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1.  Stimulation of alveolar epithelial fluid clearance in human lungs by exogenous epinephrine 
Critical care medicine  2006;34(3):676-681.
Objectives
Because several experimental studies have demonstrated that cyclic adenosine monophosphate generation following β-adrenoceptor activation can markedly stimulate alveolar fluid clearance, we determined whether the endogenous levels of catecholamines that occur in the pulmonary edema fluid and plasma of patients with acute lung injury are high enough to stimulate alveolar fluid clearance in the human lung.
Design
Observational clinical study.
Setting
Academic university hospital and laboratory.
Patients
Twenty-one patients with acute pulmonary edema plus ex vivo human lungs.
Interventions
Measurements of catecholamine levels in patient samples and controlled laboratory studies of the effects of these catecholamine levels on the rates of alveolar fluid clearance in ex vivo human lungs.
Measurements and Main Results
The concentrations of both epinephrine and norepinephrine in the pulmonary edema fluid and plasma were ~10-9 M (range of 1-8 × 10-9 M) in hydrostatic pulmonary edema (n = 6) and acute lung injury patients (n = 15). We therefore tested whether 10-9 M epinephrine or norepinephrine stimulated alveolar fluid clearance in isolated human lungs and found that these epinephrine or norepinephrine concentrations did not stimulate alveolar fluid clearance. However, higher concentrations of epinephrine (10-7 M), but not norepinephrine (10-7 M), significantly stimulated alveolar fluid clearance by 84% above control. Glibenclamide (10-5 M) and CFTRinh-172 (10-5 M), cystic fibrosis transmembrane conductance regulator inhibitors, completely inhibited the epinephrine-induced stimulation of alveolar fluid clearance.
Conclusions
These results indicate that endogenous catecholamine concentrations in pulmonary edema fluid are probably not sufficient to stimulate alveolar fluid clearance. In contrast, administration of exogenous catecholamines into the distal airspaces can stimulate alveolar fluid clearance in the human lung, an effect that is mediated in part by cystic fibrosis transmembrane conductance regulator. Therefore, exogenous cyclic adenosine monophosphate-dependent stimulation will probably be required to accelerate the resolution of alveolar edema in the lungs of patients with pulmonary edema.
doi:10.1097/01.CCM.0000201403.70636.0F
PMCID: PMC2765117  PMID: 16505652
pulmonary edema; alveolar epithelium; catecholamine; norepinephrine; cystic fibrosis transmembrane conductance regulator; glibenclamide
2.  Hypertension and catecholamine levels in sleep apnoea 
Background
Sleep-disordered breathing has been strongly associated with systemic hypertension. Increased sympathetic activity in sleep-disordered breathing may be responsible for this association.
Method
In this sleep clinic-based study, 82 newly diagnosed patients of sleep-disordered breathing were evaluated for hypertension, and their plasma and urinary levels of catecholamines were measured. Catecholamine levels were then compared separately with the severity of sleep apnoea and blood pressure (BP).
Results
The prevalence of hypertension in the study population was 46.3%. The BP showed a strong and statistically significant correlation with apnoea-hypopnoea index (diastolic, r = 0.65, P < 0.001 and systolic, r = 0.60, P < 0.001) which was maintained even after the results were analysed separately for obese and non-obese subjects. Both plasma and urinary levels of catecholamines were greater in patients with severe sleep apnoea (compared to nonsevere cases) and in those with hypertension compared to normotensives. However, statistical significance was achieved only for urine catecholamines and not for plasma catechol-amines in both the cases.
Conclusion
Hypertension is highly prevalent among Indian subjects with obstructive sleep apnoea. Catecholamine levels are significantly higher in hypertensive than in normotensive apnoeics and are also directly related to the severity of obstructive sleep apnoea. Twenty-four hour urinary catecholamine levels are more valid measures of sympathetic activity than spot plasma samples.
doi:10.1016/S0377-1237(11)60128-7
PMCID: PMC3862558  PMID: 24669036
catecholamines; hypertension; sleep apnoea; sleep-disordered breathing; sympathetic
3.  PHEOCHROMOCYTOMA: A CATECHOLAMINE AND OXIDATIVE STRESS DISORDER 
Endocrine regulations  2011;45(2):65-90.
The WHO classification of endocrine tumors defines pheochromocytoma as a tumor arising from chromaffin cells in the adrenal medulla — an intra-adrenal paraganglioma. Closely related tumors of extra-adrenal sympathetic and parasympathetic paraganglia are classified as extra-adrenal paragangliomas. Almost all pheochromocytomas and paragangliomas produce catecholamines. The concentrations of catecholamines in pheochromocytoma tissues are enormous, potentially creating a volcano that can erupt at any time. Significant eruptions result in catecholamine storms called “attacks” or “spells”. Acute catecholamine crisis can strike unexpectedly, leaving traumatic memories of acute medical disaster that champions any intensive care unit. A very well-defined genotype-biochemical phenotype relationship exists, guiding proper and cost-effective genetic testing of patients with these tumors. Currently, the production of norepinephrine and epinephrine is optimally assessed by the measurement of their O-methylated metabolites, normetanephrine or metanephrine, respectively. Dopamine is a minor component, but some paragangliomas produce only this catecholamine or this together with norepinephrine. Methoxytyramine, the O-methylated metabolite of dopamine, is the best biochemical marker of these tumors. In those patients with equivocal biochemical results, a modified clonidine suppression test coupled with the measurement of plasma normetanephrine has recently been introduced. In addition to differences in catecholamine enzyme expression, the presence of either constitutive or regulated secretory pathways contributes further to the very unique mutation-dependent catecholamine production and release, resulting in various clinical presentations.
Oxidative stress results from a significant imbalance between levels of prooxidants, generated during oxidative phosphorylation, and antioxidants. The gradual accumulation of prooxidants due to metabolic oxidative stress results in proto-oncogene activation, tumor suppressor gene inactivation, DNA damage, and genomic instability. Since the mitochondria serves as the main source of prooxidants, any mitochondrial impairment leads to severe oxidative stress, a major outcome of which is tumor development. In terms of cancer pathogenesis, pheochromocytomas and paragangliomas represent tumors where the oxidative phosphorylation defect due to the mutation of succinate dehydrogenase is the cause, not a consequence, of tumor development. Any succinate dehydrogenase pathogenic mutation results in the shift from oxidative phosphorylation to aerobic glycolysis in the cytoplasm (also called anaerobic glycolysis if hypoxia is the main cause of such a shift). This phenomenon, also called the Warburg effect, is well demonstrated by a positive [18F]-fluorodeoxyglycose positron emission tomography scan. Microarray studies, genome-wide association studies, proteomics and protein arrays, metabolomics, transcriptomics, and bioinformatics approaches will remain powerful tools to further uncover the pathogenesis of these tumors and their unique markers, with the ultimate goal to introduce new therapeutic options for those with metastatic or malignant pheochromocytoma and paraganglioma. Soon oxidative stress will be tightly linked to a multistep cancer process in which the mutation of various genes (perhaps in a logistic way) ultimately results in uncontrolled growth, proliferation, and metastatic potential of practically any cell. Targeting the mTORC, IGF-1, HIF and other pathways, topoisomerases, protein degradation by proteosomes, balancing the activity of protein kinases and phosphatases or even synchronizing the cell cycle before any exposure to any kind of therapy will soon become a reality. Facing such a reality today will favor our chances to “beat” this disease tomorrow.
PMCID: PMC3414427  PMID: 21615192
Pheochromocytoma; Paraganglioma; Catecholamines; Metanephrines; Mitochondria; Oxidative Phosphorylation; Glycolysis
4.  Neurohumoral, immunoinflammatory and cardiovascular profile of patients with severe tetanus: a prospective study 
Introduction
Autonomic disturbances in tetanus are traditionally associated with adrenergic variations and/or cardiac dysfunction, based on case report data. The objective of this study was to measure catecholamines, (TNF)-α and troponin T relative to and left ventricular ejection fraction (LVEF) in patients with severe tetanus.
