The blood-brain barrier (BBB), built by brain endothelial cells (BECs), is impermeable to biologics. Liposomes and other nanoparticles are good candidates for delivery of biologics across the BECs, as they can encapsulate numerous molecules of interest in an omnipotent manner. The liposomes need attachment of a targeting molecule, as BECs unfortunately are virtually incapable of uptake of non-targeted liposomes from the circulation. Experiments of independent research groups have qualified antibodies targeting the transferrin receptor as superior for targeted delivery of nanoparticles to BECs. Functionalization of nanoparticles via conjugation with anti-transferrin receptor antibodies leads to nanoparticle uptake by endothelial cells of both brain capillaries and post-capillary venules. Reducing the density of transferrin receptor-targeted antibodies conjugated to liposomes limits uptake in BECs. Opposing the transport of nanoparticles conjugated to high-affine anti-transferrin receptor antibodies, lowering the affinity of the targeting antibodies or implementing monovalent antibodies increase uptake by BECs and allows for further transport across the BBB. The novel demonstration of transport of targeted liposomes in post-capillary venules from blood to the brain is interesting and clearly warrants further mechanistic pursuit. The recent evidence for passing targeted nanoparticles through the BBB shows great promise for future drug delivery of biologics to the brain.

The blood-brain barrier (BBB) acts as a structural and functional barrier for brain homeostasis. This review highlights the pathological contribution of BBB dysfunction to neuroimmunological diseases, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), autoimmune encephalitis (AE) and paraneoplastic neurological syndrome (PNS). The transmigration of massive lymphocytes across the BBB caused by the activation of cell adhesion molecules is involved in the early phase of MS, and dysfunction of the cortical BBB is associated with the atrophy of gray matter in the late phase of MS. In the onset of NMOSD, increased permeability of the BBB causes the entry of circulating AQP4 autoantibodies into the central nervous system (CNS). Recent reports have shown the importance of glucose-regulated protein (GRP) autoantibodies as BBB-reactive autoantibodies in NMOSD, inducing antibody-mediated BBB dysfunction. BBB breakdown has also been observed in MOGAD, NPSLE, and AE with anti-NMDAR antibodies. Our recent report demonstrated the presence of GRP78 autoantibodies in patients with MOGAD and the molecular mechanism responsible for GRP78 autoantibody-mediated BBB impairment. Disruption of the BBB may explain the symptoms in the brain and cerebellum in the development of PNS, as it induces the entry of pathogenic autoantibodies or lymphocytes into the CNS by autoimmunity against tumors in the periphery. GRP78 autoantibodies were detected in paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome and were associated with cerebellar ataxia with anti-P/Q type voltage-gated calcium channel antibodies. This review reports that therapies affecting the BBB that are currently available for disease-modifying therapies for neuroimmunological diseases have the potential to prevent BBB damage.

A facilitative transport system exists on the blood brain barrier (BBB) that has been tacitly assumed to be a path for glutamate entry to brain. But glutamate is a non-essential amino acid whose brain content is much greater than plasma, and studies in vivo show that glutamate does not enter brain in material quantities except in those small regions with fenestrated capillaries (circumventricular organs). The situation became understandable when luminal (blood facing) and abluminal (brain facing) membranes were isolated and studied separately. Facilitative transport of glutamate and glutamine exist only on the luminal membranes whereas Na+-dependent transport systems for glutamate, glutamine and some other amino acids are present only on the abluminal membrane. The Na+-dependent cotransporters of the abluminal membrane are in a position to actively transport amino acids from the extracellular fluid (ECF) into the endothelial cells of the BBB. These powerful secondary active transporters couple the energy of the Na+-gradient to move glutamate and glutamine into the ECF whereupon glutamate can exit to blood on the luminal facilitative glutamate transporter. Glutamine may also exit brain on a separate facilitative transport system that exists on the luminal membranes or glutamine can be hydrolyzed to glutamate within the BBB thereby releasing ammonia that is freely diffusible. The γ-glutamyl participate cycle participates indirectly by producing oxoproline (pyroglutamate) that stimulates almost all secondary active transporters yet discovered in the abluminal membranes of the BBB.

Under physiological conditions the blood-brain barrier (BBB) is required for regulating the passage of substances between the bloodstream and the brain. To date, disruption of the BBB has been associated with nearly all neurological diseases. Dye and tracer experiments have been used to assess BBB integrity for decades, yet quantitative assessment of these experiments has only recently been implemented. Further, interpretation of these results requires the consideration of tracer-specific properties. Here, we describe a protocol for evaluating BBB leakage using the small molecule cadaverine in quantitative way. We also cover advantages/disadvantages of using some reagents and highlight limitations in data interpretations based on assays used to assess BBB permeability.

The effect of Alzheimer's disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. Alzheimer's disturbs the life of at least five million persons in the USA. CD4+ T cells could both exacerbate and reduce AD symptoms. Regulating CD4+ T cells homing to the leaky blood-brain barrier (BBB) constitutes a new hope for enhancing AD prognosis. Alzheimer's drugs such as Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne) and memantine are known to play an important part in regulating the neurotransmitters mechanisms. However, little is known about the effect of these drugs on CD4+ T cells homing. In this review, we focus on current and new drugs that could modulate CD4+ T cells interactions with the BBB in AD.

