Numerical simulation of flow behavior in basilar bifurcation computed tomography angiography.

In this study, a moving boundary deformation model based on four-dimensional computed tomography angiography (4D-CTA) with high temporal resolution is constructed, and blood flow dynamics of cerebral aneurysms are investigated by numerical simulation. A realistic moving boundary deformation model of a cerebral aneurysm was constructed based on 4D-CTA in each phase. Four hemodynamic factors (wall shear stress [WSS], wall shear stress divergence [WSSD], oscillatory shear index [OSI], and residual residence time [RRT]) were obtained from numerical simulations, and these factors were evaluated in basilar artery aneurysms. Comparison of the rigid body condition and the moving boundary condition investigating the relationship between wall displacement and hemodynamic factors clarified that the spatial-averaged WSS and maximum WSSD considering only the aneurysmal dome has a large difference between conditions during the peak systole, and there were also significant differences in OSI and RRT.

Infection control for COVID-19 in hospital examination room.

Healthcare providers are vulnerable to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) because of their close proximity to patients with coronavirus disease 2019. SARS-CoV-2 is mainly transmitted via direct and indirect contact with respiratory droplets, and its airborne transmission has also been identified. However, evidence for environmental factors is scarce, and evidence-based measures to minimize the risk of infection in clinical settings are insufficient. Using computational fluid dynamics, we simulated exhalation of large and small aerosol particles by patients in an otolaryngology examination room, where medical procedures require the removal of a face mask. The effects of coughing were analyzed, as well as those of humidity as a controllable environmental factor and of a suction device as an effective control method. Our results show that a suction device can minimize aerosol exposure of healthcare workers by efficiently removing both large (11.6-98.2%) and small (39.3-99.9%) aerosol particles. However, for coughing patients, the removal efficiency varies inversely with the particle size, and the humidity notably affects the aerosol behavior, indicating the need for countermeasures against smaller aerosols. Overall, these results highlight the potential and limitation of using a suction device to protect against SARS-CoV-2 and future respiratory infections.

Practical approach to prevent COVID-19 infection at breast cancer screening.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) undermines the benefits of cancer screening. To date, no study has identified specific infection control methods. We aimed to provide practical methods for COVID-19 risk reduction during breast cancer screening mammography (MMG) by examining an overview of potential contamination routes of aerosols and possible risks for patients and health care providers. METHODS: Computational fluid dynamics (CFD) simulations were conducted for airflow and aerosol dispersion in a 3D virtual model of a mobile MMG laboratory room. This model was constructed based on the actual mobile screening MMG bus 'Cosmos' in the Chiba Foundation for Health Promotion & Disease Prevention. Examiner and patient geometries were obtained by scanning an actual human using a 3D Scanner. Contamination of the room was evaluated by counting the numbers of suspended and deposited aerosols. RESULTS: We applied the CFD simulation model to the exhalation of small or large aerosols from a patient and examiner in the MMG laboratory. Only 14.5% and 54.5% of large and small aerosols, respectively, were discharged out of the room with two doors open. In contrast, the proportion of large and small aerosols discharged out of the room increased to 96.6% and 97.9%, respectively, with the addition of forced gentle wind by the blower fan. This simulation was verified by a mist aerosol experiment conducted in the mobile MMG laboratory. CONCLUSION: Adding forced ventilation to a MMG laboratory with two doors open may enable risk reduction dramatically. This could be applied to other clinical situations.

Visualizing the Flow Patterns in an Expanding and Contracting Pulmonary Alveolated Duct Based on Microcomputed Tomography Images.

