The Maugeri daily activity profile: a tool to assess physical activity in patients with chronic obstructive pulmonary disease.

Patients with chronic obstructive pulmonary disease (COPD) report reduced physical activity (PA). There are only few tools available to assess PA and sedentary behavior in these patients, and none of them aims to differentiate between sedentary and active patterns. The aim of the study was to evaluate an easy tool to profile daily activity time in a cohort of patients with COPD, compared to healthy subjects; the study was set at the Istituti Clinici Scientifici Maugeri (ICS), IRCCS of Tradate and Lumezzane, Italy, and at the Ente Ospedaliero Cantonale Novaggio, Switzerland (Italian Speaking). The populations were inpatients with COPD, healthy subjects. The items of the Maugeri Daily Activity (MaDA) profile were chosen based on literature, interviews with patients and health professionals. Time spent during sleep (ST), when awake (AT), active (ACT) or in sedentary behavior (SET) were recorded. Lung function tests, arterial blood gases, the modified Medical Research Council (mMRC), the six-minute walking distance test (6MWD), the COPD Assessment Test (CAT), and the body-mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index were also assessed in patients. Sixty patients with COPD and 60 healthy controls filled in the questionnaire. As compared to controls, patients showed longer AT and SET. Active time of patients was significantly correlated with mMRC, CAT, Bode Index and 6MWD, but not with demographics, anthropometrics or stages of disease. Using this tool, we found that patients with COPD spent longer time awake and in sedentary behavior. The MaDA may be useful to evaluate PA in patients with COPD.

Effectiveness of pulmonary rehabilitation in severe asthma: a retrospective data analysis.

Background: Pulmonary Rehabilitation (PR) is a multimodal treatment that is still poorly investigated in severe asthma where respiratory symptoms remain "uncontrolled" despite intensive pharmacological therapy. Bronchiectasis and obstructive sleep apnea (OSAS) are common comorbidities which may worsen asthma control.Aim: Aim of the present study is to investigate the effectiveness of PR on functional exercise, dyspnea, and muscle fatigue in patients with severe asthma.Methods: A total of 317 patients affected from severe asthma according to GINA guidelines who underwent a multidisciplinary 3 weeks rehabilitation program with an adherence of >80% to PR and able to complete a Six Minute Walking Test (6MWT) were retrospectively included in the analysis. Pulmonary rehabilitation included endurance training, educational meetings, chest physiotherapy, breathing exercises, and psychological support. Six-minute walking distance and Borg scale for dyspnea and muscle fatigue were recorded before and after the rehabilitation.Results: A total of 371 patients were analyzed, 39 had bronchiectasis (10.5%), 163 (43.9%) OSAS and 17 had both (4.6%). PR significantly improved 6MWT distance, Borg dyspnea and muscle fatigue (p value < 0.0001 for all outcomes) and mean SpO2 recorded during 6MWT (p value < 0.0001). Median (IQR) delta 6 minute walking distance was 33 (14-60) m. 6MWT distance (p < 0.0001) and the oxygen saturation (p < 0.01) significantly improved in severe asthma with bronchiectasis and/or OSAS.Conclusions: Our study provides evidence for the first time on a large sample of patients with severe asthma that a multidisciplinary PR program is effective in terms of exercise capacity and symptoms. In addition, exercise capacity improved in the presence of bronchiectasis and/or OSAS.

Do blood eosinophils strictly reflect airway inflammation in COPD? Comparison with asthmatic patients.

