Brain Blood Vessels Research Articles

Penerapan Posisi Lateral 30 Derajat dan Massage Menggunakan Virgin Cocunut Oil (VCO) Terhadap Risiko Kerusakan Integritas Kulit Pada Pasien Stroke

Background: Non-Hemorrhagic Stroke is a dysfunction of the central nervous system in the form of blockage of brain blood vessels which results in hemiparesis, indirectly experiencing immobilization at risk of skin integrity damage, one of the independent nursing interventions in overcoming the risk of skin integrity damage is the provision of a lateral 30 position degrees and massage using Virgin Coconut Oil (VCO). Research Methods: Descriptive with a case study approach. Results: After the implementation for 4 days by giving a 30 degree lateral position and massage using virgin coconut oil 2 times a day. The application of a 30 degree lateral position and maage using virgin coconut oil can reduce the risk of skin integrity damage in stroke patients. Conclusion: The application of a 30 degree lateral position and massage using virgin coconut oil is effective in reducing the occurrence of skin integrity damage. Suggestion: It is hoped that it can provide independent nursing interventions as a companion to pharmacological therapy to overcome nursing problems that exist in non-hemorrhagic stroke patients.

Dual U-Net-Based Conditional Generative Adversarial Network for Blood Vessel Segmentation with Reduced Cerebral MR Training Volumes.

Segmenting vessels in brain images is a critical step for many medical interventions and diagnoses of illnesses. Recent advances in artificial intelligence provide better models, achieving a human-like level of expertise in many tasks. In this paper, we present a new approach to segment Time-of-Flight Magnetic Resonance Angiography (TOF-MRA) images, relying on fewer training samples than state-of-the-art methods. We propose a conditional generative adversarial network with an adapted generator based on a concatenated U-Net with a residual U-Net architecture (UUr-cGAN) to carry out blood vessel segmentation in TOF-MRA images, relying on data augmentation to diminish the drawback of having few volumes at disposal for training the model, while preventing overfitting by using regularization techniques. The proposed model achieves 89.52% precision and 87.23% in Dice score on average from the cross-validated experiment for brain blood vessel segmentation tasks, which is similar to other state-of-the-art methods while using considerably fewer training samples. UUr-cGAN extracts important features from small datasets while preventing overfitting compared to other CNN-based methods and still achieve a relatively good performance in image segmentation tasks such as brain blood vessels from TOF-MRA.

Resolving the lineage relationship between malignant cells and vascular cells in glioblastomas.

Glioblastoma multiforme (GBM), a highly malignant and heterogeneous brain tumor, contains various types of tumor and non-tumor cells. Whether GBM cells can trans-differentiate into non-neural cell types, including mural cells or endothelial cells (ECs), to support tumor growth and invasion remains controversial. Here we generated two genetic GBM models de novo in immunocompetent mouse brains, mimicking essential pathological and molecular features of human GBMs. Lineage-tracing and transplantation studies demonstrated that, although blood vessels in GBM brains underwent drastic remodeling, evidence of trans-differentiation of GBM cells into vascular cells was barely detected. Intriguingly, GBM cells could promiscuously express markers for mural cells during gliomagenesis. Furthermore, single-cell RNA sequencing showed that patterns of copy number variations (CNVs) of mural cells and ECs were distinct from those of GBM cells, indicating discrete origins of GBM cells and vascular components. Importantly, single-cell CNV analysis of human GBM specimens also suggested that GBM cells and vascular cells are likely separate lineages. Rather than expansion owing to trans-differentiation, vascular cell expanded by proliferation during tumorigenesis. Therefore, cross-lineage trans-differentiation of GBM cells is very unlikely to occur during gliomagenesis. Our findings advance understanding of cell lineage dynamics during gliomagenesis, and have implications for targeted treatment of GBMs.

Generating 3D TOF-MRA volumes and segmentation labels using generative adversarial networks.

