Panlobular emphysema is associated with COPD disease severity: A study of emphysema subtype by computed tomography.

BACKGROUND: Computed tomography has the potential to inform COPD prognosis. We sought to determine associations of emphysema phenotype with clinical parameters including lung function, inflammatory markers, and quality of life. METHODS: Participants of this single-center observational cohort (n = 83) were 40-80 years old, had ≥10 pack-year smoking, and a diagnosis of COPD confirmed by spirometry. All participants had available historic chest CT scans which were systematically reviewed by a single expert radiologist and scored for emphysema subtype, extent, and distribution. Associations between radiographic findings and clinical parameters were determined. RESULTS: Median age of participants was 72 years, median smoking 40 pack-years, and median FEV1 59% predicted. 84% of the participants had radiographic emphysema. Of those, 26% had panlobular emphysema (PLE), 68% centrilobular emphysema (CLE), and 6% paraseptal emphysema (PSE). As compared to the participants with no radiographic emphysema, the presence of PLE-dominant emphysema was associated with a lower BMI (P = 0.012) and greater extent of emphysema (P = 0.014). After adjusting for age, sex, and pack-years smoking history, PLE was associated with greater airflow obstruction by FEV1% (48% vs 71%, P = 0.005), greater symptom burden by CAT score (18 vs 9, P = 0.015), worse quality of life by SGRQ score (43 vs 22, P = 0.025), and more systemic inflammation by erythrocyte sedimentation rate (P = 0.001). CLE- or PSE-dominant emphysema were not similarly associated with clinical features or symptom burden. CONCLUSIONS: The presence of PLE-dominant emphysema was associated with greater extent of emphysema, greater airflow obstruction, increased respiratory symptoms, worse quality of life, and systemic inflammation. Further investigation is indicated to explore the pathogenesis of the PLE phenotype and the prognostic and treatment implications of PLE.

The role of citizen science in addressing grand challenges in food and agriculture research.

The power of citizen science to contribute to both science and society is gaining increased recognition, particularly in physics and biology. Although there is a long history of public engagement in agriculture and food science, the term 'citizen science' has rarely been applied to these efforts. Similarly, in the emerging field of citizen science, most new citizen science projects do not focus on food or agriculture. Here, we convened thought leaders from a broad range of fields related to citizen science, agriculture, and food science to highlight key opportunities for bridging these overlapping yet disconnected communities/fields and identify ways to leverage their respective strengths. Specifically, we show that (i) citizen science projects are addressing many grand challenges facing our food systems, as outlined by the United States National Institute of Food and Agriculture, as well as broader Sustainable Development Goals set by the United Nations Development Programme, (ii) there exist emerging opportunities and unique challenges for citizen science in agriculture/food research, and (iii) the greatest opportunities for the development of citizen science projects in agriculture and food science will be gained by using the existing infrastructure and tools of Extension programmes and through the engagement of urban communities. Further, we argue there is no better time to foster greater collaboration between these fields given the trend of shrinking Extension programmes, the increasing need to apply innovative solutions to address rising demands on agricultural systems, and the exponential growth of the field of citizen science.

Five-year follow-up of participants diagnosed with chronic airflow obstruction in a South African Burden of Obstructive Lung Disease (BOLD) survey.

