Vascular Dynamics Research Articles

Endothelial heterogeneity in bone marrow: insights across development, adult life and leukemia.

The central role of the endothelial microenvironment in orchestrating bone marrow (BM) homeostasis and hematopoietic support has been confirmed at various developmental stages and in adult life. The BM vasculature is crucial in mediating communication between BM parenchyma and circulating blood, displaying remarkable heterogeneity in structure and function. While vascular cell diversity in other tissues has long been recognized, the molecular basis of this phenomenon in BM is just now emerging. Over the past decade, single-cell approaches and microscopic observations have expanded our understanding of BM vasculature. While solely characterized for their paracrine properties in the past, recent advances have revolutionized our perception of endothelial function, revealing distinct anatomical locations associated with diverse endothelial cell states. The identification of phenotypic differences between normal and pathological conditions has therefore deepened our understanding of vascular dynamics and their impact on hematopoiesis in health and disease. In this review, we highlight key milestones and recent advances in understanding vascular heterogeneity within BM microenvironment during development, adulthood and aging. We also explore how leukemia affects this heterogeneity and how we can take this knowledge forward to improve clinical practices. By synthesizing existing literature, we aim to address unresolved questions and outline future research directions.

Altered renal vascular patterning reduces ischemic kidney injury and limits vascular loss associated with aging.

The kidney vasculature has a complex arrangement, which runs in both series and parallel to perfuse the renal tissue and appropriately filter plasma. Recent studies have demonstrated that the development of this vascular pattern is dependent on netrin-1 secreted by renal stromal progenitors. Mice lacking netrin-1 develop an arterial tree with stochastic branching, particularly of the large interlobar vessels. The current study investigated whether abnormalities in renal vascular pattern altered kidney function or response to injury. To examine this, we analyzed kidney function at baseline as well as in response to recovery from a model of bilateral ischemic injury and measured vascular dynamics in aged mice. We found no differences in kidney function or morphology at baseline between mice with an abnormal arterial pattern compared to control. Interestingly, male and female mutant mice with stochastic vascular patterning showed a reduction in tubular injury in response to ischemia. Similarly, mutant mice also had a preservation of perfused vasculature with aging compared to a reduction in the control group. These results suggest that guided and organized patterning of the renal vasculature may not be required for normal kidney function; thus, modulating renal vascular patterning may represent an effective therapeutic strategy. Understanding how patterning and maturation of the arterial tree affects physiology and response to injury or aging has important implications for enhancing kidney regeneration and tissue engineering strategies.

Waste clearance shapes aging brain health.

Brain health is intimately connected to fluid flow dynamics that cleanse the brain of potentially harmful waste material. This system is regulated by vascular dynamics, the maintenance of perivascular spaces, neural activity during sleep, and lymphatic drainage in the meningeal layers. However, aging can impinge on each of these layers of regulation, leading to impaired brain cleansing and the emergence of various age-associated neurological disorders, including Alzheimer's and Parkinson's diseases. Understanding the intricacies of fluid flow regulation in the brain and how this becomes altered with age could reveal new targets and therapeutic strategies to tackle age-associated neurological decline.

Vascular decellularization dynamics: Optimizing Triton X-100 and SDS concentration with incubation time.

Vascular decellularization dynamics: Optimizing Triton X-100 and SDS concentration with incubation time.

The cardiac toxicity of PAMAM dendrimer drug delivery systems can be attenuated with the adjunct use of cardioprotective agents.

Polyamidoamine (PAMAM) dendrimer nanoparticles are efficient drug delivery vectors with potential clinical applications in nanomedicine. However, PAMAMs can compromise heart function, and strategies to mitigate cardiotoxicity would be beneficial. In this study, we investigated whether the adjunct use of three key cardioprotective agents could prevent the cardiac injury induced by a seventh-generation cationic PAMAM dendrimer (G7). Isolated rat hearts were subjected to ischemia and reperfusion (I/R) injury in the presence or absence of G7 or the cardioprotective agents Losartan, Epidermal Growth Factor (EGF), or S-nitroso-N-acetylpenicillamine (SNAP). I/R injury significantly compromised cardiac function, in terms of left ventricular hemodynamics, contractility, and vascular dynamics, which were markedly improved (p<0.05) by the administration of Losartan, EGF, or SNAP alone, confirming their cardioprotective effects. The administration of G7 significantly worsened cardiac function recovery following I/R(p<0.05). G7-induced impairments in cardiac and vascular dynamics were significantly improved by co-administration of Losartan, EGF, or SNAP. Treatment with G7 also significantly increased cardiac enzyme levels and infarct size, both of which were markedly reduced upon co-infusion of Losartan, EGF, or SNAP (p<0.05). Thus, G7 deteriorates the recovery of cardiac function in isolated hearts subjected to I/R injury, which can be rescued by co-administration of Losartan, EGF, or SNAP. These findings enhance our understanding of the nanotoxicology of PAMAM dendrimers in the mammalian heart and suggest that the adjunct use of cardioprotective agents is an effective strategy for mitigating the cardiotoxicity of these dendrimers and potentially other drug delivery systems.