We visualized the flow patterns in an alveolated duct model with breathing-like expanding and contracting wall motions using particle image velocimetry, and then, we investigated the effect of acinar deformation on the flow patterns. We reconstructed a compliant, scaled-up model of an alveolated duct from synchrotron microcomputed tomography images of a mammalian lung. The alveolated duct did not include any bifurcation, and its entire surface was covered with alveoli. We embedded the alveolated duct in a sealed container that was filled with fluid. We oscillated the fluid in the duct and container simultaneously and independently to control the flow and duct volume. We examined the flow patterns in alveoli, with the Reynolds number (Re) at 0.03 or 0.22 and the acinar volume change at 0%, 20%, or 80%. At the same Re, the heterogeneous deformation induced different inspiration and expiration flow patterns, and the recirculating regions in alveoli changed during respiratory cycle. During a larger acinar deformation at Re = 0.03, the flow patterns tended to change from recirculating flow to radial flow during inspiration and vice versa during expiration. Additionally, the alveolar geometric characteristics, particularly the angle between the alveolar duct and mouth, affected these differences in flow patterns. At Re = 0.22, recirculating flow patterns tended to form during inspiration and expiration, regardless of the magnitude of the acinar deformation. Our in vitro experiments suggest that the alveolated flows with nonself-similar and heterogeneous wall motions may promote particle mixing and deposition.

Voxel-based simulation of flow and temperature in the human nasal cavity.

The nasal airway is an extremely complex structure, therefore grid generation for numerical prediction of airflow in the nasal cavity is time-consuming. This paper describes the development of a voxel-based model with a Cartesian structured grid, which is characterized by robust and automatic grid generation, and the simulation of the airflow and air-conditioning in an individual human nasal airway. Computed tomography images of a healthy adult nose were used to reconstruct a virtual three-dimensional model of the nasal airway. Simulations of quiet restful inspiratory flow were then performed using a Neumann boundary condition for the energy equation to adequately resolve the flow and heat transfer. General agreements of airflow patterns, which were a high-speed jet posterior to the nasal valve and recirculating flow that occupied the anterior part of the upper cavity, and temperature distributions of the airflow and septum wall were confirmed by comparing in-vivo measurements with numerical simulation results.

Effects of lactulose on renal function and gut microbiota in adenine-induced chronic kidney disease rats.

BACKGROUND: Constipation is frequently observed in patients with chronic kidney disease (CKD). Lactulose is expected to improve the intestinal environment by stimulating bowel movements as a disaccharide laxative and prebiotic. We studied the effect of lactulose on renal function in adenine-induced CKD rats and monitored uremic toxins and gut microbiota. METHODS: Wistar/ST male rats (10-week-old) were fed 0.75% adenine-containing diet for 3 weeks to induce CKD. Then, they were divided into three groups and fed as follows: control, normal diet; and 3.0- and 7.5-Lac, 3.0% and 7.5% lactulose-containing diets, respectively, for 4 weeks. Normal diet group was fed normal diet for 7 weeks. The rats were observed for parameters including renal function, uremic toxins, and gut microbiota. RESULTS: The control group showed significantly higher serum creatinine (sCr) and blood urea nitrogen (BUN) 3 weeks after adenine feeding than at baseline, with a 8.5-fold increase in serum indoxyl sulfate (IS). After switching to 4 weeks of normal diet following adenine feeding, the sCr and BUN in control group remained high with a further increase in serum IS. In addition, tubulointerstitial fibrosis area was increased in control group. On the other hand, 3.0- and 7.5-Lac groups improved sCr and BUN levels, and suppressed tubulointerstitial fibrosis, suggesting preventing of CKD progression by lactulose. Lac groups also lowered level of serum IS and proportions of gut microbiota producing IS precursor. CONCLUSION: Lactulose modifies gut microbiota and ameliorates CKD progression by suppressing uremic toxin production.

Voxel-based modeling of airflow in the human nasal cavity.

This paper describes the simulation of airflow in human nasal airways using voxel-based modeling characterized by robust, automatic, and objective grid generation. Computed tomography scans of a healthy adult nose are used to reconstruct 3D virtual models of the nasal airways. Voxel-based simulations of restful inspiratory flow are then performed using various mesh sizes to determine the level of granularity required to adequately resolve the airflow. For meshes with close voxel spacings, the model successfully reconstructs the nasal structure and predicts the overall pressure drop through the nasal cavity.

The phospholipid flippase ATP9A is required for the recycling pathway from the endosomes to the plasma membrane.

