Mechanism of reduced maximal expiratory flow with aging.

To investigate the determinants of maximal expiratory flow (MEF) with aging, 17 younger (7 men and 10 women, 39 +/- 4 yr, mean +/- SD) and 19 older (11 men and 8 women, 69 +/- 3 yr) subjects with normal pulmonary function were studied. For further comparison, we also studied 10 middle-aged men with normal lung function (54 +/- 6 yr) and 15 middle-aged men (54 +/- 7 yr) with mild chronic airflow limitation (CAL; i.e., forced expiratory volume in 1 s/forced vital capacity = 63 +/- 8%). MEF, static lung elastic recoil pressure (Pst), and the minimal pressure for maximal flow (Pcrit) were determined in a pressure-compensated, volume-displacement body plethysmograph. Values were compared at 60, 70, and 80% of total lung capacity. In the older subjects, decreases in MEF (P < 0.01) and Pcrit (P < 0.05), compared with the younger subjects, were explained mainly by loss of Pst (P < 0.05). In the CAL subjects, MEF and Pcrit were lower (P < 0.05) than in the older subjects, but Pst was similar. Thus decreases in MEF and Pcrit were greater than could be explained by the loss of Pst and appeared to be related to increased upstream resistance. These data indicate that the loss of lung recoil explains the decrease in MEF with aging subjects, but not in the mild CAL patients that we studied.     

Effects of acute pleural effusion on respiratory system mechanics in dogs

We determined regional (Vr) and overall lung volumes in six head-up anesthetized dogs before and after the stepwise introduction of saline into the right pleural space. Functional residual capacity (FRC), as determined by He dilution, and total lung capacity (TLC) decreased by one-third and chest wall volume increased by two-thirds the saline volume added. Pressure-volume curves showed an apparent increase in lung elastic recoil and a decrease in chest wall elastic recoil with added saline, but the validity of esophageal pressure measurements in these head-up dogs is questionable. Vr was determined from the positions of intraparenchymal markers. Lower lobe TLC and FRC decreased with added saline. The decrease in upper lobe volume was less than that of lower lobe volume at FRC and was minimal at TLC. Saline increased the normal Vr gradient at FRC and created a gradient at TLC. During deflation from TLC to FRC before saline was added, the decrease in lung volume was accompanied by a shape change of the lung, with greatest distortion in the transverse (ribs to mediastinum) direction. After saline additions, deflation was associated with deformation of the lung in the cephalocaudal and transverse directions. The deformation with saline may be a result of upward displacement of the lungs into a smaller cross-sectional area of the thoracic cavity.     

Pleural pressure distribution and its relationship to lung volume and interstitial pressure

The mechanics of the pleural space has long been controversial. We summarize recent research pertaining to pleural mechanics within the following conceptual framework, which is still not universally accepted. Pleural pressure, the force acting to inflate the lung within the thorax, is generated by the opposing elastic recoils of the lung and chest wall and the forces generated by respiratory muscles. The spatial variation of pleural pressure is a result of complex force interactions among the lung and other structures that make up the thorax. Gravity contributes one of the forces that act on these structures, and regional lung expansion and pleural pressure distribution change with changes in body orientation. Forces are transmitted directly between the chest wall and the lung through a very thin but continuous pleural liquid space. The pressure in pleural liquid equals the pressure acting to expand the lung. Pleural liquid is not in hydrostatic equilibrium, and viscous flow of pleural liquid is driven by the combined effect of the gravitational force acting on the liquid and the pressure distribution imposed by the surrounding structures. The dynamics of pleural liquid are considered an integral part of a continual microvascular filtration into the pleural space. Similar concepts apply to the pulmonary interstitium. Regional differences in lung volume expansion also result in regional differences in interstitial pressure within the lung parenchyma and thus affect regional lung fluid filtration.     

