Perivascular Tissue Research Articles

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.

Sympathetic Nerves and Innate Immune System in the Spleen: Implications of Impairment in HIV-1 and Relevant Models.

The immune and sympathetic nervous systems are major targets of human, murine and simian immunodeficiency viruses (HIV-1, MAIDS, and SIV, respectively). The spleen is a major reservoir for these retroviruses, providing a sanctuary for persistent infection of myeloid cells in the white and red pulps. This is despite the fact that circulating HIV-1 levels remain undetectable in infected patients receiving combined antiretroviral therapy. These viruses sequester in immune organs, preventing effective cures. The spleen remains understudied in its role in HIV-1 pathogenesis, despite it hosting a quarter of the body’s lymphocytes and diverse macrophage populations targeted by HIV-1. HIV-1 infection reduces the white pulp, and induces perivascular hyalinization, vascular dysfunction, tissue infarction, and chronic inflammation characterized by activated epithelial-like macrophages. LP-BM5, the retrovirus that induces MAIDS, is a well-established model of AIDS. Immune pathology in MAIDs is similar to SIV and HIV-1 infection. As in SIV and HIV, MAIDS markedly changes splenic architecture, and causes sympathetic dysfunction, contributing to inflammation and immune dysfunction. In MAIDs, SIV, and HIV, the viruses commandeer splenic macrophages for their replication, and shift macrophages to an M2 phenotype. Additionally, in plasmacytoid dendritic cells, HIV-1 blocks sympathetic augmentation of interferon-β (IFN-β) transcription, which promotes viral replication. Here, we review viral–sympathetic interactions in innate immunity and pathophysiology in the spleen in HIV-1 and relevant models. The situation remains that research in this area is still sparse and original hypotheses proposed largely remain unanswered.

Vasorelaxing properties of the perivascular tissue of the human radial artery.

Perivascular adipose tissue (PVAT) surrounding the human internal thoracic artery exhibits anticontractile and vasorelaxing properties associated with the adipocyte-derived relaxing factor (ADRF). The goal of our study was to assess if perivascular tissue of the human radial artery (RA) also exhibits such anticontractile/vasorelaxant properties. It could be especially relevant in preventing RA spasms. The study was performed on isolated segments of human pedicled RA. Its skeletonized fragments were suspended on stainless steel wire hooks and gradually contracted with serotonin to establish the concentration-effect relationship in the presence/absence of PVAT. Skeletonized arterial segments were precontracted with a single dose of 10-6 M serotonin (EC80). The 5-ml PVAT aliquots (from PVAT incubated in Krebs-Henseleit solution) were transferred to the RA tissue bath resulting in its relaxation. Subsequently, we investigated if ADRF is dependent on endothelial vasorelaxants (nitric oxide and prostacyclin). We attempted to find the potassium channel responsible for mediating the activity of ADRF using different potassium channel blockers. RA without PVAT contracted more strongly in response to serotonin compared to RA with PVAT [Emax: 108.3 (20.2) vs 76.1 (13.5) mN]. The PVAT aliquot relaxed precontracted RA rings at 43% (2.4%) [72.2 (15.6) to 41.0 (5.6) mN]. ADRF is independent of endothelial vasorelaxants; hence, the addition of NG-monomethyl-l-arginine and indomethacin did not change the vasorelaxant response. Neither of the potassium channel blockers participated in the activity of ADRF. PVAT of human RA exhibits anticontractile/vasorelaxant properties that are inherently associated with ADRF secretion. We confirmed the endothelial-independent mechanism of the activity of ADRF. However, we failed to find the potassium channel responsible for the action of ADRF.

Patient-Tailored Approach for Diagnostics and Treatment of Mycotic Abdominal Aortic Aneurysm