BACKGROUND: A community-based prevalence survey performed in two suburbs in Cape Town, South Africa (SA), in 2005, using the international Burden of Obstructive Lung Disease (BOLD) method, confirmed a prevalence of chronic airflow obstruction (CAO) in 23.1% of adults aged >40 years. OBJECTIVES: To study the clinical course and prognosis over 5 years of patients with CAO identified in the 2005 survey. METHODS: Patients with CAO in 2005 were invited to participate. Standard BOLD and modified questionnaires were completed. Spirometry was performed using spirometers of the same make as in 2005. RESULTS: Of 196 eligible participants from BOLD 2005, 45 (23.0%) had died, 8 from respiratory causes, 10 from cardiovascular causes and 6 from other known causes, while in 21 cases the cause of death was not known. On multivariate analysis, only age and Global initiative for Obstructive Lung Disease (GOLD) stage 4 disease at baseline were significantly associated with death. Of the 151 survivors, 11 (5.6% of the original cohort) were unavailable and 33 (16.8%) declined or had medical exclusions. One hundred and seven survivors were enrolled in the follow-up study (54.6%, median age 63.1 years, 45.8% males). Post-bronchodilator spirometry performed in 106 participants failed to confirm CAO, defined as a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio of <0.7, in 16 participants (15.1%), but CAO was present in 90. The median decline in FEV1 was 28.9 mL/year (interquartile range -54.8 - 0.0) and was similar between GOLD stages. The median total decline in FVC was 75 mL, and was significantly greater in GOLD stage 1 (-350 mL) than in stages 2 or 3 (-80  mL and +140 mL, respectively; p<0.01). Fifty-eight participants with CAO in 2005 (64.4%) remained in the same GOLD stage, while 21 (23.3%) deteriorated and 11 (12.2%) improved by ≥1 stage. Only one-third were receiving any treatment for chronic obstructive pulmonary disease (COPD). CONCLUSIONS: The prevalence, morbidity and mortality of CAO and COPD in SA are high and the level of appropriate treatment is very low, pointing to underdiagnosis and inadequate provision of and access to effective treatments and preventive strategies for this priority chronic non-communicable disease.

Validation of the firefighter WFI treadmill protocol for predicting VO2 max.

BACKGROUND: The Wellness-Fitness Initiative submaximal treadmill exercise test (WFI-TM) is recommended by the US National Fire Protection Agency to assess aerobic capacity (VO2 max) in firefighters. However, predicting VO2 max from submaximal tests can result in errors leading to erroneous conclusions about fitness. AIMS: To investigate the level of agreement between VO2 max predicted from the WFI-TM against its direct measurement using exhaled gas analysis. METHODS: The WFI-TM was performed to volitional fatigue. Differences between estimated VO2 max (derived from the WFI-TM equation) and direct measurement (exhaled gas analysis) were compared by paired t-test and agreement was determined using Pearson Product-Moment correlation and Bland-Altman analysis. Statistical significance was set at P < 0.05. RESULTS: Fifty-nine men performed the WFI-TM. Mean (standard deviation) values for estimated and measured VO2 max were 44.6 (3.4) and 43.6 (7.9) ml/kg/min, respectively (P < 0.01). The mean bias by which WFI-TM overestimated VO2 max was 0.9ml/kg/min with a 95% prediction interval of ±13.1. Prediction errors for 22% of subjects were within ±5%; 36% had errors greater than or equal to ±15% and 7% had greater than ±30% errors. The correlation between predicted and measured VO2 max was r = 0.55 (standard error of the estimate = 2.8ml/kg/min). CONCLUSIONS: WFI-TM predicts VO2 max with 11% error. There is a tendency to overestimate aerobic capacity in less fit individuals and to underestimate it in more fit individuals leading to a clustering of values around 42ml/kg/min, a criterion used by some fire departments to assess fitness for duty.

Validation of heart rate derived from a physiological status monitor-embedded compression shirt against criterion ECG.