Deep learning requires large labeled datasets that are difficult to gather in medical imaging due to data privacy issues and time-consuming manual labeling. Generative Adversarial Networks (GANs) can alleviate these challenges enabling synthesis of shareable data. While 2D GANs have been used to generate 2D images with their corresponding labels, they cannot capture the volumetric information of 3D medical imaging. 3D GANs are more suitable for this and have been used to generate 3D volumes but not their corresponding labels. One reason might be that synthesizing 3D volumes is challenging owing to computational limitations. In this work, we present 3D GANs for the generation of 3D medical image volumes with corresponding labels applying mixed precision to alleviate computational constraints. We generated 3D Time-of-Flight Magnetic Resonance Angiography (TOF-MRA) patches with their corresponding brain blood vessel segmentation labels. We used four variants of 3D Wasserstein GAN (WGAN) with: 1) gradient penalty (GP), 2) GP with spectral normalization (SN), 3) SN with mixed precision (SN-MP), and 4) SN-MP with double filters per layer (c-SN-MP). The generated patches were quantitatively evaluated using the Fréchet Inception Distance (FID) and Precision and Recall of Distributions (PRD). Further, 3D U-Nets were trained with patch-label pairs from different WGAN models and their performance was compared to the performance of a benchmark U-Net trained on real data. The segmentation performance of all U-Net models was assessed using Dice Similarity Coefficient (DSC) and balanced Average Hausdorff Distance (bAVD) for a) all vessels, and b) intracranial vessels only. Our results show that patches generated with WGAN models using mixed precision (SN-MP and c-SN-MP) yielded the lowest FID scores and the best PRD curves. Among the 3D U-Nets trained with synthetic patch-label pairs, c-SN-MP pairs achieved the highest DSC (0.841) and lowest bAVD (0.508) compared to the benchmark U-Net trained on real data (DSC 0.901; bAVD 0.294) for intracranial vessels. In conclusion, our solution generates realistic 3D TOF-MRA patches and labels for brain vessel segmentation. We demonstrate the benefit of using mixed precision for computational efficiency resulting in the best-performing GAN-architecture. Our work paves the way towards sharing of labeled 3D medical data which would increase generalizability of deep learning models for clinical use.

Evaluation of Proton-Induced DNA Damage in 3D-Engineered Glioblastoma Microenvironments.

Glioblastoma (GBM) is a devastating cancer of the brain with an extremely poor prognosis. For this reason, besides clinical and preclinical studies, novel in vitro models for the assessment of cancer response to drugs and radiation are being developed. In such context, three-dimensional (3D)-engineered cellular microenvironments, compared to unrealistic two-dimensional (2D) monolayer cell culture, provide a model closer to the in vivo configuration. Concerning cancer treatment, while X-ray radiotherapy and chemotherapy remain the current standard, proton beam therapy is an appealing alternative as protons can be efficiently targeted to destroy cancer cells while sparing the surrounding healthy tissue. However, despite the treatment’s compelling biological and medical rationale, little is known about the effects of protons on GBM at the cellular level. In this work, we designed novel 3D-engineered scaffolds inspired by the geometry of brain blood vessels, which cover a vital role in the colonization mechanisms of GBM cells. The architectures were fabricated by two-photon polymerization (2PP), cultured with U-251 GBM cells and integrated for the first time in the context of proton radiation experiments to assess their response to treatment. We employed Gamma H2A.X as a fluorescent biomarker to identify the DNA damage induced in the cells by proton beams. The results show a higher DNA double-strand breakage in 2D cell monolayers as compared to cells cultured in 3D. The discrepancy in terms of proton radiation response could indicate a difference in the radioresistance of the GBM cells or in the rate of repair kinetics between 2D cell monolayers and 3D cell networks. Thus, these biomimetic-engineered 3D scaffolds pave the way for the realization of a benchmark tool that can be used to routinely assess the effects of proton therapy on 3D GBM cell networks and other types of cancer cells.

Editorial: The Role of Neurovascular Unit in Neurodegeneration

The neurovascular unit (NVU) is a novel concept which refers to the dynamic multicellular complex and functional interactions between brain tissues and blood vessels, Schaeffer and Iadecola. Neurons, perivascular astrocytes, microglia, pericytes, and endothelial cells (ECs), as well as basement membrane (BM) form a functional NVU complex，Bell et al. These components interact with each other in order to maintain the physiological integrity of NVU.It is suggested that NVU modulates neurovascular coupling (NVC) and maintains blood-brain barrier (BBB) functions, which are vital to brain homeostasis and functions, Bell et al. In NVC, the cerebral blood flow (CBF) and cerebral nutrition supplement demand are closely linked via molecular events to regulate intraluminal diameter of cerebral blood vessels, The exact pathophysiological role of NVU in neurodegenerative diseases still remains to be elucidated and more studies are warranted in the future. Recent findings demonstrate the molecular heterogeneity of brain NVU cells, suggesting no prototypical neurovascular unit may exist at distinct levels of cerebral NVU networks, Schaeffer and Iadecola. The cerebral NVU network seems to be more complicated than we have expected. Further studies from in vitro and in vivo models are needed to investigate the role of NVU in the pathogenesis of various neurological diseases with the hope of identifying potential therapeutic targets.

