Effect of Menstrual Cycle and Menopause on Human Gastric Electrophysiology.

Chronic gastroduodenal symptoms disproportionately affect females of childbearing age; however, the effect of menstrual cycling on gastric electrophysiology is poorly defined. To establish the effect of the menstrual cycle on gastric electrophysiology, healthy subjects underwent non-invasive Body Surface Gastric Mapping (BSGM; 8x8 array), with validated symptom logging App (Gastric AlimetryⓇ, New Zealand). Participants were premenopausal females in follicular (n=26) and luteal phases (n=18). Postmenopausal females (n=30) and males (n=51) were controls. Principal gastric frequency (PGF), BMI-adjusted amplitude, Gastric Alimetry Rhythm Index (GA-RI), fasted-fed amplitude ratio (ff-AR), meal response curves, and symptom burden were analysed. Menstrual cycle-related electrophysiological changes were then transferred to an established anatomically-accurate computational gastric fluid dynamics model (meal viscosity 0.1 Pas), to predict the impact on gastric mixing and emptying. PGF was significantly higher in the luteal vs. follicular phase (mean 3.21 cpm, SD (0.17) vs. 2.94 cpm, SD (0.17), p<0.001) and vs. males (3.01 cpm, SD (0.2), p<0.001). In the computational model, this translated to 8.1% higher gastric mixing strength and 5.3% faster gastric emptying for luteal versus follicular phases. Postmenopausal females also exhibited higher PGF than females in the follicular phase (3.10 cpm, SD (0.24) vs. 2.94 cpm, SD (0.17), p=0.01), and higher BMI-adjusted amplitude (40.7 µV (33.02-52.58) vs. 29.6 µV (26.15-39.65), p<0.001), GA-RI (0.60 (0.48-0.73) vs. 0.43 (0.30-0.60), p=0.005), and ff-AR (2.51 (1.79-3.47) vs. 1.48 (1.21-2.17), p=0.001) than males. There were no differences in symptoms. These results define variations in gastric electrophysiology with regard to human menstrual cycling and menopause.

Effects of peristaltic amplitude and frequency on gastric emptying and mixing: a simulation study.

The amplitude and frequency of peristaltic contractions are two major parameters for assessing gastric motility. However, it is not fully understood how these parameters affect the important functions of the stomach, such as gastric mixing and emptying. This study aimed to quantify the effects of peristaltic amplitude and frequency on gastric mixing and emptying using computational fluid dynamics simulation of gastric flow with an anatomically realistic model of the stomach. Our results suggest that both the increase and decrease in peristaltic amplitude have a significant impact on mixing strength and emptying rate. For example, when the peristaltic amplitude was 1.2 times higher than normal, the emptying rate was 2.7 times faster, whereas when the amplitude was half, the emptying rate was 4.2 times slower. Moreover, the emptying rate increased more than proportionally with the peristaltic frequency. The nearest contraction wave to the pylorus and the subsequent waves promoted gastric emptying. These results suggest the importance of maintaining parameters within normal ranges to achieve healthy gastric function.

Effect of cilia-induced surface velocity on cerebrospinal fluid exchange in the lateral ventricles.

Ciliary motility disorders are known to cause hydrocephalus. The instantaneous velocity of cerebrospinal fluid (CSF) flow is dominated by artery pulsation, and it remains unclear why ciliary dysfunction results in hydrocephalus. In this study, we investigated the effects of cilia-induced surface velocity on CSF flow using computational fluid dynamics. A geometric model of the human ventricles was constructed using medical imaging data. The CSF produced by the choroid plexus and cilia-induced surface velocity were given as the velocity boundary conditions at the ventricular walls. We developed healthy and reduced cilia motility models based on experimental data of cilia-induced velocity in healthy wild-type and Dpcd-knockout mice. The results indicate that there is almost no difference in intraventricular pressure between healthy and reduced cilia motility models. Additionally, it was found that newly produced CSF from the choroid plexus did not spread to the anterior and inferior horns of the lateral ventricles in the reduced cilia motility model. These findings suggest that a ciliary motility disorder could delay CSF exchange in the anterior and inferior horns of the lateral ventricles.

The influence of interstitial cells of Cajal loss and aging on slow wave conduction velocity in the human stomach.