Methods
This prospective study was carried out at two general Intensive Care Units and included 21 patients consecutively admitted with severe tetanus. Catecholamines (dopamine, norepinephrine, epinephrine and total catecholamines), tumor necrosis factor (TNF)-α and LVEF were assessed during the first week of autonomic instability and following tetanus recovery. Troponin T was measured during autonomic instability only.
Results
Mean age of patients was 46 ± 17 years, median Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 8 (range 1–23). All patients had both blood pressure and heart rate instability. Two patients were recuperated from cardiac arrest. Intensive Care Unit mortality was 14% (3 cases). No increase in total catecholamines or in TNF-α levels was observed during autonomic instability or in the recovery period. Six patients had troponin T >0.01 ng/ml and six had >0.1 ng/ml. Mean LVEF was similar during autonomic instability and after tetanus recovery, 67 ± 7% and 65 ± 7%, respectively. Troponin T levels correlated with pressoric instability during autonomic instability.
Conclusion
Our study demonstrated that in patients with severe tetanus no significant increased levels of catecholamines or TNF-α or evidence of cardiac systolic dysfunction was observed either during autonomic instability or in the recovery period. Elevated values of troponin T detected during autonomic instability were not associated with left ventricular dysfunction. Our data do not support the hypothesis that autonomic disturbances in tetanus are associated with adrenergic variations or cardiac dysfunction.
doi:10.1186/1477-5751-5-2
PMCID: PMC1434771  PMID: 16503969
5.  Upregulation of Phagocyte-Derived Catecholamines Augments the Acute Inflammatory Response 
PLoS ONE  2009;4(2):e4414.
Following our recent report that phagocytic cells (neutrophils, PMNs, and macrophages) are newly discovered sources of catecholamines, we now show that both epinephrine and norepinephrine directly activate NFκB in macrophages, causing enhanced release of proinflammatory cytokines (TNFα, IL-1β, IL-6). Both adrenal-intact (AD+) and adrenalectomized (ADX) rodents were used, because ADX animals had greatly enhanced catecholamine release from phagocytes, facilitating our efforts to understand the role of catecholamines released from phagocytes. Phagocytes isolated from adrenalectomized rats displayed enhanced expression of tyrosine-hydroxylase and dopamine-β-hydroxylase, two key enzymes for catecholamine production and exhibited higher baseline secretion of norepinephrine and epinephrine. The effects of upregulation of phagocyte-derived catecholamines were investigated in two models of acute lung injury (ALI). Increased levels of phagocyte-derived catecholamines were associated with intensification of the acute inflammatory response, as assessed by increased plasma leak of albumin, enhanced myeloperoxidase content in lungs, augmented levels of proinflammatory mediators in bronchoalveolar lavage fluids, and elevated expression of pulmonary ICAM-1 and VCAM-1. In adrenalectomized rats, development of ALI was enhanced and related to α2-adrenoceptors engagement but not to involvement of mineralocorticoid or glucocorticoid receptors. Collectively, these data demonstrate that catecholamines are potent inflammatory activators of macrophages, upregulating NFκB and further downstream cytokine production of these cells. In adrenalectomized animals, which have been used to further assess the role of catecholamines, there appears to be a compensatory increase in catecholamine generating enzymes and catecholamines in macrophages, resulting in amplification of the acute inflammatory response via engagement of α2-adrenoceptors.
doi:10.1371/journal.pone.0004414
PMCID: PMC2636885  PMID: 19212441
6.  Plasma catecholamines in the acute phase of the response to myocardial infarction. 
Plasma catecholamine (adrenaline, noradrenaline and dopamine) concentrations have been measured in 48 patients within 6 hours of the onset of symptoms of an acute myocardial infarction. The concentrations of all three catecholamines were elevated, and there were positive correlations between plasma noradrenaline concentrations and the severity of infarct as assessed by the coronary prognostic index and serum LDH levels. Plasma glucose, free fatty acid, lactate and cortisol levels were elevated while insulin levels were reduced. The site of infarction did not influence the pattern of hormonal and metabolic responses although heart rate was significantly lower in the inferior than in the anterior infarct group. Seven patients went into ventricular fibrillation shortly (less than 1.8 h) after blood sampling. Plasma catecholamine concentrations were markedly elevated in these patients with levels similar to those previously reported after cardiac arrest.
PMCID: PMC1285314  PMID: 3524599
7.  Hyperventilation and asymptomatic chronic asthma 
Thorax  2000;55(12):1016-1022.
BACKGROUND—We have consistently argued that mild asthma is an important underlying aetiological factor in patients with severe symptomatic hyperventilation. While hyperventilation has been demonstrated in acute asthma, there have been few studies in mild chronic asthma, and mechanisms are uncertain.
METHODS—Twenty three currently asymptomatic chronically asthmatic patients (occasional use of bronchodilators, normal lung function, hyperresponsive to methacholine) were studied and 17 matched normal subjects acted as controls. Ventilation, pattern of breathing, arterial carbon dioxide and oxygen tensions (PaCO2, PaO2), end tidal PCO2 (PETCO2), standard lung function, airway responsiveness to methacholine, airway inflammation assessed by eosinophils in induced sputum, and psychiatric morbidity (Spielberger STAI-Y and Beck Depression Inventory) were measured.
RESULTS—Despite the absence of current asthmatic symptoms, no clinical evidence of hyperventilation, and normal lung function in the patients with asthma, PaCO2 and PETCO2 were significantly (p<0.01) lower in the patients than in the control group (mean (SD) PaCO2 4.96 (0.43) kPa for patients versus 5.27 (0.38) kPa for controls (mean difference 0.31 kPa, 95% confidence interval (CI) 0.06 to 0.56, p<0.02)). PETCO2 was very similar to PaCO2 in both groups (mean (SD) PETCO2 4.89 (0.47) kPa for the patients and 5.28 (0.40) for the controls (mean difference 0.39 kPa, 95% CI 0.12 to 0.66,p<0.01)). There was no significant difference in ventilation or respiratory pattern between the two groups. The reduced PaCO2 in the asthmatic patients correlated significantly with the concentration of methacholine provoking a fall in FEV1 of more than 20% (PC20) (r = 0.56, p<0.01) but not with any aspect of lung function, eosinophil count, or anxiety/depression.
CONCLUSION—Mild asymptomatic asthma is not associated with clinically significant hyperventilation but is associated with a significant reduction in both arterial and end tidal PCO2 which relates to airway hyperresponsiveness rather than to the degree of airway obstruction or mucosal inflammation. Anxiety and depression appear not to be implicated.


doi:10.1136/thorax.55.12.1016
PMCID: PMC1745650  PMID: 11083886
8.  Stress-Mediated Increases in Systemic and Local Epinephrine Impair Skin Wound Healing: Potential New Indication for Beta Blockers 
PLoS Medicine  2009;6(1):e1000012.
Background
Stress, both acute and chronic, can impair cutaneous wound repair, which has previously been mechanistically ascribed to stress-induced elevations of cortisol. Here we aimed to examine an alternate explanation that the stress-induced hormone epinephrine directly impairs keratinocyte motility and wound re-epithelialization. Burn wounds are examined as a prototype of a high-stress, high-epinephrine, wound environment. Because keratinocytes express the β2-adrenergic receptor (β2AR), another study objective was to determine whether β2AR antagonists could block epinephrine effects on healing and improve wound repair.
