL · kg−1 · min−1 per year) (P<0.01). Factors associated with lower peak &OV0312;o2 include coronary artery bypass grafting (CABG), angina at stress testing, hypertension, and, in women, &bgr;-blocking medications. Nomograms are presented for individual values to be compared with mean values by age, gender, and cardiac diagnosis. These include a nomogram to convert estimated maximal metabolic equivalents to actual peak &OV0312;o2 for patients who do not undergo direct measurement of peak &OV0312;o2. Conclusions— Values of peak &OV0312;o2 on entry to CR are extremely low, particularly in women, approaching values seen with severe chronic heart failure. This underscores the importance of CR after a major cardiac event to improve physical function and long-term prognosis.

High-Calorie-Expenditure Exercise A New Approach to Cardiac Rehabilitation for Overweight Coronary Patients

Background— More than 80% of patients entering cardiac rehabilitation (CR) are overweight, and >50% have metabolic syndrome. Current CR exercise protocols result in little weight loss and minimal changes in cardiac risk factors. We sought to design an exercise protocol that would lead to greater weight loss and risk factor change. Methods and Results— We performed a randomized controlled clinical trial to evaluate the effect of high-calorie-expenditure exercise (3000- to 3500-kcal/wk exercise-related energy expenditure) compared with standard CR exercise (7 to 800 kcal/wk) on weight loss and risk factors in 74 overweight patients with coronary heart disease. Both groups were counseled for weight loss and taking evidence-based preventive medications. High-calorie-expenditure exercise resulted in double the weight loss (8.2±4 versus 3.7±5 kg; P<0.001) and fat mass loss (5.9±4 versus 2.8±3 kg; P<0.001) and a greater waist reduction (−7±5 versus −5±5 cm; P=0.02) than standard CR exercise at 5 months. High-calorie-expenditure exercise reduced insulin resistance, measured with the euglycemic hyperinsulinemic clamp, along with the ratio of total to high-density lipoprotein cholesterol and components of the metabolic syndrome, more than standard CR exercise (each P<0.01). Overall, fat mass loss best predicted improved metabolic risk, and the prevalence of metabolic syndrome decreased from 59% to 31%. Changes in cardiac risk factors included decreased insulin resistance, increased high-density lipoprotein cholesterol, and decreased measures of insulin, triglycerides, blood pressure, plasminogen activator inhibitor-1, and the ratio of total to high-density lipoprotein cholesterol (each P<0.05). Significant weight loss was maintained at 1 year. Conclusion— High-calorie-expenditure exercise promotes greater weight loss and more favorable cardiometabolic risk profiles than standard CR for overweight coronary patients.Background Over 80% of patients entering cardiac rehabilitation (CR) are overweight and >50% have metabolic syndrome. Current CR exercise protocols result in little weight loss and minimal changes in cardiac risk factors. We sought to design an exercise protocol that would lead to greater weight loss and risk factor change.

Elevation of IL-6 in the allergic asthmatic airway is independent of inflammation but associates with loss of central airway function

BackgroundAsthma is a chronic inflammatory disease of the airway that is characterized by a Th2-type of immune response with increasing evidence for involvement of Th17 cells. The role of IL-6 in promoting effector T cell subsets suggest that IL-6 may play a functional role in asthma. Classically IL-6 has been viewed as an inflammatory marker, along with TNFα and IL-1β, rather than as regulatory cytokine.ObjectiveTo investigate the potential relationship between IL-6 and other proinflammatory cytokines, Th2/Th17 cytokines and lung function in allergic asthma, and thus evaluate the potential role of IL-6 in this disease.MethodsCytokine levels in induced sputum and lung function were measured in 16 healthy control and 18 mild-moderate allergic asthmatic subjects.ResultsThe levels of the proinflammatory biomarkers TNFα and IL-1β were not different between the control and asthmatic group. In contrast, IL-6 levels were specifically elevated in asthmatic subjects compared with healthy controls (p < 0.01). Hierarchical regression analysis in the total study cohort indicates that the relationship between asthma and lung function could be mediated by IL-6. Among Th2 cytokines only IL-13 (p < 0.05) was also elevated in the asthmatic group, and positively correlated with IL-6 levels (rS = 0.53, p < 0.05).ConclusionsIn mild-moderate asthma, IL-6 dissociates from other proinflammatory biomarkers, but correlates with IL-13 levels. Furthermore, IL-6 may contribute to impaired lung function in allergic asthma.

