Brain Vessels Research Articles

Prevalence and Vascular Distribution of Multiterritorial Atherosclerosis Among Community-Dwelling Adults in Southeast China

Data are limited on the prevalence and vascular distribution of multiterritorial atherosclerotic plaque and stenosis in community populations. To investigate the prevalence and vascular distribution of multiterritorial atherosclerotic plaque and stenosis in older, community-dwelling populations in China. This cross-sectional study was based on the baseline survey from the Polyvascular Evaluation for Cognitive Impairment and Vascular Events (PRECISE) study, a population-based prospective cohort study that enrolled community-dwelling adults aged 50 to 75 years based on cluster sampling from 6 villages and 4 living communities of Lishui city in southeast China. Data were collected from May 2017 to September 2019 and analyzed from September to November 2021. Atherosclerotic plaque and stenosis at baseline were assessed in multiple vascular territories. Brain vessel wall magnetic resonance imaging (MRI) for intracranial and extracranial arteries; computed tomography angiography (CTA) for coronary, subclavian, aorta, renal, and iliofemoral arteries; and ankle-brachial index for peripheral arteries were performed at baseline survey. The extent of atherosclerosis was assessed according to the number of these 8 vascular sites affected, and polyvascular lesions were defined as at least 2 affected sites. A total of 3433 of 4202 invited individuals consented to participate in the study. After excluding 366 participants with contraindications for MRI or CTA scanning, with life expectancies of 4 years of fewer, or with mental disease, a total of 3067 community-dwelling adults were enrolled. The mean (SD) age was 61.2 (6.7) years; 1640 (53.5%) were women, and 74 (2.4%) had prevalent ASCVD. Most participants (2870 [93.6%]) had atherosclerotic plaques in at least 1 vascular territory. Atherosclerotic plaques were mostly detected in the aorta (2419 [79.6%]) and iliofemoral arteries (2312 [75.8%]), followed by subclavian (1500 [49.8%]), coronary (1366 [44.9%]), extracranial (1110 [36.4%]), renal (873 [28.7%]), and intracranial (542 [17.7%]) arteries. A substantial proportion of participants (1180 [38.5%]) had arterial stenosis of 50% or greater, predominantly affecting the coronary (542 [17.8%]) and iliofemoral (527 [17.3%]) arteries. Polyvascular atherosclerotic plaque was observed in 2541 participants (82.8%), with 1436 (46.8%) with plaque affecting 4 or more vascular territories, and polyvascular stenosis was observed in 412 patients (13.4%). In this study, atherosclerotic plaque was highly prevalent in the older community population in China, and a substantial proportion of individuals reach stenosis of 50% or greater.

Foxc1a regulates zebrafish vascular integrity and brain vascular development through targeting amotl2a and ctnnb1

Accumulating evidences have pointed that foxc1a is essential for vascular development and integrity maintenance through regulating the expression of downstream genes and interacting with signaling pathways. However, the underling cellular and molecular mechanisms of foxc1a in regulating vascular development remain undetermined. Based on two different foxc1a mutant zebrafish lines (foxc1anju18 and foxc1anju19 which generated predicted truncated foxc1a proteins with 50aa and 315aa respectively), we found that around 30 % of foxc1anju18 zebrafish exhibited severe vascular developmental defects with obvious hemorrhage in hindbrain and trunk at embryonic stages. Confocal imaging analysis revealed that the formation of middle cerebral vein (MCeV), intra-cerebral central arteries (CtAs) and dorsal longitudinal vein (DLV) of brain vessels was significantly blocked in foxc1anju18enbryos. Injection of exogenous full length and foxc1anju19 truncated foxc1a mRNA both rescued the deficiency of foxc1anju18 embryos. Transcriptome analysis revealed 186 DEGs in foxc1anju18 zebrafish among which amotl2a and ctnnb1 expression were reduced and functionally associated with adherens junctions. Dual-Luciferase assays validated amotl2a and ctnnb1 were both directly transactivated by foxc1a. Rescue experiments demonstrated that amotl2a was mainly responsible for the vascular integrity caused by foxc1a mutation and also coordinated with ctnnb1 to regulate brain vascular development. Our data point to a novel clue that foxc1a regulates vascular integrity and brain vascular development through targeting amotl2a and ctnnb1.