The existing literature on mycotic aortic aneurysm is scarce and focuses on treatment. This study evaluates the clinical characteristics, diagnostics, treatment and outcome of patients with a mycotic abdominal aortic aneurysm treated in a tertiary referral center. A retrospective cohort study was conducted including all patients with a proven mycotic abdominal aortic aneurysm admitted between May 2010 and July 2020. Primary outcome was mortality and secondary outcome included complications such as vascular graft/endograft infection. Twenty-four patients with a mycotic abdominal aortic aneurysm were included. Patients had a mean age of 68 ± 9 years and 20 (83%) were male. Thirteen patients (57%) had positive preoperative blood cultures. Streptococcus pneumoniae was most frequently isolated by blood culturing, pus, and vascular, or perivascular tissue cultures (17%). In 19 (83%) patients the mycotic abdominal aortic aneurysm was located infrarenally, in three (13%) patients suprarenally, and in one (4%) patient juxtarenally. Median follow-up was 20 (7-42) months. In 8 patients (33%) vascular graft and or endograft infection was diagnosed after surgical repair. Ten (42%) patients died during the follow-up period. The main causes of death were vascular graft/endograft infection-related (n=4) and rupture of the mycotic abdominal aortic aneurysm (n=3). No patient characteristics could be identified as predictive for mortality. This study shows a large variation in presentation, diagnostic approaches, and surgical and antibiotic treatment of mycotic abdominal aortic aneurysm. The detailed information about the diagnostic approaches to this rare disease and its antibiotic and/or other treatment contributes to existing knowledge of mycotic abdominal aortic aneurysm. Because of the individual variation patients should be discussed in a multidisciplinary team with a vascular surgeon, infectious disease specialist, and clinical microbiologist.

Intradermal injection of icariin-HP-β-cyclodextrin improved traumatic brain injury via the trigeminal epineurium-brain dura pathway

The lower bioavailability after oral administration limited icariin applications in central nervous system. Icariin/HP-β-cyclodextrin (HP-β-CD) inclusion complex was prepared for acute severe opening traumatic brain injury (TBI) via facial intradermal (i.d.) in the mystacial pad. After fluid percussion-induced TBI, icariin/HP-β-CD at 0.4 mg/kg i.d. preserved more neurons and oligodendrocytes than intranasal injection (i.n.) or intravenous injection via tail vein (i.v.) and decreased microglia and astrocyte activation. Icariin/HP-β-CD i.d. reduced apoptosis in cortical penumbra while i.n. and i.v. showed weak or no effects. Icariin/HP-β-CD i.d. reduced Evans blue leakage and altered CD34, ZO-1, Claudin-5, and beta-catenin expression after TBI. Moreover, icariin/HP-β-CD promoted human umbilical vein endothelial cells proliferation. Thus, Icariin/HP-β-CD i.d. improved TBI, including blood–brain barrier opening. Fluorescein 5-isothiocyanate (FITC) and 3,3'-Dioctadecyloxacarbocyanine perchlorate (DiOC18(3)) mimic HP-β-CD and icariin respectively. FITC and DiOC18(3) were similarly delivered to trigeminal epineurium, perineurium and perivascular spaces or tissues, caudal dura mater, and scattered in trigeminal fasciculus, indicating that icariin/HP-β-CD was delivered to the brain via trigeminal nerve-dura mater-brain pathways. In sum, intradermal injection in mystacial pad might deliver icariin/HP-β-CD to the brain and icariin/HP-β-CD improved acute severe opening TBI.

LncRNA H19 Aggravates Brain Injury in Rats following Experimental Intracerebral Hemorrhage via NF-κB Pathway.

Objective To explore the effect of long noncoding RNA H19 (lncRNA H19) on brain injury in rats following experimental intracerebral hemorrhage (ICH). Methods Rat ICH model was established with type IV collagenase. The neurological function scores were evaluated, and the water content in brain tissue was measured. The nerve injury indexes, inflammatory factors, and oxidative stress indexes were also measured. Moreover, the expression of lncRNA H19 was determined by qRT-PCR, and Western blot detected NF-κB pathway-related protein expression. Results Compared with the sham group, the neurological function scores, the water content in brain tissue, and levels of injury indicators myelin basic protein (MBP), S-100B, and neuron-specific enolase (NSE) in the ICH rats were significantly increased. Meanwhile, the levels of TNF-α, IL-6, IL-1β, ROS, and MDA were significantly increased, but the levels of SOD were significantly decreased. In addition, the expression of lncRNA H19 in the brain tissue in the ICH group was significantly higher than that in the sham group. After further interference with lncRNA H19 expression (sh-H19 group), the levels of all the above indicators were reversed and the neurological damage was improved. Western blot results showed that the expression of NF-κBp65 and IKKβ was significantly higher, and IκBα expression was lower in the perivascular hematoma tissue in the ICH group compared with the sham group. Compared with the sh-NC group, NF-κBp65 and IKKβ expression were significantly lower and IκBα was significantly higher in the sh-H19 group. Conclusion lncRNA H19 exacerbated brain injury in rats with ICH by promoting neurological impairment, brain edema, and releasing inflammatory responses and oxidative stress. This may be related to the activation of NF-κB signaling pathway.