A Novel Staining Method for Detection of Brain Perivascular Injuries Induced by Nanoparticle: Periodic Acid-Schiff and Immunohistochemical Double-Staining.

Background: To protect developing brain from any unfavorable effects, it is necessary to construct experimental techniques that can sensitively detect and evaluate developmental toxicity. We have previously shown that brain perivascular tissues, especially perivascular macrophages (PVMs), respond sensitively even to weak stimuli by foreign toxicants such as low-dose exposure to nanoparticle. This paper shows the protocol of a novel staining method that enables easy detection and rapid evaluation of brain perivascular abnormalities. Methods: As weak stimulus, low-dose of carbon black nanoparticle (95 μg/kg) or titanium dioxide nanoparticle (100 μg/kg) was intranasally administered to pregnant mice at gestational days 5 and 9. The offspring brains were used to confirm the properties of PVMs and to find suitable protocols for the detection and evaluation of the mild denaturation of PVMs. Furthermore, various procedures of novel combinational double staining including periodic acid-Schiff (PAS) staining and immunohistochemistry were examined. In addition, we checked the alterations in neurotransmitter levels and the behaviors of the offspring. Results and discussion: Maternal exposure to low-dose of nanoparticle at levels where no significant effects on the brain were observed, such as abnormal behavior, alteration of neurotransmitter levels, or microglial activation, resulted in mild denaturation of the PVMs, which was captured by PAS staining. However, it was difficult to detect and determine slight histopathological alterations. Therefore, we established PAS-immunohistochemical double-staining method for the brain. This double staining method enabled easy detection and rapid evaluation of brain perivascular abnormalities and the relationship between PVMs and the surrounding cells. In addition, this double staining allows evaluation of the histopathological denaturation of the PVMs and the associated abnormalities in the surrounding tissues in the same section. Conclusion: The slight responses of brain perivascular tissues, such as mild denaturation of PVMs, were sensitively and easily determined by the PAS-immunohistochemical double-staining method. This double staining method is a powerful tool to assess brain perivascular injuries including PVM denaturation and the relationship between the expression of various molecules and the morphology of PVMs. We propose that the observation of the tissue around brain blood vessels using the double staining provides potential endpoints to evaluate developmental neurotoxicity.

DRG2 Depletion Promotes Endothelial Cell Senescence and Vascular Endothelial Dysfunction.

Endothelial cell senescence is involved in endothelial dysfunction and vascular diseases. However, the detailed mechanisms of endothelial senescence are not fully understood. Here, we demonstrated that deficiency of developmentally regulated GTP-binding protein 2 (DRG2) induces senescence and dysfunction of endothelial cells. DRG2 knockout (KO) mice displayed reduced cerebral blood flow in the brain and lung blood vessel density. We also determined, by Matrigel plug assay, aorta ring assay, and in vitro tubule formation of primary lung endothelial cells, that deficiency in DRG2 reduced the angiogenic capability of endothelial cells. Endothelial cells from DRG2 KO mice showed a senescence phenotype with decreased cell growth and enhanced levels of p21 and phosphorylated p53, γH2AX, senescence-associated β-galactosidase (SA-β-gal) activity, and senescence-associated secretory phenotype (SASP) cytokines. DRG2 deficiency in endothelial cells upregulated arginase 2 (Arg2) and generation of reactive oxygen species. Induction of SA-β-gal activity was prevented by the antioxidant N-acetyl cysteine in endothelial cells from DRG2 KO mice. In conclusion, our results suggest that DRG2 is a key regulator of endothelial senescence, and its downregulation is probably involved in vascular dysfunction and diseases.

Metabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit.