Type IV P-type ATPases (P4-ATPases) are phospholipid flippases that translocate phospholipids from the exoplasmic (or luminal) to the cytoplasmic leaflet of lipid bilayers. In Saccharomyces cerevisiae, P4-ATPases are localized to specific subcellular compartments and play roles in compartment-mediated membrane trafficking; however, roles of mammalian P4-ATPases in membrane trafficking are poorly understood. We previously reported that ATP9A, one of 14 human P4-ATPases, is localized to endosomal compartments and the Golgi complex. In this study, we found that ATP9A is localized to phosphatidylserine (PS)-positive early and recycling endosomes, but not late endosomes, in HeLa cells. Depletion of ATP9A delayed the recycling of transferrin from endosomes to the plasma membrane, although it did not affect the morphology of endosomal structures. Moreover, depletion of ATP9A caused accumulation of glucose transporter 1 in endosomes, probably by inhibiting their recycling. By contrast, depletion of ATP9A affected neither the early/late endosomal transport and degradation of epidermal growth factor (EGF) nor the transport of Shiga toxin B fragment from early/recycling endosomes to the Golgi complex. Therefore ATP9A plays a crucial role in recycling from endosomes to the plasma membrane.

Effect of elasticity on wall shear stress inside cerebral aneurysm at anterior cerebral artery.

BACKGROUND: Many numerical studies have been published with respect to about flow structures around cerebral aneurysm assuming to be rigid. Furthermore, there is little experimental research concerning aneurysm with elastic wall. Wall shear stress in elastic wall comparing with rigid wall should be clarified in experimental approach and verified in CFD. OBJECTIVE: We have experimentally realized elastic aneurysm model accompanying with wall deformation. Wall shear stress was examined for both rigid and elastic aneurysm models in pulsatile flow. METHODS: Effect of elasticity on wall shear stress inside aneurysm induced at the apex of anterior cerebral artery was experimentally examined by particle image velocimetry in vitro. In order to adjust the wall deformation, the pressure adjustment chamber was specially equipped outside the aneurysm wall. RESULTS: Effect of elasticity on wall shear stress was noticed on the comparison with that of rigidity. Wall elasticity reduced the peak magnitude, the spatial and temporal averaged wall shear stress comparing with those of wall rigidity experimentally. These reductions were endorsed by fluid-structure interaction simulation. CONCLUSION: Elastic wall comparing with rigid wall would reduce the peak magnitude, the spatial and temporal averaged wall shear stress acting on vascular wall.

Repression of wall shear stress inside cerebral aneurysm at bifurcation of anterior cerebral artery by stents.

The effect of a simple bare metal stent on repression of wall shear stress inside a model cerebral aneurysm was experimentally investigated by two-dimensional particle image velocimetry in vitro. The flow model simulated a cerebral aneurysm induced at the apex of bifurcation between the anterior cerebral artery and the anterior communicating artery. Wall shear stress was investigated using both stented and non-stented models to assess the simple stent characteristics. The flow behavior inside the stented aneurysm sac was unusual and wall shear stress was much smaller inside the aneurysm sac. Stent placement effectively repressed the temporal and spatial variations and the magnitude of wall shear stress. Hence, there is an effective possibility that would retard the progress of cerebral aneurysms by even simple stent.

Morphometric study of the blood supply of pedunculated colon polyps: What is the optimal position on the stalk for snare resection?