Coupled pulsatile vascular and paravascular fluid dynamics in the human brain

BackgroundCardiac pulsation propels blood through the cerebrovascular network to maintain cerebral homeostasis. The cerebrovascular network is uniquely surrounded by paravascular cerebrospinal fluid (pCSF), which plays a crucial role in waste removal, and its flow is suspected to be driven by arterial pulsations. Despite its importance, the relationship between vascular and paravascular fluid dynamics throughout the cardiac cycle remains poorly understood in humans.MethodsIn this study, we developed a non-invasive neuroimaging approach to investigate the coupling between pulsatile vascular and pCSF dynamics within the subarachnoid space of the human brain. Resting-state functional MRI (fMRI) and dynamic diffusion-weighted imaging (dynDWI) were retrospectively cardiac-aligned to represent cerebral hemodynamics and pCSF motion, respectively. We measured the time between peaks (∆TTP) in ddϕfMRI\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\frac{d}{d\\phi }fMRI$$\\end{document} and dynDWI waveforms and measured their coupling by calculating the waveforms correlation after peak alignment (correlation at aligned peaks). We compared the ∆TTP and correlation at aligned peaks between younger [mean age: 27.9 (3.3) years, n = 9] and older adults [mean age: 70.5 (6.6) years, n = 20], and assessed their reproducibility within subjects and across different imaging protocols.ResultsHemodynamic changes consistently precede pCSF motion. ∆TTP was significantly shorter in younger adults compared to older adults (−0.015 vs. −0.069, p < 0.05). The correlation at aligned peaks were high and did not differ between younger and older adults (0.833 vs. 0.776, p = 0.153). The ∆TTP and correlation at aligned peaks were robust across fMRI protocols (∆TTP: −0.15 vs. −0.053, p = 0.239; correlation at aligned peaks: 0.813 vs. 0.812, p = 0.985) and demonstrated good to excellent within-subject reproducibility (∆TTP: intraclass correlation coefficient = 0.36; correlation at aligned peaks: intraclass correlation coefficient = 0.89).ConclusionThis study proposes a non-invasive technique to evaluate vascular and paravascular fluid dynamics. Our findings reveal a consistent and robust cardiac pulsation-driven coupling between cerebral hemodynamics and pCSF dynamics in both younger and older adults.

High-performance laser speckle contrast image vascular segmentation without delicate pseudo-label reliance

Laser speckle contrast imaging (LSCI) is a noninvasive, label-free technique that allows real-time investigation of the microcirculation situation of biological tissue. High-quality microvascular segmentation is critical for analyzing and evaluating vascular morphology and blood flow dynamics. However, achieving high-quality vessel segmentation has always been a challenge due to the cost and complexity of label data acquisition and the irregular vascular morphology. In addition, supervised learning methods heavily rely on high-quality labels for accurate segmentation results, which often necessitate extensive labeling efforts. Here, we propose a novel approach LSWDP for high-performance real-time vessel segmentation that utilizes low-quality pseudo-labels for nonmatched training without relying on a substantial number of intricate labels and image pairing. Furthermore, we demonstrate that our method is more robust and effective in mitigating performance degradation than traditional segmentation approaches on diverse style data sets, even when confronted with unfamiliar data. Importantly, the dice similarity coefficient exceeded 85% in a rat experiment. Our study has the potential to efficiently segment and evaluate blood vessels in both normal and disease situations. This would greatly benefit future research in life and medicine.