Methods and Findings
Migratory rates of normal human keratinocytes exposed to physiologically relevant levels of epinephrine were measured. To determine the role of the receptor, keratinocytes derived from animals in which the β2AR had been genetically deleted were similarly examined. The rate of healing of burn wounds generated in excised human skin in high and low epinephrine environments was measured. We utilized an in vivo burn wound model in animals with implanted pumps to deliver β2AR active drugs to study how these alter healing in vivo. Immunocytochemistry and immunoblotting were used to examine the up-regulation of catecholamine synthetic enzymes in burned tissue, and immunoassay for epinephrine determined the levels of this catecholamine in affected tissue and in the circulation. When epinephrine levels in the culture medium are elevated to the range found in burn-stressed animals, the migratory rate of both cultured human and murine keratinocytes is impaired (reduced by 76%, 95% confidence interval [CI] 56%–95% in humans, p < 0.001, and by 36%, 95% CI 24%–49% in mice, p = 0.001), and wound re-epithelialization in explanted burned human skin is delayed (by 23%, 95% CI 10%–36%, p = 0.001), as compared to cells or tissues incubated in medium without added epinephrine. This impairment is reversed by β2AR antagonists, is absent in murine keratinocytes that are genetically depleted of the β2AR, and is reproduced by incubation of keratinocytes with other β2AR-specific agonists. Activation of the β2AR in cultured keratinocytes signals the down-regulation of the AKT pathway, accompanied by a stabilization of the actin cytoskeleton and an increase in focal adhesion formation, resulting in a nonmigratory phenotype. Burn wound injury in excised human skin also rapidly up-regulates the intra-epithelial expression of the epinephrine synthesizing enzyme phenylethanolamine-N-methyltransferase, and tissue levels of epinephrine rise dramatically (15-fold) in the burn wounded tissue (values of epinephrine expressed as pg/ug protein ± standard error of the mean: unburned control, 0.6 ± 0.36; immediately postburn, 9.6 ± 1.58; 2 h postburn, 3.1 ± 1.08; 24 h post-burn, 6.7 ± 0.94). Finally, using an animal burn wound model (20% body surface in mice), we found that systemic treatment with βAR antagonists results in a significant increase (44%, 95% CI 27%–61%, p < 0.00000001) in the rate of burn wound re-epithelialization.
Conclusions
This work demonstrates an alternate pathway by which stress can impair healing: by stress-induced elevation of epinephrine levels resulting in activation of the keratinocyte β2AR and the impairment of cell motility and wound re-epithelialization. Furthermore, since the burn wound locally generates epinephrine in response to wounding, epinephrine levels are locally, as well as systemically, elevated, and wound healing is impacted by these dual mechanisms. Treatment with beta adrenergic antagonists significantly improves the rate of burn wound re-epithelialization. This work suggests that specific β2AR antagonists may be apt, near-term translational therapeutic targets for enhancing burn wound healing, and may provide a novel, low-cost, safe approach to improving skin wound repair in the stressed individual.
Rivkah Isseroff and colleagues describe how stress-induced elevation of epinephrine levels can impair the healing of burns in mice and suggest that β2 adrenergic receptor antagonists may have a role in improving skin wound repair.
Editors' Summary
Background.
Skin—the largest organ in the human body—protects the rest of the body against infection by forming an impervious layer over the whole external body surface. Consequently, if this layer is damaged by rubbing, cutting, or burning, it must be quickly and efficiently repaired. Wound repair (healing) involves several different processes. First, the clotting cascade stops bleeding at the wound site and immune system cells attracted into the site remove any bacteria or debris in the wound. Various factors are released by the immune cells and the other cells in and near the damaged area that encourage the migration of several different sorts of cells into the wound. These cells proliferate and prepare the wound for “re-epithelialization.” In this process, keratinocytes (a type of epithelial cell that makes a tough, insoluble protein called keratin; epithelial cells cover all the surfaces of the body) migrate into the wound site and form a new, intact epithelial layer. If any of these processes fail, the result can be a chronic (long-lasting) nonhealing wound. In particular, if the wound does not re-epithelialize, it remains open and susceptible to infection and loss of body fluids.
Why Was This Study Done?
One factor that impairs the repair of skin wounds is stress. In stressful situations (including situations in which wounds are likely to occur), the human body releases several chemicals that prepare the body for “fight or flight,” including cortisol and epinephrine (also called adrenaline). Most scientists ascribe the effects of stress on wound healing to stress-induced increases in cortisol, but might stress-induced epinephrine also affect wound healing? In this study, the researchers test whether epinephrine impairs keratinocyte migration and re-epithelialization of burn wounds (keratinocytes have a receptor for epinephrine called the β2 adrenergic receptor [β2AR] on their cell surface that allows them to respond to epinephrine). They chose to study burn wounds for two reasons. First, major burns cause a massive release of stress chemicals into the bloodstream that raises blood levels (systemic levels) of cortisol and epinephrine for days or weeks after the initial trauma. Second, despite recent therapeutic advances, many people still die from major burns (4,000 every year in the USA alone) so there is a pressing need for better ways to treat this type of wound.
What Did the Researchers Do and Find?
The researchers investigated the effects of epinephrine on wound healing in three types of experiments. First, they looked at the effect of epinephrine on keratinocytes growing in dishes (in vitro experiments). Levels of epinephrine similar to those in the blood of stressed individuals greatly inhibited the motility and migration of human keratinocytes (isolated from the foreskin of newborn babies) and of mouse keratinocytes. It also inhibited the repair of scratch wounds made in monolayers of keratinocytes growing on dishes. Treatment of the cultures with a β2AR antagonist (a chemical that prevents epinephrine activating the β2AR) reversed the effects of epinephrine. In addition, the migration of mouse keratinocytes that had been genetically altered so that they did not express β2AR was not inhibited by epinephrine. Next, the researchers investigated the healing of burn wounds made in small pieces of human skin growing in dishes (ex vivo experiments). Burn injuries rapidly increased the amount of epinephrine in these tissue explants, they report, and treatment of the explants with a βAR antagonist (an inhibitor of all types of βARs) greatly increased wound re-epithelialization. Finally, the researchers report that the re-epithelialization of burn wounds in living mice was improved when the mice were treated with a β2AR antagonist.
What Do These Findings Mean?
These findings reveal a second pathway by which stress can impair wound healing. They show that stress-induced increases in systemic and local epinephrine activate β2ARs on keratinocytes and that this activation inhibits keratinocyte motility and wound re-epithelialization. Although results obtained in animals do not always reflect what happens in people, the finding that the treatment of mice with β2AR antagonists improves the rate of burn wound re-epithelialization, suggests that beta blockers—drugs that inhibit all βARs and that are widely used to treat high blood pressure and to prevent heart disease—or specific β2AR antagonists might provide a new therapeutic approach to the treatment of burns and, perhaps, chronic nonhealing wounds.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000012.
Wikipedia has pages on wound healing, burn injuries, and epinephrine (Note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The MedlinePlus Encyclopedia has a page on burns (in English and Spanish)
MedlinePlus provides links to other information on burns (in English and Spanish)
doi:10.1371/journal.pmed.1000012
PMCID: PMC2621262  PMID: 19143471
9.  Catecholamine depletion in first-degree relatives of individuals with mood disorders: An [18F]fluorodeoxyglucose positron emission tomography study☆ 
NeuroImage : Clinical  2013;2:341-355.