The neurovascular unit (NVU) is a conceptual framework that has been proposed to better explain the relationships between the neural cells and blood vessels in the human brain, focused mainly on the brain gray matter. The major components of the NVU are the neurons, astrocytes (astroglia), microvessels, pericytes, and microglia. In addition, we believe that oligodendrocytes should also be included as an indispensable component of the NVU in the white matter. Of all these components, astrocytes in particular have attracted the interest of researchers because of their unique anatomical location; these cells are interposed between the neurons and the microvessels of the brain. Their location suggests that astrocytes might regulate the cerebral blood flow (CBF) in response to neuronal activity, so as to ensure an adequate supply of glucose and oxygen to meet the metabolic demands of the neurons. In fact, the adult human brain, which accounts for only 2% of the entire body weight, consumes approximately 20–25% of the total amount of glucose and oxygen consumed by the whole body. The brain needs a continuous supply of these essential energy sources through the CBF, because there are practically no stores of glucose or oxygen in the brain; both acute and chronic cessation of CBF can adversely affect brain functions. In addition, another important putative function of the NVU is the elimination of heat and waste materials produced by neuronal activity. Recent evidence suggests that astrocytes play pivotal roles not only in supplying glucose, but also fatty acids and amino acids to neurons. Loss of astrocytic support can be expected to lead to malfunction of the NVU as a whole, which underlies numerous neurological disorders. In this review, we shall focus on historical and recent findings with regard to the metabolic contributions of astrocytes in the NVU.

Neurodevelopmental toxicity of pyrazinamide to larval zebrafish and the restoration after intoxication withdrawal

To investigate the neurotoxicity of pyrazinamide (PZA) to larval zebrafish, the PZA effects were assessed followed by its mechanism being explored. Same as isoniazid (INH), this compound is a first-line anti-tuberculosis drug and is suggested to be a risk that inducing nerve injury with long-term intoxication. Our findings indicated that zebrafish larvae obtained severe nerve damage secondary to constant immersion in various concentrations of PZA (i.e., 0.5, 1.0, and 1.5 mM) from 4 hpf (hours post fertilization) onwards until 120 hpf. The damage presented as dramatically decrease of locomotor capacity and dopaminergic neuron (DAN)-rich region length in addition to defect of brain blood vessels (BBVs). Moreover, PZA-administrated zebrafish showed a decreased dopamine (DA) level and downregulated expression of neurodevelopment-related genes, such as shha, mbp, neurog1, and gfap. However, secondary to 48-h restoration in fish medium (i.e., at 168 hpf), the neurotoxicity described above was prominently ameliorated. The results showed that PZA at the concentrations we tested was notably neurotoxic to larval zebrafish, and this nerve injury was restorable after PZA withdrawing. Therefore, this finding will probably provide a reference for clinical medication.

Fluorescently-tagged magnetic protein nanoparticles for high-resolution optical and ultra-high field magnetic resonance dual-modal cerebral angiography.

Extremely small paramagnetic iron oxide nanoparticles (FeMNPs) (<5 nm) can enhance positive magnetic resonance imaging (MRI) contrast by shortening the longitudinal relaxation time of water (T1), but these nanoparticles experience rapid renal clearance. Here, magnetic protein nanoparticles (MPNPs) are synthesized from protein-conjugated citric acid coated FeMNPs (c-FeMNPs) without loss of the T1 MRI properties and tagged with fluorescent dye (f-MPNPs) for optical cerebrovascular imaging. The c-FeMNPs shows average size 3.8 ± 0.7 nm with T1 relaxivity (r1) of 1.86 mM-1 s-1 and transverse/longitudinal relaxivity ratio (r2/r1) of 2.53 at 11.7 T. The f-MPNPs show a higher r1 value of 2.18 mM-1 s-1 and r2/r1 ratio of 2.88 at 11.7 T, which generates excellent positive MRI contrast. In vivo cerebral angiography with f-MPNPs enables detailed microvascular contrast enhancement for differentiation of major blood vessels of murine brain, which corresponds well with whole brain three-dimensional time-of-flight MRI angiograms (17 min imaging time with 60 ms repetition time and 40 μm isotropic voxels). The real-time fluorescence angiography enables unambiguous detection of brain capillaries with diameter < 40 μm. Biodistribution examination revealed that f-MPNPs were safely cleared by the organs like the liver, spleen, and kidneys within a day after injection. Blood biochemical assays demonstrated no risk of iron overload in both rats and mice. With hybrid neuroimaging technologies (e.g., MRI-optical) on the rise, f-MPNPs built on this platform can generate exciting neuroscience applications.

