Numerical modelling and analysis of peripheral airway asymmetry and ventilation in the human adult lung.

We present a new one-dimensional model of gas transport in the human adult lung. The model comprises asymmetrically branching airways, and heterogeneous interregional ventilation. Our model differs from previous models in that we consider the asymmetry in both the conducting and the acinar airways in detail. Another novelty of our model is that we use simple analytical relationships to produce physiologically realistic models of the conducting and acinar airway trees. With this new model, we investigate the effects of airway asymmetry and heterogeneous interregional ventilation on the phase III slope in multibreath washouts. The model predicts the experimental trend of the increase in the phase III slope with breath number in multibreath washout studies for nitrogen, SF(6) and helium. We confirm that asymmetrical branching in the acinus controls the magnitude of the first-breath phase III slope and find that heterogeneous interregional ventilation controls the way in which the slope changes with subsequent breaths. Asymmetry in the conducting airways appears to have little effect on the phase III slope. That the increase in slope appears to be largely controlled by interregional ventilation inhomogeneities should be of interest to those wishing to use multibreath washouts to detect the location of the structural abnormalities within the lung.

The simultaneous role of an alveolus as flow mixer and flow feeder for the deposition of inhaled submicron particles.

In an effort to understand the fate of inhaled submicron particles in the small sacs, or alveoli, comprising the gas-exchange region of the lung, we calculated the flow in three-dimensional (3D) rhythmically expanding models of alveolated ducts. Since convection toward the alveolar walls is a precursor to particle deposition, it was the goal of this paper to investigate the streamline maps' dependence upon alveoli location along the acinar tree. On the alveolar midplane, the recirculating flow pattern exhibited closed streamlines with a stagnation saddle point. Off the midplane we found no closed streamlines but nested, funnel-like, spiral, structures (reminiscent of Russian nesting dolls) that were directed towards the expanding walls in inspiration, and away from the contracting walls in expiration. These nested, funnel-like, structures were surrounded by air that flowed into the cavity from the central channel over inspiration and flowed from the cavity to the central channel over expiration. We also found that fluid particle tracks exhibited similar nested funnel-like spiral structures. We conclude that these unique alveolar flow structures may be of importance in enhancing deposition. In addition, due to inertia, the nested, funnel-like, structures change shape and position slightly during a breathing cycle, resulting in flow mixing. Also, each inspiration feeds a fresh supply of particle-laden air from the central channel to the region surrounding the mixing region. Thus, this combination of flow mixer and flow feeder makes each individual alveolus an effective mixing unit, which is likely to play an important role in determining the overall efficiency of convective mixing in the acinus.

Geometric hysteresis of alveolated ductal architecture.

Low Reynolds number airflow in the pulmonary acinus and aerosol particle kinetics therein are significantly conditioned by the nature of the tidal motion of alveolar duct geometry. At least two components of the ductal structure are known to exhibit stress-strain hysteresis: smooth muscle within the alveolar entrance rings, and surfactant at the air-tissue interface. We hypothesize that the geometric hysteresis of the alveolar duct is largely determined by the interaction of the amount of smooth muscle and connective tissue in ductal rings, septal tissue properties, and surface tension-surface area characteristics of surfactant. To test this hypothesis, we have extended the well-known structural model of the alveolar duct by Wilson and Bachofen (1982, "A Model for Mechanical Structure of the Alveolar Duct," J. Appl. Physiol. 52(4), pp. 1064-1070) by adding realistic elastic and hysteretic properties of (1) the alveolar entrance ring, (2) septal tissue, and (3) surfactant. With realistic values for tissue and surface properties, we conclude that: (1) there is a significant, and underappreciated, amount of geometric hysteresis in alveolar ductal architecture; and (2) the contribution of smooth muscle and surfactant to geometric hysteresis are of opposite senses, tending toward cancellation. Quantitatively, the geometric hysteresis found experimentally by Miki et al. (1993, "Geometric Hysteresis in Pulmonary Surface-to-Volume Ratio during Tidal Breathing," J. Appl. Physiol. 75(4), pp. 1630-1636) is consistent with little or no smooth muscle tone in anesthetized rabbits in control conditions, and with substantial smooth muscle activation following methacholine challenge. The observed local hysteretic boundary motion of the acinar duct would result in irreversible acinar flow fields, which might be important mechanistic contributors to aerosol mixing and deposition deep in the lung.

