Work of breathing during arm bracing in normal male subjects.

OBJECTIVE: Although chronic obstructive pulmonary disease patients get relief from their dyspnea by arm bracing, the mechanics of this effect are unknown. This study aimed to investigate the mechanisms by which arm bracing affects dyspnea by measuring the work of breathing (WOB) in the arm bracing posture. METHODS: Six normal male subjects were studied in two standing postures: erect and with their arms braced. For the arm bracing posture, the subjects leaned forward with their arms stretched and rested their hands on a platform. Respiratory frequency was set at 20 tidal breaths/min with the use of a metronome, and tidal volume was set at 1 L by observing the lung volume on a monitor. All the subjects randomly adopted the two postures, and a preset respiratory pattern was measured for 30 s in each posture. Lung volume and flow rate were measured using a hot-wire flowmeter. Esophageal pressure was measured using a 12-cm balloon catheter. The WOB was estimated using modified Campbell diagrams. RESULTS: Lung volume increased and inspiratory resistive WOB decreased, while inspiratory elastic WOB increased significantly with arm bracing compared with that of the erect posture (P < 0.05). CONCLUSION: Arm bracing posture increases the chest wall expansion thereby increasing the end-expiratory lung volume and decreasing the inspiratory resistive WOB among healthy individuals.

Effects of chest wall compression on expiratory flow rates in patients with chronic obstructive pulmonary disease

Background: Manual chest wall compression (CWC) during expiration is a technique for removing airway secretions in patients with respiratory disorders. However, there have been no reports about the physiological effects of CWC in patients with chronic obstructive pulmonary disease (COPD). Objective: To compare the effects of CWC on expiratory flow rates in patients with COPD and asymptomatic controls. Method: Fourteen subjects were recruited from among patients with COPD who were receiving pulmonary rehabilitation at the University Hospital (COPD group). Fourteen age-matched healthy subjects were also consecutively recruited from the local community (Healthy control group). Airflow and lung volume changes were measured continuously with the subjects lying in supine position during 1 minute of quiet breathing (QB) and during 1 minute of CWC by a physical therapist. Results: During CWC, both the COPD group and the healthy control group showed significantly higher peak expiratory flow rates (PEFRs) than during QB (mean difference for COPD group 0.14 L/sec, 95% confidence interval (CI) 0.04 to 0.24, p<0.01, mean difference for healthy control group 0.39 L/sec, 95% CI 0.25 to 0.57, p<0.01). In the between-group comparisons, PEFR was significantly higher in the healthy control group than in the COPD group (-0.25 L/sec, 95% CI -0.43 to -0.07, p<0.01). However, the expiratory flow rates at the lung volume at the PEFR during QB and at 50% and 25% of tidal volume during QB increased in the healthy control group (mean difference for healthy control group 0.31 L/sec, 95% CI 0.15 to 0.47, p<0.01: 0.31 L/sec, 95% CI 0.15 to 0.47, p<0.01: 0.27 L/sec, 95% CI 0.13 to 0.41, p<0.01, respectively) but not in the COPD group (0.05 L/sec, 95% CI -0.01 to 0.12: -0.01 L/sec, 95% CI -0.11 to 0.08: 0.02 L/sec, 95% CI -0.05 to 0.90) with the application of CWC. Conclusion: The effects of chest wall compression on expiratory flow rates was different between COPD patients and asymptomatic controls.

Effects of chest wall compression on expiratory flow rates in patients with chronic obstructive pulmonary disease.