P-glycoprotein (Pgp) determines resistance to a broad spectrum of drugs in glioblastoma multiforme (GB) because it is highly expressed in GB stem cells and in brain-blood barrier (BBB), the peculiar endothelium surrounding brain. Inhibiting Pgp activity in BBB and GB is still an open challenge. Here, we tested the efficacy of a small library of tetrahydroisoquinoline derivatives with an EC₅₀ for Pgp < 50 nM, in primary human BBB cells and in patients-derived GB, from which we isolated differentiated/adherent cells (AC, i.e. Pgp-negative/doxorubicin-sensitive cells) and stem cells (neurospheres, NS, i.e. Pgp-positive/doxorubicin-resistant cells). At 1 nM, 3 compounds increased the delivery of doxorubicin, a typical substrate of Pgp, across BBB monolayer, without altering expression and activity of other transporters. The compounds increased the drug accumulation within NS, restoring necrosis, apoptosis and reduction in cell viability induced by doxorubicin. In co-culture systems, the compounds added to the luminal face of BBB increased the delivery of doxorubicin to NS growing under BBB and rescued the drug’s cytotoxicity. Our work identified new ligands of Pgp active at low nanomolar concentrations, that effectively reduce Pgp activity in BBB and GB, and can improve chemotherapy efficacy in this tumor.

Methylmercury is a neurotoxin present in fish tissues that permeates the blood-brain barrier after consumption. Previous research has shown that methylmercury is harmful to neurons, causing pH alterations, oxidative stress, excitotoxicity, and parenchymal damage. Methylmercury is a known factor of neurological disorders including Alzheimer's and Parkinson's. The method by which methylmercury passes through the blood-brain barrier is largely unknown. According to preliminary studies, one way methylmercury crosses the blood-brain barrier is by creating a complex with L-Cysteine, which facilitates its passage by the LATs system through mimicking another amino acid existing in the body. The human blood-brain barrier was studied using C. elegans as a model organism. It was hypothesized that if methylmercury passes through the blood-brain barrier of C. elegans faster with L-Cysteine present than without L-Cysteine present, the methylmercury's adverse effects (death and locomotive difficulty) will occur sooner. Each of the four experimental groups contained one C. elegans: the control, the L-Cysteine group, the methylmercury group, and the methylmercury and L-Cysteine combination group. The effects of L-Cysteine and methylmercury on C. elegans were studied using three metrics: viability, locomotive disability, and time for locomotive effects to occur. The group that received both methylmercury and L-Cysteine had reduced viability rates and a decreased time for locomotive difficulty to develop, supporting the hypothesis. These findings suggest that L-Cysteine aids methylmercury permeation through the blood-brain barrier. Because the experiment indicates how methylmercury penetrates the blood-brain barrier, these results aid in finding a therapeutic solution to reverse methylmercury neurotoxicity in the brain. Additionally, this study further opens channels into potential therapeutic and preventative measures for dementia, improving morbidity and mortality in neurodegenerative diseases.

The blood-brain barrier (BBB) strictly regulates the penetration of substances into the brain, which, although important for maintaining brain homeostasis, may delay drug development because of the difficulties in predicting pharmacokinetics/pharmacodynamics (PKPD), toxicokinetics/toxicodynamics (TKTD), toxicity, safety, and efficacy in the central nervous system (CNS). Moreover, BBB functional proteins show species differences; therefore, humanized in vitro BBB models are urgently needed to improve the predictability of preclinical studies. Recently, international trends in the 3Rs in animal experiments and the approval of the FDA Modernization Act 2.0 have accelerated the application of microphysiological systems (MPSs) in preclinical studies, and in vitro BBB models have become synonymous with BBB-MPSs. Recently, we developed an industrialized humanized BBB-MPS, BBB-NET. In our previous report, we reproduced transferrin receptor (TfR)-mediated transcytosis with high efficiency and robustness with hydrogels that include fibrin and collagen I microfibers (CMFs). Herein, we investigated how adding CMFs to the fibrin gel benefits BBB-NETs, showed that CMFs accelerated capillary network formation and maturation by promoting astrocyte (AC) survival, and clarified that integrin 1 is involved in the mechanism of CMFs. Our data suggest that quality control (QC) of CMFs is important for ensuring the stable production of BBB-NETs.

The blood brain barrier (BBB) is an essential component in regulating and maintaining the homeostatic microenvironment of the central nervous system (CNS). During the occurrence and development of glioblastoma (GBM), BBB is pathologically disrupted with markedly increased permeability. Due to the obstruction imposed by the BBB, strategies currently employed for GBM therapeutics still obtain a very low success rate and lead to systemic toxicity. Moreover, chemotherapy could promote pathological BBB functional restoration, accompanied with a prominent decrease of intracerebral therapeutics transportion during GBM multiple administration, resulting in chemotherapy failure for GBM treatment. The effective delivery of therapeutics into the brain still faces with severe challenges. Regulation of pathological BBB for enhanced transporting of therapeutics across the barrier may provide new opportunities for effective and safe treatment of GBM. This article reviews the structure and function of BBB in physiological state, the mechanisms underlying BBB pathological fenestration during the development of GBM, and the therapeutic strategies of GBM based on BBB intervention and therapeutic drugs transporting across the BBB.