Deciphering Vascular Dynamics Alterations in Sub-Saharan Individuals with Type 2 Diabetes: Overview and Temporal Analysis of Nitric Oxide Administration

Background: Early detection of arterial damage is essential for the primary prevention of complications linked to type 2 diabetes (T2D). The study assessed the cardiovascular risk of sub-Saharan African individuals with T2D, while exploring possible mechanisms involved in the pathogenesis of vascular complications in this population. Methodology: A crossover study of 72 sub-Saharan African adults (36 with T2D and 36 without T2D) was conducted. Outcomes including diameter size (mm) and blood velocity (cm/s) of the brachial artery, were obtained at seven time points: baseline and from 5 seconds to 600 seconds in two conditions: pre- and post Nitric Oxide (NO) administration. HbA1C, fasting glucose, age, BMI, mean arterial pressure (MAP), lipid profile, T2D duration since diagnosis, and binary indicators of insulin and oral diabetes medication were evaluated. Results: NO improved the blood flow compared to the pre-NO after adjustment for clinical factors. The beneficial effect of NO administration on vascular dynamics was influenced by age (&amp;lt;I&amp;gt;B&amp;lt;/I&amp;gt;=1.09; 95%IC: 1.07, 1.11), increased BMI (&amp;lt;I&amp;gt;B&amp;lt;/I&amp;gt;= 1.03; 95%IC: 1.01, 1.04) and insulin use (&amp;lt;I&amp;gt;B&amp;lt;/I&amp;gt; = 1.13; 95%IC 1.10, 1.16). Conclusion: The nuanced impact of these factors on blood flow improvement related to NO necessitates tailored and personalized approaches in managing T2D patients.

Strategies for multi-case physics-informed neural networks for tube flows: a study using 2D flow scenarios

Fluid dynamics computations for tube-like geometries are crucial in biomedical evaluations of vascular and airways fluid dynamics. Physics-Informed Neural Networks (PINNs) have emerged as a promising alternative to traditional computational fluid dynamics (CFD) methods. However, vanilla PINNs often demand longer training times than conventional CFD methods for each specific flow scenario, limiting their widespread use. To address this, multi-case PINN approach has been proposed, where varied geometry cases are parameterized and pre-trained on the PINN. This allows for quick generation of flow results in unseen geometries. In this study, we compare three network architectures to optimize the multi-case PINN through experiments on a series of idealized 2D stenotic tube flows. The evaluated architectures include the ‘Mixed Network’, treating case parameters as additional dimensions in the vanilla PINN architecture; the “Hypernetwork”, incorporating case parameters into a side network that computes weights in the main PINN network; and the “Modes” network, where case parameters input into a side network contribute to the final output via an inner product, similar to DeepONet. Results confirm the viability of the multi-case parametric PINN approach, with the Modes network exhibiting superior performance in terms of accuracy, convergence efficiency, and computational speed. To further enhance the multi-case PINN, we explored two strategies. First, incorporating coordinate parameters relevant to tube geometry, such as distance to wall and centerline distance, as inputs to PINN, significantly enhanced accuracy and reduced computational burden. Second, the addition of extra loss terms, enforcing zero derivatives of existing physics constraints in the PINN (similar to gPINN), improved the performance of the Mixed Network and Hypernetwork, but not that of the Modes network. In conclusion, our work identified strategies crucial for future scaling up to 3D, wider geometry ranges, and additional flow conditions, ultimately aiming towards clinical utility.

AngioMT: A MATLAB based 2D image-to-physics tool to predict oxygen transport in vascularized microphysiological systems.

Microphysiological models (MPS) are increasingly getting recognized as in vitro preclinical systems of pathophysiology and drug discovery. However, there is also a growing need to adapt and advance MPS to include the physiological contributions of the capillary vascular dynamics, because they undergo angiogenesis or vasculogenesis to deliver soluble oxygen and nutrients to its organs. Currently, the process of formation of microvessels in MPS is measured arbitrarily, and vascularized MPS do not include oxygen measurements in their analysis. Sensing and measuring tissue oxygen delivery is extremely difficult because it requires access to opaque and deep tissue, and/or requires extensive integration of biosensors that makes such systems impractical to use in the real world. Here, a finite element method-based oxygen transport program, called AngioMT, is built in MATLAB. AngioMT processes the routinely acquired 2D confocal images of microvascular networks in vitro and solves physical equations of diffusion-reaction dominated oxygen transport phenomena. This user-friendly image-to-physics transition in AngioMT is an enabling tool of MPS analysis because unlike the averaged morphological measures of vessels, it provides information of the spatial transport of oxygen both within the microvessels and the surrounding tissue regions. Further, it solves the more complex higher order reaction mechanisms which also improve the physiological relevance of this tool when compared directly against in vivo measurements. Finally, the program is applied in a multicellular vascularized MPS by including the ability to define additional organ/tissue subtypes in complex co-cultured systems. Therefore, AngioMT serves as an analytical tool to enhance the predictive power and performance of MPS that incorporate microcirculation.