Catecholamine depletion with alpha-methylparatyrosine (AMPT) has previously been shown to induce depressive symptoms in currently remitted patients with major depressive disorder (MDD) but not healthy controls. Thus sensitivity to catecholamine depletion has been hypothesized to be an endophenotype of MDD. Here we tested this hypothesis in the context of a randomized, double-blinded, placebo-controlled design by measuring changes in mood in a group of psychiatrically-healthy individuals at risk of mood disorders by virtue of family history (high-risk subjects, HRs). In addition, we tested whether HRs differed from healthy controls with no family-history of mood disorders (low-risk controls, LRs) in their cerebral metabolic response when undergoing catecholamine depletion. Eight healthy LRs (6 males, mean age = 34.1 ± 7.1) and 6 healthy HRs (3 males, mean age = 29.3 ± 4.6) participated in two, 3-day-long identical sessions during which they completed standardized measures of depression, anxiety and fatigue and an [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) scan. On one occasion participants received 4 weight-adjusted doses of AMPT and on the other occasion participants received 4 doses of placebo. The LR and HR groups did not differ from each other in their mood during sham depletion. However, during the period of peak catecholamine depletion, the HR group reported significantly more depression, anxiety and fatigue than the LR group. A region-of-interest analysis showed that during catecholamine depletion versus placebo the combined LR and HR groups displayed a significant increase in cerebral metabolic rate in the left and right ventral striata, left and right amygdalae, and left and right hippocampi (FWE-corrected p < 0.05). Whole brain voxel-wise analyses indicated significantly increased glucose metabolism in the left and right putamina (FWE-corrected p < 0.05) in the combined LR and HR groups in the AMPT versus the placebo session. In the LR group, alone, no significant elevation in glucose metabolism was observed in the regions-of-interest in the catecholamine depletion versus placebo condition. In the HR group, alone, the region-of-interest analysis showed a significant increase in cerebral metabolic rate in the left and right ventral striata (FWE-corrected p < 0.05). No regions-of-interest showed significantly different metabolism in the HR group versus the LR group in the placebo condition, however compared with the LR group, the HR group displayed nominally increased glucose metabolism in the left amygdala during catecholamine depletion (SVC-corrected p = 0.05). A region-of-interest analysis for the interaction contrast confirmed that catecholamine depletion had differential effects on HR and LR participants. Compared with the LR group, the HR group displayed significantly increased glucose metabolism in the left ventral striatum, left amygdala, and left lateral orbitofrontal cortex (OFC) (FWE-corrected p < 0.05). Our results suggest that sensitivity to catecholamine depletion may be a phenotypic marker of vulnerability to mood disorders that is characterized at the neurophysiological level by disinhibition of the striatum and its efferent projections comprising the limbic–cortical–striatal–pallidal–thalamic circuitry.
Highlights
•High-risk subjects were more depressed and fatigued during catecholamine depletion.•During depletion HR subjects > metabolism in the left striatum, amygdala, and OFC•Sensitivity to catecholamine depletion may be an endophenotype of depression.
doi:10.1016/j.nicl.2013.02.004
PMCID: PMC3778263  PMID: 24179788
Catecholamine depletion; Endophenotype; Positron emission tomography; Major depressive disorder; Bipolar disorder; Ventral striatum
10.  Variations in circulating catecholamines fail to alter human platelet alpha-2-adrenergic receptor number or affinity for [3H]yohimbine or [3H]dihydroergocryptine. 
Journal of Clinical Investigation  1984;74(3):1063-1072.
A series of studies were performed to determine the relationship between physiologic levels of circulating plasma norepinephrine and epinephrine and human platelet alpha-2 binding site number and the affinity (KD) of these sites for antagonist radioligands. In one study, alpha-2-adrenergic binding site number and affinity were compared using both [3H]yohimbine and [3H]dihydroergocryptine as radioligands. There was good absolute and relative comparison for binding site number, but only a relative relationship for KD. In 46 normal subjects, there was no significant relationship between site number or KD and age, plasma epinephrine, or plasma norepinephrine concentration. Even after plasma epinephrine was raised nearly 20-fold by means of an intravenous infusion for 4 h in seven normal subjects, neither sites (608 +/- 68 vs. 567 +/- 120 sites/platelet) nor KD (2.01 +/- 0.94 vs. 2.14 +/- 1.15 nM) were significantly changed. Similarly, neither sites (445 +/- 55 vs. 421 +/- 53 sites/platelet) nor KD (1.44 +/- 0.29 vs. 2.10 +/- 0.75 nM) were significantly changed in six normal subjects when plasma norepinephrine levels increased during oral administration of prazosin for 1 wk. Thus, in a cross-sectional analysis and after a change in plasma catecholamine concentrations, there was no relationship in normal subjects between platelet alpha-2 binding site number or affinity of these sites for antagonist radioligands and the circulating catecholamine levels to which the platelets were exposed. In a group (n = 7) of patients who lack epinephrine-induced platelet aggregation due to abnormal thrombopoiesis, binding site number was decreased (304 +/- 36 vs. 572 +/- 29 sites/platelet, P less than 0.001) and KD tended to be greater (8.69 +/- 2.44 vs. 5.40 +/- 0.31 nM, P = NS) than in normal subjects (n = 46), despite having similar plasma catecholamine levels. There was no difference in binding site number (491 +/- 116 sites/platelet) and KD (5.61 +/- 0.84 nM) in patients (n = 5) with autonomic insufficiency and low levels of upright plasma norepinephrine when compared with the normal subjects. Two patients were examined before and after the removal of a pheochromocytoma. Their binding site number and KD were normal before the operation and essentially unchanged after the tumor removal and fall of plasma catecholamines. Thus, this study demonstrates that within the physiologic and pathophysiologic range of plasma catecholamines (in men), there is no relationship between the circulating catecholamine concentration and either platelet alpha-2 adrenergic binding site number or the affinity of these sites for antagonist radioligands.
PMCID: PMC425265  PMID: 6088579
11.  Smoking in Asthma Is Associated with Elevated Levels of Corticosteroid Resistant Sputum Cytokines—An Exploratory Study 
PLoS ONE  2013;8(8):e71460.
Background
Current cigarette smoking is associated with reduced acute responses to corticosteroids and worse clinical outcomes in stable chronic asthma. The mechanism by which current smoking promotes this altered behavior is currently unclear. Whilst cytokines can induce corticosteroid insensitivity in-vitro, how current and former smoking affects airway cytokine concentrations and their responses to oral corticosteroids in stable chronic asthma is unclear.
Objectives
To examine blood and sputum cytokine concentrations in never, ex and current smokers with asthma before and after oral corticosteroids.
Methods
Exploratory study utilizing two weeks of oral dexamethasone (equivalent to 40 mg/day prednisolone) in 22 current, 21 never and 10 ex-smokers with asthma. Induced sputum supernatant and plasma was obtained before and after oral dexamethasone. 25 cytokines were measured by multiplex microbead system (Invitrogen, UK) on a Luminex platform.
Results
Smokers with asthma had elevated sputum cytokine interleukin (IL) -6, -7, and -12 concentrations compared to never smokers with asthma. Few sputum cytokine concentrations changed in response to dexamethasone IL-17 and IFNα increased in smokers, CCL4 increased in never smokers and CCL5 and CXCL10 reduced in ex-smokers with asthma. Ex-smokers with asthma appeared to have evidence of an ongoing corticosteroid resistant elevation of cytokines despite smoking cessation. Several plasma cytokines were lower in smokers with asthma compared to never smokers with asthma.