Loss of interstitial cells of Cajal (ICC) has been associated with gastric dysfunction and is also observed during normal aging at ~13% reduction per decade. The impact of ICC loss on gastric slow wave conduction velocity is currently undefined. This study correlated human gastric slow wave velocity with ICC loss and aging. High-resolution gastric slow wave mapping data were screened from a database of 42 patients with severe gastric dysfunction (n = 20) and controls (n = 22). Correlations were performed between corpus slow wave conduction parameters (frequency, velocity, and amplitude) and corpus ICC counts in patients, and with age in controls. Physiological parameters were further integrated into computational models of gastric mixing. Patients: ICC count demonstrated a negative correlation with slow wave velocity in the corpus (i.e., higher velocities with reduced ICC; r2  = .55; p = .03). ICC count did not correlate with extracellular slow wave amplitude (p = .12) or frequency (p = .84). Aging: Age was positively correlated with slow wave velocity in the corpus (range: 25-74 years; r2  = .32; p = .02). Age did not correlate with extracellular slow wave amplitude (p = .40) or frequency (p = .34). Computational simulations demonstrated that the gastric emptying rate would increase at higher slow wave velocities. ICC loss and aging are associated with a higher slow wave velocity. The reason for these relationships is unexplained and merit further investigation. Increased slow wave velocity may modulate gastric emptying higher, although in gastroparesis other pathological factors must dominate to prevent emptying.

Multiscale modeling of human cerebrovasculature: A hybrid approach using image-based geometry and a mathematical algorithm.

The cerebral vasculature has a complex and hierarchical network, ranging from vessels of a few millimeters to superficial cortical vessels with diameters of a few hundred micrometers, and to the microvasculature (arteriole/venule) and capillary beds in the cortex. In standard imaging techniques, it is difficult to segment all vessels in the network, especially in the case of the human brain. This study proposes a hybrid modeling approach that determines these networks by explicitly segmenting the large vessels from medical images and employing a novel vascular generation algorithm. The framework enables vasculatures to be generated at coarse and fine scales for individual arteries and veins with vascular subregions, following the personalized anatomy of the brain and macroscale vasculatures. In this study, the vascular structures of superficial cortical (pial) vessels before they penetrate the cortex are modeled as a mesoscale vasculature. The validity of the present approach is demonstrated through comparisons with partially observed data from existing measurements of the vessel distributions on the brain surface, pathway fractal features, and vascular territories of the major cerebral arteries. Additionally, this validation provides some biological insights: (i) vascular pathways may form to ensure a reasonable supply of blood to the local surface area; (ii) fractal features of vascular pathways are not sensitive to overall and local brain geometries; and (iii) whole pathways connecting the upstream and downstream entire-scale cerebral circulation are highly dependent on the local curvature of the cerebral sulci.

Perioperative Hemodynamic Changes in the Thoracic Aorta in Patients With Aortic Valve Stenosis: A Prospective Serial 4D-Flow MRI Study.

This study investigated hemodynamic changes in the thoracic aorta and aortic arch branches before and after aortic valve replacement (AVR) by 4D-flow MRI in patients with aortic valve stenosis (AS). Thoracic 4D-flow MRI was performed in 10 AS patients before and after AVR (mean 27 ± 1.9 days). Fifteen aortic planes and 3 aortic arch branches planes were set to evaluate the mean volume flow rate in each plane during a cardiac cycle and the angle between the main flow direction in a specified plane and the axial direction of the aorta. We also focused on the distribution and magnitude of helicity density to evaluate the flow complexity. A significant increase in the volume flow rate after AVR was found in the ascending aorta (before 59.2 ± 8.7 mL/s vs after 77.3 ± 6.2 mL/s, P < 0.05) and the aortic arch branches (before 26.5 ± 2.8 mL/s vs after 35.8 ± 3.3 mL/s, P < 0.001). The flow angle significantly decreased in the ascending aorta (before 39.2 ± 2.7 degree vs after 25.2 ± 1.7°, P < 0.0001) and the arch aorta (before 19.3 ± 2.0 degree vs after 13.4 ± 0.9°, P < 0.001). The volume flow rate in the ascending aorta and the arch branches increased within 1 month after AVR, showing an increased blood supply to the upper body, including to the brain. The postoperative change was accompanied with an increased blood flow in the ascending aorta and a decreased flow complexity proximal to the arch branches.

A computational fluid dynamics simulation of liquid swallowing by impaired pharyngeal motion: bolus pathway and pharyngeal residue.