Radial transport along the human acinar tree.

A numerical model of an expanding asymmetric alveolated duct was developed and used to investigate lateral transport between the central acinar channel and the surrounding alveoli along the acinar tree. Our results indicate that some degree of recirculation occurs in all but the terminal generations. We found that the rate of diffusional transport of axial momentum from the duct to the alveolus was by far the largest contributor to the resulting momentum in the alveolar flow but that the magnitude of the axial momentum is critical in determining the nature of the flow in the alveolus. Further, we found that alveolar flow rotation, and by implication chaotic mixing, is strongest in the entrance generations. We also found that the expanding alveolus provides a pathway by which particles with little intrinsic motion can enter the alveoli. Thus, our results offer a possible explanation for why submicron particles deposit preferentially in the acinar-entrance region.

Abrupt Deterioration of COVID-19 Patients and Spreading of SARS COV-2 Virions in the Lungs.

A unique feature of COVID-19 interstitial pneumonia is an abrupt progression to respiratory failure. Our calculation shows that this abrupt deteriorate may be caused by a sudden shift in the spread of virus-laden bioaerosols through the airways to many different regions of the lungs from the initial site of infection.

Age-dependent changes in porcine alveolar macrophage function during the postnatal period of alveolarization.

During early postnatal ontogeny in most mammals, the lung is structurally and functionally immature. In some species with relatively altricial lung morphology, there is evidence of a coupling between functional maturity of the pulmonary cellular immune system and alveolar maturation. Herein, we examine changes in alveolar macrophage (AM) number and function occurring during alveolarization in a more precocial species, the pig, to determine if heightened oxidative metabolism and phagocytic ability is similarly delayed until completion of lung morphogenesis. We assessed cell differential in lavage fluid and evaluated two main functional parameters of AM phagocytic response, the generation of reactive oxygen species (ROS), and particle internalization. AM functional maturation occurred mainly during the first postnatal week: the proportion of AMs, ROS generation, and phagocytosis all increased significantly. These results suggest maturational improvement of the impaired AM-based pulmonary immune system of the neonate piglet occurs during the postnatal period of rapid alveolarization.

Fully conjugated porphyrin tapes with electronic absorption bands that reach into infrared.

Scandium(III)-catalyzed oxidation of meso-meso-linked zinc(II)-porphyrin arrays (up to dodecamers) with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) led to efficient formation of triply meso-meso-, beta-beta-, and beta-beta-linked zinc(II)-oligoiporphyrins with 62 to 91% yields. These fused tape-shaped porphyrin arrays display extremely red-shifted absorption bands that reflect extensively pi-conjugated electronic systems and a low excitation gap. The lowest electronic absorption bands become increasingly intensified and red-shifted upon the increase in the number of porphyrins and eventually reach a peak electronic excitation for the dodecamer at approximately 3500 wavenumber. The one-electron oxidation potentials also decreased progressively upon the increase in the number of porphyrins. These properties in long and rigid molecular shapes suggest their potential use as molecular wires.

Finite element 3D reconstruction of the pulmonary acinus imaged by synchrotron X-ray tomography.

The alveolated structure of the pulmonary acinus plays a vital role in gas exchange function. Three-dimensional (3D) analysis of the parenchymal region is fundamental to understanding this structure-function relationship, but only a limited number of attempts have been conducted in the past because of technical limitations. In this study, we developed a new image processing methodology based on finite element (FE) analysis for accurate 3D structural reconstruction of the gas exchange regions of the lung. Stereologically well characterized rat lung samples (Pediatr Res 53: 72-80, 2003) were imaged using high-resolution synchrotron radiation-based X-ray tomographic microscopy. A stack of 1,024 images (each slice: 1024 x 1024 pixels) with resolution of 1.4 mum(3) per voxel were generated. For the development of FE algorithm, regions of interest (ROI), containing approximately 7.5 million voxels, were further extracted as a working subunit. 3D FEs were created overlaying the voxel map using a grid-based hexahedral algorithm. A proper threshold value for appropriate segmentation was iteratively determined to match the calculated volume density of tissue to the stereologically determined value (Pediatr Res 53: 72-80, 2003). The resulting 3D FEs are ready to be used for 3D structural analysis as well as for subsequent FE computational analyses like fluid dynamics and skeletonization.

