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Biomedical subjects

Richard Casaburi

Publications and source records attributed to Richard Casaburi.

At least 19 recordsLinked to original sources
PubMed2026

Proteomic Mediators of Chronic Obstructive Pulmonary Disease Phenotypes and Coronary Artery Calcification Burden in Ever Smokers.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) increases cardiovascular disease risk. Coronary artery calcification (CAC) predicts cardiovascular events and mortality in COPD. We hypothesized that plasma proteins linked to pulmonary phenotypes mediate CAC burden. METHODS: Pulmonary function, emphysema, airway wall thickening, Agatston CAC scores (inverse normal transformed), and relative abundance of 1305 plasma proteins (log-transformed) were assessed in 989 Phase 1 COPDGene (Genetic Epidemiology of COPD) participants. Proteins associated with both pulmonary phenotypes (FEV1[forced expiratory volume in 1 second]%predicted, FVC [forced vital capacity], FEV1/FVC, emphysema, airway wall thickness, wall area percentage) and CAC (false discovery rate P≤0.20) were evaluated using multivariable mediation. Model adjustments included sex, age, race, body mass index, smoking, comorbidities, and medications. Adjustment for pulmonary artery-to-aortic diameter ratio-a marker of pulmonary vascular pressure-was also explored. The95% bootstrap CIs that excluded zero were considered significant. RESULTS: FEV1%predicted (P=0.026) and FEV1/FVC (P=0.010) were associated with CAC. After adjusting for FEV1, visual emphysema, and visual airway wall thickening remained associated with CAC. Five proteins (TSP2 [thrombospondin-2], renin, MMP-7 [matrix metalloproteinase-7], ERBB1 [epidermal growth factor receptor], MIC-1 [macrophage inhibitory cytokine-1]) mediated the FEV1%predicted and CAC association. All except MIC-1 mediated FEV1/FVC and CAC. All except renin mediated quantitative airway wall thickness or wall area percentage and CAC. Additionally, α2-antiplasmin (alpha-2 antiplasmin) mediated airway wall thickness and CAC. ERBB1 mediated visual paraseptal emphysema and CAC. Pulmonary artery-to-aortic diameter ratio adjustment reduced or eliminated some mediation effects. ERBB1 remained an independent mediator across multiple phenotypes. CONCLUSIONS: Six plasma proteins mediated associations between COPD phenotypes and CAC burden. These effects were partially influenced by pulmonary artery-to-aortic diameter ratio A, suggesting shared molecular pathways linking lung dysfunction to cardiovascular risk in COPD.

Humans↗
PubMed2006

Effect of exercise on mRNA levels for growth factors in skeletal muscle of hemodialysis patients.

OBJECTIVES: Muscle mass and muscle mRNA levels for certain growth factors are reduced in maintenance hemodialysis (MHD) patients. This study tested the hypothesis that in MHD patients endurance exercise training (EET) increases mRNA levels for insulin-like growth factors and reduces myostatin mRNA. DESIGN: Biopsies of the right vastus lateralis muscle were performed before and at the end of 8.9 +/- 0.9 (SEM) weeks of EET in MHD patients. Muscle tissue was analyzed histologically by electron microscopy and for fiber cross-sectional area, and, in 8 pairs of biopsies, muscle was examined for mRNA levels for the following proteins: myostatin, insulin-like growth factor-I (IGF-I), IGF-I receptor (IGF-IR), IGF binding proteins (IGFBPs)-1, -2, -3, -4, and -5, and IGF-binding protein-related protein-1 (IGFBP-rP1). SETTING: Outpatient MHD centers. PATIENTS: This was a pilot study conducted in sedentary clinically stable MHD patients undergoing EET with no control group. INTERVENTION: EET that was carefully supervised by exercise trainers. MAIN OUTCOME MEASURE: Skeletal muscle mRNA levels, especially myostatin mRNA. RESULTS: With EET, skeletal muscle myostatin mRNA decreased by 51%, mRNA levels increased significantly for IGF-IR (by 41%), IGFBP-2, -4, and -5, and IGFBP-rP1. IGF-I mRNA increased by 35%; this change was not significant. IGFBP-3 mRNA did not change, and IGFBP-1 mRNA was undetectable. There were mild to moderate alterations in skeletal muscle ultrastructure that did not change significantly with EET. Muscle fiber size, measured in 5 patients, did not change. CONCLUSION: In MHD patients who undergo approximately 9 weeks of EET, skeletal muscle mRNA for myostatin decreases and mRNA for IGF-IR, IGFBPs -2, -4, and -5 and IGFBP-rP1 increases. These changes may indicate mechanisms by which EET improves muscle exercise capacity in MHD patients.