Abstract 2487: Distinct venous brain vessels provide structures for T lymphocyte recruitment to brain tumors in mouse models of intracranial melanoma

Abstract Immune checkpoint therapy has demonstrated potential for the treatment of brain metastases, but the mechanisms of lymphocyte recruitment to brain tumors are poorly understood. To monitor T cell infiltration and brain tumor growth in vivo in real time, we performed intravital microscopy of adoptively transferred and endogenous T cells in mouse models of intracranial melanoma. By spatio-temporal analysis of T cell infiltration dynamics in brain tumors we could identify a distinct type of venous blood vessels in the tumor vicinity, “peritumoral venous vessels” (PVVs). Intraluminal T cell attachment and T cell extravasation was increased at PVVs compared to intratumoral vessels. Moreover, PVVs were characterized by high perivascular T cell density, high T cell motility parameters and high expression of ICAM-1. PVVs were specifically exploited for the recruitment of T cells to melanoma brain tumors, whereas alternative T cell routes via brain structures such as brain capillaries, intratumoral blood vessels and parasagittal regions were not observed. Immune checkpoint inhibition increased T cell motility in the brain, facilitating the advance from PVV to tumor, which resulted in intracranial tumor growth inhibition. Our findings describe a distinct mechanism by which the immune system targets melanoma brain tumors, and, potentially, other intracranial pathologies. Citation Format: Julia M. Messmer, Manuel Piechutta, Varun Venkataramani, Chanté Mayer, Anna S. Berghoff, Daniel Hinze, Michael Hölzel, Iris Helfrich, Dirk Schadendorf, Wolfgang Wick, Matthia A. Karreman, Frank Winkler. Distinct venous brain vessels provide structures for T lymphocyte recruitment to brain tumors in mouse models of intracranial melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2487.

Ciliogenesis mechanisms mediated by PAK2-ARL13B signaling in brain endothelial cells is responsible for vascular stability

In the developing vasculature, cilia, microtubule-based organelles that project from the apical surface of endothelial cells (ECs), have been identified to function cell autonomously to promote vascular integrity and prevent hemorrhage. To date, the underlying mechanisms of endothelial cilia formation (ciliogenesis) are not fully understood. Understanding these mechanisms is likely to open new avenues for targeting EC-cilia to promote vascular stability. Here, we hypothesized that brain ECs ciliogenesis and the underlying mechanisms that control this process are critical for brain vascular stability. To investigate this hypothesis, we utilized multiple approaches including developmental zebrafish model system and primary cell culture systems. In the p21 activated kinase 2 (pak2a) zebrafish vascular stability mutant [redhead (rhd)] that shows cerebral hemorrhage, we observed significant decrease in cilia-inducing protein ADP Ribosylation Factor Like GTPase 13B (Arl13b), and a 4-fold decrease in cilia numbers. Overexpressing ARL13B-GFP fusion mRNA rescues the cilia numbers (1–2-fold) in brain vessels, and the cerebral hemorrhage phenotype. Further, this phenotypic rescue occurs at a critical time in development (24 h post fertilization), prior to initiation of blood flow to the brain vessels. Extensive biochemical mechanistic studies in primary human brain microvascular ECs implicate ligands platelet-derived growth factor-BB (PDGF-BB), and vascular endothelial growth factor-A (VEGF-A) trigger PAK2-ARL13B ciliogenesis and signal through cell surface VEGFR-2 receptor. Thus, collectively, we have implicated a critical brain ECs ciliogenesis signal that converges on PAK2-ARL13B proteins to promote vascular stability.

Loss of the heterogeneous expression of flippase ATP11B leads to cerebral small vessel disease in a normotensive rat model

