Lack of intracranial atherosclerosis in various atherosclerotic mouse models.

Background: Although mice are used extensively to study atherosclerosis of different vascular beds, limited data is published on the occurrence of intracranial atherosclerosis. Since intracranial atherosclerosis is a common cause of stroke and is associated with dementia, a relevant animal model is needed to study these diseases.

Methods And Results: We examined the presence of intracranial atherosclerosis in different atherogenic mouse strains and studied differences in vessel wall characteristics in mouse and human tissue in search for possible explanations for the different atherosclerotic susceptibility between extracranial and intracranial vessels.

Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid body.

Agouti-related peptide (AgRP) is a well-established potent orexigenic peptide primarily expressed in hypothalamic neurons. Nevertheless, the expression and functional significance of extrahypothalamic AgRP remain poorly understood. In this study, utilizing histological and molecular biology techniques, we have identified a significant expression of Agrp mRNA and AgRP peptide production in glomus type I cells within the mouse carotid body (CB).

Relative expression of hormone receptors by endothelial and smooth muscle cells in proliferative and non-proliferative areas of congenital arteriovenous malformations.

Background: Episodic growth due to microvascular proliferations (MVP) has been reported in congenital arteriovenous malformations (AVM), which are normally quiescent lesions composed of mature malformed vessels. Since AVM also may worsen under conditions of hormonal dysregulation, we hypothesized that hormonal influences may stimulate this process of vasoproliferative growth through potential interactions with hormone receptors (HR).

Methods: 13 Cases of AVM tissue with histologically documented vasoproliferative growth were analyzed quantitatively for the presence and tissue localization of estrogen receptor (ER), progesterone receptor (PGR), growth hormone receptor (GHR) and follicle-stimulating hormone receptor (FSHR) in relation to resident cells of interest (endothelial cells (EC), smooth muscle cells (SMC) and mast cells (MC)) by applying multiplex immunohistochemistry (IHC) staining.

Visualization of the carotid body in situ in fixed human carotid bifurcations using a xylene-based tissue clearing method.

The anatomy of the carotid body (CB) and its nerve supply are important, because it is a potential therapeutic target for treatment of various clinical conditions. Visualization of the CB in situ in fixed human anatomical specimens is hampered by obscuring adipose and connective tissues. We developed a tissue clearing method to optimize identification of the CB.

Age-Related Variation in Sympathetic Nerve Distribution in the Human Spleen.

The cholinergic anti-inflammatory pathway (CAIP) has been proposed as an efferent neural pathway dampening the systemic inflammatory response via the spleen. The CAIP activates the splenic neural plexus and a subsequent series of intrasplenic events, which at least require a close association between sympathetic nerves and T cells. Knowledge on this pathway has mostly been derived from rodent studies and only scarce information is available on the innervation of the human spleen.

A comparative anatomical and histological study on the presence of an apical splenic nerve in mice and humans.

The cranial pole of the mouse spleen is considered to be parasympathetically innervated by a macroscopic observable nerve referred to as the apical splenic nerve (ASN). Electrical stimulation of the ASN resulted in increased levels of splenic acetylcholine, decreased lipopolysaccharide-induced levels of systemic tumor necrosis factor alpha and mitigated clinical symptoms in a mouse model of rheumatoid arthritis. If such a discrete ASN would be present in humans, this structure is of interest as it might represent a relatively easily accessible electrical stimulation target to treat immune-mediated inflammatory diseases.

Sensory Innervation of Human Bone: An Immunohistochemical Study to Further Understand Bone Pain.

Skeletal diseases and their surgical treatment induce severe pain. The innervation density of bone potentially explains the severe pain reported. Animal studies concluded that sensory myelinated A∂-fibers and unmyelinated C-fibers are mainly responsible for conducting bone pain, and that the innervation density of these nerve fibers was highest in periosteum.

Sympathetic nerve distribution in human lymph nodes.

Various lymph node functions are regulated by the sympathetic nervous system as shown in rodent studies. If human lymph nodes show a comparable neural regulation, their afferent nerves could represent a potential therapeutic target to treat, for example, infectious or autoimmune disease. Little information is available on human lymph node innervation and the aim of this study is to establish a comprehensive and accurate representation of the presence and location of sympathetic nerves in human lymph nodes.

Arterial Remodeling of the Intracranial Arteries in Patients With Hypertension and Controls: A Postmortem Study.

The intracranial arteries play a major role in cerebrovascular disease, but arterial remodeling due to hypertension has not been well described in humans. We aimed to quantify this remodeling for: the basilar artery, the vertebral, internal carotid, middle/anterior (inferior)/posterior cerebral, posterior communicating, and superior cerebellar arteries of the circle of Willis. Ex vivo circle of Willis specimens, selected from individuals with (n=24) and without (n=25) a history of hypertension, were imaged at 7T magnetic resonance imaging using a 3-dimensional gradient-echo sequence.