Glioblastoma (GBM) is a prevalent type of malignancy within the central nervous system (CNS), associated with a poor prognosis. The standard treatment for GBM includes surgical resection of the tumor, followed by radiotherapy and chemotherapy; yet despite these interventions, overall treatment outcomes remain suboptimal. The blood-brain barrier (BBB), which plays a crucial role in maintaining the stability of brain tissue under normal physiological conditions of the CNS,also poses a significant obstacle to the effective delivery of therapeutic agents to GBM. Recent preclinical studies have demonstrated that nanomedicine delivery systems (NDDS) offer promising results, demonstrating both effective GBM targeting and safety, thereby presenting a potential solution for targeted drug delivery. This review explores the various strategies employed in preclinical studies to overcome the BBB for drug delivery. Subsequently, the results of clinical translation of NDDS has been summarized, highlighting the progress made. Finally, we discuss potential strategies for advancing NDDS development and accelerating their translational research through well-designed clinical trials in GBM therapy.

Blood-brain-barrier is a major obstacle in treating brain-related disorders as it does not allow to deliver drugs in the brain. In order to facilitate delivery of drugs in brain, we developed a method for predicting blood-brain-barrier penetrating peptides. These blood-brain barriers penetrating peptides (B3PPs) can act as therapeutic as well as drug delivery agents. We trained, tested, and evaluated our models on blood-brain-barrier peptides obtained from the B3Pdb database. First, we compute a wide range of peptide features then we select relevant peptide features. Finally, we developed numerous machine learning-based models for predicting blood-brain-barrier peptides using selected features. Our model based on random forest performed best on the top 80 selected features and achieved a maximum 85.08% accuracy with 0.93 AUROC. We also developed a web server, B3pred that implements our best models. It has three major modules that allow users to; i) predict B3PPs, ii) scanning B3PPs in a protein sequence, and iii) designing B3PPs using analogs. Our web server and standalone software is freely available at https://webs.iiitd.edu.in/raghava/b3pred/.

Background: Stroke is one of the leading causes of death and disability worldwide. The diagnosis of stroke remains largely clinical, yet widely used stroke scoring systems and brain imaging do not satisfactorily allow distinction of ischaemic stroke (IS) patients from stroke mimics (SM). Blood biomarkers are promising tools that could facilitate clinical triage. Methods: This study recruited 66 patients with IS and 24 SM. The levels of Glial fibrillary acidic protein (GFAP), Neuron-specific enolase (NSE), Neurofilament light chain (NfL) and blood-brain barrier (BBB) proteins [Occludin (OCLN), Zonula occludens 1 (ZO-1), Claudin-5] in blood serum were measured by enzyme-linked immunosorbent assay technique. Biomarker levels in IS patients and SM was compared using the Mann–Whitney U test. Multivariable logistic regression analysis was used to evaluate the diagnostic performance of biomarkers in combination with the National Institutes of Stroke Scale (NIHSS) score. Results: Significant differences in circulating GFAP, NfL, OCLN, ZO-1, and Claudin-5 but not NSE in IS patients compared to SM. The combination of circulating ZO-1, Claudin-5, and OCLN with NIHSS score gives the highest diagnostic accuracy, sensitivity, and specificity. Conclusion: A prediction model with Circulating BBB proteins in combination with NIHSS score differentiates between IS patients and SM.

The peripheral lymphatic system plays a crucial role in the recovery mechanisms after many pathological changes, such as infection, trauma, vascular, or metabolic diseases. The lymphatic clearance of different tissues from waste products, viruses, bacteria and toxic proteins significantly contributes to the correspondent recovery processes. However, understanding of the meningeal lymphatics functions is a challenging problem. The exploration of mechanisms of lymphatic communication with brain fluids as well as the role of the lymphatic system in the brain drainage, clearance and recovery are still in its infancy. Here we review novel concepts on the anatomy and physiology of the lymphatics in the brain, which warrant a substantial revision of our knowledge about the role of lymphatics in the rehabilitation of the brain functions after neural pathologies. We discuss a new vision on how to recruit the meningeal lymphatics by the opening of blood-brain barrier as a trigger mechanism of activation of the meningeal lymphatic drainage. This leads to innovative strategies in neurorehabilitation therapy.

Genetic factors influence medication response (pharmacogenetics), affecting the pharmacody-namics and pharmacokinetics of many medicaments used in clinical care. The ability of medica-tions to cross the blood-brain barrier (BBB) represents a critical putative factor in the effectiveness and tolerability of various central nervous system (CNS) medications at a pharmacokinetic (dosing) level. Pharmacogenetics has the potential to personalise medicine to a greater extent than has been possible, with the potential to help reduce heuristic delays to effective tolerable pharmacotherapy. Here, we critically examine and summarise the evidence, particularly for ABCB1 polymorphisms associated with various CNS medications. These transporters appear to have a role in BBB pharmacogenetics. We identify some of the most promising variants for clinical translation while spotlighting the complexities of the involved systems and limitations of the current empirical literature.