Cerebral small vessel disease (SVD) is the leading cause of vascular dementia, causes a quarter of strokes, and worsens stroke outcomes. The disease is characterised by patchy cerebral small vessel and white matter pathology, but the underlying mechanisms are poorly understood. This microvascular and tissue damage has been classically considered secondary to extrinsic factors, such as hypertension, but this fails to explain the patchy nature of the disease, the link to endothelial cell (EC) dysfunction even when hypertension is absent, and the increasing evidence of high heritability to SVD-related brain damage. We have previously shown the link between deletion of the phospholipase flippase Atp11b and EC dysfunction in an inbred hypertensive rat model with SVD-like pathology and a single nucleotide polymorphism (SNP) in ATP11B associated with human sporadic SVD. Here, we generated a novel normotensive transgenic rat model, where Atp11b is deleted, and show pathological, imaging and behavioural changes typical of those in human SVD, but that occur without hypertension. Atp11bKO rat brain and retinal small vessels show ECs with molecular and morphological changes of dysfunction, with myelin disruption in a patchy pattern around some but not all brain small vessels, similar to the human brain. We show that ATP11B/ATP11B is heterogeneously expressed in ECs in normal rat and human brain even in the same transverse section of the same blood vessel, suggesting variable effects of the loss of ATP11B on each vessel and an explanation for the patchy nature of the disease. This work highlights a link between inherent EC dysfunction and vulnerability to SVD white matter damage with a marked heterogeneity of ECs in vivo which modulates this response, occurring even in the absence of hypertension. These findings refocus our strategies for therapeutics away from antihypertensive (and vascular risk factor) control alone and towards ECs in the effort to provide alternative targets to prevent a major cause of stroke and dementia.

Unbiased analysis of mouse brain endothelial networks from two- or three-dimensional fluorescence images.

.Significance: A growing body of research supports the significant role of cerebrovascular abnormalities in neurological disorders. As these insights develop, standardized tools for unbiased and high-throughput quantification of cerebrovascular structure are needed.Aim: We provide a detailed protocol for performing immunofluorescent labeling of mouse brain vessels, using thin () or thick (50 to ) tissue sections, followed respectively by two- or three-dimensional (2D or 3D) unbiased quantification of vessel density, branching, and tortuosity using digital image processing algorithms.Approach: Mouse brain sections were immunofluorescently labeled using a highly selective antibody raised against mouse Cluster of Differentiation-31 (CD31), and 2D or 3D microscopy images of the mouse brain vasculature were obtained using optical sectioning. An open-source toolbox, called Pyvane, was developed for analyzing the imaged vascular networks. The toolbox can be used to identify the vasculature, generate the medial axes of blood vessels, represent the vascular network as a graph, and calculate relevant measurements regarding vascular morphology.Results: Using Pyvane, vascular parameters such as endothelial network density, number of branching points, and tortuosity are quantified from 2D and 3D immunofluorescence micrographs.Conclusions: The steps described in this protocol are simple to follow and allow for reproducible and unbiased analysis of mouse brain vascular structure. Such a procedure can be applied to the broader field of vascular biology.

Immunoreactivity and A New Staining Method of MCT-1 Located in Endothelial Cells of Cerebral Vessels of Human Brain in Distinguishing Cerebral Venules from Arterioles (P5-10.002)

Immunoreactivity and A New Staining Method of MCT-1 Located in Endothelial Cells of Cerebral Vessels of Human Brain in Distinguishing Cerebral Venules from Arterioles (P5-10.002)

Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate.

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5′ UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer’s disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.

Toward Sharing Brain Images: Differentially Private TOF-MRA Images With Segmentation Labels Using Generative Adversarial Networks.

Sharing labeled data is crucial to acquire large datasets for various Deep Learning applications. In medical imaging, this is often not feasible due to privacy regulations. Whereas anonymization would be a solution, standard techniques have been shown to be partially reversible. Here, synthetic data using a Generative Adversarial Network (GAN) with differential privacy guarantees could be a solution to ensure the patient's privacy while maintaining the predictive properties of the data. In this study, we implemented a Wasserstein GAN (WGAN) with and without differential privacy guarantees to generate privacy-preserving labeled Time-of-Flight Magnetic Resonance Angiography (TOF-MRA) image patches for brain vessel segmentation. The synthesized image-label pairs were used to train a U-net which was evaluated in terms of the segmentation performance on real patient images from two different datasets. Additionally, the Fréchet Inception Distance (FID) was calculated between the generated images and the real images to assess their similarity. During the evaluation using the U-Net and the FID, we explored the effect of different levels of privacy which was represented by the parameter ϵ. With stricter privacy guarantees, the segmentation performance and the similarity to the real patient images in terms of FID decreased. Our best segmentation model, trained on synthetic and private data, achieved a Dice Similarity Coefficient (DSC) of 0.75 for ϵ = 7.4 compared to 0.84 for ϵ = ∞ in a brain vessel segmentation paradigm (DSC of 0.69 and 0.88 on the second test set, respectively). We identified a threshold of ϵ <5 for which the performance (DSC <0.61) became unstable and not usable. Our synthesized labeled TOF-MRA images with strict privacy guarantees retained predictive properties necessary for segmenting the brain vessels. Although further research is warranted regarding generalizability to other imaging modalities and performance improvement, our results mark an encouraging first step for privacy-preserving data sharing in medical imaging.