Common practices to improve the ability to swallow include modifying physical properties of foods and changing the posture of patients. Here, we quantified the effects of the viscosity of a liquid bolus and patient posture on the bolus pathway and pharyngeal residue using a computational fluid dynamics simulation. We developed a computational model of an impaired pharyngeal motion with a low pharyngeal pressure and no pharyngeal adaptation. We varied viscosities from 0.002 to 1 Pa·s and postures from -15° to 30° (from nearly vertical to forward leaning). In the absence of pharyngeal adaptation, a honey-like liquid bolus caused pharyngeal residue, particularly in the case of forward-leaning postures. Although the bolus speed was different among viscosities, the final pathway was only slightly different. The shape, location, and tilting of the epiglottis effectively invited a bolus to two lateral pathways, suggesting a high robustness of the swallowing process.NEW & NOTEWORTHY Thickening agents are often used for patients with dysphagia. An increase in bolus viscosity not only reduces the risk of aspiration but also can cause a residual volume in the pharynx. Because information obtained from videofluoroscopic swallowing studies is only two-dimensional, measurement of pharyngeal residue is experimentally difficult. We successfully quantified the three-dimensional bolus pathway and the pharyngeal residual volume using computational modeling and simulation.

Quantification of gastric emptying caused by impaired coordination of pyloric closure with antral contraction: a simulation study.

Proper coordination of gastric motor functions is required for healthy gastric emptying. However, pyloric function may be impaired by functional disorders or surgical procedures. Here, we show how coordination between pyloric closure and antral contraction affects the emptying of liquid contents. We numerically simulated fluid dynamics using an anatomically realistic gastrointestinal geometry. Peristaltic contractions in the proximal stomach resulted in gastric emptying at a rate of 3-8 ml min-1. When the pylorus was unable to close, the emptying rate increased to 10-30 ml min-1, and instantaneous retrograde flow from the duodenum to the antrum occurred during antral relaxation. Rapid emptying occurred if the pylorus began to open during the terminal antral contraction, and the emptying rate was negative if the pylorus only opened during the antral relaxation phase. Our results showed that impaired coordination between antral contraction and pyloric closure can result in delayed gastric emptying, rapid gastric emptying and bile reflux.

Factors Diminishing Cytoadhesion of Red Blood Cells Infected by Plasmodium falciparum in Arterioles.

Cytoadhesion of red blood cells infected by Plasmodium falciparum (Pf-IRBCs) is predominantly found in postcapillary venules, rather than in arterioles. However, factors influencing this phenomenon remain unclear. Here, we conduct a systematic study using a numerical model coupling the fluid and solid mechanics of the cells and cellular environment with the biochemical ligand-receptor interaction. Our results show that, once a Pf-IRBC adheres to the vascular wall, the Pf-IRBC can withstand even arteriole shear stresses, and exhibits either rolling or firm adhesion. We also perform a simulation of the multistep process of cytoadhesion, consisting of flow, margination, capture, and rolling or firm adhesion. This multistep simulation suggests that a lower probability of contact with the vascular wall at high shear rates may diminish adherent Pf-IRBCs in the arterioles.

Capture of microparticles by bolus flow of red blood cells in capillaries.

Previous studies have concluded that microparticles (MPs) can more effectively approach the microvessel wall than nanoparticles because of margination. In this study, however, we show that MPs are not marginated in capillaries where the vessel diameter is comparable to that of red blood cells (RBCs). We numerically investigated the behavior of MPs with a diameter of 1 µm in various microvessel sizes, including capillaries. In capillaries, the flow mode of RBCs shifted from multi-file flow to bolus (single-file) flow, and MPs were captured by the bolus flow of the RBCs instead of being marginated. Once MPs were captured, they rarely escaped from the vortex-like flow structures between RBCs. These capture events were enhanced when the hematocrit was decreased, and reduced when the shear rate was increased. Our results suggest that microparticles may be rather inefficient drug carriers when targeting capillaries because of capture events, but nanoparticles, which are more randomly distributed in capillaries, may be more effective carriers.

Effects of combination of mitiglinide with various oral antidiabetic drugs in streptozotocin-nicotinamide-induced type 2 diabetic rats and Zucker fatty rats.

We examined the effects of combining the rapid insulin secretagogue, mitiglinide, with various oral hypoglycaemic drugs including biguanides, pioglitazone, α-glucosidase inhibitors, and sodium-glucose co-transporter 2 inhibitors in a rat model of type 2 diabetes. The oral glucose tolerance test (OGTT) using glucose, sucrose, or a liquid meal was used to compare the effects of mitiglinide with those of the four oral hypoglycaemic drugs and examine their combined effects on blood glucose levels and insulin secretion in the rat model. The combination of mitiglinide with other oral hypoglycaemic drugs suppressed the plasma glucose levels more than either agent did alone. Furthermore, the combination of these agents decreased insulin secretion more than mitiglinide did alone. These results indicate that mitiglinide is suitable for use in combination with other hypoglycaemic drugs because it inhibits postprandial hyperglycaemia by rapidly stimulating insulin secretion.