BACKGROUND: Manual chest wall compression (CWC) during expiration is a technique for removing airway secretions in patients with respiratory disorders. However, there have been no reports about the physiological effects of CWC in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVE: To compare the effects of CWC on expiratory flow rates in patients with COPD and asymptomatic controls. METHOD: Fourteen subjects were recruited from among patients with COPD who were receiving pulmonary rehabilitation at the University Hospital (COPD group). Fourteen age-matched healthy subjects were also consecutively recruited from the local community (Healthy control group). Airflow and lung volume changes were measured continuously with the subjects lying in supine position during 1 minute of quiet breathing (QB) and during 1 minute of CWC by a physical therapist. RESULTS: During CWC, both the COPD group and the healthy control group showed significantly higher peak expiratory flow rates (PEFRs) than during QB (mean difference for COPD group 0.14 L/sec, 95% confidence interval (CI) 0.04 to 0.24, p<0.01, mean difference for healthy control group 0.39 L/sec, 95% CI 0.25 to 0.57, p<0.01). In the between-group comparisons, PEFR was significantly higher in the healthy control group than in the COPD group (-0.25 L/sec, 95% CI -0.43 to -0.07, p<0.01). However, the expiratory flow rates at the lung volume at the PEFR during QB and at 50% and 25% of tidal volume during QB increased in the healthy control group (mean difference for healthy control group 0.31 L/sec, 95% CI 0.15 to 0.47, p<0.01: 0.31 L/sec, 95% CI 0.15 to 0.47, p<0.01: 0.27 L/sec, 95% CI 0.13 to 0.41, p<0.01, respectively) but not in the COPD group (0.05 L/sec, 95% CI -0.01 to 0.12: -0.01 L/sec, 95% CI -0.11 to 0.08: 0.02 L/sec, 95% CI -0.05 to 0.90) with the application of CWC. CONCLUSION: The effects of chest wall compression on expiratory flow rates was different between COPD patients and asymptomatic controls.

Trans-homophilic interaction of CADM1 activates PI3K by forming a complex with MAGuK-family proteins MPP3 and Dlg.

CADM1 (Cell adhesion molecule 1), a cell adhesion molecule belonging to the immunoglobulin superfamily, is involved in cell-cell interaction and the formation and maintenance of epithelial structure. Expression of CADM1 is frequently downregulated in various tumors derived from epithelial cells. However, the intracellular signaling pathways activated by CADM1-mediated cell adhesion remain unknown. Here, we established a cell-based spreading assay to analyze the signaling pathway specifically activated by the trans-homophilic interaction of CADM1. In the assay, MDCK cells expressing exogenous CADM1 were incubated on the glass coated with a recombinant extracellular fragment of CADM1, and the degree of cell spreading was quantified by measuring their surface area. Assay screening of 104 chemical inhibitors with known functions revealed that LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), efficiently suppressed cell spreading in a dose-dependent manner. Inhibitors of Akt and Rac1, downstream effectors of PI3K, also partially suppressed cell spreading, while the addition of both inhibitors blocked cell spreading to the same extent as did LY294002. Furthermore, MPP3 and Dlg, membrane-associated guanylate kinase homologs (MAGuK) proteins, connect CADM1 with p85 of PI3K by forming a multi-protein complex at the periphery of cells. These results suggest that trans-homophilic interaction mediated by CADM1 activates the PI3K pathway to reorganize the actin cytoskeleton and form epithelial cell structure.

Trans-homophilic interaction of CADM1 activates PI3K by forming a complex with MAGuK-family proteins MPP3 and Dlg.

CADM1 (Cell adhesion molecule 1), a cell adhesion molecule belonging to the immunoglobulin superfamily, is involved in cell-cell interaction and the formation and maintenance of epithelial structure. Expression of CADM1 is frequently down-regulated in various tumors derived from epithelial cells. However, the intracellular signaling pathways activated by CADM1-mediated cell adhesion remain unknown. Here, we established a cell-based spreading assay to analyze the signaling pathway specifically activated by the trans-homophilic interaction of CADM1. In the assay, MDCK cells expressing exogenous CADM1 were incubated on the glass coated with a recombinant extracellular fragment of CADM1, and the degree of cell spreading was quantified by measuring their surface area. Assay screening of 104 chemical inhibitors with known functions revealed that LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), efficiently suppressed cell spreading in a dose-dependent manner. Inhibitors of Akt and Rac1, downstream effectors of PI3K, also partially suppressed cell spreading, while the addition of both inhibitors blocked cell spreading to the same extent as did LY294002. Furthermore, MPP3 and Dlg, membrane-associated guanylate kinase homologs (MAGuK) proteins, connect CADM1 with p85 of PI3K by forming a multi-protein complex at the periphery of cells. These results suggest that trans-homophilic interaction mediated by CADM1 activates the PI3K pathway to reorganize the actin cytoskeleton and form epithelial cell structure.