INTRODUCTION: Airway eosinophilic inflammation is a characteristic of asthmatic patients and of a sub group of COPD subjects. Blood eosinophils are deemed as a good surrogate marker of sputum eosinophilic inflammation; however, controversial data have been published particularly in COPD. The aim of our study was to compare blood and sputum eosinophils in COPD and asthmatic patients in "real life". METHODS: Sputum was induced in stable patients with COPD or asthma with hypertonic saline solution and blood eosinophils were evaluated. Frequency of comorbidities was recorded. Correlations were performed stratifying patients by disease and comorbidities. RESULTS: 146 patients, 57 with COPD and 89 with asthma were evaluated. Blood and sputum eosinophils expressed as percentages were correlated in COPD (rho = 0.40; p = 0.004), but the entity of correlation was lower compared with asthmatic subjects (rho = 0.71; p < 0.0001). When blood eosinophils were expressed as counts the correlation was slightly lower than when expressed as percentages in COPD (rho = 0.35; p = 0.01) and in asthmatic patients (rho = 0.68; p < 0.0001). In COPD patients older than 73 years or with blood eosinophils higher than the median value (210.6 eos/µl), or co-diagnosed with hypertension, ischemic heart disease or atrial fibrillation no correlation between blood and sputum eosinophils was found. However, the effect of ischemic heart disease and atrial fibrillation could be driven by hypertension since most of these patients have this comorbidity. CONCLUSION: Blood eosinophils correlated with sputum eosinophils to a lesser degree in COPD than in asthmatic patients. Older age, high blood eosinophils and hypertension affected the correlation between blood and sputum eosinophils, more studies are needed to evaluate the role of other cardiac comobidities.

Effects of Pulmonary Rehabilitation in Patients with Non-Cystic Fibrosis Bronchiectasis: A Retrospective Analysis of Clinical and Functional Predictors of Efficacy.

BACKGROUND: International guidelines recommend the inclusion of patients with bronchiectasis in pulmonary rehabilitation (PR) to improve exercise capacity and health-related quality of life (HRQoL). At present, the effect of PR in these patients has been poorly investigated. OBJECTIVE: The aim of our retrospective analysis was to evaluate the effects and predictors of success for a PR program in patients with bronchiectasis not related to cystic fibrosis (non-CF bronchiectasis). METHODS: One hundred and thirty-five non-CF bronchiectasis inpatients, allocated to a 3-week PR program, were retrospectively evaluated. Exercise capacity (6-min walk distance, 6MWD), dyspnea (Baseline/Transition Dyspnea Index, BDI/TDI), and HRQoL [EuroQol visual analogue scale (EQ-VAS)] were assessed before and after PR. The relationship between baseline parameters and changes in outcome measures after PR was assessed. Both univariate and multiple logistic analyses were performed to evaluate the presence of independent predictors of the efficacy of PR. RESULTS: One hundred and eight patients [49 males, mean age 71 years, mean forced expiratory volume in 1 s (FEV1) 76% predicted] were included. After PR, there was a significant improvement in 6MWD, TDI, and EQ-VAS score (p < 0.001). Changes in 6MWD and EQ-VAS score correlated with baseline FEV1, FEV1/vital capacity (VC), residual volume, transfer factor of the lung for carbon monoxide, and the number of exacerbations in the previous year. Both univariate and multivariate logistic regression analyses showed that male gender, baseline FEV1/VC <70%, and >2 exacerbations in the previous year were independent predictors of PR efficacy in terms of an improvement in 6MWD. CONCLUSIONS: Our study supports the inclusion of patients with bronchiectasis in PR programs. Clinical and functional baseline findings partially predict the response to PR in terms of exercise tolerance. Further prospective, randomized, controlled trials are needed.

An aspartate residue in the external vestibule of GLYT2 (glycine transporter 2) controls cation access and transport coupling.

Synaptic glycine levels are controlled by GLYTs (glycine transporters). GLYT1 is the main regulator of synaptic glycine concentrations and catalyses Na+-Cl--glycine co-transport with a 2:1:1 stoichiometry. In contrast, neuronal GLYT2 supplies glycine to the presynaptic terminal with a 3:1:1 stoichiometry. We subjected homology models of GLYT1 and GLYT2 to molecular dynamics simulations in the presence of Na+. Using molecular interaction potential maps and in silico mutagenesis, we identified a conserved region in the GLYT2 external vestibule likely to be involved in Na+ interactions. Replacement of Asp471 in this region reduced Na+ affinity and Na+ co-operativity of transport, an effect not produced in the homologous position (Asp295) in GLYT1. Unlike the GLYT1-Asp295 mutation, this Asp471 mutant increased sodium leakage and non-stoichiometric uncoupled ion movements through GLYT2, as determined by simultaneously measuring current and [3H]glycine accumulation. The homologous Asp471 and Asp295 positions exhibited distinct cation-sensitive external accessibility, and they were involved in Na+ and Li+-induced conformational changes. Although these two cations had opposite effects on GLYT1, they had comparable effects on accessibility in GLYT2, explaining the inhibitory and stimulatory responses to lithium exhibited by the two transporters. On the basis of these findings, we propose a role for Asp471 in controlling cation access to GLYT2 Na+ sites, ion coupling during transport and the subsequent conformational changes.