Toward a brighter constellation: multiorgan neuroimaging of neural and vascular dynamics in the spinal cord and brain.

Pain comprises a complex interaction between motor action and somatosensation that is dependent on dynamic interactions between the brain and spinal cord. This makes understanding pain particularly challenging as it involves rich interactions between many circuits (e.g., neural and vascular) and signaling cascades throughout the body. As such, experimentation on a single region may lead to an incomplete and potentially incorrect understanding of crucial underlying mechanisms. We aimed to develop and validate tools to enable detailed and extended observation of neural and vascular activity in the brain and spinal cord. The first key set of innovations was targeted to developing novel imaging hardware that addresses the many challenges of multisite imaging. The second key set of innovations was targeted to enabling bioluminescent (BL) imaging, as this approach can address limitations of fluorescent microscopy including photobleaching, phototoxicity, and decreased resolution due to scattering of excitation signals. We designed 3D-printed brain and spinal cord implants to enable effective surgical implantations and optical access with wearable miniscopes or an open window (e.g., for one- or two-photon microscopy or optogenetic stimulation). We also tested the viability for BL imaging and developed a novel modified miniscope optimized for these signals (BLmini). We describe "universal" implants for acute and chronic simultaneous brain-spinal cord imaging and optical stimulation. We further describe successful imaging of BL signals in both foci and a new miniscope, the "BLmini," which has reduced weight, cost, and form-factor relative to standard wearable miniscopes. The combination of 3D-printed implants, advanced imaging tools, and bioluminescence imaging techniques offers a coalition of methods for understanding spinal cord-brain interactions. Our work has the potential for use in future research into neuropathic pain and other sensory disorders and motor behavior.

Transcranial Doppler Sonography in Acute Viral Encephalitis with Special Reference to Dengue Encephalitis

Abstract Introduction: Acute viral encephalitis syndrome including dengue encephalitis (DE) is an important tropical illness with a guarded prognosis. The cerebral blood flow may be affected in acute viral encephalitis. Transcranial Doppler (TCD) sonography can quantitatively determine intracranial vascular flow dynamics in acute viral encephalitis. Aim: We aimed to investigate the intracranial blood flow characteristics in patients with DE and compare with nondengue acute viral encephalitis patients. Materials and Methods: In this prospective study, all the cases of acute viral encephalitis including dengue were enrolled over 18 months and followed up at 3 months. TCD was performed to determine the mean velocity pulsatility index (PI) and resistive index (RI) across the middle cerebral artery, anterior cerebral artery, posterior cerebral artery (PCA), vertebral artery, and basilar artery and compared it among dengue versus nondengue group as well as outcome at 3 months. Results: Out of 39 patients, 19 were diagnosed with DE, whereas 20 patients suffered from the nondengue group. The elevated PI and RI in the left PCA were found to statistically significant (P = 0.001 and 0.008, respectively) in the DE group. There was no significant difference in any other TCD indices in any other vessel among both the groups. In addition, an initial low Glasgow Outcome Scale (GOS) and higher brain imaging abnormality were significantly associated with poor GOS of &lt;5 in both the groups. Conclusion: An elevated PI and RI of PCA could be an important initial TCD parameter in DE. TCD parameters did not affect the outcome of acute viral encephalitis.

Microphysiologically Engineered Vessel-Tumor Model to Investigate Vascular Transport Dynamics of Immune Cells.