Morphological hallmarks facilitating distinction of omental milky spots and lymph nodes: an exploratory study on their discriminative capacity.

Background: Omental milky spots (OMSs) are the primary lymphoid structures of the greater omentum. However, the presence of lymph nodes (LNs) has occasionally been mentioned as well. Understanding which lymphoid structures are present is of significance, especially in gastric tumor metastasis; tumor deposits in omental LNs suggest local lymphatic spread, whereas tumor deposits in OMSs suggest peritoneal spread and hence extensive disease.

Comparison of Two Different Immunohistochemical Quadruple Staining Approaches to Identify Innate Lymphoid Cells in Formalin-fixed Paraffin-embedded Human Tissue.

Lack of specific markers for innate lymphoid cells (ILCs) limit our knowledge on their spatial organization in situ. We compared two quadruple-color staining protocols for detection of the three principal human ILC subsets in formalin-fixed paraffin-embedded specimens. ILC subset-associated archetypical transcription factors (TFs) T-bet, GATA3, and RORγt were used as positive identifiers in combination with lymphoid lineage markers to exclude non-ILCs.

Profiling the unique protective properties of intracranial arterial endothelial cells.

Cardiovascular disorders, like atherosclerosis and hypertension, are increasingly known to be associated with vascular cognitive impairment (VCI). In particular, intracranial atherosclerosis is one of the main causes of VCI, although plaque development occurs later in time and is structurally different compared to atherosclerosis in extracranial arteries. Recent data suggest that endothelial cells (ECs) that line the intracranial arteries may exert anti-atherosclerotic effects due to yet unidentified pathways.

Extracellular traps derived from macrophages, mast cells, eosinophils and neutrophils are generated in a time-dependent manner during atherothrombosis.

Extracellular traps generated by neutrophils contribute to thrombus progression in coronary atherosclerotic plaques. It is not known whether other inflammatory cell types in coronary atherosclerotic plaque or thrombus also release extracellular traps. We investigated their formation by macrophages, mast cells, and eosinophils in human coronary atherosclerosis, and in relation to the age of thrombus of myocardial infarction patients.

Neutrophil Extracellular Traps Participate in All Different Types of Thrombotic and Haemorrhagic Complications of Coronary Atherosclerosis.

Acute coronary syndromes can be initiated by either atherosclerotic fibrous cap ruptures, superficial plaque erosions or intraplaque haemorrhages (IPHs). Since neutrophil extracellular traps (NETs) display pro-inflammatory and pro-thrombotic properties, we investigated the presence, extent and distribution of neutrophils and NETs in different types of plaque complications in relation to the age of overlying thrombus mass or haemorrhage. Sixty-four paraffin-embedded coronary plaque segments of 30 acute myocardial infarction patients were retrieved from the autopsy archives, which contained 44 complicated plaques (17 IPHs, 9 erosions and 18 ruptures) and 20 intact plaques.

Immunophenotypic analysis of the chronological events of tissue repair in aortic medial dissections.

Acute medial dissection of aorta can occur in the context of a sudden and unexpected death. For medico-legal reasons it is important to estimate as accurately the histological age of dissections. We evaluated the additional value of a systematic application of immunohistochemistry, compared with conventional histology only, in determining chronological steps of injury and repair.

Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy.

Background: Photodynamic therapy (PDT) induces tumor cell death by oxidative stress and hypoxia but also survival signaling through activation of hypoxia-inducible factor 1 (HIF-1). Since perihilar cholangiocarcinomas are relatively recalcitrant to PDT, the aims were to (1) determine the expression levels of HIF-1-associated proteins in human perihilar cholangiocarcinomas, (2) investigate the role of HIF-1 in PDT-treated human perihilar cholangiocarcinoma cells, and (3) determine whether HIF-1 inhibition reduces survival signaling and enhances PDT efficacy.

Results: Increased expression of VEGF, CD105, CD31/Ki-67, and GLUT-1 was confirmed in human perihilar cholangiocarcinomas.

Accurate quantitation of Ki67-positive proliferating hepatocytes in rabbit liver by a multicolor immunohistochemical (IHC) approach analyzed with automated tissue and cell segmentation software.

Determination of hepatocyte proliferation activity is hampered by the presence of Ki67-positive non-parenchymal cells. We validated a multicolor immunohistochemical (IHC) approach using multispectral tissue and cell segmentation software. Portal vein branches to the cranial liver lobes of 10 rabbits were embolized, leading to atrophy of the cranial lobes and hyperplasia of the caudal lobes.