We have modeled the time-course of Ca2+ binding to calmodulin, troponin, parvalbumin, and myosin in response to trains of transient increases in the free myoplasmic calcium ion concentration (pCa). A simple mathematical expression was used to describe each pCa transient, the shape and duration of which is qualitatively similar to those thought to occur in vivo. These calculations assumed that all individual metal binding sites are noninteracting and that Ca2+ bind competitively to the Ca2+-Mg2+ sites of troponin, parvalbumin, and myosin. All the on-and-off rate constants for both Ca2+ and Mg2+ were obtained either from the literature or from our own research. The percent saturation of the Ca2+-Mg2+ sites with Ca2+ was found to change very little in response to each pCa transient in the presence of 2.5 X 10(-3)M Mg2+. Our analysis suggests that the Ca2+ content of these sites is a measure of the intensity and frequency of recent muscle activity because large changes in the Ca2+ occupancy of these sites can occur with repeated stimulation. In contrast, large rapid changes in the amount of Ca2+ bound to the Ca2+-specific sites of troponin and calmodulin are induced by each pCa transient. Thus, only sites of the "Ca2+-specific" type can act as rapid Ca2+-regulatory sites in muscle. Fluctuation in the total amount of Ca2+ bound to these sites in response to various types of pCa transients further suggests that in vivo only about one-half to one-third of the total steady-state myofibrillar Ca2+-binding capacity exchanges Ca2+ during any single transient.

The spectral parameters of hyperpolarized 129Xe exchanging between airspaces, interstitial barrier, and red blood cells (RBCs) are sensitive to pulmonary pathophysiology. This study sought to evaluate whether the dynamics of 129Xe spectroscopy provide additional insight, with particular focus on quantifying cardiogenic oscillations in the RBC resonance. 129Xe spectra were dynamically acquired in eight healthy volunteers and nine subjects with idiopathic pulmonary fibrosis (IPF). 129Xe FIDs were collected every 20 ms (TE = 0.932 ms, 512 points, dwell time = 32 μs, flip angle ≈ 20°) during a 16 s breathing maneuver. The FIDs were pre-processed using the spectral improvement by the Fourier thresholding technique and fit in the time domain to determine the airspace, interstitial barrier, and RBC spectral parameters. The RBC and gas resonances were fit to a Lorentzian lineshape, while the barrier was fit to a Voigt lineshape to account for its greater structural heterogeneity. For each complex resonance the amplitude, chemical shift, linewidth(s), and phase were calculated. The time-averaged spectra confirmed that the RBC to barrier amplitude ratio and RBC chemical shift are both reduced in IPF subjects. Their temporal dynamics showed that all three 129Xe resonances are affected by the breathing maneuver. Most notably, several RBC spectral parameters exhibited prominent oscillations at the cardiac frequency, and their peak-to-peak variation differed between IPF and healthy volunteers. In the IPF versus healthy cohort, oscillations were more prominent in the RBC amplitude (16.8 ± 5.2 versus 9.7 ± 2.9%; P = 0.008), chemical shift (0.43 ± 0.33 versus 0.083 ± 0.05 ppm; P < 0.001), and phase (7.7 ± 5.6 versus 1.4 ± 0.8°; P < 0.001). Dynamic 129Xe spectroscopy is a simple and sensitive additional tool that probes the temporal variability of gas exchange and may prove useful in discerning the underlying causes of its impairment.

Immunological and clinical profiles were evaluated in 2 groups: human immunodeficiency virus (HIV)-uninfected and HIV-infected patients, with newly diagnosed pulmonary tuberculosis (TB), and tuberculin-skin-test-reactive healthy control subjects. HIV-uninfected patients with TB were also followed up longitudinally during and after chemotherapy. At the time of diagnosis, purified protein derivative (PPD)-stimulated production of interferon (IFN)-gamma by peripheral blood mononuclear cells from TB patients was depressed, compared with that of healthy control subjects, whereas levels of transforming growth factor (TGF)-beta and interleukin (IL)-10 were increased. In longitudinal studies, PPD stimulated production of IL-10 and TGF-beta returned to baseline by 3 months, whereas IFN-gamma production remained depressed for at least 12 months. These data indicate that the immunosuppression of TB is not only immediate and apparently dependent (at least in part) on immunosuppressive cytokines early during the course of Mycobacterium TB infection but is also long lasting, presumably relating to a primary abnormality in T-cell function.

Background Assessing functional impairment, therapeutic response, and disease progression in patients with idiopathic pulmonary fibrosis (IPF) continues to be challenging. Hyperpolarized 129Xe MRI can address this gap through its unique capability to image gas transfer three-dimensionally from airspaces to interstitial barrier tissues to RBCs. This must be validated by testing the degree to which it correlates with pulmonary function tests (PFTs) and CT scores and its spatial distribution reflects known physiology and patterns of disease. Methods 13 healthy individuals (33.6±15.7 years) and 12 IPF patients (66.0±6.4 years) underwent 129Xe MRI to generate 3D quantitative maps depicting the 129Xe ventilation distribution, its uptake in interstitial barrier tissues, and its transfer to RBCs. For each map, mean values were correlated with PFTs and CT fibrosis scores and their patterns were tested for the ability to depict functional gravitational gradients in healthy lung, and to detect the known basal and peripheral predominance of disease in IPF. Results 129Xe MRI depicted functional impairment in IPF patients, whose mean barrier uptake increased by 188% compared to the healthy reference population. 129Xe MRI metrics correlated poorly and insignificantly with CT fibrosis scores, but strongly with pulmonary function tests. Barrier uptake and RBC transfer both correlated significantly with DLCO (r=−0.75, p<0.01 and r=0.72, p<0.01), while their ratio (RBC/barrier) correlated strongly (r=0.94, p<0.01). RBC transfer exhibited significant anterior-posterior gravitational gradients in healthy volunteers, but not in IPF, where it was significantly impaired in the basal (p=0.02) and sub-pleural (p<0.01) lung. Conclusions Hyperpolarized 129Xe MRI is a rapid and well-tolerated exam that provides region-specific quantification of interstitial barrier thickness and RBC transfer efficiency. With further development, it could become a robust tool for measuring disease progression and therapeutic response in IPF patients, sensitively and non-invasively.