Characteristics of adverse drug reactions in a vemurafenib early post-marketing phase vigilance study in Japan.

BACKGROUND: Post-approval research or monitoring is important to determine real-world safety of new products; however, evidence is scant for vemurafenib in Japanese patients. In Japan, a unique system is officially obligated to investigate post-approval safety. Here we report the first adverse drug reaction (ADR) data from vemurafenib-treated Japanese patients with metastatic melanoma. Data were collected in an early post-marketing phase vigilance (EPPV) study. METHODS: ADRs were events for which a causal relationship with vemurafenib could not be ruled out or was unknown. ADR data were collected for patients treated with vemurafenib (960 mg bid) between 26 February and 25 August 2015. RESULTS: Among 95 patients, 46 patients had 118 ADRs (24 serious ADRs in 13 patients). The most common serious ADRs were hypersensitivity (n = 1; 3 events), arthralgia (n = 2; 2 events), pyrexia (n = 2; 2 events) and drug eruption (n = 2; 2 events). Seven patients had serious skin disorders or hypersensitivity, six of whom had prior anti-programmed cell death-1 (PD-1) antibodies 5-35 days before starting vemurafenib. ADR reports of serious skin disorders appeared to be collected more rapidly than previously reported. Cutaneous squamous cell carcinoma developed in only one patient. CONCLUSIONS: EPPV in Japanese vemurafenib-treated patients identified no new safety signals. The most serious skin and hypersensitivity ADRs occurred in patients with prior anti-PD-1 exposure. Cutaneous squamous cell carcinoma appeared to be rare in Japanese patients. Further research is needed to clarify whether prior treatment with anti-PD-1 agents or racial differences affect the characteristic profile of cutaneous ADRs in Japanese patients.

Dissipative particle dynamics simulation of flow generated by two rotating concentric cylinders: boundary conditions.

The dissipative particle dynamics (DPD) method was used to simulate the flow in a system comprised of a fluid occupying the space between two cylinders rotating with equal angular velocities. The fluid, initially at rest, ultimately reaches a steady, linear velocity distribution (a rigid-body rotation). Since the induced flow field is solely associated with the no-slip boundary condition at the walls, we employed this system as a benchmark to examine the effect of bounce-back reflections, specular reflections, and Pivkin-Karniadakis no-slip boundary conditions, upon the steady-state velocity, density, and temperature distributions. An additional advantage of the foregoing system is that the fluid occupies inherently a finite bounded domain so that the results are affected by the prescribed no-slip boundary conditions only. Past benchmark systems such as Couette flow between two infinite parallel plates or Poiseuille flow in an infinitely long cylinder must employ artificial periodic boundary conditions at arbitrary upstream and downstream locations, a possible source of spurious effects. In addition, the effect of the foregoing boundary conditions on the time evolution of the simulated velocity profile was compared with that of the known, time-dependent analytical solution. It was shown that bounce-back reflection yields the best results for the velocity distributions with small fluctuations in density and temperature at the inner fluid domain and larger deviations near the walls. For the unsteady solutions a good fit is obtained if the DPD friction coefficient is proportional to the kinematic viscosity. Based on dimensional analysis and the numerical results a universal correlation is suggested between the friction coefficient and the kinematic viscosity.

Deficiency in WT1-targeting microRNA-125a leads to myeloid malignancies and urogenital abnormalities.

The Wilms' tumor gene WT1 is overexpressed in leukemia and solid tumors and has an oncogenic role in leukemogenesis and tumorigenesis. However, precise regulatory mechanisms of WT1 overexpression remain undetermined. In the present study, microRNA-125a (miR-125a) was identified as a miRNA that suppressed WT1 expression via binding to the WT1-3'UTR. MiR-125a knockout mice overexpressed WT1, developed myeloproliferative disorder (MPD) characterized by expansion of myeloid cells in bone marrow (BM), spleen and peripheral blood, and displayed urogenital abnormalities. Silencing of WT1 expression in hematopoietic stem/progenitor cells of miR-125a knockout MPD mice by short-hairpin RNA inhibited myeloid colony formation in vitro. Furthermore, the incidence and severity of MPD were lower in miR-125a (-/-) mice than in miR-125a (+/-) mice, indicating the operation of compensatory mechanisms for the complete loss of miR-125a. To elucidate the compensatory mechanisms, miRNA array was performed. MiR-486 was occasionally induced in compete loss of miR-125a and inhibited WT1 expression instead of miR-125a, resulting in the cancellation of MPD occurrence. These results showed for the first time the post-transcriptional regulatory mechanisms of WT1 by both miR-125a and miR-486 and should contribute to the elucidation of mechanisms of normal hematopoiesis and kidney development.