Conclusion
Cigarette smoking in asthma is associated with a corticosteroid insensitive increase in multiple airway cytokines. Distinct airway cytokine profiles are present in current smokers and never smokers with asthma and could provide an explanatory mechanism for the altered clinical behavior observed in smokers with asthma.
doi:10.1371/journal.pone.0071460
PMCID: PMC3739804  PMID: 23951170
12.  Stress-related cardiomyopathies 
Stress-related cardiomyopathies can be observed in the four following situations: Takotsubo cardiomyopathy or apical ballooning syndrome; acute left ventricular dysfunction associated with subarachnoid hemorrhage; acute left ventricular dysfunction associated with pheochromocytoma and exogenous catecholamine administration; acute left ventricular dysfunction in the critically ill. Cardiac toxicity was mediated more by catecholamines released directly into the heart via neural connection than by those reaching the heart via the bloodstream. The mechanisms underlying the association between this generalized autonomic storm secondary to a life-threatening stress and myocardial toxicity are widely discussed. Takotsubo cardiomyopathy has been reported all over the world and has been acknowledged by the American Heart Association as a form of reversible cardiomyopathy. Four "Mayo Clinic" diagnostic criteria are required for the diagnosis of Takotsubo cardiomyopathy: 1) transient left ventricular wall motion abnormalities involving the apical and/or midventricular myocardial segments with wall motion abnormalities extending beyond a single epicardial coronary artery distribution; 2) absence of obstructive epicardial coronary artery disease that could be responsible for the observed wall motion abnormality; 3) ECG abnormalities, such as transient ST-segment elevation and/or diffuse T wave inversion associated with a slight troponin elevation; and 4) the lack of proven pheochromocytoma and myocarditis. ECG changes and LV dysfunction occur frequently following subarachnoid hemorrhage and ischemic stroke. This entity, referred as neurocardiogenic stunning, was called neurogenic stress-related cardiomyopathy. Stress-related cardiomyopathy has been reported in patients with pheochromocytoma and in patients receiving intravenous exogenous catecholamine administration. The role of a huge increase in endogenous and/or exogenous catecholamine level in critically ill patients (severe sepsis, post cardiac resuscitation, post tachycardia) to explain the onset of myocardial dysfunction was discussed. Further research is needed to understand this complex interaction between heart and brain and to identify risk factors and therapeutic and preventive strategies.
doi:10.1186/2110-5820-1-39
PMCID: PMC3224539  PMID: 21933374
13.  Use of Exhaled Nitric Oxide Measurement to Identify a Reactive, at-Risk Phenotype among Patients with Asthma 
Rationale: Exhaled nitric oxide (FeNO) is a biomarker of airway inflammation in mild to moderate asthma. However, whether FeNO levels are informative regarding airway inflammation in patients with severe asthma, who are refractory to conventional treatment, is unknown. Here, we hypothesized that classification of severe asthma based on airway inflammation as defined by FeNO levels would identify a more reactive, at-risk asthma phenotype.
Methods: FeNO and major features of asthma, including airway inflammation, airflow limitation, hyperinflation, hyperresponsiveness, and atopy, were determined in 446 individuals with various degrees of asthma severity (175 severe, 271 nonsevere) and 49 healthy subjects enrolled in the Severe Asthma Research Program.
Measurements and Main Results: FeNO levels were similar among patients with severe and nonsevere asthma. The proportion of individuals with high FeNO levels (>35 ppb) was the same (40%) among groups despite greater corticosteroid therapy in severe asthma. All patients with asthma and high FeNO had more airway reactivity (maximal reversal in response to bronchodilator administration and by methacholine challenge), more evidence of allergic airway inflammation (sputum eosinophils), more evidence of atopy (positive skin tests, higher serum IgE and blood eosinophils), and more hyperinflation, but decreased awareness of their symptoms. High FeNO identified those patients with severe asthma characterized by the greatest airflow obstruction and hyperinflation and most frequent use of emergency care.
Conclusions: Grouping of asthma by FeNO provides an independent classification of asthma severity, and among patients with severe asthma identifies the most reactive and worrisome asthma phenotype.
doi:10.1164/rccm.200905-0695OC
PMCID: PMC2874447  PMID: 20133930
nitric oxide; severe asthma; phenotype; airway reactivity; exhaled breath
14.  Plasma catecholamines during exercise-induced bronchoconstriction in bronchial asthma. 
Thorax  1980;35(11):823-827.
Plasma levels of adrenaline and noradrenaline during and after submaximal exercise in patients with bronchial asthma were investigated. Three groups were studied comprising 10 patients with exercise-induced bronchoconstriction (EIB), 10 asthmatic patients without EIB and four normal control subjects. Plasma catecholamines were measured at rest, at the end of exercise, and five and 15 minutes after exercise. Changes in airway resistance were assessed by measuring peak expiratory flow rate. Significant differences in catecholamine levels between reacting and non-reacting patients were found. In 10 patients developing EIB adrenaline and noradrenaline levels had risen significantly by the end of exercise and remained elevated up to the fifth minute of recovery. The rise in catecholamine levels in non-reacting asthmatics was insignificant. In control subjects noradrenaline had increased significantly by the end of exercise.
PMCID: PMC471391  PMID: 7221977
15.  Acute myocardial infarction is associated with endothelial glycocalyx and cell damage and a parallel increase in circulating catecholamines 
Critical Care  2013;17(1):R32.
Introduction
Excessive sympathoadrenal activation in critical illness contributes directly to organ damage, and high concentrations of catecholamines damage the vascular endothelium. This study investigated associations between potential drivers of sympathoadrenal activation, circulating catecholamines and biomarkers of endothelial damage and outcome in ST segment elevation myocardial infarction (STEMI)-patients, hypothesizing that the catecholamine surge would reflect shock degree and correlate with biomarkers of endothelial damage.
Methods
This was a prospective study of 678 consecutive STEMI-patients admitted to a single high-volume invasive heart centre for primary percutaneous coronary intervention (pPCI) from September 2006 to July 2008. Blood samples were drawn immediately before pPCI. Plasma adrenaline, noradrenaline, syndecan-1 and thrombomodulin were measured retrospectively with complete data in 571 patients (84%). Median follow-up time was 28 (IQR 23 to 34) months. Follow-up was 99.7% complete. Outcomes were all-cause and cardiovascular mortality, re-myocardial infarction and admission due to heart failure.
Results
Circulating noradrenaline and adrenaline correlated weakly but independently with syndecan-1 (rho = 0.15 and rho = 0.13, both P <0.01) and thrombomodulin (rho = 0.11 and rho = 0.17, both P <0.01), biomarkers of glycocalyx and endothelial cell damage, respectively. Considering biomarkers, patients with shock pre-pPCI had higher adrenaline and syndecan-1 and patients admitted to ICU post-pPCI had higher syndecan-1 (all P <0.05), and in the patients with shock (n = 51) catecholamines correlated strongly with thrombomodulin and syndecan-1 (rho = 0.31 to 0.42, all P <0.05). During follow-up, 78 (14%) patients died (37 cardiovascular deaths) and 65 (11%) were admitted with heart failure. By multivariate Cox proportional hazards analyses, one quartile higher plasma adrenaline was weakly but independently associated with both 30-day and long term mortality and heart failure (30-day all-cause mortality hazard ratio (95% CI) 1.39 (1.01 to 1.92), P = 0.046; 30-day heart failure 1.65 (1.17 to 2.34), P = 0.005; and long-term cardiovascular mortality 1.49 (1.08 to 2.04), P = 0.014). Furthermore, one quartile higher syndecan-1 was also weakly but independently associated with long-term all cause mortality (1.26 (1.02 to 1.57), P = 0.034).