Double rule-out technique for evaluation of acute chest pain using 128-row multidetector CT

To evaluate the feasibility and image quality of the double rule-out (DRO) technique using 128-row multidetector computed tomography (CT) for simultaneous evaluation of the aorta and coronary arteries in patients with acute non-specific chest pain. Sixty-eight patients underwent electrocardiography (ECG)-gated coronary CT followed by non-ECG-gated abdominal CT. The contrast-to-noise ratio and signal-to-noise ratio between the vessels and adjacent perivascular fat tissue were calculated for both the aorta and coronary arteries. Dose-length products were recorded. Two blinded readers graded the image quality of the aorta and coronary arteries on a two-point and a four-point scale, respectively. In addition, the severity of coronary stenosis was independently analysed for each coronary vessel. The average attenuation was more than 350 HU for the aorta and >330 HU for the coronary arteries. The average (±standard deviation) volume of contrast media was 69.5±12.5 ml. Interobserver agreement on the image quality of aortic and coronary data sets was perfect and substantial, respectively. There was almost perfect interobserver agreement for the all observations of the severity of coronary stenosis. The DRO technique with a standard volume (approximately 70 ml) of contrast media is useful for acute chest pain evaluation in patients suspected of having acute aortic syndrome or acute coronary syndrome. It is also accurate and safe while maintaining the average CT attenuation of the aorta and coronary arteries >330 HU.

Perivascular Adipose Tissue – Orchestrator of Cardiovascular Disturbances Sequel.

Perivascular adipose tissue is a biologically active morphofunctional unit that is an active regulator of endovascular homeostasis, endothelial functioning, and the phenotypic state of smooth muscle. Under physiological conditions, perivascular adipose tissue maintains normal vascular function by releasing anti-atherogenic, anti-inflammatory, and vasodilating biologically active substances. Until recently, adipose tissue was considered a morphological unit with only a thermoregulatory and shock-absorbing function; however, with the development and improvement of modern medical science, we can confidently assert that adipose tissue is a factory for the production of biologically active substances with a broad spectrum of action. The released biologically active substances have both autocrine and paracrine effects, thus playing a pivotal role in maintaining the morphophysiological balance of the whole organism. Various theories are put forward about the possible key role of perivascular adipose tissue in the pathogenesis of various diseases. It has been shown that perivascular tissue is an independent cardiovascular risk factor, even without visceral obesity. When exposed to specific pathogens, the regulation of adipocytes is disrupted, and a subsequent rearrangement of the adipocyte production profile occurs. The secretion of damaged adipocytes exhibits the following properties: anti-atherogenic, anti-inflammatory, and vasodilating, with subsequent initiation or progression of cardiovascular disease. Within the framework of this review article, the following are raised and comprehensively discussed: the function of perivascular adipose tissue in health and disease and its contribution to the pathogenesis of cardiovascular disease. This review aims to analyze the data of modern literature, reflecting the photomorphogenesis of changes in the secretory activity of perivascular adipose tissue, along with the molecular mechanisms of cardiovascular system alteration.

Vascular inflammation in the central nervous system.

Vascular inflammation in the central nervous system.

AGE FEATURES OF THE STRUCTURE OF THE BLOOD VESSELS OF THE SOME DIGESTIVE GLANDS AND ITS RESTRUCTURING IN THE INITIAL STAGES OF EXPERIMENTAL DIABETES MELLITUS

The aim: The purpose of the work was to study the peculiarities of blood supply the pancreatic islet of the 24-month-old rat, and its restructuring during the initial periods of experimental diabetes mellitus. Materials and methods: The work was performed on 20 white outbred rats - males weighing 340-420g. 24 months of age, kept in standard vivarium conditions in compliance with all accepted ethical rules. Experimental streptozotocin diabetes mellitus was simulated in 16 animals. The material was taken on the 14th and 28th day of the experiment. Results: Reorganization of the endocrine part of the pancreas in the early stages of experimental diabetes is characterized by a decrease in the number and area of pancreatic islets, a decrease in the diameter of the lumen of arterioles, precapillaries, postcapillaries compared to the control group of animals by 7% and 5%. The diameter of the capillaries decreases by 16% and reaches 3.8 ± 0.62 μm2, and the diameter of the venules increases by 12%. In some blood vessels there are phenomena of desolation and edema of perivascular connective tissue, which is manifested by a decrease in optical density and stratification of collagen fibers. Conclusions: Thus, the reorganization of the circulatory system of the endocrine part of the pancreas of 24-month-old rats in the early stages of experimental diabetes mellitus is characterized by a decrease in the number and area of pancreatic islets.