Adult↗
PubMed2006

Reduction of hyperinflation by pharmacologic and other interventions.

Hyperinflation of the lungs is associated with activity limitation and reduced quality of life of patients with chronic obstructive pulmonary disease (COPD). Cardiopulmonary exercise testing has proven useful, not only in establishing this link, but also in determining which interventions modify exercise endurance and the mechanisms by which this is achieved. In COPD, dynamic hyperinflation is reduced during exercise by interventions that either increase the potential for expiratory flow or increase the time available for expiration. Two classes of intervention improve exercise tolerance by increasing expiratory flow. Bronchodilators reduce expiratory airflow resistance by increasing the diameter of the airways. An alternative intervention, though less practical, is to reduce the density of the gas exhaled through obstructed airways, such as occurs when breathing a mixture of helium and oxygen (heliox). In contrast, supplemental oxygen and exercise rehabilitation programs improve endurance by reducing respiratory ventilatory drive and, therefore, respiratory rate. The different mechanisms exploited by these interventions to reduce dynamic hyperinflation suggest that combination treatments should yield additive benefits. This has been proven in the case of combinations of rehabilitative exercise training with supplemental oxygen, or with the bronchodilator tiotropium, both of which have been found to yield additive effects. With such interventions, we already have options for improving the mobility of patients with COPD. With a firm understanding of the physiologic basis of exercise limitation, we can focus on defining new and better strategies to improve exercise tolerance.

Bronchodilator Agents↗
PubMed2005

The effects of volatile salivary acids and bases on exhaled breath condensate pH.

RATIONALE: Recent studies have reported acidification of exhaled breath condensate (EBC) in inflammatory lung diseases. This phenomenon, designated "acidopnea," has been attributed to airway inflammation. OBJECTIVES: To determine whether salivary acids and bases can influence EBC pH in chronic obstructive pulmonary disease (COPD). METHODS: Measurements were made of pH, electrolytes, and volatile bases and acids in saliva and EBC equilibrated with air in 10 healthy subjects and 10 patients. RESULTS: The average EBC pH in COPD was reduced (normal, 7.24 +/- 0.24 SEM; range, 6.11-8.34; COPD, 6.67 +/- 0.18; range, 5.74-7.64; p = 0.079). EBCs were well buffered by NH(4)(+)/NH(3) and CO(2)/HCO(3)(-) in all but four patients, who had NH(4)(+) concentrations under 60 micromol/L, and acetate concentrations that approached or exceeded those of NH(4)(+). Saliva contained high concentrations of acetate (approximately 6,000 micromol/L) and NH(4)(+) (approximately 12,000 micromol/L). EBC acetate increased and EBC NH(4)(+) decreased when salivary pH was low, consistent with a salivary source for these volatile constituents. Nonvolatile acids did not play a significant role in determining pH of condensates because of extreme dilution of respiratory droplets by water vapor (approximately 1:12,000). Transfer of both acetic acid and NH(3) from the saliva to the EBC was in the gas phase rather than droplets. CONCLUSIONS: EBC acidification in COPD can be affected by the balance of volatile salivary acids and bases, suggesting that EBC pH may not be a reliable marker of airway acidification. Salivary acidification may play an important role in acidopnea.

Acetic Acid↗
PubMed2005

Pulmonary rehabilitation for COPD.