Relationship between spontaneous expiratory flow-volume curve pattern and air-flow obstruction in elderly COPD patients.

BACKGROUND: Assessment of the degree of air-flow obstruction is important for determining the treatment strategy in COPD patients. However, in some elderly COPD patients, measuring FVC is impossible because of cognitive dysfunction or severe dyspnea. In such patients a simple test of airways obstruction requiring only a short run of tidal breathing would be useful. We studied whether the spontaneous expiratory flow-volume (SEFV) curve pattern reflects the degree of air-flow obstruction in elderly COPD patients. METHODS: In 34 elderly subjects (mean ± SD age 80 ± 7 y) with stable COPD (percent-of-predicted FEV(1) 39.0 ± 18.5%), and 12 age-matched healthy subjects, we measured FVC and recorded flow-volume curves during quiet breathing. We studied the SEFV curve patterns (concavity/convexity), spirometry results, breathing patterns, and demographics. The SEFV curve concavity/convexity prediction accuracy was examined by calculating the receiver operating characteristic curves, cutoff values, area under the curve, sensitivity, and specificity. RESULTS: Fourteen subjects with COPD had a concave SEFV curve. All the healthy subjects had convex SEFV curves. The COPD subjects who had concave SEFV curves often had very severe airway obstruction. The percent-of-predicted FEV(1)% (32.4%) was the most powerful SEFV curve concavity predictor (area under the curve 0.92, 95% CI 0.83-1.00), and had the highest sensitivity (0.93) and specificity (0.88). CONCLUSIONS: Concavity of the SEFV curve obtained during tidal breathing may be a useful test for determining the presence of very severe obstruction in elderly patients unable to perform a satisfactory FVC maneuver.

Abundance of prereplicative complexes (Pre-RCs) facilitates recombinational repair under replication stress in fission yeast.

Mcm2-7 complexes are loaded onto chromatin with the aid of Cdt1 and Cdc18/Cdc6 and form prereplicative complexes (pre-RCs) at multiple sites on each chromosome. Pre-RCs are essential for DNA replication and surviving replication stress. However, the mechanism by which pre-RCs contribute to surviving replication stress is largely unknown. Here, we isolated the fission yeast mcm6-S1 mutant that was hypersensitive to methyl methanesulfonate (MMS) and camptothecin (CPT), both of which cause forks to collapse. The mcm6-S1 mutation impaired the interaction with Cdt1 and decreased the binding of minichromosome maintenance (MCM) proteins to replication origins. Overexpression of Cdt1 restored MCM binding and suppressed the sensitivity to MMS and CPT, suggesting that the Cdt1-Mcm6 interaction is important for the assembly of pre-RCs and the repair of collapsed forks. MMS-induced Chk1 phosphorylation and Rad22/Rad52 focus formation occurred normally, whereas cells containing Rhp54/Rad54 foci, which are involved in DNA strand exchange and dissociation of the joint molecules, were increased. Remarkably, G(1) phase extension through deletion of an S phase cyclin, Cig2, as well as Cdt1 overexpression restored pre-RC assembly and suppressed Rhp54 accumulation. A cdc18 mutation also caused hypersensitivity to MMS and CPT and accumulation of Rhp54 foci. These data suggest that an abundance of pre-RCs facilitates a late step in the recombinational repair of collapsed forks in the following S phase.