Pre-steady-state and reverse transport currents in the GABA transporter GAT1.

The role of internal substrates in the biophysical properties of the GABA transporter GAT1 has been investigated electrophysiologically in Xenopus oocytes heterologously expressing the cotransporter. Increments in Cl(-) and/or Na(+) concentrations caused by intracellular injections did not produce significant effects on the pre-steady-state currents, while a positive shift of the charge-voltage (Q-V) and decay time constant (τ)-voltage (τ-V) curves, together with a slowing of τ at positive potentials, was observed following treatments producing cytosolic Cl(-) depletion. Activation of the reverse transport mode by injections of GABA caused a reduction in the displaced charge. In the absence of external Cl(-), a stronger reduction in the displaced charge, together with a significant increase in reverse transport current, was observed. Therefore, complementarity between pre-steady-state and transport currents, observed in the forward mode, is preserved in the reverse mode. All these findings can be qualitatively reproduced by a kinetic scheme in which, in the forward mode, the Cl(-) ion is released first, after the inward charge movement, while the two Na(+) ions can be released only after binding of external GABA. In the reverse mode, internal GABA must bind first to the empty transporter, followed by internal Na(+) and Cl(-).

Temperature effects on the kinetic properties of the rabbit intestinal oligopeptide cotransporter PepT1.

The effects of temperature on the functional properties of the intestinal oligopeptide transporter PepT1 from rabbit have been investigated using electrophysiological methods. The dipeptide Gly-Gln at pH 6.5 or 7.5 was used as substrate. Raising the temperature in the range 20-30 °C causes an increase in the maximal transport-associated current (I (max)) with a Q (10) close to 4. Higher temperatures accelerate the rate of decline of the presteady-state currents observed in the absence of organic substrate. The voltage dependencies of the intramembrane charge movement and of the time constant of decline are both shifted towards more negative potentials by higher temperatures. The shift is due to a stronger action of temperature on the outward rate of charge movement compared to the inward rate, indicating a lower activation energy for the latter process. Consistently, the activation energy for the complete cycle is similar to that of the inward rate of charge movement. Temperature also affects the binding rate of the substrate: the K (0.5) -V curve is shifted to more negative potentials by higher temperatures, resulting in a lower apparent affinity in the physiological range of potentials. The overall efficiency of transport, estimated as the I (max)/K (0.5) ratio is significantly increased at body temperature.

GABA reverse transport by the neuronal cotransporter GAT1: influence of internal chloride depletion.

The role of intracellular ions on the reverse GABA transport by the neuronal transporter GAT1 was studied using voltage-clamp and [(3)H]GABA efflux determinations in Xenopus oocytes transfected with heterologous mRNA. Reverse transport was induced by intracellular GABA injections and measured in terms of the net outward current generated by the transporter. Changes in various intracellular ionic conditions affected the reverse current: higher concentrations of Na(+) enhanced the ratio of outward over inward transport current, while a considerable decrease of the outward current and a parallel reduction of the transporter-mediated GABA efflux were observed after treatments causing a diminution of the intracellular Cl(-) concentration. Particularly interesting was the impairment of the reverse transport observed after depletion of internal Cl(-) generated by the activity of a coexpressed K(+)-Cl(-) exporter KCC2. This finding suggests that reverse GABA transport may be physiologically regulated during early neuronal development, similarly to the functional alterations seen in GABA receptors caused by KCC2 activity.

Residues R282 and D341 act as electrostatic gates in the proton-dependent oligopeptide transporter PepT1.

The oligopeptide transporter PepT1 is a protein found in the membrane of the cells of the intestinal walls, and represents the main route through which proteic nutrients are absorbed by the organism. Along the polypeptidic chain of this protein, two oppositely charged amino acids, an arginine in position 282 and an aspartate in position 341 of the sequence, have been hypothesised to form a barrier in the absorption pathway. In this paper we show that appropriate mutations of these amino acids change the properties of PepT1 in a way that confirms that these parts of the protein indeed act as an electrostatic gate in the transport process. The identification of the structural basis of the functional mechanism of this transporter is important because, in addition to its role in nutrient uptake, PepT1 represents a major pathway for the absorption of several therapeutic drugs.