BACKGROUND AND STUDY AIMS: Bleeding after colonoscopic resection of pedunculated polyps cannot be easily predicted. The aims of this study were to evaluate the blood supply in pedunculated polyps and to clarify the optimal position on the polyp stalk for snare placement to prevent post-polypectomy hemorrhage. ] PATIENTS AND METHODS: In one institution, 11 pedunculated polyps from 11 patients were studied prospectively. All polyps were resected at the base of the stalk using a snare wire with electrocautery. Histologic axial sections from the apex and base of the stalk were examined with hematoxylin eosin and elastica stains. Elastica stains were used to identify blood vessels. The cross-sectional area of the stalk, total vessel area, maximum diameter of artery/arteriole lumen, number of thick (≥ 0.1 mm) vessels, and number of arteries/arterioles were measured in each section with image processing software. Wilcoxon signed-ranks test was used for comparison. RESULTS: The median polyp diameter was 16 mm (range 7 to 24 mm) and median length of the stalk was 11 mm (range 7 to 23 mm). Two invasive cancers (T1) were included. The maximum diameter of the arterial/arteriolar lumen was greater at the base (P = 0.0044), whereas the ratio of the vessel area to the cross-section area was greater at the apex (P = 0.016). The number of thick vessels and arteries/arterioles were equivalent between apex and base. CONCLUSIONS: Morphometric study of the blood supply of pedunculated polyps confirmed that the optimal site for the excision of pedunculated polyps is in the middle of the stalk.

Phospholipid flippase activities and substrate specificities of human type IV P-type ATPases localized to the plasma membrane.

Type IV P-type ATPases (P4-ATPases) are believed to translocate aminophospholipids from the exoplasmic to the cytoplasmic leaflets of cellular membranes. The yeast P4-ATPases, Drs2p and Dnf1p/Dnf2p, flip nitrobenzoxadiazole-labeled phosphatidylserine at the Golgi complex and nitrobenzoxadiazole-labeled phosphatidylcholine (PC) at the plasma membrane, respectively. However, the flippase activities and substrate specificities of mammalian P4-ATPases remain incompletely characterized. In this study, we established an assay for phospholipid flippase activities of plasma membrane-localized P4-ATPases using human cell lines stably expressing ATP8B1, ATP8B2, ATP11A, and ATP11C. We found that ATP11A and ATP11C have flippase activities toward phosphatidylserine and phosphatidylethanolamine but not PC or sphingomyelin. By contrast, ATPase-deficient mutants of ATP11A and ATP11C did not exhibit any flippase activity, indicating that these enzymes catalyze flipping in an ATPase-dependent manner. Furthermore, ATP8B1 and ATP8B2 exhibited preferential flippase activities toward PC. Some ATP8B1 mutants found in patients of progressive familial intrahepatic cholestasis type 1 (PFIC1), a severe liver disease caused by impaired bile flow, failed to translocate PC despite their delivery to the plasma membrane. Moreover, incorporation of PC mediated by ATP8B1 can be reversed by simultaneous expression of ABCB4, a PC floppase mutated in PFIC3 patients. Our findings elucidate the flippase activities and substrate specificities of plasma membrane-localized human P4-ATPases and suggest that phenotypes of some PFIC1 patients result from impairment of the PC flippase activity of ATP8B1.

Murine pulmonary acinar mechanics during quasi-static inflation using synchrotron refraction-enhanced computed tomography.

We visualized pulmonary acini in the core regions of the mouse lung in situ using synchrotron refraction-enhanced computed tomography (CT) and evaluated their kinematics during quasi-static inflation. This CT system (with a cube voxel of 2.8 µm) allows excellent visualization of not just the conducting airways, but also the alveolar ducts and sacs, and tracking of the acinar shape and its deformation during inflation. The kinematics of individual alveoli and alveolar clusters with a group of terminal alveoli is influenced not only by the connecting alveolar duct and alveoli, but also by the neighboring structures. Acinar volume was not a linear function of lung volume. The alveolar duct diameter changed dramatically during inflation at low pressures and remained relatively constant above an airway pressure of ∼8 cmH2O during inflation. The ratio of acinar surface area to acinar volume indicates that acinar distension during low-pressure inflation differed from that during inflation over a higher pressure range; in particular, acinar deformation was accordion-like during low-pressure inflation. These results indicated that the alveoli and duct expand differently as total acinar volume increases and that the alveolar duct may expand predominantly during low-pressure inflation. Our findings suggest that acinar deformation in the core regions of the lung is complex and heterogeneous.

Indeterminacy in the WHO classification of tumors: an example of the histopathological diagnosis of brain tumors.