MGP Regulates Perivascular Adipose-Derived Stem Cells Differentiation Toward Smooth Muscle Cells Via BMP2/SMAD Pathway Enhancing Neointimal Formation

Perivascular adipose-derived stem cells (PV-ADSCs) could differentiate into smooth muscle cells (SMCs), participating in vascular remodeling. However, its underlying mechanism is not well explored. Our previous single-cell RNA-sequencing dataset identified a unique expression of matrix Gla protein (MGP) in PV-ADSCs compared with subcutaneous ADSCs. MGP involves in regulating SMC behaviors in vascular calcification and atherosclerosis. In this study, we investigated MGP’s role in PV-ADSCs differentiation toward SMCs in vitro and in vascular remodeling in vivo. PV-ADSCs were isolated from perivascular regions of mouse aortas. Quantitative reverse transcription–polymerase chain reaction (qRT-PCR), Western blot, and immunofluorescence confirmed higher MGP expression in PV-ADSCs. The MGP secretion increased along PV-ADSCs differentiation toward SMCs in response to transforming growth factor–beta 1 (TGF-β1). Lentivirus knockdown of MGP markedly promoted the bone morphogenetic protein 2 (BMP2) expression and phosphorylation of SMAD1/5/8 in PV-ADSCs, subsequently inhibiting its differentiation toward SMCs. Such inhibition could be partially reversed by further application of BMP2 inhibitors. On the contrary, exogenous MGP inhibited BMP2 expression and SMAD1/5/8 phosphorylation in PV-ADSCs, thereby promoting its differentiation toward SMCs. Transplantation of cultured PV-ADSCs, which was pretreated by MGP knockdown, in mouse femoral artery guide-wire injury model significantly alleviated neointimal hyperplasia. In conclusion, MGP promoted the differentiation of PV-ADSCs toward SMCs through BMP2/SMAD-mediated signaling pathway. This study offers a supplement to the society of perivascular tissues and PV-ADSCs.

Biochemical markers of connective tissue metabolism in the diagnostics of respiratory diseases in human and animals: retrospective analysis (1984–2010)

The aim: to analyze the literature data for the period from 1984 to 2010 on the use of biochemical markers of disorders of connective tissue metabolism in diseases of the respiratory system in humans and animals.
 Materials and methods. The research was conducted by the method of scientific literature open source analysis: PubMed, Elsevier, electronic resources of the National Library named after V.I. Vernadsky (1984–2010).
 Results. In the case of diseases of the respiratory system in humans, the pathogenesis of pneumonia is the development of inflammation in the interstitial, peribronchial, perivascular and perilobular connective tissue, lymphatic vessels of the lungs, followed by involvement of alveoli and bronchioles in the inflammation. The morphological basis of these changes may be pneumofibrosis and pneumosclerotic changes. In the chronic course of pneumonia, chronic obstructive pulmonary disease develops. This pathology is closely related to the action of inflammatory cytokines that regulate connective tissue proliferation. Similar studies were performed on eosinophilic bronchopneumonia in dogs, but the material for the study was bronchoalveolar lavage. The current method of diagnosing respiratory diseases using cytokines (interleukin-4, interferon-γ) and bronchoalveolar lavage has no diagnostic information in chronic bronchitis and bronchial asthma in cats. Fundamental studies of connective tissue biopolymers in clinically healthy and bronchopneumonia piglets have recently been conducted in veterinary medicine.
 Conclusions. Recently, in medicine of particular interest to researchers is the determination of the content in biological fluids of indicators of connective tissue metabolism (hydroxyproline, glycosaminoglycans, glycoproteins, sialic acids) to diagnose diseases of the respiratory system. To diagnose connective tissue disorders in lung diseases in medical practice use indicators of oxyproline in serum and urine. Oxyproline is one of the most important components of lung collagen. An increase in the content of free oxyproline in the blood indicates an increased rate of collagen breakdown in the lung tissue. Analysis of oxyproline fractions, as indicators of the direction of collagen metabolism, allows to assess the condition of the connective tissue of the lungs and can serve as a prognostic criterion for the course of the disease. Thus, the indicators of connective tissue metabolism showed significant diagnostic information, which allowed to recommend them for use in the practice of veterinary medicine.