The 5-Repetition Sit-to-Stand Test as an Outcome Measure for Pulmonary Rehabilitation in Subjects With Asthma.

BACKGROUND: The 5-repetition sit-to-stand test (5STS) is valid and responsive in subjects with COPD, but there is a lack of information in subjects with asthma. We aimed to evaluate the usefulness of the 5STS as an outcome measure of pulmonary rehabilitation in subjects with asthma as compared to subjects with COPD. METHODS: We conducted a retrospective evaluation of subjects with asthma or COPD who underwent pulmonary rehabilitation. Both before and after in-patient pulmonary rehabilitation, subjects underwent the 5STS and the 6-min walk test; dyspnea was assessed with the Medical Research Council scale and the Barthel Index for dyspnea, and the burden of symptoms was assessed with the COPD Assessment Test. RESULTS: Of 475 patients admitted during the study period, 103 subjects with asthma and 108 with COPD were included. After pulmonary rehabilitation, the 5STS improved significantly in both populations (by a median value of -1.7 s [interquartile range -4.2 to -0.5] and -1.1 s [interquartile range -3.4 to 0.0] in subjects with asthma and COPD, respectively; P < .001 for both, P = .17 between groups) independent of body mass index, as did other outcome measures. The baseline 5STS correlated slightly but significantly with age, the 6-min walk test, and the Barthel Index for dyspnea in both populations, whereas it correlated significantly with the Medical Research Council scale only in subjects with asthma and correlated with COPD Assessment Test only in subjects with COPD. No significant correlations between changes in the 5STS and in other assessed outcome measures before and after pulmonary rehabilitation were observed in subjects with asthma, whereas changes in the 5STS correlated slightly but significantly only with changes in 6-min walk test in subjects with COPD. CONCLUSIONS: The 5STS was a reliable outcome measure of pulmonary rehabilitation in subjects with asthma. It must be specifically assessed and may be included in the tools for assessment of effects of pulmonary rehabilitation also in these patients.

GABA transporter lysine 448: a key residue for tricyclic antidepressants interaction.

The effects of three tricyclic antidepressants (TCAs) and two serotonin selective reuptake inhibitors (SSRIs) have been studied with an electrophysiological approach on Xenopus laevis oocytes expressing the rat GABA (gamma-Aminobutyric-acid) transporter rGAT1. All tested TCAs and SSRIs inhibit the GABA-associated current in a dose-dependent way with low but comparable efficacy. The pre-steady-state and uncoupled currents appear substantially unaffected. The efficacy of desipramine, but not of the other drugs, is strongly increased in the lysine-glutamate or -aspartate mutants K448E and K448D. Comparison of I(max) and K(0.5GABA) in the absence and presence of desipramine showed that both parameters are reduced by the drug in the wild-type and in the K448E mutant. This suggests an uncompetitive inhibition, in which the drug can bind only after the substrate, an explanation in agreement with the lack of effects on the pre-steady-state and leak currents, and with the known structural data.

Effectiveness of a Pulmonary Rehabilitation Program on Persistent Asthma Stratified for Severity.

BACKGROUND: Asthma is defined by airway inflammation associated with various respiratory symptoms, and pharmacologic treatment is based on inhaled corticosteroids and bronchodilators. Physical activity, educational training, nutritional support, and psychological counseling are considered part of non-pharmacologic treatment; however, studies so far have investigated the effect of single non-pharmacologic treatment. There are few studies that demonstrate the effect of comprehensive pulmonary rehabilitation, but no clear data are available regarding factors that can predict who could benefit the most. Our study aimed to assess the effect of a comprehensive 3-week pulmonary rehabilitation program on exercise tolerance and to identify baseline subject characteristics that may predict a better response to treatment. METHODS: This was a retrospective study. A team planned a pulmonary rehabilitation program: educational support; endurance training; and optional components, such as respiratory exercises and airway clearance techniques. The following data were collected before and after pulmonary rehabilitation: subject characteristics, smoking history, asthma severity, respiratory function and 6-min walk test (6MWT). RESULTS: We collected data on 515 subjects (202 males 39.2%), age, mean ± SD 63.9 ± 10.4 y), with 413 (80.2%) having moderate-to-severe disease; and 455 (88.4%) with stable respiratory symptoms 455 (88.35%). At baseline, the percentage of predicted 6MWT in all subjects categorized by the Global Initiative for Asthma (GINA) steps was in the normal range, except for the subjects at step 5, for which it was significantly lower (P = .01). All subjects showed a significant improvement in exercise tolerance and oxygen saturation, together with a decrease in baseline dyspnea, muscle fatigue, and heart rate after pulmonary rehabilitation. Improvement of 6MWT was statistically significant, irrespective of the GINA categorization. The variables related to the improvement in 6MWT were age (P < .001), smoking habit (P = .034), and baseline 6MWT (P < .001). CONCLUSIONS: Subjects with asthma at any GINA step seemed to benefit from a pulmonary rehabilitation program; analysis of our data highlighted that pulmonary rehabilitation was more beneficial in younger subjects with a smoking history and worse baseline exercise tolerance.