The WHO classifications of tumors are the global standards of tumor diagnosis. In spite of the detailed descriptions of the histopathological features of tumors in the classifications, tumors may be difficult to diagnose or the diagnosis can be improper. One of the reasons is that the diagnostic criteria have indeterminacy. In this article, we clarify this indeterminacy and discuss the diagnostic problems associated with indeterminacy. Indeterminacy of the histopathological features is classified according to the following three points: specificity, constancy, and exclusiveness. We consider an oblique (ambiguous description), variable (not always present), or duplicative feature as an indeterminate feature. Under indeterminacy, pathologists make their diagnosis on the basis of their experience and heuristic reasoning, which can lead to improper diagnosis. Not only the histopathological features, but also the diagnostic criterion, will have indeterminacy, which may be the direct influence of the indeterminacy of the features. Also, it is possible for there to be too many combinations of findings that satisfy a criterion, preventing an exhaustive description. The diagnostic criteria of the WHO classification have indeterminacy. Users should therefore verify their diagnosis. Further efforts by WHO editors to improve the diagnostic criteria also are desirable.

Modified pluck method in en bloc nephroureterectomy with bladder cuff for upper urothelial cancer.

AIM: To evaluate the surgical results of the en bloc removal of the kidney and ureter with a bladder cuff by using our modified pluck method. METHODS: We employed this procedure in 28 patients with renal pelvic and ureteral cancer. The clinical stages of the 28 patients were T(1-3)N(0-1)M(0). These patients were operated on by nephrectomy with standard open or retroperitoneoscopic surgery, and then standard or blind dissection of the distal ureter. After simultaneously making a transurethral circular incision of the ureteral meatus with a J-shaped electrode, the ureteral end was plucked out of the bladder, and en bloc removal of the kidney and ureter was performed from the wound. RESULTS: The mean operating time for nephroureterectomy using the pluck method was 278 min in all cases. The mean time for the pluck procedure after nephrectomy was 24 min in 22 cases, and 73 min in six cases where the nephrectomy was carried out via a new lower pararectal wound. There were no intra- or postoperative complications associated with these procedures. Within the mean follow-up period of 25 months, there was no recurrence of tumors in the perivesical retroperitoneal space; however, the usual rate of intravesical recurrence was observed. Three patients died, two of metastatic urothelial cancer and one of heart disease. CONCLUSIONS: En bloc nephroureterectomy using our modified pluck method is a useful procedure for patients with upper urothelial cancer because of the simplicity and ease of the procedure.

Conditional entropy as an indicator of pleomorphism in astrocytic tumors.

The entropies of nuclear arrangements as an indicator of pleomorphism are assessed using a morphometric method. Sixty astrocytic tumors (grades I, II, III and IV; 15 cases each) were reviewed and analyzed. All slides were stained with HE and MIB-1 antibody. The MIB-1 labeling index (LI) was assessed by counting nuclei under a microscope. Images of HE-stained slides were digitized and segmented using the watershed algorithm. Then, six nuclear parameters were measured automatically: (i) the number of total nuclei in the image, (ii) percentage of total nuclear area in the image, (iii) the mean area of the nucleus, (iv) the standard deviation of the area of the nucleus, (v) the entropy of nuclear arrangement (Entropysimple), and (vi) conditional entropy of nuclear arrangement (Entropyconditional). Entropysimple was defined according to the area of the nucleus and Entropyconditional was defined according to both the area of the nucleus and the area of its neighboring nuclei. Image processing and image analysis were performed with public domain software developed in the laboratory. Segmentation of the images resulted in inappropriate segmentation in a few percent of the images. The measurements obtained for each parameter were classified using discriminant analysis. The percentage of correct classification with Entropyconditional was 62%, which was the highest value among all the measurements. Classification based on the combination of all measurements resulted in a rate of correct classification of 88%. Thus, conditional entropy of nuclear arrangement is useful for grading of astrocytic tumors and it is proposed as an indicator of pleomorphism.