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.

Genesis of Antibiotic Resistance (AR) LXXX: Turbulence Modeling(TM) of Hemodynamics in Simplified Severe Sepsis Protocol‐2 (SSSP‐2)‐NCT01663701: Temporal Correlation of Fluid Bolus, CPPopt(PRx), “Zone of Obstruction”, Comatose (GCS 3), and In‐Hospital Mortality (ihm)

Based on Flow‐3DÒ Hydro FD simulation Model 04 (Courtesy: Flow‐3DÒ) and fluid flow patterns, here we present a plausible scheme of hemodyn. sequel in ERP induced fluid volume expansion, that lead to 100% ihm usual care cohort of SSSP‐2 (PMID: 28973227). Rationale: From the pressure‐volume curve of D ICP vs DCBV (ΔV cm3) of the intracerebral space Figure1. https://cppopt.org/prx/ (PMID: 632857) it is proposed that subsequent to fluid bolus, the patients in usual care and sepsis protocol cohort of SSSP‐2 may have had a good compensatory reserve (part I) within&lt; 24hrs. The exponential part of the curve (part II) would likely represent the patients who have had a poor compensatory reserve with a slow ΔV of the intracerebral space (CBV) that caused a significant change in the ICP in less than ~48 hrs. The cause of 100% ihm in usual care cohort, could be derived as the patients with high CBV and consequently high ICP levels (part III)that lead to cerebral vessels collapse and impairing pressure‐volume relationship implied in impaired positive brain vessel function index possibly by capillary pruning‐string events within ~ 48hrs to ~72 hrs. An increase in CVP, lead to an anaerobic milieu to spur the growth of anaerobic AR‐ClPr (G+/G‐) bacilli merging with “Zone of Obstruction” (ZoO), hitherto DDx, CC/MCC/CCI/DRG, Comorbidity–polypharmacy score (CPS) and ultimately Comatose (GCS 3‐8) (PMID: 31474933). Hemodynamically, when there is an ÝABP/ CPP/CBV the arterioles dilate and hence the CBF, CBV and consequently the ÝICP. Geometry: (Table 2.1 p63, ISBN: 9780128024089). Hemodyn/neurol monitoring parameters:CPPopt, CVP ≥ 8 cm H20, ScVO2 ≤ 70%, GCS 3‐8, and time to event 120 hrs ± 48 hrs. Governing. Equation(s): Dimensional form of Momentum equation (9.10) at the wall u= v=0, considering the pressure gradient dp/dx&lt;0, then [d2u/dy2]y=0=1/μ *dp/dx Eq 9.42; Fig 9.5 Flow separation and formation of wake behind ZoO (LPE Aggregates ‐Toxins of AR‐ClPr origin) form blunt bodies/streamline bodies referred as “ZoO” of unknown dimension; Fig 9.6 velocity distribution within a boundary layer; considered panel a: favorable pressure gradient = dp/dx&lt;0; panel b: APG = dp/dx&gt;0 (p468 – 471; ISBN:13:978‐0071329194). Derivation &amp; Prospect: Subsequent to fluid bolus, within 120 hrs., BLS occurs expediting the ZoO, in metarteriole, capillary bed, and arteriovenous anastomosis doffing off vaso vasorum in turn vasomotion of the limbic region in particular cingulate nuclei, Amygdala, amygdaloid body, thalamic nuclei, parahippocampal gyrus, hypothalamus. Such an increase in CPPopt, and CBV engendered APG, eddies, ZoO, in cerebral pre‐capillary bed followed by a vasoconstriction of capillary sphincters, the collapse of arteriovenous anastomosis, possible occlusion of thoroughfare channel in true capillaries form a cyclical aerobic‐anaerobic milieu in vivo (en vivo) for the growth G+/G‐ AR‐ClPr, in turn spur toxic shock syndrome, CCP to GCS 3 consequential 100% ihm, within 120 hrs. in SSSP‐2.