Minimum Clinically Important Difference in 30-s Sit-to-Stand Test After Pulmonary Rehabilitation in Subjects With COPD.

BACKGROUND: The sit-to-stand (STS) test is a feasible tool for measuring peripheral muscle strength of the lower limbs. There is evidence of increasing use of STS tests in patients with COPD. We sought to evaluate in subjects with COPD the minimum clinically important difference in 30-s STS test after pulmonary rehabilitation. METHODS: Stable COPD subjects undergoing a 30-s STS test and a 6-min walk test (6MWT) before and after pulmonary rehabilitation were included. Responsiveness to pulmonary rehabilitation was determined by the change in 30-s STS test results (Δ 30-s STS) before and after pulmonary rehabilitation. The minimum clinically important difference was evaluated using an anchor-based method. RESULTS: 96 subjects with moderate-to-severe COPD were included. At baseline, 30-s STS test results were significantly related to distance covered in a 6MWT (6MWD) (r = 0.65, P < .001), FVC (r = 0.46, P < .001), PaCO2 (r = -0.42, P < .001), FEV1 (r = 0.39, P < .001), and age (r = -0.31, P = .002). After pulmonary rehabilitation, a significant improvement in 30-s STS test results was observed (mean difference +2 repetitions, P < .001). The Δ30-s STS was positively related to Δ6MWD (r = 0.62, P < .001), transitional dyspnea index (r = 0.67, P < .001), and baseline residual volume (r = 0.27, P = .007). The receiver operating characteristic curves method identified a Δ 30-s STS cut-off of 2 repetitions as the best discriminating value (area under the curve: 0.892, P < .001) to identify the minimum clinically important difference for Δ6MWD (30 m). In a multivariate logistic regression model, baseline 30-s STS (odds ratio 2.63; 95% CI 1.09-6.35, P = .031) and diffusing capacity of the lung for carbon monoxide (< 53% predicted) (odds ratio 2.49, 95% CI 1.04-5.98, P = .041) predict the risk to have a Δ 30-s STS ≥ 2 repetitions. CONCLUSIONS: Our study indicates that in stable subjects with moderate-to-severe COPD, the 30-s STS test was a sensitive tool to assess the efficacy of pulmonary rehabilitation. A Δ 30-s STS of ≥ 2 repetitions represented the minimum clinically important difference, which may be predicted by the baseline ability in the 30-s STS test and lung function in terms of diffusing lung capacity (ClinicalTrials.gov registration NCT03627624).

The one repetition maximum test and the sit-to-stand test in the assessment of a specific pulmonary rehabilitation program on peripheral muscle strength in COPD patients.