Dose escalation study of paclitaxel in combination with fixed-dose irinotecan in patients with advanced non-small cell lung cancer (JCOG 9807).

BACKGROUND: Both irinotecan (CPT) and paclitaxel (Pac) are effective against non-small cell lung cancer (NSCLC), and besides, preclinical studies have demonstrated an additive or synergistic interaction between camptothecin and taxane. METHODS: We conducted a phase I/II study of combination chemotherapy consisting of Pac and CPT to determine qualitative and quantitative toxicities and efficacy of the combination against advanced NSCLC. We fixed the dose of CPT at 60 mg/m(2) and escalated the Pac dose in 10 or 20 mg/m(2) increments from a starting dose of 80 mg/m(2), and repeated the cycle every 2 weeks. Prophylactic G-CSF was also administered. RESULTS: Between February 1999 and April 2001, 24 patients were registered in the study. None of the patients had a history of prior chemotherapy, but surgical resection had been performed in 3 of them. None of the patients experienced dose-limiting toxicity (DLT) up to and including level 6. At dose level 7 of Pac, 180 mg/m(2), 2 patients experienced DLT, that is grades 2 and 3 dyspnea due to pneumonitis. Another patient experienced grade 1 dyspnea due to pneumonitis. Neutropenia, diarrhea, and other toxicities were mild; however, we concluded that dose level 7 of Pac was the maximum-tolerated dose. An objective response was observed in 58.3%. The median survival time was 370 days, and the 1-year survival rate was 54.2%. CONCLUSION: Pneumonitis was the DLT in this study, and Pac 160 mg/m(2) and CPT 60 mg/m(2) every 2 weeks are recommended for the phase II study. This combination shows appreciable activity against NSCLC.

Phase I/II study of escalating doses of nedaplatin in combination with irinotecan for advanced non-small-cell lung cancer.

We conducted a phase I/II study of combination chemotherapy with nedaplatin (NDP) and irinotecan to determine the effects against advanced non-small-cell lung cancer (NSCLC) and to determine the qualitative and quantitative toxicities of the combination chemotherapy. NDP was given on day 1 and irinotecan on days 1 and 8. The treatment cycle was designed to be repeated every 3 weeks. We fixed the dose of irinotecan as 60 mg/m(2) and escalated the NDP dose from a starting dose of 50 mg/m(2) by 10-mg/m(2) increments until the maximum tolerated dose (MTD) was reached. The MTD was defined as the dose level at which at least two of three or three of six patients experienced a dose-limiting toxicity (DLT). Between April 1997 and November 2000, 42 patients were registered in the study. Of the 42 patients, 37 had no prior treatment, 3 had received whole-brain irradiation, 1 had undergone surgical resection, and 1 had had one regimen of chemotherapy before enrolling in this study. In the phase I study, we observed DLTs such as grade 4 neutropenia lasting 7 days and grade 3 diarrhea lasting 1 day in one patient at level 2, grade 3 elevated of GPT in one patient at level 3, and acute myocardial infarction in one patient at level 6. We could not determine the MTD until dose level 6 was reached, so decided on a recommended dose of 100 mg/m(2) NDP, which is recommended for NDP-alone chemotherapy. Because of prolonged neutropenia in the phase I study, we repeated the treatment every 4 weeks in the phase II study. In the phase II study, a total of 16 patients, including 6 patients from the phase I study, were registered and a total of 42 cycles were administered. Grade 3 or 4 neutropenia, grade 3 anemia and grade 3 or 4 thrombocytopenia occurred in 50%, 12% and 7% of cycles, respectively. Febrile neutropenia occurred in eight cycles (19%) but there were no severe infections. Grade 3 elevation of GPT occurred in one patient. Of the 16 patients, 7 had an objective response. Of the 42 patients, 13 achieved a partial response (PR) and the overall response rate was 31.0%. The median duration of PRs was 226 days (range 59 to 646 days). The median survival time was 341 days and the 1-year survival rate was 45.2%. In conclusion, the combination of NDP and irinotecan was highly effective and well tolerated in NSCLC.