Pulmonary rehabilitation is a therapeutic process, which entails taking a holistic approach to the welfare of the patient with chronic respiratory illness--most commonly chronic obstructive pulmonary disease (COPD). Pulmonary rehabilitation is considered essential throughout the lifetime management of patients with symptomatic chronic respiratory disease. It requires the coordinated action of a multidisciplinary healthcare team in order to deliver an individualised rehabilitation programme to best effect--incorporating multiple modalities, such as advice on smoking cessation, exercise training and patient self-management education, among others. As core components of pulmonary rehabilitation, exercise training and self-management education have been shown to be beneficial in improving health-related quality of life (HRQoL) in patients with chronic respiratory disease. Physical training can help to reduce the muscle de-conditioning that occurs when the activity of patients is restricted by their breathlessness and fatigue, and is often associated with an increase in patient HRQoL. HRQoL can also be improved by the use of self-management education, which is designed to provide the patient with the skills to manage the health consequences of their disease. In doing so, patients are better able to cope with disease symptoms, potentially leading to reduced healthcare costs. A great deal of research has been conducted to try and fully define which patients will benefit most from pulmonary rehabilitation. Although progress has been made, many questions remain as to the best means of delivering rehabilitation, particularly with respect to the optimum programme of physical training and patient self-management education.

Bronchodilator Agents↗
PubMed2005

Epithelial lining fluid solute concentrations in chronic obstructive lung disease patients and normal subjects.

The exhaled breath condensate (EBC) method represents a new, noninvasive way to detect inflammatory and metabolic markers in the fluid that covers the airways [epithelial lining fluid (ELF)]. However, respiratory droplets represent only a very small and variable fraction of the EBC, most (approximately 99.99%) of which is water vapor. Our objective was to show that ELF concentrations could be calculated from EBC values by using any of three dilutional indicators (urea, total cations, and conductivity) in nine normal and nine chronic obstructive lung disease (COPD) subjects. EBC concentrations of Na(+), K(+), Ca(2+), Mg(2+), total cations, urea, and conductivity varied over a 10-fold range among individuals, but concentrations of these constituents (except Ca(2+)) remained well correlated (r(2) = 0.44-0.83, P < 0.001). Dilution (D) of respiratory droplets in water vapor was calculated by dividing plasma concentrations of the dilutional indicators by EBC concentrations. Estimates of D were not significantly different among these indicators, and urea D averaged 10,800 +/- 2,100 (SE) in normal and 12,600 +/- 3,300 in COPD subjects. Although calculated Na(+) concentrations in the ELF were less than one-half those in plasma, and concentrations of K(+), Ca(2+), and Mg(2+) exceeded those in plasma, total cation concentrations in ELF were not significantly different from those in plasma, indicating that ELF is isotonic in both normal and COPD subjects. EBC amylase concentrations (measured with an ultrasensitive procedure) indicated that saliva represented <10% of the respiratory (ELF) droplets in all but three samples. Dilutional and salivary markers are essential for interpretation of EBC studies.

Aged↗
PubMed2005

Endurance exercise training during haemodialysis improves strength, power, fatigability and physical performance in maintenance haemodialysis patients.

BACKGROUND: Endurance training improves cardiopulmonary fitness in maintenance haemodialysis (MHD). Because many MHD patients are profoundly deconditioned and exhibit significant muscle weakness, endurance training may also improve muscle strength and physical performance in these patients. This study assessed this possibility. METHODS: Twelve MHD patients performed incremental and constant work rate cycle exercise tests to determine peak work rate, VO(2)peak and endurance time (ET). Lower extremity strength, power and fatigability, stair-climbing time, 10 m walk time and a timed up-and-go were assessed before and after 8.6+/-2.3 weeks of thrice weekly, progressive, semi-recumbent, leg-cycle training during haemodialysis. Initial training intensity and duration targets were set at 50% peak work rate (WR) and 20 min, respectively, with a goal of progressing to 40 min at the highest WR tolerable. Non-exercising MHD patients and healthy volunteers with similar age, gender and race/ethnicity served as comparison groups. RESULTS: None of the subjects tolerated the initial target intensity. Therefore, WR was reduced to 19+/-9 watts (30% of peak WR) for 19.9 min/session. At end of training, subjects cycled at 29+/-25 watts (46% initial peak WR; P = 0.01) for 38+/-8 min (P<0.001). VO(2)peak and ET improved 22% (P = 0.018) and 144% (P = 0.001), respectively. Quadriceps strength, power and fatigability improved 16% (P = 0.002), 15% (P = 0.115) and 43% (P = 0.029), respectively. The three measures of physical performance improved by 14-17% (P<0.031). Total work performed in training increased by 5.5+/-21.1 kJ/week (17%); a 165% increase during the study period. CONCLUSIONS: Nine weeks of leg-cycling during haemodialysis in MHD patients improves not only cardiopulmonary fitness and endurance but also muscle strength, power, fatigability and physical function. These data underscore the value of endurance training in MHD.