Proper blood-brain barrier (BBB) function is essential to maintain homeostasis keeping the central nervous system healthy. Disruption of the BBB has been described in nearly all neurological disease and injury contexts. Given the various physical and metabolic roles of the BBB and gliovascular unit (GVU), dysfunction should be assessed across multiple levels to pinpoint the exact nature of the impairment. Here we describe imaging techniques for evaluating various aspects of BBB and GVU integrity and function, tailored for use in mouse models with protocols for quantitative image analysis. These imaging techniques complement classical dye tracer experiments and reveal underlying molecular causes of BBB dysfunction.

The main neurovascular unit of the Blood Brain Barrier (BBB) consists of a cellular component, which includes endothelial cells, astrocytes, pericytes, microglia, neurons and oligodendrocytes, as well as a non-cellular component resulting from the extracellular matrix. The endothelial cells are the major vital component of the BBB able to preserve the brain homeostasis; these cells are situated along the demarcation line between the bloodstream and the brain. Therefore, an alteration or the progressive disruption of the endothelial layer may clearly impair the brain homeostasis. The proper functioning of the brain endothelial cells is generally ensured by two elements: 1) the presence of junction proteins; 2) the preservation of a specific polarity involving an apical-luminal and a basolateral-abluminal membrane. In view of the above, this review intends to identify the molecular mechanisms underlying BBB function and their changes occurring in early stages of neurodegenerative processes in order to develop novel therapeutic strategies aimed to counteract neurodegenerative disorders.

Device-mediated, non-invasive drug delivery across the blood-brain barrier (BBB) represents a significant advancement in treating neurological diseases. The BBB is a tightly packed layer of endothelial cells that shields the brain from harmful substances in the blood, allowing necessary nutrients to pass through. It is a highly selective barrier, which poses a challenge to delivering therapeutic agents into the brain. Several non-invasive techniques and devices have been proposed or investigated to enhance drug delivery across the BBB. This paper presents the current state of the art and case studies that address the pharmacology, technology, delivery systems, regulatory approval, ethical concerns, and future possibilities.

The blood-brain barrier (BBB) acts as a specialized structure separating the brain from peripheral blood circulation and plays an important role in brain function. Following an ischaemic stroke or cerebral ischaemia, the BBB is damaged leading to degraded proteins being released into blood circulation. However, little is known about cerebral ischaemia and reperfusion (I/R) induced BBB damage and changes in circulatory biomarkers. This study aims to use both immunohistochemistry and western blotting (WB) to examine neuronal death, glial cell alterations and changes in BBB tight junction (TJ) proteins such as zonula occludens-1 (ZO-1), Occludin and Claudin-5 in the hippocampus in a murine model of cerebral I/R. The changes in these proteins in the blood serum of this model were assessed by enzyme-linked immunosorbent assay. The results showed neuronal death and a significant increase in glial fibrillary acidic protein (GFAP), a protein primarily expressed in astrocytes and a significant decrease in TJ proteins, ZO-1, Occludin and Claudin-5 in the hippocampus of occluded mice as compared to sham-operated mice. These changes are associated with an increased level of these proteins in blood serum in ischaemic mice, suggesting that these proteins can be used as potential biomarkers for determining ischaemic stroke.

The neurodegenerative diseases (Alzheimers, Parkinsons, amyotrophic lateral sclerosis, Huntingdons) and the prion disorders, have in common a dysregulation of metalloprotein chemistry involving redox metals (Cu,Fe,Mn). The consequent oxidative stress gives rise to protein plaques and neuronal cell death. An equilibrium exists between the functional requirement of the brain for Cu and Fe and their destructive potential with the production of reactive oxygen species. The importance of the brain barrier is highlighted in regulating the import of these metals. Upregulation of key transporters occurs in foetal and neonatal life when brain metal requirement is high and is down-regulated in adult life when need is minimal. By contrast a neonatal mode of CTR1 upregulation persists in feral N.Ronaldsay sheep. This has led to the premise that metal regulation may return to the default setting in ageing with implications for neurodegenerative disease.

One of the hallmarks of Alzheimer’s disease (AD) is the accumulation of beta-amyloid peptide (Aβ) leading to formation of soluble neurotoxic Aβ oligomers and insoluble amyloid plaques in various parts of the brain. Aβ undergoes post-translational modifications that alter its pathogenic properties. Aβ is produced not only in brain, but also in the peripheral tissues. Such Aβ, including its post-translationally modified forms, can enter the brain from circulation by binding to RAGE and contribute to the pathology of AD. However, the transport of modified forms of Aβ across the blood–brain barrier (BBB) has not been investigated. Here, we used a transwell BBB model as a controlled environment for permeability studies. We found that Aβ42 containing isomerized Asp7 residue (iso-Aβ42) and Aβ42 containing phosphorylated Ser8 residue crossed the BBB better than unmodified Aβ42, which correlated with different contribution of endocytosis mechanisms to the transport of these isoforms. Using microscale thermophoresis, we observed that RAGE binds to iso-Aβ42 an order of magnitude weaker than to Aβ42. Thus, post-translational modifications of Aβ increase the rate of its transport across the BBB and modify the mechanisms of the transport, which may be important for AD pathology and treatment.