Cancer immunotherapy has emerged as a promising therapeutic strategy to combat cancer effectively. However, it is hard to observe and quantify how this in vivo process happens. Three-dimensional (3D) microfluidic vessel-tumor models offer valuable capability to study how immune cells transport during cancer progression. We presented an advanced 3D vessel-supported tumor model consisting of the endothelial lumen and vessel network for the study of T cells' transportation. The process of T cell transport through the vessel network and interaction with tumor spheroids was represented and monitored in vitro. Specifically, we demonstrate that the endothelial glycocalyx serving in the T cells' transport can influence the endothelium-immune interaction. Furthermore, after vascular transport, how programmed cell death protein 1 (PD-1) immune checkpoint inhibition influences the delivered activated-T cells on tumor killing was evaluated. Our in vitro vessel-tumor model provides a microphysiologically engineered platform to represent T cell vascular transportation during tumor immunotherapy. The reported innovative vessel-tumor platform is believed to have the potential to explore the tumor-induced immune response mechanism and preclinically evaluate immunotherapy's effectiveness.

Automated Liver Tumor Segmentation in DCE-MRI with 4D Deep Learning Integrating 3D CNNS and ConvLSTM

A state-of-the-art method for automatically segmenting liver tumours using Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) is shown in this study. This study is significant because it uses a 4D information deep learning model to tackle the hard problem of liver tumor segmentation. A combination of 3D CNNs and ConvLSTM networks, specifically built to capture spatial and temporal information inside the dynamic imaging sequence of DCE-MRI, is what the suggested model is all about. Utilizing diffusion-computed tomography (DCE-MRI) gives a lot of information vital for precise tumor segmentation by providing a complete picture of the vascular dynamics in the liver. The model makes use of spatial and temporal elements by combining 3D Convolutional Neural Networks (CNNs) with ConvLSTM networks; this allows for a more detailed comprehension of the changes that are happening over time. To overcome the difficulties caused by the constantly changing nature of DCE-MRI data, this integration of 4D information greatly improves the accuracy and consistency of liver tumor segmentation. Implementing and optimizing the suggested deep learning model are the main goals of this work. The training and calibration of the model to accurately capture liver tumor characteristics in dynamic imaging sequences is of utmost importance.

The Essential Role of PGF2α/PTGFR in Molding Endometrial Breakdown and Vascular Dynamics, Regulated by HIF-1α in a Mouse Menstrual-like Model.

In women of childbearing age, extensive decidualization, shedding and remodeling of the endometrium during the menstrual cycle are fundamental for successful pregnancy. The role of prostaglandins (PGs) in menstruation has long been proposed in humans, and the rate-limiting enzyme cyclooxygenase was shown to play a key role in endometrial breakdown and shedding in a mouse menstrual-like model in our previous study. However, the specific types of PGs involved and their respective roles remain unclear. Therefore, our objective was to investigate the mechanism through which PGs regulate endometrial disintegration. In this study, the microscopy was observed by HE; the protein levels of prostaglandins E1 (PGE1), prostaglandins E2 (PGE2), prostaglandin F2α (PGF2α) and Prostaglandin I2 (PGI2) were detected by ELISA; the mRNA level of Pfgfr2, Vascular Endothelial Growth Factor(Vegf), Angiostatin and Hypoxia inducible factor-1α (Hif1α) were examined by real-time PCR; PTGFR Receptor (PTGFR), VEGF, Angiostatin and HIF-1α protein levels were investigated by western blotting; the locations of protein were observed by Immunohistochemistry; HIF-1α binding PTGFR promoter was detected by Chromatin Immunoprecipitation (ChIP) and real-time PCR. We found that the concentrations of PGE1, PGE2, and PGF2α all increased significantly during this process. Furthermore, Ptgfr mRNA increased soon after Progesterone (P4) withdrawal, and PTGFR protein levels increased significantly during abundant endometrial breakdown and shedding processes. PTGFR inhibitors AL8810 significantly suppressed endometrial breakdown and shedding, promoted Angiostatin expression, and reduced VEGF-A expressions and vascular permeability. And HIF-1α and PTGFR were mainly located in the luminal/gland epithelium, vascular endothelium, and pre-decidual zone. Interestingly, HIF-1α directly bound to Ptgfr promoter. Moreover, a HIF-1α inhibitor 2-methoxyestradiol (2ME) significantly reduced PTGFR expression and suppressed endometrial breakdown which was in accord with PTGFR inhibitor's effect. Similar changes occurred in human stromal cells relevant to menstruation in vitro. Our study provides evidence that PGF2α/PTGFR plays a vital role in endometrial breakdown via vascular changes that are regulated by HIF-1α during menstruation.