Adult↗
PubMed2005

Dose-dependent effects of testosterone on sexual function, mood, and visuospatial cognition in older men.

CONTEXT: The relationships between testosterone dose and its effects on sexual function, mood, and visuospatial cognition are poorly understood. OBJECTIVE: To elucidate testosterone dose-response relationships in older men, we examined the effects of graded testosterone doses on sexual function, mood, and visuospatial cognition in healthy, older men (age, 60-75 yr). SETTING: This study was performed at the General Clinical Research Center. INTERVENTION/METHODS: Subjects each received a long-acting GnRH agonist to suppress endogenous testosterone production and were randomized to receive one of five doses (25, 50, 125, 300, and 600 mg) of testosterone enanthate weekly for 20 wk. Questionnaires were used to evaluate sexual function. Scores for overall sexual function as well as subcomponents of sexual function (libido, sexual activity, and erectile function) were calculated. RESULTS: Changes in overall sexual function (P = 0.003) and waking erections (P = 0.024) differed by dose. An interaction between libido and being sexually active was observed, such that libido changed by testosterone dose only among men who reported being sexually active at the beginning of the study (P = 0.009). Men's log-transformed free testosterone levels during treatment were positively correlated with overall sexual function (P = 0.001), waking erections (P = 0.040), spontaneous erections (P = 0.047), and libido (P = 0.027), but not with intercourse frequency (P = 0.428) or masturbation frequency (P = 0.814). No effects of testosterone dose were observed on two measures of mood: Hamilton's Depression Inventory (P = 0.359) and Young's Mania Scale (P = 0.851). The number of trials completed on a computer-based test of visuospatial cognition differed by dose (P = 0.042), but the number of squares correctly completed on this task did not differ by dose (P = 0.159). CONCLUSIONS: Different aspects of male behavior respond differently to testosterone. When considered together with previous data from young men, these data indicate that testosterone dose-response relationships for sexual function and visuospatial cognition differ in older and young men.

Affect↗
PubMed2005

Factors determining constant work rate exercise tolerance in COPD and their role in dictating the minimal clinically important difference in response to interventions.

Constant work rate exercise testing has been used to assess effectiveness of therapeutic interventions in chronic obstructive pulmonary disease. It has been noted to yield larger fractional increases in exercise tolerance than other measures. Reasons for this are rooted in physiological determinants of the time course of pulmonary ventilation. Following exercise onset, ventilation increases in three phases; the slowest phase is seen only at high exercise intensities. In chronic obstructive pulmonary disease exercise proceeds until ventilation reaches a limiting value. Because both ventilatory requirement for exercise and limiting ventilation can be manipulated by several interventions (exercise training, oxygen inhalation, bronchodilator administration), constant work rate tolerance responds to these interventions. The power-duration relationship predicts the effect of the work rate imposed on tolerated duration of a constant work rate test. Arguments are presented that a pre-intervention constant work rate duration of 4-7 minutes is desirable. At present, the recommended strategy to achieve this target duration is to choose a work rate equal to 85% of peak work rate achieved in a constant work rate test. There is clearly insufficient information to reliably determine a minimal clinically important difference for this test. A lower bound of 1.75 minutes is suggested.

Data Interpretation, Statistical↗
PubMed2005

Utility of exhaled breath condensates in chronic obstructive pulmonary disease: a critical review.