When less is more: Non-contrast head CT alone to work-up hypertensive intracerebral hemorrhage

Hypertension is a common cause of intracerebral hemorrhage (ICH). The work up typically involves neuroimaging of the brain and blood vessels to determine etiology. However, extensive testing may be unnecessary for presumed hypertensive hemorrhages, and instead prolong hospital stay and increase costs. This study evaluates the predictive utility of hemorrhage location on the non-contrast head CT in determining hypertensive ICH. Patients presenting with non-traumatic ICH between March 2014 and June 2019 were prospectively enrolled. Hemorrhage etiology was determined based on previously defined criteria. Chi square and Student’s t tests were used to determine the association between patient demographics, ICH severity, neuroimaging characteristics, and medical variables, with hypertensive etiology. Multivariable regression models and an ROC analysis determined utility of CT to accurately diagnose hypertensive ICH. Data on 380 patients with ICH were collected; 42% were determined to be hypertensive. Along with deep location on CT, black race, history of hypertension, renal disease, left ventricular hypertrophy, and higher admission blood pressure were significantly associated with hypertensive etiology, while atrial fibrillation and anticoagulation were associated with non-hypertensive etiologies. Deep location alone resulted in an area under the curve of 0.726. When history of hypertension was added, this improved to 0.771. Additional variables did not further improve the model’s predictability. Hypertensive ICH is associated with several predictive factors. Using deep location and history of hypertension alone correctly identifies the majority of hypertensive ICH without additional work-up. This model may result in more efficient diagnostic testing without sacrificing patient care.

Beyond Classic Anastomoses Training Models: Overview of Aneurysm Creation in Rodent Vessel Model.

Nowadays, due to the decline in the number of microsurgical clippings for cerebral aneurysms and revascularization procedures, young neurosurgeons have fewer opportunities to participate and train on this type of surgery. Vascular neurosurgery is a demanding subspecialty that requires skills that can only be acquired with technical experience. This background pushes the new generations to be ready for such challenging cases by training hard on different available models, such as synthetic tubes, chicken wings, or placenta vessels. Although many training models for vascular neurosurgery have been described worldwide, one of the best is the rodent vessels model. It offers pulsation, coagulation, and real blood flow conditions in a physiologic atmosphere that mimics perfectly the intracranial human vessels environment, especially in terms of size. However, the current differences in governmental different regulations about the use of living animals in medical experimentation and the social awareness, as well as the lack of financial support, cause more difficulties for neurosurgeons to start with that kind of training. In this review, we describe the tools and techniques as basic steps for vascular microsurgery training by using rodent models, that provide an accurate copy of brain vessels environment under stable conditions. The initial three classical known microanastomoses for neurosurgeons are end-to-end, end-to-side, and side-to-side, but in literature, there have been described other more complex exercises for training and investigation, such as aneurysm models. Although there is still little data available, we aim to summarize and discuss aneurysm's training models and reviewed the current literature on the subject and its applications, including a detailed description of the techniques.

Arterial Ischemic Stroke in Moyamoya Patients Who Underwent Vaginal Delivery and Cesarean Section

Moyamoya disease (MMD) is characterized by stenosis, occlusion, and formation of aberrant collaterals of brain vessels. This derangement in the brain vessels in conditions associated with changes in intracranial pressure can lead to arterial ischemic stroke (AIS). A major challenge for stroke physicians is to recommend the safest method of delivery for pregnant patients with MMD. Using a large national database, our objective in this study was to analyze the risk of AIS in patients with MMD who underwent vaginal delivery (VD) and cesarean section (C-section). We used the National Inpatient Sample database for the years 2013-2018 to identify patients with a diagnosis of MMD who underwent VD or C-section. Multiple logistic regression was performed to assess the risk of AIS in VD versus C-section. Of 2166 female patients with MMD, 97 underwent VD or C-section: 49 (50.51%) underwent VD, and 48 (49.48%) underwent C-section. The analysis of outcomes between VD and C-section showed a higher prevalence of AIS after VD compared with C-section (8.2% vs 6.3%, P= 0.716). The multivariate analysis for AIS showed that VD is not an independent risk factor compared with C-section (odds ratio= 2.1, 95% CI= 0.3-13.3, P= 0.417). Our data did not find evidence that VD and C-section are risk factors for AIS in pregnant patients with MMD.