An arm assisting device to enable flexion and extension for stroke victims

Stroke is caused by a blood vessel burst or some other interference with the blood supply to the most vulnerable area of the human brain. Ischemic strokes are caused by unexpected damage to the conduits supplying the mind, either as a result of a blood clot at the site of harm or as a result of a blood clot shaped in another piece of the dissemination, whereas hemorrhagic strokes are caused by draining from one of the cerebrum's vessels into the human brain tissue or blood vessel draining in the space between the meninges. Existing therapies given by a physiotherapist and occupational therapist provide assistance only for a stipulated time. Also, it requires human interaction and does not help the subjects to perform their daily activities independently. Thus, to overcome this, the present rehabilitation system will provide therapy without the aid of the therapist by measuring the voltage generated during upper arm flexion and extension. The entire system is run by motor and controlled by a microcontroller to enable upper arm movements. Force sensitive resistors were used to measure voltage generated during upper arm flexion and extension. Voltage values differed depending on the age of the subjects. It was encountered that subjects over the age of 45 seem to be more likely than other age groups to suffer the consequences of a stroke.

Primary Angiitis of the Central Nervous System - Diagnosis and Management.

Primary angiitis of central nervous system (PACNS) is a rare idiopathic disorder affecting blood vessels of brain, spinal cord, and meninges, consequently leading to infarct and less frequently hemorrhage. CNS vasculitis can also occur as part of systemic vasculitis or secondary to autoimmune diseases or infections. The clinical manifestations of PACNS are non-specific and no single laboratory investigation or neuroimaging finding can reliably diagnose this condition. Histopathological evidence of transmural inflammation of blood vessels of CNS is the gold standard, but is generally pursued subsequent to conventional angiogram (CA) because of its invasive nature. The differentials of PACNS are exhaustive and include systemic vasculitis, secondary vasculitis, non-inflammatory intracranial vasculopathies, demyelination, and neoplasm. These alternative conditions can often be distinguished by history, examination, immunological testing, cerebrospinal fluid analysis, and neuroimaging. CA can detect vasculitic changes in the large to medium cerebral arteries but the specificity is low. Recent advancements in vessel wall imaging techniques have further enabled the distinction of various intracranial vasculopathies from CNS vasculitis. The disease has considerable morbidity and fatality unless timely treatment with immunosuppressive agents is initiated. Induction therapy with glucocorticoids and cyclophosphamide followed by azathioprine, mycophenolate mofetil, or methotrexate as maintenance therapy is the cornerstone of management. Biological agents such as rituximab and anti-tumour necrosis factor alpha inhibitors (infliximab and etanercept) may be used in refractory cases. This review discusses the approach to the diagnosis, determinants of outcome, and management.

On the Blood Pressure in the Cardiovascular System

Background: Hemodynamics is a practical and complicated theoretical problem. The aim of this paper is to analyze the characteristics of blood pressure in the cardiovascular system changing with the mechanical parameters of blood vessels and the storage of some visceral organs. Method: The fluid network model was used for the study. The cardiovascular system was modeled as a system consisting of 20 segments of vessels. The main controlling parameters were determined first by using dimensional analysis. Then the responses of blood pressure of each segment of vessels were analyzed by changing the controlling parameters. Results: The parameters of the blood vessel of brain have the least influence on the pressures of other parts. The pressures of the system of blood vessels will decrease if some blood is stored in the liver or the abdominal vein system. Vice versa. The effects of regulation of blood on the variation of blood pressure are larger than the other controlling parameters. Conclusions: The controlling parameters of the abdominal aorta and ascending aorta affect greatly the blood pressure of each vessel.