Conclusions
In STEMI patients treated with pPCI, catecholamines correlated weakly with biomarkers of endothelial damage, with the strongest correlations and highest adrenaline and syndecan-1 levels in patients with shock. Furthermore, adrenaline and syndecan-1 were weakly but independently associated with mortality and heart failure. Acute myocardial infarction appears to cause significant endothelial cell and glycocalyx injury and a parallel increase in circulating catecholamines.
doi:10.1186/cc12532
PMCID: PMC4057225  PMID: 23433357
16.  Enhanced Dense Core Granule Function and Adrenal Hypersecretion in a Mouse Model of Rett Syndrome 
Rett Syndrome (RTT) is a progressive developmental disorder resulting from loss of function mutations in the gene encoding MeCP2 (methyl-CpG-binding protein 2), a transcription regulatory protein. The RTT phenotype is complex and includes severe cardiorespiratory abnormalities, dysautonomia and behavioral symptoms of elevated stress. These findings have been attributed to an apparent hyperactivity of the sympathetic nervous system due to defects in brainstem development; however, the possibility that the peripheral sympathoadrenal axis itself is abnormal has not been explored. The present study demonstrates that the adrenal medulla and sympathetic ganglia of Mecp2 null mice exhibit markedly reduced catecholamine content compared to wildtype controls. Despite this, null animals exhibit significantly higher plasma epinephrine levels, suggesting enhanced secretory granule function in adrenal chromaffin cells. Indeed, we find that Mecp2 null chromaffin cells exhibit a cell autonomous hypersecretory phenotype characterized by significant increases in the speed and size of individual secretory granule fusion events in response to electrical stimulation. These findings appear to indicate accelerated formation and enhanced dilation of the secretory granule fusion pore, resulting in elevated catecholamine release. Our data therefore highlight abnormal catecholamine function in the sympathoadrenal axis as a potential source of autonomic dysfunction in RTT. These findings may help to explain the apparent “overactivity” of the sympathetic nervous system reported in RTT patients.
doi:10.1111/j.1460-9568.2009.06858.x
PMCID: PMC2758854  PMID: 19674087
exocytosis; chromaffin; sympathetic; neurosecretion; neuroendocrine
17.  Nocturnal asthma and urinary adrenaline and noradrenaline excretion 
Thorax  1977;32(6):677-683.
Soutar, C. A., Carruthers, M., and Pickering, C. A. C. (1977).Thorax, 32, 677-683. Nocturnal asthma and urinary adrenaline and noradrenaline excretion. Urinary adrenaline and noradrenaline excretion, heart rate, and peak expiratory flow rate have been measured every two hours for 24 hours in seven asthmatic patients suffering from nocturnal or early morning exacerbations of dyspnoea. The excretions of these catecholamines were normal or slightly raised, this being consistent with a normal response to asthma or the conditions of the test.
The expected physiological fall in catecholamine excretion occurred at night. In every patient the peak expiratory flow rate fell to its lowest values during the period of lowest catecholamine excretion, and the mean two-hourly peak expiratory flow rate for all seven patients was significantly related to the sum of the mean adrenaline and noradrenaline excretion in each preceding two-hour period (p<0·05).
Individually, in three patients the relationship between peak expiratory flow rate and adrenaline and noradrenaline excretion during the evening and night was so close as to be consistent with the hypothesis that changes in sympathetic tone mediated the changes in asthma. In a further three patients the relationship was present but less clear, and in one the changes in peak flow rate and catecholamine excretion were dissociated.
Studies of mean heart rate and sinus arrhythmia gap suggested that an increase in vagal tone at night might have mediated the early morning asthma in the patient in whom changes in catecholamine excretion were dissociated from change in peak flow rate.
These findings would be consistent with the view that the physiological reduction in sympathetic tone at night mediates the nocturnal and early morning exacerbation of dyspnoea in some asthmatics, although other mechanisms such as alterations in vagal tone must be important in others. Confirmation of a causal relationship requires further study.
PMCID: PMC470812  PMID: 601729
18.  Features of severe asthma in school-age children: Atopy and increased exhaled nitric oxide 
Background
Children with severe asthma have persistent symptoms despite treatment with inhaled corticosteroids (ICSs). The differentiating features of severe asthma in children are poorly defined.
Objective
To identify features of severe versus mild-to-moderate asthma in school-age children using noninvasive assessments of lung function, atopy, and airway inflammation.
Methods
A total of 75 children (median age, 10 years) with asthma underwent baseline characterization including spirometry and lung volume testing, methacholine bronchoprovocation, allergy evaluation, and offline measurement of exhaled nitric oxide (FENO). Twenty-eight were followed longitudinally over 6 months. Participants were assigned to the severe asthma subgroup if they required high-dose ICS plus 2 or more minor criteria.
Results
Children with severe versus mild-to-moderate asthma had more symptoms, greater airway obstruction, more gas trapping, and increased bronchial responsiveness to methacholine. Subjects with severe asthma also had higher concentrations of FENO and significantly greater sensitization to aeroallergens. With long-term study, both the reduction in FEV1 and increase in FENO persisted in the severe versus mild-to-moderate group. Furthermore, despite adjustments in ICS doses, the frequency of exacerbations was significantly higher in subjects with severe (83%) versus mild-to-moderate asthma (43%).
Conclusion
Severe asthma in childhood is characterized by poor symptom control despite high-dose ICS treatment and can be differentiated from mild-to-moderate asthma by measurement of lung function and FENO.
Clinical implications
Clinicians should suspect severe asthma in children with poor response to ICS, airway obstruction, and high FENO.
doi:10.1016/j.jaci.2006.08.019
PMCID: PMC2878140  PMID: 17157650
Children; asthma; atopy; nitric oxide; pulmonary function testing
19.  Evaluation and Validation of a Method for Determining Platelet Catecholamine in Patients with Obstructive Sleep Apnea and Arterial Hypertension 
PLoS ONE  2014;9(6):e98407.
Background
Measurements of plasma and urinary catecholamine are susceptible to confounding factors that influence the results, complicating the interpretation of sympathetic nervous system (SNS) activity in the Obstructive sleep apnea (OSA) and arterial hypertension (HYP) conditions.
Objective
In this study, we validated a test for platelet catecholamine and compared the catecholamine levels (adrenaline and noradrenaline) in urine, plasma and platelets in patients with OSA and HYP compared with controls.
Methods
In the validation, 30 healthy, nonsmoking volunteers who were not currently undergoing treatment or medication were selected as the control group. One hundred fifty-four individuals (114 OSA, 40 non-OSA) were consecutively selected from the outpatient clinic of the Sleep Institute and underwent clinical, polysomnographic and laboratory evaluation, including the urinary, plasma and platelet levels of adrenaline (AD) and noradrenaline (NA). Patients were then allocated to groups according to the presence of OSA and/or hypertension.
Results
A logistic regression model, controlled for age and BMI, showed that urinary AD and urinary NA were risk factors in the OSA+HYP group and the HYP group; however, the model showed higher levels of platelet NA for OSA without HYP. After 1 year of CPAP (continuous upper airway pressure) treatment, patients (n = 9) presented lower levels of urinary NA (p = 0.04) and platelet NA (p = 0.05).
Conclusion
Urinary NA and AD levels were significantly associated with the condition of hypertension with and without OSA, whereas platelet NA with OSA without comorbidity. These findings suggest that platelet catecholamine levels might reflect nocturnal sympathetic activation in OSA patients without hypertension.
doi:10.1371/journal.pone.0098407
PMCID: PMC4049580  PMID: 24911183
20.  Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study 
PLoS Medicine  2014;11(7):e1001669.
In this study, Granell and colleagues used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in the Avon Longitudinal Study of Parents and Children (ALSPAC) and found that higher BMI increases the risk of asthma in mid-childhood.
Please see later in the article for the Editors' Summary
Background
Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.
Methods and Findings
We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38–4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19–3.03) than for atopic asthma (1.37, 95% CI 0.89–2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11–1.79) per 0.5 kg and 2.25 (95% CI 1.23–4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.
Conclusions
Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The global burden of asthma, a chronic (long-term) condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs), has been rising steadily over the past few decades. It is estimated that, nowadays, 200–300 million adults and children worldwide are affected by asthma. Although asthma can develop at any age, it is often diagnosed in childhood—asthma is the most common chronic disease in children. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke, becoming narrower so that less air can enter the lungs. Exercise, cold air, and infections can also trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
We cannot halt the ongoing rise in global asthma rates without understanding the causes of asthma. Some experts think obesity may be one cause of asthma. Obesity, like asthma, is increasingly common, and observational studies (investigations that ask whether individuals exposed to a suspected risk factor for a condition develop that condition more often than unexposed individuals) in children have reported that body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) is positively associated with asthma. Observational studies cannot prove that obesity causes asthma because of “confounding.” Overweight children with asthma may share another unknown characteristic (confounder) that actually causes both obesity and asthma. Moreover, children with asthma may be less active than unaffected children, so they become overweight (reverse causality). Here, the researchers use “Mendelian randomization” to assess whether BMI has a causal effect on asthma. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the effect of a modifiable risk factor and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if a higher BMI leads to asthma, genetic variants associated with increased BMI should be associated with an increased risk of asthma.
