We study the statistical properties of the combined emission of a population of discrete sources. In particular, we consider the dependence of their total luminosity (Ltot = capital sigma kLk) and ...fractional rmstot variability on the number of sources n or on the normalization of the luminosity function. We show that due to small number statistics a regime exists, in which Ltot grows non-linearly with n. This is in apparent contradiction with the seemingly obvious prediction Ltot = {integral}LdN/dLdL ~ n. In this non-linear regime, the rmstot decreases with n significantly more slowly than expected from the rms ~ 1/n1/2 averaging law. Only in the limit of n >> 1 do these quantities behave as intuitively expected, Ltot ~ n and rmstot ~ 1/n1/2. Using the total X-ray luminosity of a galaxy due to its X-ray binary population as an example, we show that the LX-SFR and LX-M relations predicted from the respective ``universal'' luminosity functions of high and low mass X-ray binaries are in a good agreement with observations.
Inhibition of the enzyme(s) that produce the Amyloid beta (Aβ) peptide, namely BACE and γ-secretase, is considered an attractive target for Alzheimer’s disease therapy. However, the optimal ...pharmacokinetic–pharmacodynamic modelling method to describe the changes in Aβ levels after drug treatment is unclear. In this study, turnover models were employed to describe Aβ levels following treatment with the γ-secretase inhibitor RO5036450, in the wild type rat. Initially, Aβ level changes in the brain, cerebral spinal fluid (CSF) and plasma were modeled as separate biological compartments, which allowed the estimation of a compound
IC
50
and Aβ turnover. While the data were well described, the model did not take into consideration that the CSF pool of Aβ most likely originates from the brain via the CSF drainage pathway. Therefore, a separate model was carried out, with the assumption that CSF Aβ levels originated from the brain. The optimal model that described the data involved two brain Aβ 40 sub-compartments, one with a rapid turnover, from which CSF Aβ 40 is derived, and a second quasi-static pool of ~20%. Importantly, the estimated in vivo brain
IC
50
was in a good range of the in vitro
IC
50
(ratio, 1.4). In conclusion, the PK/PD models presented here are well suited for describing the temporal changes in Aβ levels that occur after treatment with an Aβ lowering drug, and identifying physiological parameters.
Inhibition of the enzyme(s) that produce the Amyloid beta (Aβ) peptide, namely BACE and γ-secretase, is considered an attractive target for Alzheimer's disease therapy. However, the optimal ...pharmacokinetic-pharmacodynamic modelling method to describe the changes in Aβ levels after drug treatment is unclear. In this study, turnover models were employed to describe Aβ levels following treatment with the γ-secretase inhibitor RO5036450, in the wild type rat. Initially, Aβ level changes in the brain, cerebral spinal fluid (CSF) and plasma were modeled as separate biological compartments, which allowed the estimation of a compound IC ^sub 50^ and Aβ turnover. While the data were well described, the model did not take into consideration that the CSF pool of Aβ most likely originates from the brain via the CSF drainage pathway. Therefore, a separate model was carried out, with the assumption that CSF Aβ levels originated from the brain. The optimal model that described the data involved two brain Aβ 40 sub-compartments, one with a rapid turnover, from which CSF Aβ 40 is derived, and a second quasi-static pool of ~20%. Importantly, the estimated in vivo brain IC ^sub 50^ was in a good range of the in vitro IC ^sub 50^ (ratio, 1.4). In conclusion, the PK/PD models presented here are well suited for describing the temporal changes in Aβ levels that occur after treatment with an Aβ lowering drug, and identifying physiological parameters.PUBLICATION ABSTRACT
The effects of exercise on right ventricular function were evaluated in 14 patients who underwent supine rest and exercise right ventricular angiography, on the basis of coronary anatomy and exercise ...left ventricular regional wall motion analysis, these were classified into two groups: Group 1 (n = 7) had no or only mild coronary artery disease and Group 2 (n = 7) had significant coronary disease and exercise-induced left ventricular wall motion abnormalities suggesting ischemia.
Chamber stiffness at rest was higher in Group 2 (48 × 10−3ml−1/m2) than in Group 1 (18 × 10−3ml−1, p = 0.006). During exercise, right ventricular filing rate in the second half of diastole was significantly lower in Group 2 (126 versus 276 ml/m2per s, p < 0.03). The time constant of right ventricular pressure decay decreased signiicantly in both groups with exercise; however, both groups displayed a parallel upward shift of the pressure-volume curve with exercise. Because ischemia could not be demonstrated in Group 1, it is an unlikely explanation for this shift. was not a significant factor with exercise.
Because of an increase in left ventricular end-diastolic volume with exercise and a close correlation between right and left ventricular end-diastolic pressures (r = 0.96 for Group 1 and r = 0.76 for Group 2), pericardial constraint is the most likely cause for this upward shift of the pressure-volume carve. Therefore, an increase in right ventricular end-diastolic pressure may lot be a reliable indicator of ischemia during exercise because this pressure is coupled to changes in left ventricular volume and pericardial constraint.
To evaluate the effects of exercise and coronary artery disease on right ventricular (RV) systolic function, rest and exercise biplane RV angiograms were recorded in 20 patients undergoing diagnostic ...cardiac catheterization. Thirteen patients had exercise angiograms of sufficient quality to undergo analysis and were classified into 2 groups. Group 1 had no or only mild coronary artery disease; group 2 had significant coronary artery disease as manifested by new, exercise-induced, left ventricular regional wall motion abnormalities. RV systolic pressure increased in both groups during exercise: 33 to 57 mm Hg in group 1 (p = 0.0002) and 33 to 55 mm Hg in group 2 (p = 0.0004). Pulmonary resistance did not change in group 1 during exercise but increased in group 2 (3.2 to 4.8 Wood units, p = 0.04). RV ejection fraction increased slightly, but not significantly, during exercise in group 1, but decreased in group 2 (73 vs 58% with exercise p = 0.01). The change in RV ejection fraction from rest to exercise correlated closely with the change in pulmonary resistance from rest to exercise (r = -0.89, p less than 0.0001). RV regional wall motion analysis demonstrated a generalized decline in regional ejection fraction in group 2 during exercise, even in patients without right coronary artery disease. In conclusion, there is a decline in RV ejection fraction during exercise in patients with significant coronary artery disease. The generalized reduction in regional RV ejection fraction coupled with the close correlation with the change in pulmonary resistance suggests that increased afterload, rather than RV ischemia, is the cause.
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