Management of Endothelial Dysfunction in Systemic Sclerosis: Current and Developing Strategies.

Systemic Sclerosis (SSc) is an autoimmune disease marked by dysregulation of the immune system, tissue fibrosis and dysfunction of the vasculature. Vascular damage, remodeling and inadequate endothelial repair are hallmarks of the disease. Since early stages of SSc, damage and apoptosis of endothelial cells (ECs) can lead to perivascular inflammation, oxidative stress and tissue hypoxia, resulting in multiple clinical manifestations. Raynaud's phenomenon, edematous puffy hands, digital ulcers, pulmonary artery hypertension, erectile dysfunction, scleroderma renal crisis and heart involvement severely affect quality of life and survival. Understanding pathogenic aspects and biomarkers that reflect endothelial damage in SSc is essential to guide therapeutic interventions. Treatment approaches described for SSc-associated vasculopathy include pharmacological options to improve blood flow and tissue perfusion and, more recently, cellular therapy to enhance endothelial repair, promote angiogenesis and heal injuries. This mini-review examines the current knowledge on cellular and molecular aspects of SSc vasculopathy, as well as established and developing therapeutic approaches for improving the vascular compartment.

Advanced platelet-rich fibrin (A-PRF) has an impact on the initial healing of gingival regeneration after tooth extraction

ObjectivesPlatelet-rich fibrin (PRF) is widely used in wound healing because it contains several growth factors, including vascular endothelial growth factor (VEGF). In this study, we investigated the effects of advanced PRF (A-PRF) in early-stage gingival regeneration after tooth extraction. MethodsBlood sample was collected from females beagle dogs (age: 12 months) before tooth extraction for A-PRF preparation. All animals were sacrificed by perfusion-fixation on postoperative days 1, 3, and 7. The upper jaws were prepared for hematoxylin and eosin staining and immunostaining (for CD34 and VEGF). The lower jaw samples were prepared for scanning electron microscope observations. Blood flow in the gingiva before and after surgery was measured using laser Doppler flowmetry. ResultsIn the A-PRF group, a large number of microvessels were observed in the gingival tissue on postoperative day 1. The microvessels in the control group were fewer and sparse. Regarding the vascular resin cast, a large number of new blood vessels were observed on postoperative day 1 in the A-PRF group. A stronger CD34-positive signal was obtained around the blood vessels in the A-PRF group than in the control group. Further, a strong VEGF-positive signal was observed in the perivascular tissue in the A-PRF group. Gingival blood flow was significantly higher in the A-PRF group after surgery. ConclusionA-PRF had a positive impact on angiogenesis in the gingiva through the induction of VEGF expression. Thus, A-PRF may be beneficial for gingival tissue regeneration.

Development and Characterization of Alkaline Phosphatase-Positive Human Umbilical Cord Perivascular Cells.

Human umbilical cord perivascular cells (HUCPVCs), harvested from human umbilical cord perivascular tissue, show potential for future use as an alternative to mesenchymal stromal cells. Here, we present the results for the characterization of the properties alkaline phosphatase-positive HUCPVCs (ALP(+)-HUCPVCs). These ALP(+)-HUCPVCs were created from HUCPVCs in this study by culturing in the presence of activated vitamin D3, an inhibitor of bone morphogenetic protein signaling and transforming growth factor-beta1 (TGF-β1). The morphological characteristics, cell proliferation, gene expression, and mineralization-inducing ability of ALP(+)-HUCPVCs were investigated at the morphological, biological, and genetic levels. ALP(+)-HUCPVCs possess high ALP gene expression and activity in cells and a slow rate of cell growth. The morphology of ALP(+)-HUCPVCs is fibroblast-like, with an increase in actin filaments containing alpha-smooth muscle actin. In addition to ALP expression, the gene expression levels of type I collagen, osteopontin, elastin, fibrillin-1, and cluster of differentiation 90 are increased in ALP(+)-HUCPVCs. ALP(+)-HUCPVCs do not have the ability to induce mineralization nodules, which may be due to the restriction of phosphate uptake into matrix vesicles. Moreover, ALP(+)-HUCPVCs may produce anti-mineralization substances. We conclude that ALP(+)-HUCPVCs induced from HUCPVCs by a TGF-β1 stimulation possess myofibroblast-like properties that have little mineralization-inducing ability.