Prenatal Diagnosis of COL4A1 Mutations in Eight Cases: Further Delineation of the Neurohistopathological Phenotype.

Increasing number of mutations responsible for vascular lesions, leading to ischemic or hemorrhagic stroke in young adults, has been identified in the recent years. It has been demonstrated in both mice and humans, that mutations in COL4A1 gene promote cerebral hemorrhages. In humans, both adults and children may be affected, and the spectrum has been broadened recently to neonates and fetuses. We present a cohort of eight COL4A1 mutated fetuses in which cerebral hemorrhages were detected by ultrasound leading to elective terminations of pregnancy. Our neuropathological studies demonstrated a strikingly similar pathological pattern, dominated by supra- and infratentorial multifocal hemorrhagic lesions of various abundance and age in the vicinity of enlarged small vessels having a discontinuous wall. This was constantly associated with a spectrum of supratentorial post-ischemic damages of the grey and white matters. Morphometric studies of brain vessels confirmed vascular dilation and hypervascularization in both grey and white matters and severe attenuation of the smooth-muscle actin staining in the white matter. These observations add to the rare human neuropathological phenotype of COL4A1 mutations. Its recognition is mandatory to enhance the number of tested patients in the future, as well as the genetic counseling of parents.

Recent Advances of LncRNA H19 in Diabetes LncRNA H19 in Diabetes.

Diabetes mellitus (DM) causes damage to major organs, including the heart, liver, brain, kidneys, eyes, and blood vessels, threatening the health of the individuals. Emerging evidence has demonstrated that lncRNAs has important functions in the pathogenesis of human diseases, such as cancers, neurodegenerative diseases, cardiac fibroblast phenotypes, hypertension, heart failure, atherosclerosis and diabetes. Recently, H19, a lncRNA, has been reported to shown to participate in the regulatory process of muscle differentiation, glucose metabolism, and tumor metastasis, as well as endometrial development. However, the roles of H19 in DM were still not completely understood. This review was conducted to summarize the functions of H19 in diabetes and discuss the challenges and possible strategies of H19 in DM.

Structural changes of brain vessels in cardiosurgery patients with postoperative stroke

Hypoxic-ischemic lesions of the brain of cardiac surgery patients as a leading factor in stroke have been studied. The importance of prolonged thrombosis, embolism, which exacerbate the general degenerative changes in the central nervous system is recognized.&#x0D; The aim of the research – to study the morphological changes of the vessels of the brain of cardiac surgery patients with postoperative stroke on the background of hypoxic-ischemic complications.&#x0D; Materials and methods. Pieces of cerebral vessels were subjected to microscopic examination. Histological sections were stained according to Van Gieson.&#x0D; Results and their discussion. The study of the structure of the vessels of the brain of persons who were in the group intact to neurological pathology control, showed the presence of anatomical and functional changes that are fully consistent with the sex-age norms of postnatal human ontogenesis.&#x0D; The drugs of the clinical observation group contained signs of pathological changes characteristic of hypoxic-ischemic disorders. It is obvious that their appearance and intensification contributed to the development of ischemic stroke. Structural and functional changes mainly concerned the vascular walls, their layers, paravasal spaces, the blood system as a liquid phase, in fact. Endothelial layer with signs of desquamation. Endothelial cells are characterized by signs of hyperchromia of the nuclei, the shift of the latter in the direction of one of the poles of the cells, the appearance of heterochromatin. Contacts between cells are weakened, defects are visible in the surface layer. Perovascular edema, which is formed in the case of increased permeability, leads to a certain isolation of individual vessels from the surrounding tissues, followed by the development of hypoxia. Defects of the wall layers lead to the activation of the migratory properties of platelets, encourage the appearance of megakaryocytes, erythrocyte thrombi, which are in close contact with the endothelial layer of blood vessels. On histological specimens, brick-red blood clots abundantly cover the damaged inner layer of vascular walls, sometimes completely filling their openings. Over time, defects in the layers of the walls are accompanied by thrombosis, inflammation, edema.&#x0D; Conclusions. Hypoxic-ischemic brain lesions in cardiac surgery patients play a leading role in stroke. Priority is given to hypoxia, which contributes to ischemia, trophic disorders, atrophy, necrosis, necrobiotic changes. The latter are the organic basis of pathogenetic patterns of focal cerebral infarction (with progressive destruction of brain cells, its vessels, the development of prolonged thrombosis, embolism, increased general degenerative changes in the central nervous system)