Variation in Mental Foramen of Mandible among South Indian Population- A Radiographic Analysis

Background: The mental foramen (MF) is a hole in the body of the mandible that is placed on the antero-lateral side. Between the upper and lower mandibular borders, it can be found. It sends signals to the brain's nerves and blood vessels. Many researches have documented variations in the placement of the MF among different ethnic groups, as well as variations in its forms. It's commonly found beneath the first premolar teeth. The study's goal is to look at where mental foramen are found in the South Indian population.&#x0D; Materials and Methods: A total of 100 distinct OPGs from the South Indian population were used in the investigation. The position of mental foramen for various mandibles was visually examined using OPGs, and the data was tallied and analyzed using SPSS.&#x0D; Results: From the results it is suggested that the maximum frequency for the right side is at location 2 which is in the longitudinal axis of 1st premolar. 14.0% at location 1, 31.6% at location 2, 21.1% at location 3. 17.3% at location 4. 10% at location 5, 6% at location 6. The situation of mental foramen at the axis of 1st premolar was observed to have a high frequency of occurrence in the age group of 26-35.&#x0D; Conclusion: The Mental foramen in study population is mostly found in the longitudinal axis of 1st premolar. The clinical students and surgeons should know the existence of mental foramen at surgical procedures using mandibular premolar and molar regions. Future studies with large sample sizes should be conducted to make the results conclusive.

Clinicopathological features, imaging characteristics and surgical management in a novel tumour entity - aggressive meningiomas

Meningiomas are common neoplasms of the central nervous system, comprising between 24 and 30% of primary intracranial tumours, most commonly affecting females in their middle age or later adult life [1] [2].&#x0D; Meningiomas are classified as benign, atypical or anaplastic meningiomas depending mostly on histopathological criteria known to be associated with worse prognosis in terms of tumour progression, recurrence risk after surgery and overall survival. The 2016 edition of the World Health Organization (WHO) classification of Central Nervous System (CNS) tumours recognizes brain invasion as an independent criterion for diagnosing an atypical grade II meningioma [3]. Meningioma grading based on the WHO classification of CNS tumours thoroughly impacts therapeutic management and tumour prognosis.&#x0D; Aggressive meningiomas, a different phenotype of tumours, characterized by rapid growth and involvement of adjacent brain tissue, blood vessels and bone, was not previously listed as an independent entity in the WHO classification of meningothelial-cell tumours. &#x0D; Regarding the increasing importance of tumour grading in meningioma treatment strategies, the authors here provide an overview of clinicopathological and radiographic features, surgical management and long-term prognosis of this novel meningothelial tumour entity, the aggressive meningioma. In particular, we aimed to describe pre-, intra- and postoperative methods for recognizing aggressive meningiomas and explore the implications of this diagnosis on both surgical strategies and adjuvant therapy.

Quantum dots assisted in vivo two-photon microscopy with NIR-II emission

With the advantages of high resolution and deep penetration depth, two-photon excited NIR-II (900–1880 nm) fluorescence (2PF) microscopic bioimaging is promising. However, due to the lack of imaging systems and suitable probes, few such works, to our best knowledge, were demonstrated utilizing NIR-II excitation and NIR-II fluorescence simultaneously. Herein, we used aqueously dispersible PbS/CdS quantum dots with bright NIR-II fluorescence as the contrast agents. Under the excitation of a 1550 nm femtosecond (fs) laser, they emitted bright 2PF in the NIR-II region. Moreover, a 2PF lifetime imaging microscopic (2PFLIM) system was implemented, and in vivo 2PFLIM images of mouse brain blood vessels were obtained for the first time to our best knowledge. To improve imaging speed, an in vivo two-photon fluorescence microscopy (2PFM) system based on an InGaAs camera was implemented, and in vivo 2PFM images of QDs-stained mouse brain blood vessels were obtained.

The Effect of Flux Dysconnectivity Functions on Concentration Gradients Changes in a Multicomponent Model of Convectional Reaction-Diffusion by the Example of a Neurovascular Unit