Angiostrongylus cantonensis, a zoonotic parasite, can invade the human central nervous system (CNS) and cause acute eosinophilic meningitis or eosinophilic meningoencephalitis. Mice infected with A. cantonensis show elevated levels of pro-inflammatory cytokines, plasminogen activators, and matrix metalloproteinase-9, resulting in disruption of the blood-brain barrier (BBB) and immune cell infiltration into the CNS. Caveolin-1 (Cav-1) regulates the permeability of the BBB, which affects immune cells and cerebrospinal fluid. This intricate interaction ultimately fuels the progression of brain damage and edema. This study aims to investigate the regulatory role of Cav-1 in the pathogenesis of meningoencephalitis induced by A. cantonensis infection. We investigate pathological alterations by triphenyl-tetrazolium chloride, brain water content, BBB permeability, Western blot analysis, and gelatin zymography in BALB/c mice after A. cantonensis. The study evaluates the critical role of Cav-1 regulation through the TLR4 / MyD88 signaling pathway, modulates tight junction proteins, influences BBB permeability, and contributes to brain damage in A. cantonensis-induced meningoencephalitis.

Over past decades, a frequent co-morbidity of cerebrovascular pathology and Alzheimer's disease pathology has been observed. Numerous published studies indicate that preservation of healthy cerebrovascular endothelium can be an important therapeutic target. By incorporating appropriate drug(s) into biomimetic (lipid cubic-phase) nanocarriers, one obtains a multitasking combination therapeutic which targets certain cell-surface scavenger receptors, mainly class B type 1 (i.e., SR-BI), and crosses the blood-brain barrier. This targeting allows for various Alzheimer’s-related cell types to be simultaneously searched out for localized drug treatment in vivo.

The neurovascular niche is crucial for constant blood supply and blood-brain barrier (BBB) function and is altered in a number of different neurological conditions, making this an intensely active field of research. Brain vasculature is unique for its tight association of endothelial cells with astrocytic endfeet processes. Separation of the vascular compartment by centrifugation-based methods confirmed enrichment of astrocytic endfeet processes, making it possible to study the entire vascular niche with such methods. Several centrifugation-based separation protocols are found in the literature; however, with some constraints which limit their applicability and the scope of the studies. Here, we describe and validate a protocol for physically separating the neurovascular niche from the parenchyma, which is optimized for smaller tissue quantities. Using endothelial, neuronal and astrocyte markers, we show that quantitative Western blot-based target detection can be performed of both the vascular and parenchymal fractions using as little as a single mouse brain hemisphere. Validation of our protocol in rodent stroke models by detecting changes in serum albumin signals and astrocyte activation, i.e. increased glial fibrillary acidic protein expression, between the ipsilateral and the lesion-free contralateral hemisphere demonstrates this protocol as a new way of detecting BBB breakdown and astrogliosis, respectively.

The blood-brain barrier (BBB) is a selectively permeable boundary that separates the circulating blood from the extracellular fluid of the brain and is an essential component for brain homeostasis. In glioblastoma (GBM), the BBB of peritumoral vessels is often disrupted. Pericytes, being important to maintain the BBB integrity, can be functionally modified by GBM cells by inducing proliferation and cell motility via the TGF-β-mediated induction of central epithelial to mesenchymal transition (EMT) factors., We demonstrate that pericytes strengthen the integrity of the BBB in primary endothelial cell/pericyte co-cultures as in vitro BBB model, using TEER measurement of the barrier integrity. In contrast, this effect was abrogated by TGF-β or conditioned medium from TGF-β secreting GBM cells, finally leading to the disruption of a so far intact and tight BBB. TGF-β dramatically changed the metabolic behavior of pericytes, such as shutting down the TCA cycle, driving energy generation from oxidative phosphorylation towards glycolysis, and by shifting the cells towards the activation of pathways that are necessary to produce molecules used for proliferation and cell division. Furthermore, combined metabolomics and RNASeq analyses indicated that the observed functional changes of TGF-β-treated pericytes are closely connected with their behavior.

Pericytes are increasingly recognized as being important in the control of blood-brain barrier permeability and vascular flow. Research on this important cell type has been hindered by widespread confusion regarding the phenotypic identity and nomenclature of pericytes and other perivascular cell types. In addition, pericyte heterogeneity and mouse-human species differences have contributed to confusion. Herein we summarize our present knowledge on the identification of pericytes and pericyte subsets in humans, primarily focusing on recent findings in humans and nonhuman primates. Precise identification and definition of pericytes and pericyte subsets in humans may help us to better understand pericyte biology and develop new therapeutic approaches specifically targeting disease-associated pericyte subsets.