Shear-induced platelet aggregation and distribution of thrombogenesis at stenotic vessels.

OBJECTIVE: SIPA, which is mediated by vWF, is a key mechanism in arterial thrombosis under an abnormally high shear rate of blood flow. We investigated the influence of SIPA on thrombogenesis, focusing on alterations in blood flow at stenotic vessels. METHODS: We carried out a computer simulation of thrombogenesis in stenotic vessels at three different injury positions (ie, upstream, apex, and downstream of the stenosis) to evaluate the effect of SIPA. RESULTS: The results demonstrated that thrombus volume increased downstream of the stenosis. In particular, growth was enhanced significantly as blood flow velocity and severity of stenosis increased. The influence of SIPA was induced by continuous exposure to high shear rate; thus, SIPA had a greater effect from the apex to downstream of the stenosis along the vessel wall. The asymmetry of the impact of SIPA contributed to the distribution of the thrombus. Furthermore, we found that the degree of SIPA was prolonged in a stenotic vessel with a distal injury, whereas it was moderate with thrombus growth in a nonstenosed vessel. This occurred because platelets and vWF that underwent a high shear rate around the apex were transported to the region downstream of the stenosis. CONCLUSIONS: These results suggest that thrombus formation downstream of the stenosis is easily affected by SIPA and hemodynamics.

Relationship between gastric motility and liquid mixing in the stomach.

The relationship between gastric motility and the mixing of liquid food in the stomach was investigated with a numerical analysis. Three parameters of gastric motility were considered: the propagation velocity, frequency, and terminal acceleration of peristaltic contractions. We simulated gastric flow with an anatomically realistic geometric model of the stomach, considering free surface flow and moving boundaries. When a peristaltic contraction approaches the pylorus, retropulsive flow is generated in the antrum. Flow separation then occurs behind the contraction. The extent of flow separation depends on the Reynolds number (Re), which quantifies the inertial forces due to the peristaltic contractions relative to the viscous forces of the gastric contents; no separation is observed at low Re, while an increase in reattachment length is observed at high Re. While mixing efficiency is nearly constant for low Re, it increases with Re for high Re because of flow separation. Hence, the effect of the propagation velocity, frequency, or terminal acceleration of peristaltic contractions on mixing efficiency increases with Re.

Functional physiology of the human terminal antrum defined by high-resolution electrical mapping and computational modeling.

High-resolution (HR) mapping has been used to study gastric slow-wave activation; however, the specific characteristics of antral electrophysiology remain poorly defined. This study applied HR mapping and computational modeling to define functional human antral physiology. HR mapping was performed in 10 subjects using flexible electrode arrays (128-192 electrodes; 16-24 cm2) arranged from the pylorus to mid-corpus. Anatomical registration was by photographs and anatomical landmarks. Slow-wave parameters were computed, and resultant data were incorporated into a computational fluid dynamics (CFD) model of gastric flow to calculate impact on gastric mixing. In all subjects, extracellular mapping demonstrated normal aboral slow-wave propagation and a region of increased amplitude and velocity in the prepyloric antrum. On average, the high-velocity region commenced 28 mm proximal to the pylorus, and activation ceased 6 mm from the pylorus. Within this region, velocity increased 0.2 mm/s per mm of tissue, from the mean 3.3 ± 0.1 mm/s to 7.5 ± 0.6 mm/s (P < 0.001), and extracellular amplitude increased from 1.5 ± 0.1 mV to 2.5 ± 0.1 mV (P < 0.001). CFD modeling using representative parameters quantified a marked increase in antral recirculation, resulting in an enhanced gastric mixing, due to the accelerating terminal antral contraction. The extent of gastric mixing increased almost linearly with the maximal velocity of the contraction. In conclusion, the human terminal antral contraction is controlled by a short region of rapid high-amplitude slow-wave activity. Distal antral wave acceleration plays a major role in antral flow and mixing, increasing particle strain and trituration.

Cell adhesion during bullet motion in capillaries.