PURPOSE OF REVIEW: Evaluation of the utility of exhaled breath condensates in chronic obstructive pulmonary disease. RECENT FINDINGS: Exhaled breath condensates have recently been introduced as a simple, noninvasive method of sampling respiratory fluid in inflammatory lung disorders, including chronic obstructive pulmonary disease. Increases in condensate concentrations of at least 12 markers of inflammation have been reported in these disorders. Furthermore, condensate pH appears to be decreased in both chronic obstructive lung disease and bronchial asthma. This has been referred to as acidopnea and could reflect airway acidification by inflammatory cells. Although safer and more convenient than bronchoalveolar lavage, interpretation of condensate data is complicated by uncertainty regarding the source of condensate solutes and by variable dilution of respiratory droplets from condensed water vapor, which represents more than 99.9% of condensate volumes. This dilution can be estimated from the dilution of plasma constituents such as urea or electrolytes. Because the principal buffer in condensate is NH4, much of which is derived from bacterial degradation of urea in the mouth, condensate pH measurements may not provide accurate estimates of airway pH. Nevertheless, acidification of condensate may be indicative of gastroesophageal reflux, which frequently occurs in obstructive lung diseases and may contribute to cough and bronchospasm. SUMMARY: It is too early to tell how useful condensate studies will be to pulmonary investigators and clinicians. Realization of the enormous potential of this approach will require a thorough understanding of the manner in which these solutions are generated and how they should be analyzed.

Acidosis, Respiratory↗
PubMed2005

Skeletal muscle mRNA for IGF-IEa, IGF-II, and IGF-I receptor is decreased in sedentary chronic hemodialysis patients.

BACKGROUND: Maintenance hemodialysis patients often display evidence for protein-energy malnutrition, inflammation, and sarcopenia. We therefore investigated whether sedentary maintenance hemodialysis patients have decreased skeletal muscle mRNA levels and muscle and serum protein concentrations of certain growth factors. METHODS: Fifty-one clinically stable maintenance hemodialysis patients (32 men and 19 women), and 21 normal adults (16 men and five women) of similar age, gender mix, racial/ethnic backgrounds, serum albumin, body composition, and level of sedentary activity were studied. Individuals underwent biopsy of the right vastus lateralis muscle, and real-time polymerase chain reaction (PCR) amplification of mRNAs for insulin-like growth factor-I (IGF-I), IGF-II, IGF-I receptor (IGF-IR), IGF-IIR, and myostatin (44 patients) was performed. Serum and muscle IGF-I and IGF-II, serum proinflammatory cytokines, and leg muscle strength, power, and fatigability were measured. RESULTS: Maintenance hemodialysis patients displayed significantly reduced mRNA levels for IGF-IEa mRNA (P < 0.05), IGF-II (P < 0.001), and IGF-IR (P < 0.001), and no difference in mRNAs for IGF-IEc, IGF-IIR, or myostatin as compared to normal controls. Muscle mRNA levels, in general, followed the same pattern in male and female maintenance hemodialysis patients considered separately. In the maintenance hemodialysis patients, muscle IGF-I protein, serum IGF-II and tumor necrosis factor-alpha (TNF-alpha) were each increased, whereas serum C-reactive protein (CRP) and interleukin-6 (IL-6) were normal. Muscle strength and power, but not fatigability, were reduced in the maintenance hemodialysis patients. CONCLUSION: In sedentary, clinically stable maintenance hemodialysis patients as compared to sedentary normal individuals, the mRNA levels for IGF-IEa, IGF-II, and the IGF-I receptor are decreased in vastus lateralis muscle. Protein levels for muscle IGF-I and serum IGF-II are increased.

Adult↗
PubMed2005

Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD.