Targeting drugs to the central nervous system (CNS) is challenging due to the presence of the blood-brain barrier. (BBB). The cutting edge in nanotechnology generates optimism to overcome the growing challenges in biomedical sciences through effective engineering of nanogels. The primary objective of the present report was to develop and characterize biocompatible natural chitosan (CS)-based NG that can be tracked thanks to the tricarbocyanine (CNN) fluorescent probe addition of the biopolymer backbone. FTIR shed light on the chemical groups involved in the CS and CNN interactions and between CNN-CS with tripolyphosphate, the cross-linking agent. Both in vitro and in vivo experiments were carried out to determine if CS-NG can be utilized as therapeutic delivery vehicles directed towards the brain. An ionic gelation method was chosen to generate cationic CNN-CS-NG. DLS and TEM confirmed that these entities size fell into nanoscale. CNN-CS-NG was found to be non-cytotoxic as determined in the SH-SY5Y neuroblastoma cell line through biocompatibility assays. After cellular internalization, the occurrence of an endo-lysosomal escape (a crucial event for an efficient drug delivery) of CNN-CS-NG was detected. Furthermore, CNN-CS-NG administered intraperitoneally to female CF-1 mice were detected in different brain regions after 2 h of administration using fluorescence microscopy. To conclude, the obtained findings in the present report can be useful in the field of neuro-nanomedicine when designing drug vehicles with the purpose of delivering drugs to the CNS.

Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). In murine models, chronic SF can impair endothelial function and induce cognitive declines. These deficits are likely mediated, at least in part, by alterations in Blood-Brain Barrier (BBB) integrity. Male C57Bl/6J mice were randomly assigned to SF or sleep control (SC) conditions for 4 or 9 weeks, and in a subset 2 or 6 weeks of normal sleep recovery. Presence of inflammation and microglia activation were evaluated. Explicit memory function was assessed with the novel object recognition (NOR) test, while BBB permeability was determined by systemic dextran-4kDA-FITC injection and Claudin 5 expression. SF exposures resulted in decreased NOR performance and in increased inflammatory markers and microglial activation as well as enhanced BBB permeability. Explicit memory and BBB permeability were significantly associated. BBB permeability remained elevated after 2 weeks of sleep recovery (p<0.01) and returned to baseline values only after 6 weeks. Chronic SF exposures mimicking the fragmentation of sleep that characterizes patient with OSA elicits evidence of inflammation in brain regions and explicit memory impairments in mice. Similarly, SF is also associated with increased BBB permeability, the magnitude of which is closely associated with cognitive functional losses. Despite normalization of sleep patterns, BBB functional recovery is a protracted process that merits further investigation.

The lymphatic system of the brain meninges and head plays a crucial role in the clearance of amyloid-β protein (Aβ), a peptide thought to be pathogenic in Alzheimer’s disease (AD), from the brain. The development of methods to modulate lymphatic clearance of Aβ from the brain coild be a revolutionary step in the therapy of AD. The opening of the blood-brain barrier (OBBB) by focused ultrasound is considered as a possible tool for stimulation of clearance of Aβ from the brain of humans and animals. Here, we propose an alternative method of non-invasive music-induced OBBB that is accompanied by the activation of clearance of fluorescent Aβ (Fαβ) from the mouse brain. Using confocal imaging, fluorescence microscopy and magnetic resonance tomography, we clearly demonstrate that OBBB by music stimulates the movement of Fαβ and Omniscan in the cerebrospinal fluid and lymphatic clearance of Fαβ from the brain. We propose the extended detrended fluctuation analysis (EDFA) as a promising method for the identification of OBBB markers in the electroencephalographic (EEG) patterns. These pilot results suggest that music-induced OBBB and the EDFA analysis of EEG can be a non-invasive, low cost, labelling free, clinical perspective and completely new approach for the treatment and monitoring of AD.

Cardiovascular risk factors (CRFs) such as hypertension, high cholesterol, and diabetes are increasingly implicated in cognitive decline and cerebral small vessel disease (cSVD). White matter hyperintensities (WMH), a hallmark of cSVD, are strongly linked to cognitive impairment, but their underlying mechanisms remain unclear. Blood-brain barrier (BBB) dysfunction has been proposed as a potential contributor to WMH development. This study aimed to explore the relationships between CRFs, BBB integrity, and WMH burden. We analyzed 155 participants from the Biomarkers and Cognition Study, Singapore, assessing CRFs through blood tests for glucose and lipid profiles, alongside blood pressure measurements. WMH volume was quantified using MRI, and an in vitro assay evaluated the impact of plasma on BBB integrity using human brain microvascular endothelial cells. Results showed that plasma from participants with higher WMH burden correlated with increased BBB disruption, which was further associated with higher blood pressure, elevated blood glucose, and lipid levels. Both periventricular and subcortical WMH were linked to BBB disruption. These findings suggest that CRFs contribute to BBB dysfunction, promoting WMH development and cognitive decline in cSVD. Further research is needed to clarify the precise mechanisms driving these associations.