Essential role of IL-6 in protection against H1N1 influenza virus by promoting neutrophil survival in the lung.

Influenza virus infection is considered a major worldwide public health problem. Seasonal infections with the most common influenza virus strains (e.g., H1N1) can usually be resolved, but they still cause a high rate of mortality. The factors that influence the outcome of the infection remain unclear. Here, we show that deficiency of interleukin (IL)-6 or IL-6 receptor is sufficient for normally sublethal doses of H1N1 influenza A virus to cause death in mice. IL-6 is necessary for resolution of influenza infection by protecting neutrophils from virus-induced death in the lung and by promoting neutrophil-mediated viral clearance. Loss of IL-6 results in persistence of the influenza virus in the lung leading to pronounced lung damage and, ultimately, death. Thus, we demonstrate that IL-6 is a vital innate immune cytokine in providing protection against influenza A infection. Genetic or environmental factors that impair IL-6 production or signaling could increase mortality to influenza virus infection.

A Lipidomics Analysis of the Relationship Between Dietary Fatty Acid Composition and Insulin Sensitivity in Young Adults

Relative to diets enriched in palmitic acid (PA), diets rich in oleic acid (OA) are associated with reduced risk of type 2 diabetes. To gain insight into mechanisms underlying these observations, we applied comprehensive lipidomic profiling to specimens collected from healthy adults enrolled in a randomized, crossover trial comparing a high-PA diet to a low-PA/high-OA (HOA) diet. Effects on insulin sensitivity (SI) and disposition index (DI) were assessed by intravenous glucose tolerance testing. In women, but not men, SI and DI were higher during HOA. The effect of HOA on SI correlated positively with physical fitness upon enrollment. Principal components analysis of either fasted or fed-state metabolites identified one factor affected by diet and heavily weighted by the PA/OA ratio of serum and muscle lipids. In women, this factor correlated inversely with SI in the fasted and fed states. Medium-chain acylcarnitines emerged as strong negative correlates of SI, and the HOA diet was accompanied by lower serum and muscle ceramide concentrations and reductions in molecular biomarkers of inflammatory and oxidative stress. This study provides evidence that the dietary PA/OA ratio impacts diabetes risk in women.

Gender, Age, and Season at Immunization Uniquely Influence the Genetic Control of Susceptibility to Histopathological Lesions and Clinical Signs of Experimental Allergic Encephalomyelitis: Implications for the Genetics of Multiple Sclerosis

Multiple sclerosis (MS), the principal inflammatory demyelinating disease of the central nervous system (CNS), is believed to have an immunopathological etiology arising from gene-environment interactions. In this study, we examined the effect of sex, age, and season at immunization on the susceptibility of (B10.S x SJL/J) F(2) intercross mice to experimental allergic encephalomyelitis (EAE), the foremost animal model of MS. Results of logistic regression analyses suggest that female mice were more likely to exhibit CNS lesions than male mice [odds ratio (OR) = 2.28 for brain lesions; OR = 2.37 for spinal cord (SC) lesions]. Although statistically significant associations were seen between brain and SC lesions and age at the time of injection or month of injection when examined separately; these associations disappeared when controlling for sex in multiple logistic regression analyses. These results suggest that the sex of the mouse is more important in influencing the development of brain and SC lesions than was either age or month of immunization. When examining clinical disease as the endpoint, the OR for the age at immunization is 1.04, indicating that the odds of being affected increase by 4% for each increasing week of age. When controlled for age, the OR for injection in the summer months (July through September) is 1.90, suggesting that the odds of being clinically affected are 90% greater for F(2) intercross animals injected in the summercompared to those injected in the winter to spring months (February through May). In contrast to CNS lesions, the age and season at immunization significantly and independently influenced susceptibility to clinical EAE and did so equally in both males and females. Linkage analysis to eae5, the H2-linked locus controlling susceptibility to clinical disease, was performed using 6- to 12- and >12-week-old cohorts as well as summer and winter/spring cohorts of F(2) mice. Significant linkage of clinical EAE to eae5 was observed with the 6- to 12-week-old and summer populations. In contrast, linkage of clinical EAE to eae5 was not detected with the >12-week-old and winter/spring populations. These results indicate that age and seasonal effects are capable of overriding eae5-dependent genetic control of susceptibility to clinical EAE and have significant implications for the genetics of MS.

