Mucociliary clearance as an outcome measure for cystic fibrosis clinical research

Current concepts of cystic fibrosis (CF) pathophysiology link ion transport abnormalities to reduced airway surface liquid (ASL) hydration and impaired mucus clearance. It is likely that correction of the defects that cause ASL dehydration will prevent degradation of mucus clearance, thereby preventing the initiation and/or progression of CF lung disease. A number of novel therapeutic agents aimed at the earliest steps in disease pathogenesis are now under development for the treatment of CF lung disease. Consequently, there is a tremendous need to develop methods that directly assess the effects of these agents on the underlying pathophysiologic process in the target organ. The measurement of mucociliary clearance (MCC) is a highly biologically relevant outcome, but one that is in need of further development. Here, we describe important methodologic aspects of MCC measurement and issues that have limited its use as an outcome measure in the past. Furthermore, we outline the steps that are being carried out now, and will be carried out in the future, to improve the performance of these studies in clinical trials. A systematic approach to optimizing and standardizing the measurement of MCC should greatly advance our ability to assess novel therapies at a relatively early stage of drug development. The resulting data may then be used to select those candidates that should be rapidly advanced into larger clinical trials

Hind foot drumming : morphofunctional analysis of the hind limb osteology in three species of African mole‐rats (Bathyergidae)

Hind foot drumming is a form of seismic signaling that plays a vital role in the communication of several Bathyergidae species. Hind foot drumming is initiated by the rapid movement of the whole hind limb by flexion and extension of the hip and knee. This study aimed to determine if morphological adaptations of the hind limb osteology were measurable using established morphometric analyses in two drumming (Bathyergus suillus and Georychus capensis) and one non‐drumming (Cryptomys hottentotus natalensis) African mole‐rat species. Forty‐three linear measurements of the hind limb were taken in 48 limbs (n = 16 limbs per species) and 32 indices were calculated. Mixed model analysis of variance was used to compare the three species and sexes within a species. Thirteen indices had significant differences between species. Eleven indices had significant differences between sexes within a species. Significant differences between the drumming (B. suillus and G. capensis) and the non‐drumming species were observed in three indices. The femoral greater trochanter was relatively shorter in the drumming species compared to the non‐drumming species, which is proposed to allow for increased hip joint mobility, thereby permitting drummers to move their limbs at the rapid speed required to generate seismic signals. Furthermore, the small in‐lever (shorter greater trochanter) may increase the velocity of limb motion. The robust tibias in the drumming species, as indicated by the tibial robustness index, are likely to counter the additional biomechanical load caused by the muscles involved in hind foot drumming. The relatively small hind feet seen in the drumming species allows for reduced limb weight needed for the rapid extension and flexion motion required during hind foot drumming. The significant differences reflected in the hind limb osteological indices between B. suillus and G. capensis and the non‐drumming species are indicative of adaptations for hind foot drumming.The National Research Foundation (NRF) and SARChi Mammal Behavioural Ecology and Physiology.http://wileyonlinelibrary.com/journal/jmor2021-02-07hj2020Mammal Research InstituteZoology and Entomolog

The influence of nonlinearities on the symmetric hydrodynamic response of a 10,000 TEU Container ship

The prediction of wave-induced motions and loads is of great importance for the design of marine structures. Linear potential flow hydrodynamic models are already used in different parts of the ship design development and appraisal process. However, the industry demands for design innovation and the possibilities offered by modern technology imply the need to also understand the modelling assumptions and associated influences of nonlinear hydrodynamic actions on ship response. At first instance, this paper presents the taxonomy of different Fluid Structure Interaction (FSI) methods that may be used for the assessment of ship motions and loads. Consequently, it documents in a practical way the effects of weakly nonlinear hydrodynamics on the symmetric wave-induced responses for a 10,000TEU Container ship. It is shown that the weakly nonlinear FSI models may be useful for the prediction of symmetric wave-induced loads and responses of such ship not only in way of amidships but also at the extremities of the hull. It is concluded that validation of hydrodynamic radiation and diffraction forces and their respective influence on ship response should be especially considered for those cases where the variations of the hull wetted surface in time may be noticeable

Polar Perturbations of Self-gravitating Supermassive Global Monopoles

Spontaneous global symmetry breaking of O(3) scalar field gives rise to point-like topological defects, global monopoles. By taking into account self-gravity,the qualitative feature of the global monopole solutions depends on the vacuum expectation value v of the scalar field. When v < sqrt{1 / 8 pi}, there are global monopole solutions which have a deficit solid angle defined at infinity. When sqrt{1 / 8 pi} <= v < sqrt{3 / 8 pi}, there are global monopole solutions with the cosmological horizon, which we call the supermassive global monopole. When v >= sqrt{3 / 8 pi}, there is no nontrivial solution. It was shown that all of these solutions are stable against the spherical perturbations. In addition to the global monopole solutions, the de Sitter solutions exist for any value of v. They are stable against the spherical perturbations when v sqrt{3 / 8 pi}. We study polar perturbations of these solutions and find that all self-gravitating global monopoles are stable even against polar perturbations, independently of the existence of the cosmological horizon, while the de Sitter solutions are always unstable.Comment: 10 pages, 6 figures, corrected some type mistakes (already corrected in PRD version