Rossette formation between stromal and hemopoietic cells: a simple assay for the supportive activity of stromal cells.

Hemopoietic stromal cells play an important role in the proliferation and differentiation of hemopoietic cells in vitro. Recently, it has been emphasized that the attachment of hemopoietic cells to stromal cells is the first step in this process and that this is necessary in hemopoiesis in vitro. A rosette formation technique was developed to quantitatively measure this attachment. The murine leukemic cell line ELM-D, which grows only in close contact with stromal cells, was used to represent hemopoietic cells. Rosettes were formed with about 75% of the normal murine bone marrow derived hemopoietic supportive stromal cells (MS-1). However, ELM-D formed rosettes with only 15% of the hemopoietic non-supportive stromal cells (MS-K). The maximum rosette formation was obtained at an ELM-D to MS-1 ratio of 20:1. When MS-1 and MS-K were mixed and seeded as stromal cells, MS-K did not alter the attachments of ELM-D to MS-1; the percentage of rosette formation increased in parallel with the increase in the number of MS-1 cells in the stromal layer. These findings suggest that MS-K does not have an inhibitory effect. Rosette formation is a simple, quantitative technique for assaying the hemopoietic supportive activity of stromal cells in vitro.

A metagenetic approach for revealing community structure of marine planktonic copepods.

Marine planktonic copepods are an ecologically important group with high species richness and abundance. Here, we propose a new metagenetic approach for revealing the community structure of marine planktonic copepods using 454 pyrosequencing of nuclear large subunit ribosomal DNA. We determined an appropriate similarity threshold for clustering pyrosequencing data into molecular operational taxonomic units (MOTUs) using an artificial community containing 33 morphologically identified species. The 99% similarity threshold had high species-level resolution for MOTU clustering but overestimated species richness. The artificial community was appropriately clustered into MOTUs at 97% similarity, with little inflation in MOTU numbers and with relatively high species-level resolution. The number of sequence reads of each MOTU was correlated with dry weight of that taxon, suggesting that sequence reads could be used as a proxy for biomass. Next, we applied the method to field-collected samples, and the results corresponded reasonably well with morphological analysis of these communities. Numbers of MOTUs were well correlated with species richness at 97% similarity, and large numbers of sequence reads were generally observed in MOTUs derived from species with large biomass. Further, MOTUs were successfully classified into taxonomic groups at the family level at 97% similarity; similar patterns of species richness and biomass were revealed within families with metagenetic and morphological analyses. At the 99% similarity threshold, MOTUs with high proportions of sequence reads were identified as biomass-dominant species in each field-collected sample. The metagenetic approach reported here can be an effective tool for rapid and comprehensive assessment of copepod community structure.

Prophylactic effects of neuroleptics in symptom-free schizophrenics: a comparative dose-response study of timiperone and sulpiride.

Remitted schizophrenic outpatients were prophylactically treated to prevent relapse with three different doses of timiperone or sulpiride for a year in a double-blind controlled study employing a randomized design. Each drug's ability to prevent relapse was by counting the number of subjects with different outcomes (remission, relapse, adverse reactions) during the trial and/or the number of symptom-free days for each patient before any sign of relapse or adverse reactions appeared. Patients were randomly assigned to the following drugs, which were orally administered once every night: placebo; timiperone 1 mg, 3 mg, 6 mg; sulpiride 100 mg, 300 mg, 600 mg. Data from previous studies involving haloperidol and propericiazine were utilized as a retrospective placebo group to compare the characteristics of the four drugs for maintenance treatment of remitted schizophrenic outpatients. Both timiperone and sulpiride increased the number of patients in remission and decreased the number of patients who relapsed, compared with the placebo group. With timiperone, there was an especially marked increase in the number of patients who showed signs of adverse reactions compared with sulpiride. Sulpiride was the only drug that increased the number of dose-dependent symptom-free days. However, both of these drugs significantly increased the number of symptom-free days compared with placebo. By comparing the dose-response curves of four drugs tested in the same fashion, haloperidol and sulpiride were superior to propericiazine and timiperone because they displayed a wider dose range for the maintenance treatment of remitted schizophrenic outpatients.