Cutting Edge: The Y Chromosome Controls the Age-Dependent Experimental Allergic Encephalomyelitis Sexual Dimorphism in SJL/J Mice

Multiple sclerosis is a sexually dimorphic, demyelinating disease of the CNS, and experimental allergic encephalomyelitis (EAE) is its principal autoimmune model. Young male SJL/J mice are relatively resistant to EAE whereas older males and SJL/J females of any age are susceptible. By comparing a wide age range of proteolipid protein peptide 139–151 immunized mice, we found that female disease severity remains constant with age. In contrast, EAE disease severity increases with age in SJL/J males, with young males having significantly less severe disease and older males having significantly more disease than equivalently aged females. To determine whether the Y chromosome contributes to this sexual dimorphism, EAE was induced in consomic SJL/J mice carrying a B10.S Y chromosome (SJL.YB10.S). EAE was significantly more severe in young male SJL.YB10.S mice compared with young male SJL/J mice. These studies show that a Y chromosome-linked polymorphism controls the age-dependent EAE sexual dimorphism observed in SJL/J mice.

Individuals with non-specific low back pain use a trunk stiffening strategy to maintain upright posture

There is increasing evidence that individuals with non-specific low back pain (LBP) have altered movement coordination. However, the relationship of this neuromotor impairment to recurrent pain episodes is unknown. To assess coordination while minimizing the confounding influences of pain we characterized automatic postural responses to multi-directional support surface translations in individuals with a history of LBP who were not in an active episode of their pain. Twenty subjects with and 21 subjects without non-specific LBP stood on a platform that was translated unexpectedly in 12 directions. Net joint torques of the ankles, knees, hips, and trunk in the frontal and sagittal planes as well as surface electromyographs of 12 lower leg and trunk muscles were compared across perturbation directions to determine if individuals with LBP responded using a trunk stiffening strategy. Individuals with LBP demonstrated reduced peak trunk torques, and enhanced activation of the trunk and ankle muscle responses following perturbations. These results suggest that individuals with LBP use a strategy of trunk stiffening achieved through co-activation of trunk musculature, aided by enhanced distal responses, to respond to unexpected support surface perturbations. Notably, these neuromotor alterations persisted between active pain periods and could represent either movement patterns that have developed in response to pain or could reflect underlying impairments that may contribute to recurrent episodes of LBP.

A history of low back pain associates with altered electromyographic activation patterns in response to perturbations of standing balance

People with a history of low back pain (LBP) exhibit altered responses to postural perturbations, and the central neural control underlying these changes in postural responses remains unclear. To characterize more thoroughly the change in muscle activation patterns of people with LBP in response to a perturbation of standing balance, and to gain insight into the influence of early- vs. late-phase postural responses (differentiated by estimates of voluntary reaction times), this study evaluated the intermuscular patterns of electromyographic (EMG) activations from 24 people with and 21 people without a history of chronic, recurrent LBP in response to 12 directions of support surface translations. Two-factor general linear models examined differences between the 2 subject groups and 12 recorded muscles of the trunk and lower leg in the percentage of trials with bursts of EMG activation as well as the amplitudes of integrated EMG activation for each perturbation direction. The subjects with LBP exhibited 1) higher baseline EMG amplitudes of the erector spinae muscles before perturbation onset, 2) fewer early-phase activations at the internal oblique and gastrocnemius muscles, 3) fewer late-phase activations at the erector spinae, internal and external oblique, rectus abdominae, and tibialis anterior muscles, and 4) higher EMG amplitudes of the gastrocnemius muscle following the perturbation. The results indicate that a history of LBP associates with higher baseline muscle activation and that EMG responses are modulated from this activated state, rather than exhibiting acute burst activity from a quiescent state, perhaps to circumvent trunk displacements.