What Did the Researchers Do and Find?
The researchers investigated causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in 4,835 children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC, a long-term health project that started in 1991). They calculated an allele score for each child based on 32 BMI-related genetic variants, and estimated associations between this score and BMI, fat mass and lean mass (both measured using a special type of X-ray scanner; in children BMI is not a good indicator of “fatness”), and asthma. They report that the allele score was strongly associated with BMI, fat mass, and lean mass, and with childhood asthma. The estimated causal relative risk (risk ratio) for the effect of BMI on asthma was 1.55 per kg/m2. That is, the relative risk of asthma increased by 55% for every extra unit of BMI. The estimated causal relative risks for the effects of fat mass and lean mass on asthma were 1.41 per 0.5 kg and 2.25 per kg, respectively.
What Do These Findings Mean?
These findings suggest that a higher BMI increases the risk of asthma in mid-childhood and that global increases in BMI toward the end of the 20th century may have contributed to the global increase in asthma that occurred at the same time. It is possible that the observed association between BMI and asthma reported in this study is underpinned by “genetic pleiotropy” (a potential limitation of all Mendelian randomization analyses). That is, some of the genetic variants included in the BMI allele score could conceivably also increase the risk of asthma. Nevertheless, these findings suggest that public health interventions designed to reduce obesity may also help to limit the global rise in asthma.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001669.
The US Centers for Disease Control and Prevention provides information on asthma and on all aspects of overweight and obesity (in English and Spanish)
The World Health Organization provides information on asthma and on obesity (in several languages)
The UK National Health Service Choices website provides information about asthma, about asthma in children, and about obesity (including real stories)
The Global Asthma Report 2011 is available
The Global Initiative for Asthma released its updated Global Strategy for Asthma Management and Prevention on World Asthma Day 2014
Information about the Avon Longitudinal Study of Parents and Children is available
MedlinePlus provides links to further information on obesity in children, on asthma, and on asthma in children (in English and Spanish
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001669
PMCID: PMC4077660  PMID: 24983943
21.  A pathogenic role of visceral fat beta 3-adrenoceptors in obesity. 
Journal of Clinical Investigation  1995;95(3):1109-1116.
Increased release of free fatty acids (FFA) from visceral fat cells to the portal venous system may cause several metabolic disturbances in obesity. However, this hypothesis and the underlying mechanism remain to be demonstrated. In this study catecholamine-induced lipid mobilization through lipolysis in omental adipose tissue was investigated in vitro in 25 markedly obese subjects (body mass index range 35-56 kg/m2) undergoing weight reduction surgery and in 19 nonobese subjects (body mass index range 20-28 kg/m2) undergoing cholecystectomy. Release of FFA and glycerol, induced by norepinephrine or adrenergic receptor subtype-specific agonists, were determined in isolated omental fat cells. The obese subjects had higher fat cell volume, blood pressure, plasma insulin levels, blood glucose, plasma triglycerides, and plasma cholesterol than the controls. There was evidence of upper-body fat distribution in the obese group. The rate of FFA and glycerol response to norepinephrine was increased twofold in the cells of obese subjects; no significant reutilization of FFA during catecholamine-induced lipolysis was observed in any of the groups (glycerol/FFA ratio near 1:3). There were no differences in the lipolytic sensitivity to beta 3- or beta 2-adrenoceptor specific agonists between the two groups. However, beta 3-adrenoceptor sensitivity was approximately 50 times enhanced (P = 0.0001), and the coupling efficiency of these receptors was increased from 37 to 56% (P = 0.01) in obesity. Furthermore, the obese subjects demonstrated a sixfold lower alpha 2-adrenoceptor sensitivity (P = 0.04). beta 3-Adrenoceptor sensitivity, but not alpha 2-, beta 1-, or beta 2-adrenoceptor sensitivity, correlated with norepinephrine-induced lipolysis (r = -0.67, P = 0.0001) and fat cell volume (r = -0.71, P = 0.0001). In conclusion, catecholamine-induced rate of FFA mobilization from omental fat cells is accelerated due to elevated rate of lipolysis in obesity, mainly because of an increased beta 3-adrenoceptor function, but partly also because of a decreased alpha 2-adrenoceptor function. This promotes an increased release of FFA to the portal system, which may contribute to the parallel metabolic disturbances observed in upper-body obesity.
PMCID: PMC441447  PMID: 7883959
22.  Regulation of glucose turnover during exercise in pancreatectomized, totally insulin-deficient dogs. Effects of beta-adrenergic blockade. 
Journal of Clinical Investigation  1988;81(6):1759-1767.
To examine whether glucose metabolic clearance increases and whether catecholamines influence glucose turnover during exercise in total insulin deficiency, 24-h fasted and insulin-deprived pancreatectomized dogs were studied before and during exercise (60 min; 100 m/min; 10% slope) with (n = 8) and without (n = 8) propranolol infusion (PI, 5 micrograms/kg-min). Exercise with or without PI was accompanied by four and fivefold increments in norepinephrine and epinephrine respectively, while glucagon (extrapancreatic) fell slightly. Basal plasma glucose and FFA concentrations and rates of tracer-determined (3[3H]glucose) hepatic glucose production (Ra) and total glucose clearance (including urinary glucose loss) were 459 +/- 24 mg/dl, 1.7 +/- 0.5 mmol/liter, 7.8 +/- 0.9 mg/kg-min and 1.6 +/- 0.1 ml/kg-min, respectively. When corrected for urinary glucose excretion, basal glucose metabolic clearance rate (MCR) was 0.7 +/- 0.1 mg/kg-min and rose twofold (P less than 0.0001) during exercise. Despite lower lactate (3.3 +/- 0.6 vs. 6.6 +/- 1.3 mmol/liter; P less than 0.005) and FFA levels (1.1 +/- 0.2 vs. 2.2 +/- 0.2 mmol/liter; P less than 0.0001) with PI, PI failed to influence MCR during exercise. Ra rose by 3.7 +/- 1.7 mg/kg-min during exercise (P less than 0.02) while with PI the increase was only 1.9 +/- 0.7 mg/kg-min (P less than 0.002). Glucose levels remained unchanged during exercise alone but fell slightly with PI (P less than 0.0001). Therefore, in total insulin deficiency, MCR increases marginally with exercise (13% of normal); the beta adrenergic effects of catecholamines that stimulate both FFA mobilization and muscle glycogenolysis do not regulate muscle glucose uptake. The exercise-induced rise in hepatic glucose production does not require an increase in glucagon levels, but is mediated partially by catecholamines. Present and previous data in normal and alloxan-diabetic dogs, suggest that (a) in total insulin deficiency, control of hepatic glucose production during exercise is shifted from glucagon to catecholamines and that this may involve catecholamine-induced mobilization of peripheral substrates for gluconeogenesis and/or hepatic insensitivity to glucagon, and (b) insulin is not essential for a small exercise-induced increase in muscle glucose uptake, but normal insulin levels are required for the full response. Furthermore, the catecholamines appear to regulate muscle glucose uptake during exercise only when sufficient insulin is available to prevent markedly elevated FFA levels. We speculate that the main role of insulin is not to regulate glucose uptake by the contracting muscle directly, but to restrain lipolysis and thereby also FFA oxidation in the muscle.