Background/Aims: Obstructive sleep apnea syndrome (OSAS) affects a large part of the aging population. It is characterized by chronic intermittent hypoxia and associated with neurocognitive dysfunction. One hypothesis is that the blood-brain barrier (BBB) functions could be altered by exosomes. Exosomes are nanovesicles found in biological fluids. Through the study of exosomes and their content in tau and amyloid beta (Ab), the aim of this study was to show how exosomes could be used as biomarkers of OSAS and of their cognitive disorders. Methods: Two groups of 15 volunteers from the PROOF cohort were selected: severe apnea (AHI >30) and control (AHI <5). After exosome isolation from blood serum, we characterized and quantified them (CD81, CD9, CD63) by western blot and ELISAs and put them 5h in contact with an in vitro BBB model. The apparent permeability of the BBB was measured using sodium-fluorescein and TEER. Cell ELISAs were performed on tight junctions (ZO-1, claudin-5, occludin). The amount of tau and Ab proteins found in the exosomes was quantified using ELISAs. Results: Compared to controls, OSAS patients had a greater quantity of exosomes, tau and Ab proteins in their blood sera, which induced an increase in BBB permeability in the model and was reflected by a loss of tight junction’expression. Conclusion: Elderly patients suffering severe OSAS released more exosomes in serum from the brain compartment than controls. Such exosomes increased BBB permeability. The impact of such alterations on risk of developing cognitive dysfunction and/or neurodegenerative diseases is questioned.

Neurodegenerative diseases encompass a broad spectrum of profoundly disabling disorders that impact millions of individuals globally. While their underlying causes and pathophysiol-ogy display considerable diversity and remain incompletely understood, a mounting body of evidence indicates that the disruption of blood-brain barrier (BBB) permeability, resulting in brain damage and neuroinflammation, constitutes a shared characteristic among them. Con-sequently, targeting the BBB has emerged as an innovative therapeutic strategy for address-ing neurological diseases. Within this review, we not only explore the neuroprotective, neu-rotrophic, and immunomodulatory benefits of mesenchymal stem cells (MSCs) in combating neurodegeneration but also delve into their recent role in modulating the BBB. We will delve into the cellular and molecular mechanisms through which MSC treatment impacts primary age-related neurological disorders like Alzheimer’s disease, Parkinson’s disease, and stroke as well as immune-mediated conditions such as multiple sclerosis. Our focus will center on how MSCs participate in the modulation of cell transporters, matrix remodeling, stabilization of cell-junction components, and restoration of BBB network integrity in these pathological con-texts.

The appearance of brain metastasis is the most serious complication of breast cancer with mostly fatal outcomes. To reach the brain, tumor cells need to pass the blood-brain barrier (BBB). The molecular mechanisms underlying penetration of the BBB are largely unknown. Previously we found that tumor-infiltrating T lymphocytes enhance the development of brain metastasis of estrogen receptor-negative (ER-) breast cancer. In the current study, we investigate the contribution of T lymphocytes and the IFN- pathway in enabling breast cancer cells to pass the in vitro BBB. CD8+ cells display the strongest stimulatory effect on breast cancer cell passage. We show that inhibition of the IFN- receptor in MDA-MB-231 breast cancer cells, or neutralization of soluble IFN-, impairs the in vitro trespassing of breast cancer cells. Importantly, we validated our findings using gene expression data of breast cancer patients. CXCL-9,-10,-11/CXCR3 axis, dependent on IFN- signaling activity, was overexpressed in primary breast cancer samples of patients who developed brain metastasis. The data support a role for T-lymphocytes and the IFN- pathway in the formation of brain metastasis of ER- breast cancer, and offer targets to design future therapies for preventing breast cancer cells to cross the BBB.

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of blood-brain barrier (BBB) seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aβ aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.

Dynamic contrast-enhanced MRI (DCE-MRI) is increasingly used to quantify and map the spatial distribution of blood-brain barrier (BBB) leakage in neurodegenerative disease, including cerebral small vessel disease and dementia. However, the subtle nature of leakage and resulting small signal changes make quantification challenging. While simplified one-dimensional simulations have probed the impact of noise, scanner drift, and model assumptions, the impact of spatio-temporal effects such as gross motion, k-space sampling and motion artefacts on parametric leakage maps has been overlooked. Moreover, evidence on which to base the design of imaging protocols is lacking due to practical difficulties and the lack of a reference method. To address these problems, we present an open-source computational model of the DCE-MRI acquisition process for generating four-dimensional Digital Reference Objects (DROs), using a high-resolution brain atlas and incorporating realistic patient motion, extra-cerebral signals, noise and k-space sampling. Simulations using the DROs demonstrated a dominant influence of spatio-temporal effects on both the visual appearance of parameter maps and on measured tissue leakage rates. The computational model permits a greater understanding of the sensitivity and limitations of subtle BBB leakage measurement and provides a non-invasive means of testing and optimising imaging protocols for future studies.

Mild traumatic brain injury mTBI is a common occurrence around the world, associated with a variety of blunt force and torsion injuries affecting all age groups. Most never reach medical attention, and identification of acute injury and later clearance to return to usual activities is relegated to clinical evaluation particularly in sports injuries. Advanced structural imaging is rarely performed due to the usual absence of associated acute anatomic/hemorrhagic changes. This review targets physiologic imaging techniques available to identify subtle blood brain barrier dysfunction and white matter tract shear injury, and their association with chronic traumatic encephalopathy. These techniques provide needed objective measures to assure recovery from injury in those patients with persistent cognitive/emotional symptoms and in the face of repetitive mTBI.