Firefighters are subject to extreme environments and high physical demands when performing duty-related tasks. Recently, physiological status monitors (PSM) have been embedded into a compression shirt to enable firefighters to measure, visualize, log, and transmit vital metrics such as heart rate (HR) to aid in cardiovascular risk identification and mitigation, thereby attempting to improve the health, fitness, and safety of this population. The purpose of this study was to validate HR recorded by the PSM-embedded compression shirt against a criterion standard laboratory ECG-derived HR when worn concurrently with structural firefighting personal protective equipment (PPE) during four simulated firefighting activities. Ten healthy, college-age men (mean ± SD: age: 21 ± 1 yr; body mass: 91 ± 10 kg; body mass index: 26.9 ± 3.1 kg/m(2)) completed four tasks that are routinely performed during firefighting operations: outdoor fast-paced walking (FW), treadmill walking (TW), searching/crawling (SC), and ascending/descending stairs (AD). They wore the PSM-embedded compression shirt under structural firefighting PPE. HR was recorded concurrently by the PSM-embedded compression shirt and a portable metabolic measurement system accompanied with a standard 12-lead electrocardiograph that was used to provide criterion measures of HR. For all four tasks combined there was very high correlation of PSM and ECG HR (r > 0.99; SEE 0.84 /min) with a mean difference (bias) of -0.02 /min and limits of agreement of -0.07 to 0.02 /min. For individual tasks, the correlations were also high (r-values = 0.99; SEE 0.81-0.89). The mean bias (limits of agreement) was: FW 0.03 (-0.09 to 0.14); TW 0.04 (-0.05 to 0.12); SC -0.01 (-0.12 to 0.10); AD -0.13 (-0.21 to -0.04) /min. These findings demonstrate that the PSM-embedded compression shirt provides a valid measure of HR during simulated firefighting activities when compared with a standard 12-lead ECG.

Determinants of dynamic hyperinflation during metronome-paced tachypnea in COPD and normal subjects.

In COPD, dynamic hyperinflation (DH) occurs during exercise and during metronome-paced tachypnea (MPT). We investigated the relationship of DH with breathing pattern and ventilation (V˙E) in COPD and normal subjects (NS). In 35 subjects with moderate COPD and 17 younger healthy volunteers we measured inspiratory capacity (IC), breathing frequency (fR), expiratory time (TE), ventilation (V˙E) and end-tidal carbon dioxide tension (PETCO2) at baseline and after 30s of MPT at 40breaths/min with metronome-defined I:E ratios of 1:1 and 1:2. A reduction in IC (ΔIC) was taken to indicate DH. In COPD subjects, DH correlated with TE but not with V˙E or PETCO2, and was best predicted by total lung capacity. NS also showed DH (although less than in COPD), which correlated with PETCO2 but not with fR, TE or V˙E. We conclude that MPT evokes DH in both NS and patients with COPD. TE is the most important determinant of DH during MPT in patients with COPD.

A review of the GOLD guidelines for the diagnosis and treatment of patients with COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death in the USA, and represents a major health, social and economic burden. COPD is underdiagnosed and often misdiagnosed, which likely contributes to the continuing increases in the prevalence, morbidity and mortality associated with this disease. This is unfortunate because whereas COPD cannot be cured, it can be treated effectively, particularly during the earlier stages of the disease. Evidence-based guidelines, developed to assist in the prevention, diagnosis and management of COPD, are available to healthcare professionals interested in learning more about COPD. These guidelines are updated and revised on a regular basis to reflect recent advances in our understanding of the pathophysiology of and treatments available for COPD. Nevertheless, primary-care physicians have reported a lack of awareness of the fundamental concepts underpinning the optimal treatment and management of COPD presented in the guidelines. Thus, the objective of this article is to summarise key physiologic, diagnostic and management concepts provided in the most recent update of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, which were published in November 2006.

On issues of confidence in determining the time constant for oxygen uptake kinetics.