Shape of the chest wall in the prone and supine anesthetized dog

The shape of the passive chest wall of six anesthetized dogs was determined at total lung capacity (TLC) and functional residual capacity (FRC) in the prone and supine body positions by use of volumetric-computed tomographic images. The transverse cross-sectional areas of the rib cage, mediastinum, and diaphragm were calculated every 1.6 mm along the length of the thorax. The changes in the volume and the axial distribution of transverse area of the three chest wall components with lung volume and body position were evaluated. The decrease of the transverse area within the rib cage between TLC and FRC, as a fraction of the area at TLC, was uniform from the apex of the thorax to the base. The volume of the mediastinum increased slightly between TLC and FRC (14% of its TLC volume supine and 20% prone), squeezing the lung between it and the rib cage. In the transverse plane, the heart was positioned in the midthorax and moved little between TLC and FRC. The shape, position, and displacement of the diaphragm were described by contour plots. In both postures, the diaphragm was flatter at FRC than at TLC, because of larger displacements in the dorsal than in the ventral region of the diaphragm. Rotation from the prone to supine body position produced a lever motion of the diaphragm, displacing the dorsal portion of the diaphragm cephalad and the ventral portion caudad. In five of the six dogs, bilateral isovolume pneumothorax was induced in the supine body position while intrathoracic gas volume was held constant.(ABSTRACT TRUNCATED AT 250 WORDS)     

<Emphasis Type="Italic">TRAF1/C5</Emphasis>polymorphism is not associated with increased mortality in rheumatoid arthritis: two large longitudinal studies

Introduction  

Recently an association between a genetic variation in TRAF1/C5 and mortality from sepsis or cancer was found in rheumatoid arthritis (RA). The most prevalent cause of death, cardiovascular disease, may have been missed in that study, since patients were enrolled at an advanced disease stage. Therefore, we used an inception cohort of RA patients to investigate the association between TRAF1/C5 and cardiovascular mortality, and replicate the findings on all-cause mortality. As TRAF1/C5 associated mortality may not be restricted to RA, we also studied a large cohort of non-RA patients.     

Mesenchymal stem cells in autoimmune diseases: hype or hope?

Intervention with mesenchymal stem cells (MSCs) represents a promising therapeutic tool in treatment-refractory autoimmune diseases. A new report by Schurgers and colleagues in a previous issue of Arthritis Research & Therapy sheds novel mechanistic insight into the pathways employed by MSCs to suppress T-cell proliferation in vitro, but, at the same time, indicates that MSCs do not influence T-cell reactivity and the disease course in an in vivo arthritis model. Such discrepancies between the in vitro and in vivo effects of potent cellular immune modulators should spark further research and should be interpreted as a sign of caution for the in vitro design of MSC-derived interventions in the setting of human autoimmune diseases.     

Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study

Background

Novel pentacycloundecane (PCU)-lactone-CO-EAIS peptide inhibitors were designed, synthesized, and evaluated against wild-type C-South African (C-SA) HIV-1 protease. Three compounds are reported herein, two of which displayed IC₅₀ values of less than 1.00 μM. A comparative MM-PB(GB)SA binding free energy of solvation values of PCU-lactam and lactone models and their enantiomers as well as the PCU-lactam-NH-EAIS and lactone-CO-EAIS peptide inhibitors and their corresponding diastereomers complexed with South African HIV protease (C-SA) was performed. This will enable us to rationalize the considerable difference between inhibitory concentration (IC₅₀) of PCU-lactam-NH-EAIS and PCU-lactone-CO-EAIS peptides.

Results

The PCU-lactam model exhibited more negative calculated binding free energies of solvation than the PCU-lactone model. The same trend was observed for the PCU-peptide inhibitors, which correspond to the experimental activities for the PCU-lactam-NH-EAIS peptide (IC₅₀ = 0.076 μM) and the PCU-lactone-CO-EAIS peptide inhibitors (IC₅₀ = 0.850 μM). Furthermore, a density functional theory (DFT) study on the natural atomic charges of the nitrogen and oxygen atoms of the three PCU-lactam, PCU-lactim and PCU-lactone models were performed using natural bond orbital (NBO) analysis. Electrostatic potential maps were also used to visualize the electron density around electron-rich regions. The asymmetry parameter (η) and quadrupole coupling constant (χ) values of the nitrogen and oxygen nuclei of the model compounds were calculated at the same level of theory. Electronic molecular properties including polarizability and electric dipole moments were also calculated and compared. The Gibbs theoretical free solvation energies of solvation (∆G_solv) were also considered.

Conclusions

A general trend is observed that the lactam species appears to have a larger negative charge distribution around the heteroatoms, larger quadrupole constant, dipole moment and better solvation energy, in comparison to the PCU-lactone model. It can be argued that these characteristics will ensure better eletronic interaction between the lactam and the receptor, corresponding to the observed HIV protease activities in terms of experimental IC₅₀ data.

Electronic supplementary material

The online version of this article (doi:10.1186/s12929-015-0115-5) contains supplementary material, which is available to authorized users.