A numerical analysis is presented of cell adhesion in capillaries whose diameter is comparable to or smaller than that of the cell. In contrast to a large number of previous efforts on leukocyte and tumor cell rolling, much is still unknown about cell motion in capillaries. The solid and fluid mechanics of a cell in flow was coupled with a slip bond model of ligand-receptor interactions. When the size of a capillary was reduced, the cell always transitioned to "bullet-like" motion, with a consequent decrease in the velocity of the cell. A state diagram was obtained for various values of capillary diameter and receptor density. We found that bullet motion enables firm adhesion of a cell to the capillary wall even for a weak ligand-receptor binding. We also quantified effects of various parameters, including the dissociation rate constant, the spring constant, and the reactive compliance on the characteristics of cell motion. Our results suggest that even under the interaction between P-selectin glycoprotein ligand-1 (PSGL-1) and P-selectin, which is mainly responsible for leukocyte rolling, a cell is able to show firm adhesion in a small capillary. These findings may help in understanding such phenomena as leukocyte plugging and cancer metastasis.

Deformation of a micro-torque swimmer.

The membrane tension of some kinds of ciliates has been suggested to regulate upward and downward swimming velocities under gravity. Despite its biological importance, deformation and membrane tension of a ciliate have not been clarified fully. In this study, we numerically investigated the deformation of a ciliate swimming freely in a fluid otherwise at rest. The cell body was modelled as a capsule with a hyperelastic membrane enclosing a Newtonian fluid. Thrust forces due to the ciliary beat were modelled as torques distributed above the cell body. The effects of membrane elasticity, the aspect ratio of the cell's reference shape, and the density difference between the cell and the surrounding fluid were investigated. The results showed that the cell deformed like a heart shape, when the capillary number was sufficiently large. Under the influence of gravity, the membrane tension at the anterior end decreased in the upward swimming while it increased in the downward swimming. Moreover, gravity-induced deformation caused the cells to move gravitationally downwards or upwards, which resulted in a positive or negative geotaxis-like behaviour with a physical origin. These results are important in understanding the physiology of a ciliate's biological responses to mechanical stimuli.

Numerical methods for simulating blood flow at macro, micro, and multi scales.

In the past decade, numerical methods for the computational biomechanics of blood flow have progressed to overcome difficulties in diverse applications from cellular to organ scales. Such numerical methods may be classified by the type of computational mesh used for the fluid domain, into fixed mesh methods, moving mesh (boundary-fitted mesh) methods, and mesh-free methods. The type of computational mesh used is closely related to the characteristics of each method. We herein provide an overview of numerical methods recently used to simulate blood flow at macro and micro scales, with a focus on computational meshes. We also discuss recent progress in the multi-scale modeling of blood flow.

Hemodynamics in the microcirculation and in microfluidics.

Hemodynamics in microcirculation is important for hemorheology and several types of circulatory disease. Although hemodynamics research has a long history, the field continues to expand due to recent advancements in numerical and experimental techniques at the micro-and nano-scales. In this paper, we review recent computational and experimental studies of blood flow in microcirculation and microfluidics. We first focus on the computational studies of red blood cell (RBC) dynamics, from the single cellular level to mesoscopic multiple cellular flows, followed by a review of recent computational adhesion models for white blood cells, platelets, and malaria-infected RBCs, in which the cell adhesion to the vascular wall is essential for cellular function. Recent developments in optical microscopy have enabled the observation of flowing blood cells in microfluidics. Experimental particle image velocimetry and particle tracking velocimetry techniques are described in this article. Advancements in micro total analysis system technologies have facilitated flowing cell separation with microfluidic devices, which can be used for biomedical applications, such as a diagnostic tool for breast cancer or large intestinal tumors. In this paper, cell-separation techniques are reviewed for microfluidic devices, emphasizing recent advances and the potential of this fast-evolving research field in the near future.

Flow of a circulating tumor cell and red blood cells in microvessels.

Quantifying the behavior of circulating tumor cells (CTCs) in the blood stream is of fundamental importance for understanding metastasis. Here, we investigate the flow mode and velocity of CTCs interacting with red blood cells (RBCs) in various sized microvessels. The flow of leukocytes in microvessels has been described previously; a leukocyte forms a train with RBCs in small microvessels and exhibits margination in large microvessels. Important differences in the physical properties of leukocytes and CTCs result from size. The dimensions of leukocytes are similar to those of RBCs, but CTCs are significantly larger. We investigate numerically the size effects on the flow mode and the cell velocity, and we identify similarities and differences between leukocytes and CTCs. We find that a transition from train formation to margination occurs when (R-a)/t(R)≈1, where R is the vessel radius, a is the cell radius, and t(R) is the thickness of RBCs, but that the motion of RBCs differs from the case of leukocytes. Our results also show that the velocities of CTCs and leukocytes are larger than the average blood velocity, but only CTCs move faster than RBCs for microvessels of R/a≈1.5-2.0. These findings are expected to be useful not only for understanding metastasis, but also for developing microfluidic devices.