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 noninvasive Body Surface Gastric Mapping (BSGM; 8x8 array) with the validated symptom logging App (Gastric Alimetry, New Zealand). Participants included were premenopausal females in follicular (n = 26) and luteal phases (n = 18) and postmenopausal females (n = 30) and males (n = 51) were controls. Principal gastric frequency (PGF), body mass index (BMI) adjusted amplitude, Gastric Alimetry Rhythm Index (GA-RI), Fed:Fasted Amplitude Ratio (ff-AR), meal response curves, and symptom burden were analyzed. 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 versus follicular phase [mean 3.21 cpm, SD (0.17) vs. 2.94 cpm, SD (0.17), P < 0.001] and versus 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.NEW & NOTEWORTHY This study evaluates gastric electrophysiology in relation to the menstrual cycle using a novel noninvasive high-resolution methodology, revealing substantial variations in gastric activity with menstrual cycling and menopause. Gastric slow-wave frequency is significantly higher in the luteal versus follicular menstrual phase. Computational modeling predicts that this difference translates to higher rates of gastric mixing and liquid emptying in the luteal phase, which is consistent with previous experimental data evaluating menstrual cycling effects on gastric 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.

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.

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.

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.

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.

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.

Fluctuation of cilia-generated flow on the surface of the tracheal lumen.

Although we inhale air that contains many harmful substances, including, for example, dust and viruses, these small particles are trapped on the surface of the tracheal lumen and transported towards the larynx by cilia-generated flow. The transport phenomena are affected not only by the time- and space-average flow field but also by the fluctuation of the flow. Because flow fluctuation has received little attention, we investigated it experimentally in mice. To understand the origin of flow fluctuation, we first measured the distribution of ciliated cells in the trachea and individual ciliary motions. We then measured the detailed flow field using a confocal micro-PTV system. Strong flow fluctuations were observed, caused by the unsteadiness of the ciliary beat and the spatial inhomogeneity of ciliated cells. The spreading of particles relative to the bulk motion became diffusive if the time scale was sufficiently larger than the beat period. Finally, we quantified the effects of flow fluctuation on bulk flow by evaluating the Peclet number of the system, which indicated that the directional transport was an order of magnitude larger than the isotropic diffusion. These results are important in understanding transport phenomena in the airways on a cellular scale.

Antral recirculation in the stomach during gastric mixing.

We investigate flow in the stomach during gastric mixing using a numerical simulation with an anatomically realistic geometry and free-surface flow modeling. Because of momentum differences between greater and lesser curvatures during peristaltic contractions, time-averaged recirculation is generated in the antrum, with retropulsive flow away from the pylorus and compensation flow along the greater curvature toward the pylorus. Gastric content in the distal stomach is continuously transported to the distal antrum by the forward flow of antral recirculation, and it is then mixed by the backward retropulsive flow. Hence, the content inside the antral recirculation is well mixed independently of initial location, whereas the content outside the recirculation is poorly mixed. Free-surface modeling enables us to analyze the effects of posture on gastric mixing. In the upright, prone, and right lateral positions, most of the antrum is filled with content, and the content is well mixed by antral recirculation. In contrast, in the supine and left lateral positions, most of the content is located outside antral recirculation, which results in poor mixing. The curved, twisted shape of the stomach substantially supports gastric mixing in fluid mechanical terms.

Computational study on thrombus formation regulated by platelet glycoprotein and blood flow shear.

Thrombogenesis results from the interaction between glycoprotein receptors and their ligands, although a thrombus is affected by multiple factors such as blood flow, platelet interactions, and changes in ligand characteristics. In this study, we propose a platelet adhesion and aggregation model, focusing on the interaction between the glycoprotein receptor and its ligand. First, we conducted thrombogenesis simulations to compare physiological and pathological conditions. The results suggested that simulations of thrombogenesis differed in distribution, volume, and stability of the thrombus based on disorders of platelet adhesion, aggregation, and the activation. For example, distribution and volume were affected by the activation of GPIIb/IIIa with a GPIb/IX/V deficiency. The thrombus was also unstable, but formed from the upstream side of the injured site, with a GPIIb/IIIa deficiency. Second, we investigated thrombogenesis enhanced by the shear-induced platelet aggregation (SIPA) mechanism. The results demonstrated that the degree of SIPA decreased gradually with thrombus growth in a straight vessel. This result suggests that SIPA is a key hemostasis mechanism in an injured healthy arteriole, although it can lead to the formation of an occlusive thrombus in stenosed vessels.