BACKGROUND: TauVO(2 )at the onset of constant work rate (CWR) exercise is a variable of aerobic fitness that shortens with physical training and lengthens with cardiopulmonary disease. Determination of tauVO(2) with sufficiently high confidence has typically required multiple exercise transitions limiting its clinical application. OBJECTIVES: To design a protocol to determine tauVO(2) reliably but simply. METHODS: On each of three days, five healthy men performed two CWR tests on a cycle ergometer below the metabolic threshold (VO(2)theta) for blood lactate accumulation as determined by gas exchange measurements followed by an incremental work rate (IWR) test. TauVO(2) was determined (a) from the on-transit (on-tauVO(2)) and off-transit (off-tauVO(2)) of six CWR tests both individually and superimposed, using non-linear regression with a monoexponential model, and (b) by geometric analysis of the IWR tests (ramp-tauVO(2)). RESULTS: Group means (SD) were: VO(2)max 3.84 (0.44) litres/min, VO(2)theta 1.88 (0.23) litres/min, steady state exercise VO(2) 1.67 (0.07) litres/min, on-tauVO(2) 38.0 (5.3) seconds, off-tauVO(2) 39.0 (4.3) seconds, and ramp-tauVO(2) 60.8 (15.4) seconds. On-tauVO(2) correlated with off-tauVO(2) (r = 0.87), VO(2)max (r = -0.73), and VO(2)theta (r = 0.89). The pooled mean tauVO(2) from six superimposed tests agreed with the arithmetic grand mean of the six tests. CONCLUSIONS: The average of on-tauVO(2) and off-tauVO(2) fell within the 95% confidence interval of the pooled mean by the second test. Ramp-tauVO(2) was longer and less reproducible. These findings support the use of both on- and off-transit data for the determination of tauVO(2), an approach that reduces the number of transitions necessary for accurate determination of tauVO(2), potentially enhancing its clinical application.

Exercise in chronic pulmonary disease: limitations and rehabilitation.

Chronic pulmonary disease is common in the community and increasing in prevalence. Although numerous etiologies exist, chronic obstructive pulmonary disease secondary to tobacco smoking, and asthma constitute the majority of cases. The important impact of these diseases on patients is disabling breathlessness and impairment of functional exercise capacity. The symptoms set up a vicious cycle leading to physical deconditioning and worsening exercise performance. The discipline of pulmonary rehabilitation has been conclusively shown to reverse this process, resulting in improved functional capacity and reduced breathlessness. Pulmonary rehabilitation, therefore, should be viewed as essential secondary preventative care for the majority of patients with chronic pulmonary disease. As such, early disease recognition and implementation of exercise reconditioning is important. In order to be maximally effective, pulmonary rehabilitation must recognize the complex underlying pathophysiology in chronic pulmonary disease and be customized to the individual patient. The chosen mode of exercise training should recognize that in order to be truly beneficial, any physiological responses need to translate readily into improvements in activities of daily living. Therefore, sessions in pulmonary rehabilitation should concentrate on exercises that have proven useful in this regard. Aerobic and resistance exercise prescriptions should be rigorous, scientifically based, and derived from an understanding of the basic principles of the human response to exercise prescription. Each of these exercise prescriptions should encompass the basic principles of intensity, frequency, duration, and progression suitably modified for the individual patient with chronic pulmonary disease.

Exercise in chronic pulmonary disease: aerobic exercise prescription.

Endurance exercise training (EXT) is singly the most important aspect of rehabilitation for patients with chronic pulmonary disease. When effective, this modality of physical reconditioning leads to improved functional exercise capacity and reduced breathlessness. Early implementation is desirable to obtain more meaningful responses (e.g., when FEV1 falls below 50% of the predicted value in patients with chronic obstructive disease). Preparation for effective EXT requires optimization of respiratory system mechanics (e.g., using bronchodilator therapy), prevention of gas exchange failure (i.e., using supplemental oxygen), nutritional guidance, and psychological support (e.g., to overcome stigmata of disability, fear, and inclination to panic). EXT should be applied using a rigorous, scientifically based aerobic exercise prescription (AXRx) that recognizes basic principles of the human response to exercise prescription while considering individual pathophysiological limitations and identifying safety thresholds for exercise participation. The mode of aerobic exercise should use large muscle groups of the legs (e.g., treadmill or cycle ergometer). The recommended duration is an accumulation of 30 min of exercise per session at the target intensity, achieved by continuous or interval training. EXT should be supervised with a recommended frequency of at least three times per week for 6--8 wk. Target exercise intensity can be monitored by oxygen uptake, work rate, heart rate, or perceived exertion. Target intensity can be determined initially on the basis of 40% of a reference value for maximum oxygen uptake and linked to other variables through predictable interrelationships. All aspects of the AXRx must be reviewed with regard to progression during training. Pulmonary rehabilitation must recognize the importance of achieving clinically meaningful responses (e.g., increased 6-min walking distance of 54 m) as well as the need for maintenance exercise program to sustain the benefits.

alpha(4)-integrin mediates neutrophil-induced free radical injury to cardiac myocytes.