Peri-vascular adipose tissue attenuation on chest computed tomography in patients with Marfan Syndrome: a case series.

Marfan Syndrome is a genetic disorder that determines histopathological alterations of the aortic vascular wall leading to increased inflammatory component. The peri-vascular adipose tissue attenuation is a method able to capture localized vascular inflammation by mapping spatial changes of perivascular tissue attenuation on computed tomography. We measured peri-vascular adipose tissue attenuation around the ascending aorta in three consecutive subjects with confirmed genetic diagnosis of Marfan Syndrome. All subjects received the genetic diagnosis of fibrillin-1 gene mutation as part of the family screening of patients with known Marfan Syndrome. Chest computed tomography was performed in such asymptomatic subjects after genetic confirmation of Marfan Syndrome. None of these subjects showed aortic aneurysms or suffered from chronic inflammatory/infectious disease. In the three subjects identified with Marfan Syndrome the value of aortic peri-vascular adipose tissue attenuation measured at chest computed tomography was higher than normal and the volume of aortic peri-vascular adipose tissue was lower. These preliminary observations suggest that peri-vascular adipose tissue attenuation is unexpectedly high in patients with Marfan Syndrome, notwithstanding the normal aortic diameter at the time of computed tomography. Whether this observation may find a clinical use in suspected Marfan Syndrome or in predicting aortic complications in Marfan Syndrome is worth to be assessed in prospective studies.

Multiple Sclerosis: Microglia, Monocytes, and Macrophage-Mediated Demyelination.

This study examined the roles of microglia and monocytes in myelin destruction in patients with early multiple sclerosis (MS). Twenty-two cases were studied; the clinical duration was <9 weeks in 10 cases. Twenty myeloid cell subtypes or categories were identified including 2 cell types not known previously to occur in demyelinating diseases. Commencing myelin breakdown in plaques and in perivascular and subpial tissues occurred in the immediate presence of infiltrating monocytes and was effected by a homogeneous population of IgG-positive Fc receptor-bearing early phagocytes interacting with abnormal myelin. Oligodendrocyte apoptosis was observed in intact myelinated tissue bordering areas of active demyelination. Capillaries in the cerebral cortex plugged by large numbers of monocytes were common in acute cases of MS and in a patient with a neuromyelitis optica variant and extreme systemic recruitment of monocytes. In an MS patient with progressive disease, microglial nodules centered on MHC-II-positive capillaries plugged by monocytes were present in the cerebral cortex. This constitutes a new gray matter lesion in MS.

Lesional activation of Tc 17 cells in Behçet disease and psoriasis supports HLA class I-mediated autoimmune responses.

Behçet disease (BD) presents with lymphocytic and neutrophilic vasculitis of unknown aetiology. HLA-B*51, the endoplasmic reticulum aminopeptidase 1 (ERAP1), and interleukin 23 receptor (IL23R)/IL12R are genetic risk factors. IL-23 regulates IL-17A, which controls the recruitment and activation of neutrophils. To determine pathological changes in BD skin lesions related to the complex genetic predisposition. We characterized the expression of IL-17A and IL-23A in various cell types by immunohistological double staining of sections from papulopustular skin lesions of acute attacks of BD and psoriasis vulgaris lesions, another HLA-class I-associated T-cell-mediated autoimmune disease in which excessive T-cell-derived IL-17A production promotes neutrophil activation. We found that in BD lesions, as in psoriasis, actively expanding CD8+ T cells were the predominant source of IL-17A. IL-17A+ CD8+ T (Tc 17) cells outnumbered infiltrating IL-17A+ CD4+ T cells. Unlike the epidermal localization of CD8+ T cells in psoriasis, Tc 17 cells in BD lesions mainly infiltrated the perivascular tissue and the blood vessel walls of dermis and subcutaneous tissue. They co-localised with a marked IL-23A expression by CD11c+ dendritic cells and CD68+ macrophages. IL-17A expression was associated with extensive recruitment of neutrophils around blood vessels that formed neutrophil extracellular traps (NETs). In BD, the genetic predisposition may mediate antigen-specific activation and differentiation of a Tc 17 response, possibly targeting endothelial (auto)antigens. Neutrophils recruited by IL-17A in this process may enhance tissue damage by extensive NET formation (NETosis). Thus, the IL-23/IL-17 axis presumably controls neutrophilic inflammation in BD vasculitis in the context of a predominant antigen-specific CD8+ T-cell response.