Mucus clearance and lung function in cystic fibrosis with hypertonic saline

BACKGROUND: Abnormal homeostasis of the volume of airway surface liquid in patients with cystic fibrosis is thought to produce defects in mucus clearance and airway defense. Through osmotic forces, hypertonic saline may increase the volume of airway surface liquid, restore mucus clearance, and improve lung function. METHODS: A total of 24 patients with cystic fibrosis were randomly assigned to receive treatment with inhaled hypertonic saline (5 ml of 7 percent sodium chloride) four times daily with or without pretreatment with amiloride. Mucus clearance and lung function were measured during 14-day baseline and treatment periods. RESULTS: Long-term inhalation of hypertonic saline without pretreatment with amiloride (i.e., with placebo pretreatment) resulted in a sustained (≥8 hours) increase in 1-hour rates of mucus clearance, as compared with those with amiloride pretreatment (14.0±2.0 vs. 7.0±1.5 percent, respectively; P = 0.02) and increased 24-hour rates of mucus clearance over baseline. Furthermore, inhalation of hypertonic saline with placebo improved the forced expiratory volume in one second (FEV 1) between the baseline period and the treatment period (mean difference, 6.62 percent; 95 percent confidence interval, 1.6 to 11.7; P = 0.02), whereas hypertonic saline with amiloride did not improve FEV 1 (mean difference, 2.9 percent; 95 percent confidence interval, -2.2 to 8.0; P = 0.23). Forced vital capacity (FVC), the forced expiratory flow between 25 and 75 percent of FVC (FEF 25-75), and respiratory symptoms also significantly improved in patients treated with hypertonic saline and placebo, whereas the residual volume as a proportion of total lung capacity (RV:TLC) did not change in either group. A comparison of the changes in lung function in the two groups showed no significant difference. In vitro data suggested that sustained hydration of airway surfaces was responsible for the sustained improvement in mucus clearance, whereas inhibition of osmotically driven water transport by amiloride accounted for the observed loss of clinical benefit. CONCLUSIONS: In patients with cystic fibrosis, inhalation of hypertonic saline produced a sustained acceleration of mucus clearance and improved lung function. This treatment may protect the lung from insults that reduce mucus clearance and produce lung disease

Antimatter from the cosmological baryogenesis and the anisotropies and polarization of the CMB radiation

We discuss the hypotheses that cosmological baryon asymmetry and entropy were produced in the early Universe by phase transition of the scalar fields in the framework of spontaneous baryogenesis scenario. We show that annihilation of the matter-antimatter clouds during the cosmological hydrogen recombination could distort of the CMB anisotropies and polarization by delay of the recombination. After recombination the annihilation of the antibaryonic clouds (ABC) and baryonic matter can produce peak-like reionization at the high redshifts before formation of quasars and early galaxy formation. We discuss the constraints on the parameters of spontaneous baryogenesis scenario by the recent WMAP CMB anisotropy and polarization data and on possible manifestation of the antimatter clouds in the upcoming PLANCK data.Comment: PRD in press with minor change

A Trans-Nasal Aerosol Delivery Device for Efficient Pulmonary Deposition

Background: Efficient delivery of aerosols to the lungs via the nasal route has been difficult to achieve, but it may offer benefits over the traditional oral route for a range of patient populations. Because slow, continuous delivery of short-acting agents could improve safety, tolerability, compliance, and efficacy when compared with the rapid, intermittent aerosol treatments delivered by mouthpiece or mask, a novel trans-nasal pulmonary aerosol delivery (tPAD) device was developed. The tPAD incorporates an aerosol particle-size selection chamber and a custom nasal cannula that are specifically optimized for aerosol delivery to the lung via the nasal route. The tPAD device produced a steady aerosol output (∼2 mL/h) from an optimized nasal cannula with negligible rainout in the cannula for up to 8 hours. The generated aerosol particles were small enough to minimize nasal deposition [volume median diameter (VMD) = 1.4 μm]. Methods: In this proof-of-concept study, gamma scintigraphy was used to quantitate deposition efficiency of 99mTc-labeled DTPA in 7% NaCl (hypertonic saline) in healthy human subjects (n = 6) during a short dosing period (15 minutes). A comparison was made with a standard oral jet nebulizer in the same subjects. Results: The tPAD device achieved high pulmonary deposition (39% ± 8%), based on emitted dose, and matched that of the oral jet nebulizer (36% ± 9%). Low fractions of aerosol deposition in the head and nose region were observed for tPAD (6% ± 6%) and jet nebulizer deliver (1% ± 1%) as well. Conclusions: A profile of high pulmonary deposition efficiency and low nasal dose may enable the sustained use of the tPAD platform with a variety of therapeutic agents for a range of pulmonary disorders