A convectional diffusion of nutrients around the blood vessels in brain occurs in well-structured neurovascular units (NVU) including neurons, glia and micro vessels. A common feature of the process is a combination of a relatively high-speed delivery solution stream inside the blood vessel and a low-speed convectional flow in parenchyma. The specific trait of NVU is the existence of a tight cover layer around the vessels which is formed by shoots (end-feet) of astrocytes. This layer forms so called blood-brain barrier (BBB). Under different pathological states the permeability of BBB is changed. The concentration gradient of a chemical compound in NVU has been modelled using a combination of mathematical description of a cerebral blood flow (CBF) and further 3D diffusion away from the blood vessels borders. The governing equation for the blood flow is the non-steady-state Navier–Stokes equation for an incompressible non-Newtonian fluid flow without buoyancy effects. BBB is modeled by the flux dysconnectivity functions. The velocity of fluid flow in the paravascular space was estimated using Darcy's law. Finally, the diffusion of the nutrient is considered as a convectional reaction-diffusion in a porous media. By the example of glucose, it was shown that increased permeability of BBB yields an increased level of the nutrient even under essential (on 70%) decrease of CBF. Contrarily, a low BBB permeability breeds a decreased concentration level under increased (on 50%) CBF. Such a phenomenon is explained by a smooth enlarge of the direct diffusion area for a blood-to-brain border glucose transport having three-level organization.

Diphenylarsinic acid induced activation of MAP kinases, transcription factors, and oxidative stress-responsive factors and hypersecretion of cytokines in cultured normal human cerebellar astrocytes

Diphenylarsinic acid (DPAA) is a non-natural pentavalent organic arsenic and was detected in well water in Kamisu, Ibaraki, Japan in 2003. Individuals that had consumed this arsenic-contaminated water developed cerebellar symptoms such as myoclonus. We previously revealed that DPAA exposure in rats in vitro and in vivo specifically affected astrocytes rather than neurons among cerebellar cells. Here, we evaluated adverse effects of DPAA in cultured normal human cerebellar astrocytes (NHA), which were compared with those in normal rat cerebellar astrocytes (NRA) exposed to DPAA at 10 μM for 96 h, focusing on aberrant activation of astrocytes; increase in cell viability, activation of MAP kinases (ERK1/2, p38MAPK, and SAPK/JNK) and transcription factors (CREB, c-Jun, and c-Fos), upregulation of oxidative stress-responsive factors (Nrf2, HO-1, and Hsp70), and also hypersecretion of brain cytokines (MCP-1, adrenomedullin, FGF-2, CXCL1, and IL-6) as reported in NRA. While DPAA exposure at 10 μM for 96 h had little effect on NHA, a higher concentration (50 μM for 96 h) and longer exposure (10 μM for 288 h) induced similar aberrant activation. Moreover, exposure to DPAA at 50 μM for 96 h or 10 μM for 288 h in NHA induced hypersecretion of cytokines induced in DPAA-exposed NRA (MCP-1, adrenomedullin, FGF-2, CXCL1, and IL-6), and IL-8 besides into culture medium. These results suggested that aberrantly activated human astrocytes by DPAA exposure might play a pivotal role in the pathogenesis of cerebellar symptoms, affecting adjacent neurons, microglia, brain blood vessels, or astrocyte itself through these brain cytokines in human.

The pathogenic role of Pb in cerebral amyloid angiopathy and Alzheimer’s disease

Lead (Pb) is an environmental factor has been suspected of contributing to Alzheimer's disease (AD) and related dementia. Our previous study has shown that chronic Pb exposure increased brain levels of beta-amyloid (Aβ) and parenchymal amyloid plaques, a pathological hallmark for AD, in APP transgenic mice. Interestingly, Aβ is also exists in the walls of leptomeningeal and cortical arterioles and capillary as the cerebral amyloid angiopathy (CAA), which is observed in approximately 85%-95% of AD patients. However, it remains unclear whether Pb exposure is able to induce CAA. This study was designed to investigate whether exposure of Pb at 27 mg/kg induced CAA in both leptomeningeal and brain parenchymal areas by using the APP transgenic mice. Tg-APP mice were administrated with Pb-acetate at three different doses by oral gavage for two months. Immunohistochemistry and ELISA were used to quantify amyloid burden as well as Aβ1-40 and Aβ1-42. Pb treatments at 27 mg/kg for two months significantly induced vessel-associated amyloid and parenchymal amyloid in Tg-APP mice (4 mice with NaAc and 4 with PbAc). The ratios of Aβ40/42 were also significantly increased in both brain parenchyma and blood vessels. Interestingly, Pb also induced hypoperfusion in these mice, possible resulting from CAA-mediated brain ischemia. These data agreed with our hypothesis that chronic exposure of Pb, at levels currently believed to be subtoxic or safe, preferentially induces CAA by inducing Aβ40/42 ratio, to further develop to AD and related dementia.