STUDY OBJECTIVES: Pulmonary rehabilitation (PR) improves exercise tolerance in COPD patients. Tiotropium is a once-daily, inhaled anticholinergic bronchodilator that provides sustained 24-h improvements in airflow and lung hyperinflation reduction. We hypothesized that ventilatory mechanics improvements from tiotropium would permit enhanced ability to train muscles of ambulation and therefore augment exercise tolerance benefits of PR. DESIGN: In a randomized, double-blind, placebo-controlled trial (tiotropium, n = 47; placebo, n = 44), tiotropium (18 microg qd) was administered to COPD patients participating in 8 weeks of PR (treadmill training three times a week; >/= 30 min per session) at 17 sites. Study drug was administered 5 weeks prior to, 8 weeks during, and 12 weeks following PR. The primary end point was treadmill walking (0% incline) endurance time at 80% of maximum speed attained in an initial incremental test. The transition dyspnea index (TDI), St. George's respiratory questionnaire (SGRQ), and rescue albuterol use were secondary end points. PARTICIPANTS: Mean age of the 93 participants was 67 years, 57% were men, and mean FEV(1) was 0.88 L (34% predicted). RESULTS: Mean endurance time differences (tiotropium minus placebo) prior to PR, at the end of PR, and 12 weeks after PR were 1.65 min (p = 0.183), 5.35 min (p = 0.025), and 6.60 min (p = 0.018), respectively. Mean TDI focal scores at the end of PR were 1.75 for tiotropium and 0.91 for placebo (p > 0.05). At 12 weeks after PR, TDI focal scores were 1.75 for tiotropium and 0.08 for placebo (p < 0.05). Relative to placebo, tiotropium improved SGRQ total scores by 3.86 at the end of PR and 4.44 at 12 weeks after PR (p > 0.05). Mean albuterol use declined following PR plus tiotropium, compared to PR alone (p </= 0.05 for 17 of 25 weeks). CONCLUSIONS: Tiotropium in combination with PR improved endurance of a constant work rate treadmill task and produced clinically meaningful improvements in dyspnea and health status compared to PR alone. Improvements with tiotropium were sustained for 3 months following PR completion.

Administration, Inhalation↗
PubMed2005

Exercise training decreases ventilatory requirements and exercise-induced hyperinflation at submaximal intensities in patients with COPD.

STUDY OBJECTIVES: We hypothesized that endurance exercise training would reduce the degree of hyperinflation for a given level of exercise and thereby improve submaximal exercise endurance. METHODS: Twenty-four patients with COPD (mean FEV(1), 36.4 +/- 8.5% of predicted [+/- SD]) undertook a high-intensity cycle ergometer exercise training program for 45 min, three times a week for 7 weeks. Before and after training, the patients performed both an incremental exercise test to maximum and a constant work rate (CWR) test on a cycle ergometer at 75% of the peak work rate obtained in the pretraining incremental test. Ventilatory variables were measured breath-by-breath, and inspiratory capacity (IC) was measured every 2 min to assess changes in end-expiratory lung volume. RESULTS: After training, the increase in peak oxygen uptake was not statistically significant; however, the peak work rate increased by 12.9 +/- 10.3 W (p < 0.01). For the CWR test performed at the same work rate both before and after training, ventilation and breathing frequency (f) were lower after training (average, 1.97 L/min and 3.2 breaths/min, respectively; p < 0.01) and IC was greater (by an average of 133 mL, p < 0.05), signifying decreased hyperinflation. The increase in IC at the point of termination in the shortest CWR test for each individual (defined as isotime) correlated well with both the decreased f (r = 0.63, p = 0.001) and with the increase in CWR exercise endurance (average, 13.1 min, r = 0.46, p = 0.023). CONCLUSIONS: Exercise training in patients with severe COPD dramatically improves submaximal exercise endurance. Decreased dynamic hyperinflation may, in part, mediate the improvement in exercise endurance by delaying the attainment of a critically high inspiratory lung volume.

Aged↗
PubMed2004

Lung function improvements with once-daily tiotropium in chronic obstructive pulmonary disease.

The defining feature of chronic obstructive pulmonary disease (COPD) is progressive deterioration in lung function. Measures of lung function are used to confirm the diagnosis, assess the severity of disease, and evaluate the efficacy of interventions. Forced expiratory volume in 1 second (FEV1), determined by spirometry, is the best known of these measures; however, it does not correlate well with dyspnea or exercise capacity, which are important targets for improvement in COPD management. Airflow obstruction in COPD often causes lung hyperinflation, which further inhibits the patient's ability to breathe. The degree of hyperinflation has been shown to correlate well with dyspnea and exercise capacity, but it is less convenient to measure than FEV1. This article briefly reviews the key lung function measurements used in monitoring patients with COPD. To illustrate how these measurements can be used to demonstrate the improvements in lung function elicited by effective bronchodilator therapy, the changes associated with the once-daily, long-acting bronchodilator tiotropium are presented.

Bronchodilator Agents↗