Drug Nanocrystals: Focus on Brain Delivery from Therapeutic to Diagnostic Applications.

The development of new drugs is often hindered by low solubility in water, a problem common to nearly 90% of natural and/or synthetic molecules in the discovery pipeline. Nanocrystalline drug technology involves the reduction in the bulk particle size down to the nanosize range, thus modifying its physico-chemical properties with beneficial effects on drug bioavailability. Nanocrystals (NCs) are carrier-free drug particles surrounded by a stabilizer and suspended in an aqueous medium. Due to high drug loading, NCs maintain a potent therapeutic concentration to produce desirable pharmacological action, particularly useful in the treatment of central nervous system (CNS) diseases. In addition to the therapeutic purpose, NC technology can be applied for diagnostic scope. This review aims to provide an overview of NC application by different administration routes, especially focusing on brain targeting, and with a particular attention to therapeutic and diagnostic fields. NC therapeutic applications are analyzed for the most common CNS pathologies (i.e., Parkinson’s disease, psychosis, Alzheimer’s disease, etc.). Recently, a growing interest has emerged from the use of colloidal fluorescent NCs for brain diagnostics. Therefore, the use of NCs in the imaging of brain vessels and tumor cells is also discussed. Finally, the clinical effectiveness of NCs is leading to an increasing number of FDA-approved products, among which the NCs approved for neurological disorders have increased.

Pial Vessel-Associated Microglia/Macrophages Increase in Female Dahl-SS/Jr Rats Independent of Pregnancy History.

As the resident immune cells of the central nervous system, microglia have a wide range of functions such as surveillance, phagocytosis, and signaling through production of chemokines and cytokines. Recent studies have identified and characterized macrophages residing at the meninges, a series of layers surrounding the brain and spinal cord. While perivascular microglia within the brain parenchyma increase following chronic hypertension, there are no reports of changes at the meninges, and specifically, associated with the pial vasculature. Thus, we used female Sprague Dawley and Dahl salt-sensitive (SS/Jr) rat brains, stained for ionized calcium-binding adapter molecule (Iba1), and characterized microglia/macrophages associated with pial vessels in the posterior brain. Results indicate that Iba1+ pial vessel-associated microglia (PVAM) completely surrounded the vessels in brains from the Dahl-SS/Jr rats. PVAM density was significantly higher and distance between PVAMs lower in Dahl-SS/Jr compared to the Sprague Dawley rat brains. Pregnancy history did not affect these findings. While the functional role of these cells are not known, we contextualize our novel findings with that of other studies assessing or characterizing myeloid cells at the borders of the CNS (meninges and choroid plexus) and perivascular macrophages and propose their possible origin in the Dahl-SS/Jr model of chronic hypertension.

Oxidative Stress-Induced Hypertension of Developmental Origins: Preventive Aspects of Antioxidant Therapy.

Hypertension remains the leading cause of disease burden worldwide. Hypertension can originate in the early stages of life. A growing body of evidence suggests that oxidative stress, which is characterized as a reactive oxygen species (ROS)/nitric oxide (NO) disequilibrium, has a pivotal role in the hypertension of developmental origins. Results from animal studies support the idea that early-life oxidative stress causes developmental programming in prime blood pressure (BP)-controlled organs such as the brain, kidneys, heart, and blood vessels, leading to hypertension in adult offspring. Conversely, perinatal use of antioxidants can counteract oxidative stress and therefore lower BP. This review discusses the interaction between oxidative stress and developmental programming in hypertension. It will also discuss evidence from animal models, how oxidative stress connects with other core mechanisms, and the potential of antioxidant therapy as a novel preventive strategy to prevent the hypertension of developmental origins.