Previous work has demonstrated that circulating neutrophils (polymorphonuclear leukocytes [PMNs]) adhere to cardiac myocytes via beta(2)-integrins and cause cellular injury via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme system. Since PMNs induced to leave the vasculature (emigrated PMNs) express the alpha(4)-integrin, we asked whether (a) these PMNs also induce myocyte injury via NADPH oxidase; (b) beta(2)-integrins (CD18) still signal oxidant production, or if this process is now coupled to the alpha(4)-integrin; and (c) dysfunction is superoxide dependent within the myocyte or at the myocyte-PMN interface. Emigrated PMNs exposed to cardiac myocytes quickly induced significant changes in myocyte function. Myocyte shortening was decreased by 30-50% and rates of contraction and relaxation were reduced by 30% within the first 10 min. Both alpha(4)-integrin antibody (Ab)-treated PMNs and NADPH oxidase-deficient PMNs were unable to reduce myocyte shortening. An increased level of oxidative stress was detected in myocytes within 5 min of PMN adhesion. Addition of an anti-alpha(4)-integrin Ab, but not an anti-CD18 Ab, prevented oxidant production, suggesting that in emigrated PMNs the NADPH oxidase system is uncoupled from CD18 and can be activated via the alpha(4)-integrin. Addition of exogenous superoxide dismutase (SOD) inhibited all parameters of dysfunction measured, whereas overexpression of intracellular SOD within the myocytes did not inhibit the oxidative stress or the myocyte dysfunction caused by the emigrated PMNs. These findings demonstrate that profound molecular changes occur within PMNs as they emigrate, such that CD18 and associated intracellular signaling pathways leading to oxidant production are uncoupled and newly expressed alpha(4)-integrin functions as the ligand that signals oxidant production. The results also provide pathological relevance as the emigrated PMNs have the capacity to injure cardiac myocytes through the alpha(4)-integrin-coupled NADPH oxidase pathway that can be inhibited by extracellular, but not intracellular SOD.

Cross-talk between G-protein and protein kinase C modulation of N-type calcium channels is dependent on the G-protein beta subunit isoform.

The modulation of N-type calcium current by protein kinases and G-proteins is a factor in the fine tuning of neurotransmitter release. We have previously shown that phosphorylation of threonine 422 in the alpha(1B) calcium channel domain I-II linker region resulted in a dramatic reduction in somatostatin receptor-mediated G-protein inhibition of the channels and that the I-II linker consequently serves as an integration center for cross-talk between protein kinase C (PKC) and G-proteins (Hamid, J., Nelson, D., Spaetgens, R., Dubel, S. J., Snutch, T. P., and Zamponi, G. W. (1999) J. Biol. Chem. 274, 6195-6202). Here we show that opioid receptor-mediated inhibition of N-type channels is affected to a lesser extent compared with that seen with somatostatin receptors, hinting at the possibility that PKC/G-protein cross-talk might be dependent on the G-protein subtype. To address this issue, we have examined the effects of four different types of G-protein beta subunits on both wild type and mutant alpha(1B) calcium channels in which residue 422 has been replaced by glutamate to mimic PKC-dependent phosphorylation and on channels that have been directly phosphorylated by protein kinase C. Our data show that phosphorylation or mutation of residue 422 antagonizes the effect of Gbeta(1) on channel activity, whereas Gbeta(2), Gbeta(3), and Gbeta(4) are not affected. Our data therefore suggest that the observed cross-talk between G-proteins and protein kinase C modulation of N-type channels is a selective feature of the Gbeta(1) subunit.

Minimal domain requirement for cation transport by the potassium-dependent Na/Ca-K exchanger. Comparison with an NCKX paralog from Caenorhabditis elegans.