PMCID: PMC442622  PMID: 3290252
23.  The protective effect of a beta 2 agonist against excessive airway narrowing in response to bronchoconstrictor stimuli in asthma and chronic obstructive lung disease. 
Thorax  1991;46(1):9-14.
Beta 2 agonists reduce airway hypersensitivity to bronchoconstrictor stimuli acutely in patients with asthma and chronic obstructive lung disease. To determine whether these drugs also protect against excessive airway narrowing, the effect of inhaled salbutamol on the position and shape of the dose-response curves for histamine or methacholine was investigated in 12 patients with asthma and 11 with chronic obstructive lung disease. After pretreatment with salbutamol (200 or 400 micrograms) or placebo in a double blind manner dose-response curves for inhaled histamine and methacholine were obtained by a standard method on six days in random order. Airway sensitivity was defined as the concentration of histamine or methacholine causing a 20% fall in FEV1 (PC20). A maximal response plateau on the log dose-response curve was considered to be present if two or more data points for FEV1 fell within a 5% response range. In the absence of a plateau, the test was continued until a predetermined level of severe bronchoconstriction was reached. Salbutamol caused an acute increase in FEV1 (mean increase 11.5% predicted in asthma, 7.2% in chronic obstructive lung disease), and increase in PC20 (mean 15 fold in asthma, fivefold in chronic obstructive lung disease), and an increase in the slope of the dose-response curves in both groups. In subjects in whom a plateau of FEV1 response could be measured salbutamol did not change the level of the plateau. In subjects without a plateau salbutamol did not lead to the development of a plateau, despite achieving a median FEV1 of 44% predicted in asthma and 39% in chronic obstructive lung disease. These results show that, although beta 2 agonists acutely reduce the airway response to a given strength of bronchoconstrictor stimulus, they do not protect against excessive airflow obstruction if there is exposure to relatively strong stimuli. This, together with the steepening of the dose-response curve, could be a disadvantage of beta 2 agonists in the treatment of moderate and severe asthma or chronic obstructive lung disease.
PMCID: PMC1020906  PMID: 1871705
24.  Direct relationship between mononuclear leukocyte and lung beta-adrenergic receptors and apparent reciprocal regulation of extravascular, but not intravascular, alpha- and beta-adrenergic receptors by the sympathochromaffin system in humans. 
To examine putative relationships between adrenergic receptors on accessible circulating cells and relatively inaccessible extravascular catecholamine target tissues, we measured mononuclear leukocyte (MNL) and lung beta-adrenergic receptors and platelet and lung alpha-adrenergic receptors in tissues obtained from 15 patients undergoing pulmonary resection. Plasma catecholamine concentrations were measured concurrently to explore potential regulatory relationships between the activity of the sympathochromaffin system and both intravascular and extravascular adrenergic receptors. MNL and lung membrane beta-adrenergic receptor densities were correlated highly (r = 0.845, P less than 0.001). Platelet alpha 2-adrenergic receptor and lung alpha 1-adrenergic receptor densities were not. Lung alpha 1-adrenergic receptor densities were positively related to plasma norepinephrine (r = 0.840, P less than 0.01) and epinephrine (r = 0.860, P less than 0.01) concentrations; in contrast, lung beta-adrenergic receptor densities were not positively related to plasma catecholamine concentrations (they tended to be inversely related to plasma norepinephrine and epinephrine [r = -0.698, P less than 0.05] levels). This apparent reciprocal regulation of alpha- and beta-adrenergic receptors by the sympathochromaffin system was only demonstrable with adrenergic receptor measurements in the extravascular catecholamine target tissue. Neither MNL beta-adrenergic receptor nor platelet alpha-adrenergic receptor densities were correlated with plasma catecholamine levels. Thus, although measurements of beta-adrenergic receptors on circulating mononuclear leukocytes can be used as indices of extravascular target tissue beta-adrenergic receptor densities (at least in lung and heart), it would appear that extravascular tissues should be used to study adrenergic receptor regulation by endogenous catecholamines in humans. These data provide further support for the concept of up regulation, as well as down regulation, of some adrenergic receptor populations during short-term activation of the sympathochromaffin system in humans.
PMCID: PMC303475  PMID: 2839552
25.  Respiratory symptoms in adults are related to impaired quality of life, regardless of asthma and COPD: results from the European community respiratory health survey 
Background
Respiratory symptoms are common in the general population, and their presence is related to Health-related quality of life (HRQoL). The objective was to describe the association of respiratory symptoms with HRQoL in subjects with and without asthma or COPD and to investigate the role of atopy, bronchial hyperresponsiveness (BHR), and lung function in HRQoL.
Methods
The European Community Respiratory Health Survey (ECRHS) I and II provided data on HRQoL, lung function, respiratory symptoms, asthma, atopy, and BHR from 6009 subjects. Generic HRQoL was assessed through the physical component summary (PCS) score and the mental component summary (MCS) score of the SF-36.
Factor analyses and linear regressions adjusted for age, gender, smoking, occupation, BMI, comorbidity, and study centre were conducted.
Results
Having breathlessness at rest in ECRHS II was associated with mean score (95% CI) impairment in PCS of -8.05 (-11.18, -4.93). Impairment in MCS score in subjects waking up with chest tightness was -4.02 (-5.51, -2.52). The magnitude of HRQoL impairment associated with respiratory symptoms was similar for subjects with and without asthma/COPD. Adjustments for atopy, BHR, and lung function did not explain the association of respiratory symptoms and HRQoL in subjects without asthma and/or COPD.
Conclusion
Subjects with respiratory symptoms had poorer HRQoL; including subjects without a diagnosis of asthma or COPD. These findings suggest that respiratory symptoms in the absence of a medical diagnosis of asthma or COPD are by no means trivial, and that clarifying the nature and natural history of respiratory symptoms is a relevant challenge.
Several community studies have estimated the prevalence of common respiratory symptoms like cough, dyspnoea, and wheeze in adults [1-3]. Although the prevalence varies to a large degree between studies and geographical areas, respiratory symptoms are quite common. The prevalences of respiratory symptoms in the European Community Respiratory Health Study (ECRHS) varied from one percent to 35% [1]. In fact, two studies have reported that more than half of the adult population suffers from one or more respiratory symptoms [4,5].
Respiratory symptoms are important markers of the risk of having or developing disease. Respiratory symptoms have been shown to be predictors for lung function decline [6-8], asthma [9,10], and even all-cause mortality in a general population study [11]. In patients with a known diagnosis of asthma or chronic obstructive pulmonary disease (COPD), respiratory symptoms are important determinants of reduced health related quality of life (HRQoL) [12-15]. The prevalence of respiratory symptoms exceeds the combined prevalences of asthma and COPD, and both asthma and COPD are frequently undiagnosed diseases [16-18]. Thus, the high prevalence of respipratory symptoms may mirror undiagnosed and untreated disease.
The common occurrence of respiratory symptoms calls for attention to how these symptoms affect health also in subjects with no diagnosis of obstructive airways disease. Impaired HRQoL in the presence of respiratory symptoms have been found in two population-based studies [6,19], but no study of respiratory sypmtoms and HRQoL have separate analyses for subjects with and without asthma and COPD, and no study provide information about extensive objective measurements of respiratory health.
The ECRHS is a randomly sampled, multi-cultural, population based cohort study. The ECRHS included measurements of atopy, bronchial hyperresponsiveness (BHR), and lung function, and offers a unique opportunity to investigate how respiratory symptoms affect HRQoL among subjects both with and without obstructive lung disease.
In the present paper we aimed to: 1) Describe the relationship between respiratory symptoms and HRQoL in an international adult general population and: 2) To assess whether this relationship varied with presence of asthma and/or COPD, or presence of objective functional markers like atopy and BHR.
doi:10.1186/1477-7525-8-107
PMCID: PMC2954977  PMID: 20875099

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