Thickness Asymmetry of the Vertebral Artery Groove: A Dried Vertebrae Study.

The vertebral artery groove (VAG), located on the posterior arch of the first cervical (atlas) vertebra plays a pivotal role in guiding the vertebral artery's (VA) third part (V3). Deviations in VAG morphology and morphometry (dimensions) can influence vascular dynamics and pose clinical implications. The current study delves into the morphometric variants and explores the less-explored morphometric variable of the VAG thickness, highlighting possible laterality (asymmetry). A morphometric investigation was conducted on 141 dried atlas (73 male and 68 female) vertebrae from a Greek adult population. The VAG's minimum thickness was investigated by considering the laterality (sides' differences), gender, and age impact on it. Measurements were performed by two independent researchers, ensuring the data reliability. A significant asymmetry was identified in the VAG thickness between the left (3.9 ± 0.9 mm) and right (4.1 ± 1.1 mm) (p=0.005) sides, with the left side having the mean minimum thickness. Gender had a significant impact on VAG thickness only on the left side, with females presenting a significantly thinner left-sided VAG (3.6 ± 0.9 mm) than males (4.10 ± 0.7 mm) (p=0.001). Age had no significant impact on the VAG thickness. Conclusion: The present study underscores the significance of asymmetry in the VAG thickness in craniocervical interventions. This less-explored morphometric variable warrants careful consideration by surgeons during preoperative planning to minimize potential complications. The current findings highlight the importance of understanding the VAG thickness asymmetry and its clinical implications, as this osseous variable may be an index of a different diameter of the VA by side. It is recommended that surgeons incorporate this variable into their preoperative assessments to improve the safety and efficacy of craniocervical interventions.

Effect of insulin versus dietary restriction alone on umbilical cord and placental arterio-venous anastomoses in women with gestational diabetes mellitus

Background: Gestational diabetes mellitus (GDM) induces structural alterations in the umbilical cord and placental vessels. This study aims to understand the potential impact of insulin therapy on arteriovenous anastomosis (AVA) in placenta and umbilical cord. Materials and methods: We collected 52 normal and 59 GDM placentas and umbilical cords from the labour room. GDM specimens were categorized into those treated with diet (GDM-Diet) (n = 23) and those treated with insulin (GDM-Insulin) (n= 36). The umbilical cord was dissected near its insertion to expose the vessels, and arteriovenous anastomoses were documented. Tissues underwent processing and staining for microscopic confirmation of AV anastomosis. Comparison was done between normal and GDM specimens, and notably, between GDM-Diet and GDM-Insulin specimens. Results: Our examination of 59 GDM and 52 normal placentas with attached umbilical cords revealed AV anastomoses in 24 cases. AV anastomosis was observed in 22 (37.3%, n= 59) GDM cases and 2 (3.8%, n=52) normal cases (p=0.0001). Among GDM-Insulin group umbilical cords, 10 (27.78%, n = 36) exhibited AV anastomoses, while GDM-diet specimens displayed a notably higher proportion, with 12 (52.17%, n = 23) demonstrating AV anastomoses (p = 0.05). Conclusion: AV anastomoses are markedly more prevalent in the umbilical cords and placentas of individuals with GDM. Interestingly, within the GDM cohort, prevalence is significantly higher in those managed with diet. Our study highlights the association between GDM management strategies and AVC prevalence, emphasizing the importance of considering vascular dynamics in the management of GDM pregnancies. Keywords: placenta; umbilical cord; fetal- maternal health; gestational diabetes mellitus