CT Radiomic Features of Superior Mesenteric Artery Involvement in Pancreatic Ductal Adenocarcinoma: A Pilot Study.

Background Current imaging methods for prediction of complete margin resection (R0) in patients with pancreatic ductal adenocarcinoma (PDAC) are not reliable. Purpose To investigate whether tumor-related and perivascular CT radiomic features improve preoperative assessment of arterial involvement in patients with surgically proven PDAC. Materials and Methods This retrospective study included consecutive patients with PDAC who underwent surgery after preoperative CT between 2012 and 2019. A three-dimensional segmentation of PDAC and perivascular tissue surrounding the superior mesenteric artery (SMA) was performed on preoperative CT images with radiomic features extracted to characterize morphology, intensity, texture, and task-based spatial information. The reference standard was the pathologic SMA margin status of the surgical sample: SMA involved (tumor cells ≤1 mm from margin) versus SMA not involved (tumor cells >1 mm from margin). The preoperative assessment of SMA involvement by a fellowship-trained radiologist in multidisciplinary consensus was the comparison. High reproducibility (intraclass correlation coefficient, 0.7) and the Kolmogorov-Smirnov test were used to select features included in the logistic regression model. Results A total of 194 patients (median age, 66 years; interquartile range, 60-71 years; age range, 36-85 years; 99 men) were evaluated. Aside from surgery, 148 patients underwent neoadjuvant therapy. A total of 141 patients' samples did not involve SMA, whereas 53 involved SMA. A total of 1695 CT radiomic features were extracted. The model with five features (maximum hugging angle, maximum diameter, logarithm robust mean absolute deviation, minimum distance, square gray level co-occurrence matrix correlation) showed a better performance compared with the radiologist assessment (model vs radiologist area under the curve, 0.71 [95% CI: 0.62, 0.79] vs 0.54 [95% CI: 0.50, 0.59]; P < .001). The model showed a sensitivity of 62% (33 of 53 patients) (95% CI: 51, 77) and a specificity of 77% (108 of 141 patients) (95% CI: 60, 84). Conclusion A model based on tumor-related and perivascular CT radiomic features improved the detection of superior mesenteric artery involvement in patients with pancreatic ductal adenocarcinoma. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Do and Kambadakone in this issue.

Arachnoid membrane as a source of sphingosine-1-phosphate that regulates mouse middle cerebral artery tone

Growing evidence indicates that perivascular tissue is critical to modulate vessel function. We hypothesized that the arachnoid membrane surrounding middle cerebral artery (MCA) regulates its function via sphingosine-1-phosphate (S1P)-induced vasoconstriction. The MCA from 3- to 9-month-old male and female wild-type (Oncine France 1 and C57BL/6) mice and sphingosine kinase 2 knockout (SphK2-/-) mice in the C57BL/6 background was mounted in pressure myographs with and without arachnoid membrane. Raman microspectroscopy and imaging were used for in situ detection of S1P. The presence of arachnoid tissue was associated with reduced external and lumen MCA diameters, and with an increase in basal tone regardless of sex and strain background. Strong S1P-positive signals were detected in the arachnoid surrounding the MCA wall in both mice models, as well as in a human post-mortem specimen. Selective S1P receptor 3 antagonist TY 52156 markedly reduced both MCA vasoconstriction induced by exogenous S1P and arachnoid-dependent basal tone increase. Compared to 3-month-old mice, the arachnoid-mediated contractile influence persisted in 9-month-old mice despite a decline in arachnoid S1P deposits. Genetic deletion of SphK2 decreased arachnoid S1P content and vasoconstriction. This is the first experimental evidence that arachnoid membrane regulates the MCA tone mediated by S1P.