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.

Reorientation of a nonspherical capsule in creeping shear flow.

The dynamics of a capsule and a biological cell is of great interest in chemical engineering and bioengineering. Although the dynamics of a rigid spheroid is well understood by Jeffery's theory, that of a spheroidal capsule remains unclear. In this Letter, the motion of a spheroidal capsule or a red blood cell in creeping shear flow is investigated. The results show that the orientation of a nonspherical capsule is variant under time reversal, though that of a rigid spheroid is invariant. Surprisingly, the alignment of a nonspherical capsule over a long time duration shows a transition depending on the shear rate, which can be utilized for a particle-alignment technique. These findings form a fundamental basis of the suspension mechanics of capsules and biological cells.

Inertial migration of cancer cells in blood flow in microchannels.

The circulating tumor cell test is used to evaluate the condition of breast cancer patients by counting the number of cancer cells in peripheral blood samples. Although microfluidic systems to detect or separate cells using the inertial migration effect may be applied to this test, the hydrodynamic forces acting on cancer cells in high hematocrit blood flow are incompletely understood. In the present study, we investigated the inertial migration of cancer cells in high hematocrit blood flow in microchannels. The maximum hematocrit used in this study was about 40%. By measuring the cell migration probability, we examined the effects of cell-cell interactions, cell deformability, and variations in cell size on the inertial migration of cancer cells in blood. The results clearly illustrate that cancer cells can migrate towards equilibrium positions up to a hematocrit level of 10%. We also performed simple scaling analysis to explain the differences in migration length between rigid particles and cancer cells as well as the effect of hematocrit on cancer cell migration. These results will be important for the design of microfluidic devices for separating cells from blood.

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.

Asymmetry of blood flow and cancer cell adhesion in a microchannel with symmetric bifurcation and confluence.

Bifurcations and confluences are very common geometries in biomedical microdevices. Blood flow at microchannel bifurcations has different characteristics from that at confluences because of the multiphase properties of blood. Using a confocal micro-PIV system, we investigated the behaviour of red blood cells (RBCs) and cancer cells in microchannels with geometrically symmetric bifurcations and confluences. The behaviour of RBCs and cancer cells was strongly asymmetric at bifurcations and confluences whilst the trajectories of tracer particles in pure water were almost symmetric. The cell-free layer disappeared on the inner wall of the bifurcation but increased in size on the inner wall of the confluence. Cancer cells frequently adhered to the inner wall of the bifurcation but rarely to other locations. Because the wall surface coating and the wall shear stress were almost symmetric for the bifurcation and the confluence, the result indicates that not only chemical mediation and wall shear stress but also microscale haemodynamics play important roles in the adhesion of cancer cells to the microchannel walls. These results provide the fundamental basis for a better understanding of blood flow and cell adhesion in biomedical microdevices.

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.

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.

Effects of unique biomedical education programs for engineers: REDEEM and ESTEEM projects.

Current engineering applications in the medical arena are extremely progressive. However, it is rather difficult for medical doctors and engineers to discuss issues because they do not always understand one another's jargon or ways of thinking. Ideally, medical engineers should become acquainted with medicine, and engineers should be able to understand how medical doctors think. Tohoku University in Japan has managed a number of unique reeducation programs for working engineers. Recurrent Education for the Development of Engineering Enhanced Medicine has been offered as a basic learning course since 2004, and Education through Synergetic Training for Engineering Enhanced Medicine has been offered as an advanced learning course since 2006. These programs, which were developed especially for engineers, consist of interactive, modular, and disease-based lectures (case studies) and substantial laboratory work. As a result of taking these courses, all students obtained better objective outcomes, on tests, and subjective outcomes, through student satisfaction. In this article, we report on our unique biomedical education programs for engineers and their effects on working engineers.