BACKGROUND: Individuals with COPD may present reduced peripheral muscle strength, leading to impaired mobility. Comprehensive pulmonary rehabilitation (PR) should include strength training, in particular to lower limbs. Furthermore, simple tools for the assessment of peripheral muscle performance are required. OBJECTIVES: To assess the peripheral muscle performance of COPD patients by the sit-to-stand test (STST), as compared to the one-repetition maximum (1-RM), considered as the gold standard for assessing muscle strength in non-laboratory situations, and to evaluate the responsiveness of STST to a PR program. METHODS: Sixty moderate-to-severe COPD inpatients were randomly included into either the specific strength training group or into the usual PR program group. Patients were assessed on a 30-second STST and 1-minute STST, 1-RM, and 6-minute walking test (6MWT), before and after PR. Bland-Altman plots were used to evaluate the agreement between 1-RM and STST. RESULTS: The two groups were not different at baseline. In all patients, 1-RM was significantly related to the 30-second STST (r=0.48, P<0.001) and to 1-minute STST (r=0.36, P=0.005). The 30-second STST was better tolerated in terms of the perceived fatigue (P=0.002) and less time consuming (P<0.001) test. In the specific strength training group significant improvements were observed in the 30-second STST (P<0.001), 1-minute STST (P=0.005), 1-RM (P<0.001), and in the 6MWT (P=0.001). In the usual PR program group, significant improvement was observed in the 30-second STST (P=0.042) and in the 6MWT (P=0.001). CONCLUSION: Our study shows that in stable moderate-to-severe inpatients with COPD, STST is a valid and reliable tool to assess peripheral muscle performance of lower limbs, and is sensitive to a specific PR program.

Bronchial hyperresponsiveness, airway inflammation, and reversibility in patients with chronic obstructive pulmonary disease.

BACKGROUND: Bronchial hyperresponsiveness (BHR), sputum eosinophilia, and bronchial reversibility are often thought to be a hallmark of asthma, yet it has been shown to occur in COPD as well. OBJECTIVES: To evaluate the relationship between BHR, lung function, and airway inflammation in COPD patients. METHODS: Thirty-one, steroid-free patients with stable, mild and moderate COPD were studied. The following tests were carried out: baseline lung function, reversibility, provocative dose of methacholine causing a 20% fall in forced expiratory volume in 1 second, a COPD symptom score, and sputum induction. RESULTS: Twenty-nine patients completed the procedures. About 41.4% had BHR, 31.0% had increased sputum eosinophils, and 37.9% had bronchial reversibility. Some of the patients had only one of these characteristics while others had two or the three of them. Patients with BHR had higher sputum eosinophils than patients without BHR (P=0.046) and those with sputum eosinophils ≥3% had more exacerbations in the previous year and a higher COPD symptom score than patients with sputum eosinophils <3% (P=0.019 and P=0.031, respectively). In patients with BHR, the cumulative dose of methacholine was negatively related to the symptom score and the number of exacerbations in the previous year. When patients with bronchial reversibility were considered, bronchodilation was positively related to sputum eosinophils. CONCLUSION: Our study showed that BHR, sputum eosinophilia, and bronchial reversibility were not clustered in one single phenotype of COPD but could be present alone or together. Of interest, BHR and airway eosinophilia were associated with clinical data in terms of exacerbations and symptoms. Further investigation is needed to clarify this topic.

Estimation of minimal clinically important difference in EQ-5D visual analog scale score after pulmonary rehabilitation in subjects with COPD.

BACKGROUND: The effect of pulmonary rehabilitation (PR) on the EuroQol Group's 5-dimension questionnaire (EQ-5D) in COPD has been poorly investigated. In addition, conflicting results were reported about the visual analog scale component of EQ-5D (EQ-VAS). The purpose of this study was to evaluate the responsiveness of EQ-VAS to PR and its relationship with clinical and functional parameters in subjects with COPD, as well as to define the minimal clinically important difference (MCID) estimate for the EQ-VAS after PR. METHODS: A total of 468 in-patients with stable moderate-to-severe COPD, allocated to a 3-wk PR program, were retrospectively evaluated. EQ-VAS was assessed before and after PR, and its relationship with baseline pulmonary function, changes in 6-min walk test, and baseline, and transitional dyspnea index (BDI/TDI) after PR were evaluated. Using an anchor-based approach and receiver operating characteristic curves, the EQ-VAS change cutoff that identified subjects achieving the known MCID for TDI after PR was identified. RESULTS: Four hundred and thirty-nine subjects (94%, mean FEV1 55.3% predicted) completed pre- and post-PR EQ-VAS scores. After PR, EQ-VAS increased from 58 ± 17 to 72 ± 15 (ΔEQ-VAS 14 ± 12, P < .001). ΔEQ-VAS was negatively related to baseline FEV1 (r = -0.32, P < .001) and positively to TDI (r = 0.50, P < .001) and 6-min walk distance (r = 0.46, P < .001) changes. Receiver operating characteristic curves identified an EQ-VAS change cutoff of 8 as the best discriminating value to identify the MCID for TDI (0.78 sensitivity and 0.81 specificity; area under curve: 0.845, P < .001). CONCLUSIONS: Our study shows that, in in-patients with stable moderate-to-severe COPD, EQ-VAS is a valid and reliable tool to assess the responsiveness to PR, with an estimated MCID of 8 points. The EQ-VAS can be a practical alternative to more time-consuming measures of health-related quality of life.