Homogeneity of Aerosol Deposition and Mucociliary Clearance are Improved Following Ivacaftor Treatment in Cystic Fibrosis

Background: Using planar gamma scintigraphy of inhaled radioaerosols, we have developed new analytical methods for assessing homogeneity of aerosol deposition and time-dependent particle clearance on a pixel-by-pixel basis, and applied them to a therapeutic cystic fibrosis (CF) study. Methods: At baseline and 1 month after beginning treatment with ivacaftor, a cystic fibrosis transmembrane regulator modulator for CF patients with at least one copy of the G551D mutation (n = 13), initial deposition and subsequent mucociliary clearance (MCC) of radiolabeled particles ( 99m Technetium-sulfur colloid, 5 μm mass median aerodynamic diameter) inhaled under controlled breathing conditions were measured. Results: Improved homogeneity of deposition, that is, decreased areas of higher and lower particle deposition in the lungs, was observed following ivacaftor treatment. The mean number ratio (NR) of pixels with higher deposition, relative to lung size, decreased from 0.14 to 0.09 (p = 0.003) and mean NR of colder pixels decreased from 0.23 to 0.19 (p = 0.004). Particle clearance was also improved following treatment, with mean MCC through 60 minutes equal to 12% versus 24%, without and with treatment, respectively (p = 0.010). Pixel-level analysis of MCC showed that (1) the fraction of pixels clearing >30% at 60 minutes was increased from 0.13 to 0.32 (p = 0.007); and (2) the fraction of pixels clearing <5% at 60 minutes was decreased from 0.54 to 0.37 (p = 0.014), indicating an overall recruitment of more fast-clearing lung regions with ivacaftor treatment. Conclusion: These detailed pixel analyses of deposition and clearance homogeneity may supplement traditional methods that use large regions of interest for assessing efficacy and mechanisms of therapeutic intervention in patients with airways disease

A Binary Lensing Event Toward the LMC: Observations and Dark Matter Implications

The MACHO collaboration has recently analyzed 2.1 years of photometric data for about 8.5 million stars in the Large Magellanic Cloud (LMC). This analysis has revealed 8 candidate microlensing events and a total microlensing optical depth of $\tau_{meas} = 2.9 +1.4/-0.9 \times 10^{-7}$. This significantly exceeds the number of events (1.1) and the microlensing optical depth predicted from known stellar populations: $\tau_{back} = 5.4\times 10^{-8}$, but it is consistent with models in which about half of the standard dark halo mass is composed of Machos of mass \sim 0.5 \msun. One of these 8 events appears to be a binary lensing event with a caustic crossing that is partially resolved which allows us to estimate the distance to the lenses. If the source star is not a short period binary star, then we show that the lens system is very likely to reside in the LMC. However, if we assume that the optical depth for LMC-LMC lensing is large enough to account for our entire lensing signal, then the binary event does not appear to be consistent with lensing of a single LMC source star by a binary residing in the LMC. Thus, while the binary lens may indeed reside in the LMC, there is no indication that most of the lenses reside in the LMC.Comment: 5 pages, 3 postscript figures included; To appear in the Proceedings of the Dark Matter '96 Conference held in Santa Monica, CA, Feb., 199

Cross-Correlation Studies with CMB Polarization Maps

The free-electron population during the reionized epoch rescatters CMB temperature quadrupole and generates a now well-known polarization signal at large angular scales. While this contribution has been detected in the temperature-polarization cross power spectrum measured with WMAP data, due to the large cosmic variance associated with anisotropy measurements at tens of degree angular scales only limited information related to reionization, such as the optical depth to electron scattering, can be extracted. The inhomogeneities in the free-electron population lead to an additional secondary polarization anisotropy contribution at arcminute scales. While the fluctuation amplitude, relative to dominant primordial fluctuations, is small, we suggest that a cross-correlation between arcminute scale CMB polarization data and a tracer field of the high redshift universe, such as through fluctuations captured by the 21 cm neutral Hydrogen background or those in the infrared background related to first proto-galaxies, may allow one to study additional details related to reionization. For this purpose, we discuss an optimized higher order correlation measurement, in the form of a three-point function, including information from large angular scale CMB temperature anisotropies in addition to arcminute scale polarization signal related to inhomogeneous reionization. We suggest that the proposed bispectrum can be measured with a substantial signal-to-noise ratio and does not require all-sky maps of CMB polarization or that of the tracer field. A measurement such as the one proposed may allow one to establish the epoch when CMB polarization related to reionization is generated and to address if the universe was reionized once or twice.Comment: 13 pages, 7 figures; Version in press with Phys. Rev.