300 Intracranial Tumors Hijack the Meningeal Venolymphatic Network Through VEGFR-2 Signaling

INTRODUCTION: Glioblastoma and other intracranial neoplasms have been associated with breakdown of the blood brain barrier. Other protective CNS barriers have sparsely been studied in brain tumors. Here, we identify the ability of intracranial neoplasms to hijack the meningeal venolymphatic network, which is driven through VEGFR-2/VEGF-A signaling. METHODS: C57BL/6J mice were stereotactically injected with syngeneic SB28 (glioblastoma) cell lines. Mice were treated with either isotype control or a VEGFR-2 inhibitor. Two-photon microscopy was used to visualize vascular cytoarchitecture and dynamics in vivo. Meningeal whole mounts, brains and spleens were also collected and analyzed by confocal microscopy and high parameter flow cytometry. Human dura mater from glioblastoma patients underwent multiplex immunohistochemistry to confirm the translatability of our findings. RESULTS: Our imaging studies revealed that glioblastomas can generate an extensive de novo network of meningeal blood vessels and lymphatics both in mice and humans. Lymphatic vessels were often observed developing in parallel to the newly formed vasculature. Intravital two-photon microscopy further revealed that the peritumoral vascular bed in the meninges of mice was leaky, dysfunctional, and generated a hypoxic microenvironment. Importantly, inhibition of VEGFR signaling impeded formation of this faulty venolymphatic network, which slowed tumor growth, reduced peritumoral hypoxia, enhanced immune infiltration, and increased survival. CONCLUSIONS: Our results demonstrate that glioblastomas can invade the meninges and hijack the venolymphatic network through VEGFR-2 and PECAM-1 signaling. While VEGFR-2 is associated with angiogenesis, our data suggest that it may also have an important role in regulating the simultaneous development of de novo meningeal venous and lymphatic drainage during glioblastoma.

Novel wireless laser doppler flowmeter-based investigation of earlobe vascular dynamics in cardiopulmonary exercise testing.

[Purpose] A new wireless laser Doppler blood flowmeter has facilitated easier, more stable measurement of skin perfusion during exercise. However, earlobe blood flow during the cardiopulmonary exercise test remains unascertained. This study aimed to clarify the characteristics of earlobe blood flow during incremental exercise load in healthy individuals. [Participants and Methods] Among 25 healthy males (age 23.6 ± 2.5 years), cycle ergometer-based symptom-limited cardiopulmonary exercise test, after 4 minutes of rest, was conducted with a 4-minute 20W warm-up and a continuous 2W-increase in the work rate every 6 seconds; earlobe blood flow was measured using a wireless laser Doppler blood flowmeter. [Results] Compared with that at rest, earlobe blood flow increased significantly from 50% of exercise peak intensity to a maximum of 1.7 times, but decreased immediately after exercise. The earlobe blood flow %change did not significantly correlate with hemodynamic parameters and its inflection point 36.4% Loadpeak was significantly lower than the anaerobic metabolic threshold 58.1% Loadpeak. [Conclusion] In healthy participants, earlobe blood flow during cardiopulmonary exercise test increased gradually with low-intensity exercise from approximately 1.5 times the resting rate and approached the anaerobic metabolic threshold with a maximum of 1.7 times the resting earlobe blood flow, but decreased quickly after exercise.

PyPPG: a Python toolbox for comprehensive photoplethysmography signal analysis

Objective. Photoplethysmography is a non-invasive optical technique that measures changes in blood volume within tissues. It is commonly and being increasingly used for a variety of research and clinical applications to assess vascular dynamics and physiological parameters. Yet, contrary to heart rate variability measures, a field which has seen the development of stable standards and advanced toolboxes and software, no such standards and limited open tools exist for continuous photoplethysmogram (PPG) analysis. Consequently, the primary objective of this research was to identify, standardize, implement and validate key digital PPG biomarkers. Approach. This work describes the creation of a standard Python toolbox, denoted pyPPG, for long-term continuous PPG time-series analysis and demonstrates the detection and computation of a high number of fiducial points and digital biomarkers using a standard fingerbased transmission pulse oximeter. Main results. The improved PPG peak detector had an F1-score of 88.19% for the state-of-the-art benchmark when evaluated on 2054 adult polysomnography recordings totaling over 91 million reference beats. The algorithm outperformed the open-source original Matlab implementation by ∼5% when benchmarked on a subset of 100 randomly selected MESA recordings. More than 3000 fiducial points were manually annotated by two annotators in order to validate the fiducial points detector. The detector consistently demonstrated high performance, with a mean absolute error of less than 10 ms for all fiducial points. Significance. Based on these fiducial points, pyPPG engineered a set of 74 PPG biomarkers. Studying PPG time-series variability using pyPPG can enhance our understanding of the manifestations and etiology of diseases. This toolbox can also be used for biomarker engineering in training data-driven models. pyPPG is available on https://physiozoo.com/.