Unified modeling of the mammalian and fish proton-dependent oligopeptide transporter PepT1.

Electrophysiological and biophysical analyses were used to compare the partial and complete transport cycles of the intestinal oligopeptide transporter PepT1 among three species (seabass, zebrafish and rabbit). On the whole, the presteady-state currents of the fish transporters were similar to each other. Rabbit PepT1 differed from the fish transporters by having slower-decaying currents, and the charge vs. potential (Q/V) and time constant vs. potential (τ/V) curves shifted to more positive potentials. All of the isoforms were similarly affected by external pH, showing acidity-induced slowing of the transients and positive shifts in the Q/V and τ/V curves. Analysis of the pH-dependence of the unidirectional rates of the intramembrane charge movement suggested that external protonation of the protein limits the speed of this process in both directions. The complete cycle of the transporter was studied using the neutral dipeptide Gly-Gln. Michaelis-Menten analysis confirmed that, in all species, acidity significantly increases the apparent affinity for the substrate but does not strongly impact maximal transport current. Simulations using a kinetic model incorporating the new findings showed good agreement with experimental data for all three species, both with respect to the presteady-state and the transport currents.

Transient currents in the glycine cotransporter GlyT1 reveal different steps in transport mechanism.

The relation between presteady-state (transient) currents elicited by voltage steps in the absence of organic substrate and transport-associated currents in the presence of glycine was investigated in Xenopus oocytes expressing the neuronal glycine transporter GlyT1b. Saturating amounts of glycine converted the transient currents in steady transport currents. Analysis of the transient currents abolished by the substrate confirmed the intramembrane nature of the underlying charge movement process. The sigmoidal Q/V relationship had a moderate slope consistent with the known GlyT1b stoichiometry. The transient currents were best fitted by the sum of two exponentials, with the slow time constant (tau (slow)) being in the order of tens of milliseconds. The apparent affinity for glycine was in the micromolar range and voltage-dependent, slightly decreasing at positive potentials. Numerical simulations show that a simplified, three-state model is sufficient to explain the main features of GlyT1b operation.

Chronic delta 9-tetrahydrocannabinol during adolescence provokes sex-dependent changes in the emotional profile in adult rats: behavioral and biochemical correlates.

Few and often contradictory reports exist on the long-term neurobiological consequences of cannabinoid consumption in adolescents. The endocannabinoid system plays an important role during the different stages of brain development as cannabinoids influence the release and action of different neurotransmitters and promote neurogenesis. This study tested whether long-lasting interference by cannabinoids with the developing endogenous cannabinoid system during adolescence caused persistent behavioral alterations in adult rats. Adolescent female and male rats were treated with increasing doses of Delta(9)-tetrahydrocannabinol (THC) for 11 days (postnatal day (PND) 35-45) and left undisturbed until adulthood (PND 75) when behavioral and biochemical assays were carried out. CB1 receptor level and CB1/G-protein coupling were significantly reduced by THC exposure in the amygdala (Amyg), ventral tegmental area (VTA) and nucleus accumbens (NAc) of female rats, whereas male rats had significant alterations only in the amygdala and hippocampal formation. Neither female nor male rats showed any changes in anxiety responses (elevated plus maze and open-field tests) but female rats presented significant 'behavioral despair' (forced swim test) paralleled by anhedonia (sucrose preference). In contrast, male rats showed no behavioral despair but did present anhedonia. This different behavioral picture was supported by biochemical parameters of depression, namely CREB alteration. Only female rats had low CREB activity in the hippocampal formation and prefrontal cortex and high activity in the NAc paralleled by increases in dynorphin expression. These results suggest that heavy cannabis consumption in adolescence may induce subtle alterations in the emotional circuit in female rats, ending in depressive-like behavior, whereas male rats show altered sensitivity to rewarding stimuli.