Prophylactic effects of neuroleptics in symptom-free schizophrenics: roles of dopaminergic and noradrenergic blockers.

A clinical trial was undertaken to determine the role of dopaminergic and noradrenergic blockers in the maintenance treatment of remitted schizophrenics. One hundred and six remitted schizophrenic outpatients were treated with one of nine treatments, viz., thioridazine 25 mg or 75 mg, pimozide 2 mg or 6 mg, and their respective combinations, for 1 year in a double-blind controlled study employing a randomized design. The data from a previous study were utilized as a retrospective placebo group. Pimozide prolonged the number of symptom-free days in a dose-dependent manner and did so more markedly than thioridazine. Combined administration of pimozide and thioridazine prolonged the number of symptom-free days to a greater extent than their single administration. However, an inverted U-shaped dose-response curve was obtained with the combined administration of these agents. These data suggest that both the dopaminergic and noradrenergic blocking action of neuroleptics are important in preventing relapse in remitted schizophrenics.

Effects of age and stress on regional noradrenaline metabolism in the rat brain.

Levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), were determined in eight brain regions of non-stressed rats at 2, 10 and 15 months of age, and of rats at 2 and 15 months of age stressed by immobilization for 3 hours. The NA levels in older rats were significantly lower in the hypothalamus, pons + med.obl. and midbrain, and higher in the amygdala, thalamus, hippocampus and cerebral cortex as compared to those of 2 month old rats. The MHPG-SO4 levels in the older rats were significantly lower in the hypothalamus, amygdala, pons + med.obl. and midbrain, and higher only in the cerebral cortex than those in 2 month old rats. Immobilization stress caused significant increases in NA turnover in all brain regions of both 2 and 15 month old rats. Age-related difference in the degree of stress-induced change in NA metabolism was found only in the hypothalamus; the increase of MHPG-SO4 by stress was greater in 2 month old rats than in 15 month old rats, although both age groups of rats showed the same degree of NA reduction by stress. These data suggest that brain NA metabolism changes in an age-related fashion, and that apparent regional differences exist in the pattern of these changes. Specifically, it appears that there is an age-related difference in the response of noradrenergic neurons to stress in the hypothalamus.

Relation of atrial size and function to Doppler indexes of diastolic function in normal human fetuses.

Fetal atrial function is compared with diastolic ventricular function indexes. The falloff of hyperfunction in fetal atrial contraction patterns matches sequentially the lessening of A wave dominance in the Doppler filling patterns for both ventricles.

Effect of left ventricular wall mass on Doppler filling patterns in the developing normal human heart.

To assess gestational age- and growth-related changes in left ventricular (LV) size, LV wall, and LV transmitral flow velocity patterns, 2-dimensional (2-D) and Doppler echocardiographic studies were performed in 89 normal fetuses aged 16 to 38 weeks. Serial studies were designed in 7 fetuses. Variables measured from 4-chamber views were chamber areas and myocardial wall areas. From these measurements, area shortening fraction and ratio of myocardial wall area to end-diastolic chamber area were calculated. LV end-diastolic chamber area and myocardial wall area increased exponentially with advancing gestational age (r = 0.88 and 0.90, respectively, p < 0.001). Area shortening fraction showed no significant changes with gestational age. Ratio of myocardial wall area to LV end-diastolic chamber area decreased gradually with increasing gestational age (r = -0.77, p < 0.001). With increasing gestational age, mitral peak velocities of early diastole increased (r = 0.82, p < 0.01) with little change in peak velocity during atrial contraction. Multiple regression analysis showed that age-related increases in peak velocity of early diastole were related to advancing gestational age and also to decreases in ratio of myocardial wall area to LV end-diastolic chamber area. Low peak filling velocities during early diastole in younger fetuses may be related partly to relative increase in LV wall mass. The gestational age-related decreases in LV wall mass may be one of the important mechanisms of gestational age-related alterations in diastolic properties, especially relaxation processes.