The retinal rod Na/Ca-K exchanger (NCKX) is a unique calcium extrusion protein utilizing both inward sodium gradient and outward potassium gradient. Three mammalian rod NCKX cDNAs have been cloned to date, but quantitative analysis of NCKX function in heterologous systems has proven difficult. Here, we describe a simple system for quantitative analysis of NCKX function; stable transformation of cultured insect cells with the novel pEA1/153A vector containing NCKX cDNAs was combined with measurements of potassium-dependent (45)Ca uptake in sodium-loaded cells. We carried out structure-function studies on NCKX with the following results: 1) two-thirds of the full-length sequence of bovine NCKX could be deleted without affecting potassium-dependent calcium transport and without affecting key properties of the potassium binding site; 2) the affinity of NCKX for potassium was about 10-fold greater in choline medium when compared with lithium medium; this shift was observed in rod outer segments or in cells expressing full-length rod NCKX, the above deletion mutant, or a distantly related NCKX paralog cloned from Caenorhabditis elegans. We conclude that the potassium binding site is highly conserved among members of the NCKX family and is formed by residues located within the two sets of transmembrane spanning segments in the NCKX sequence.

cDNA cloning and functional expression of the dolphin retinal rod Na-Ca+K exchanger NCKX1: comparison with the functionally silent bovine NCKX1.

cDNAs of human and bovine retinal rod Na+-Ca2++K+ exchanger (NCKX1) have previously been cloned, but potassium-dependent Na-Ca exchange activity upon heterologous expression has not been demonstrated. We have cloned NCKX1 cDNA from dolphin, examined function upon transfection in HEK293 cells, and compared the dolphin sequence encoded by the cDNA with those of human and bovine. The dolphin NCKX1 cDNA encodes 1013 amino acid residues. Comparison to bovine and human NCKX1 revealed strong conservation in the transmembrane domains (>95%), but relatively low conservation in the large extracellular ( approximately 50%) and cytosolic (<50%) domains. The dolphin cytosolic domain differs from the bovine sequence by the absence of a stretch of 114 amino acids. HEK293 cells transfected with dolphin NCKX1 cDNA showed K+-dependent Na-Ca exchange in >95% of the experiments, whereas transfection with bovine NCKX1 yielded no function. The bovine NCKX1 phenotype was imparted on dolphin NCKX1 when the dolphin cytosolic loop was replaced by that from bovine. Conversely, deletion of 114 amino acids from the bovine sequence to match the dolphin sequence resulted in a mutant bovine NCKX1 which performed K+-dependent Na-Ca exchange. These results suggest that domains within the large cytosolic loop of NCKX1 control functional activity when expressed in heterologous systems.

Treadmill exercise duration and dyspnea recovery time in chronic obstructive pulmonary disease: effects of oxygen breathing and repeated testing.

Oxygen supplementation is known to improve exercise capacity in patients with chronic obstructive pulmonary disease (COPD). Although some COPD patients use oxygen after exercise to relieve dyspnea, the effect of oxygen during recovery from exercise is not clearly understood. Exercise duration and dyspnea recovery time were studied in 18 patients with stable COPD. Patients exercised at a constant submaximal work rate on a treadmill ergometer until they no longer wished to continue. Oxygen, room air and compressed air were randomly administered in three consecutive post-exercise recovery periods. Dyspnea was scored on a 100 mm visual analog scale at 30 s intervals until return to baseline. An additional 20 minute post-recovery resting period was allowed between each test. No significant differences were found in dyspnea recovery time breathing oxygen (271 s), room air (290 s) or compressed air (311 s) When the groups were sorted by sequence of testing, there was a highly significant increase in recovery time (208 s, 307 s and 358 s for the first, second and third tests; P < 0.005) and a non-statistically significant decrease in exercise duration (89 s, 79 s and 76 s). Post-exercise oxygen supplementation had no effect on dyspnea recovery time in these COPD patients. Repeated bouts of exercise increased dyspnea recovery time and tended to decrease exercise duration. These findings suggest that, despite recovery of symptoms, physiological recovery from prior exercise is incomplete.