There is a huge interest in developing novel hollow fiber (HF) membranes able to modulate neural differentiation to produce in vitro blood-brain barrier (BBB) models for biomedical and pharmaceutical research, due to the low cell-inductive properties of the polymer HFs used in current BBB models. In this work, poly(ε-caprolactone) (PCL) and composite PCL/graphene (PCL/G) HF membranes were prepared by phase inversion and were characterized in terms of mechanical, electrical, morphological, chemical, and mass transport properties. The presence of graphene in PCL/G membranes enlarged the pore size and the water flux and presented significantly higher electrical conductivity than PCL HFs. Biocompatibility assay showed that PCL/G HFs significantly increased C6 cells adhesion and differentiation towards astrocytes, may be attributed to their higher electrical conductivity in comparison to PCL HFs. On the other hand, PCL/G membranes produced a cytotoxic effect on the endothelial cell line HUVEC presumably related with a higher production of intracellular reactive oxygen species induced by the nanomaterial in this particular cell line. These results prove the potential of PCL HF membranes to grow endothelial cells and PCL/G HF membranes to differentiate astrocytes, the two characteristic cell types that could develop in vitro BBB models in future 3D co-culture systems.

Background. Transferrin receptor 1 (TfR1), glucose transporter 1 (GLUT1), and CD98hc are candidates for targeted therapy at the blood-brain barrier (BBB). Our objective was to challenge the expression of TfR1, GLUT1, and CD98hc in brain capillaries by the histone deacetylase inhibitor (HDACi) valproic acid (VPA). Methods. Primary mouse brain capillary endothelial cells (BCECs) and brain capillaries isolated from mice injected intraperitoneally with VPA were examined using RT-qPCR and ELISA. Targeting to the BBB was performed by injecting monoclonal anti-TfR1 (Ri7217)-conjugated gold nanoparticles measured using ICP-MS. Results. In BCECs co-cultured with glial cells, Tfrc mRNA expression was significantly higher after 6 h VPA returning to baseline after 24 h. In vivo Glut1 mRNA expression was significantly higher in males, but not females', receiving VPA, whereas Cd98hc mRNA expression was unaffected by VPA. TfR1 increased significantly in vivo after VPA, whereas GLUT1 and CD98hc were unchanged. Uptake of anti-TfR1-conjugated nanoparticles was unaltered by VPA in spite upregulated TfR expression. Conclusions. VPA upregulates TfR1 in brain endothelium in vivo and in vitro. VPA does not increase GLUT1 and CD98hc proteins. The increase in TfR1 does not result in higher anti-TfR1 antibody targetability, suggesting targeting sufficiently occurs with available transferrin receptors without further contribution from accessory VPA-induced TfR1.

This review article focuses on the upstream pertinent pathophysiology leading to neurodegenerative disease. Specifically, the nexus appears to be blood brain barrier (BBB) leakiness resulting in a two-prong inflammatory disease spectrum damaging the microvasculature and corrupted protein synthesis and degradation with accumulating misfolded toxic proteins. The suboptimal results of removing misfolded proteins means a new approach to disease in the preclinical state is required aimed at other targets.Validated noninvasive imaging and serologic biomarkers of early preclinical disease implemented in the high-risk patient cohort along with periodic surveillance once effective treatments are developed will be required.This review discusses the physiology and pathophysiology of the BBB, new MRI imaging techniques identifying the leak and altered fluid dynamic effects in the preclinical state. The risk factors for disease development, preventative measures, and potential treatment targets are also discussed.

Natural killer (NK) cell therapy is one of the most promising treatments for Glioblastoma Multiforme (GBM). However, this emerging technology is limited by the availability of sufficient numbers of fully functional cells. Here, we investigated the efficacy of NK cells that were expanded and treated by interleukin-2 (IL-2) and heat shock protein70 (HSP70), both in vitro and in vivo. Proliferation and cytotoxicity assays were used to assess the functionality of NK cells in vitro, after which treated and naïve NK cells were administrated intra-cranially and systemically to compare the potential antitumor activities in our in vivo rat GBM models. In vitro assays provided strong evidence of NK cell efficacy against C6 tumor cells. In vivo tracking of NK cells showed efficient homing around and within the tumor site. Furthermore, significant amelioration of the tumor in rats treated with HSP70/Il-2 treated NK cells as compared to those subjected to non-treated NK cells, as confirmed by MRI, proved the efficacy of adoptive NK cell therapy. Moreover, results obtained with systemic injection confirmed migration of activated NK cells over the blood brain barrier and subsequent targeting of GBM tumor cells. Our data suggest that administration of HSP70/Il-2 treated NK cells may be a promising therapeutic approach to be considered in the treatment of GBM.

Temporal lobe epilepsy (TLE) is associated with reorganization of hippocampal neuronal net-works, gliosis, neuroinflammation, loss of integrity of the blood-brain barrier (BBB) in humans and animal models. More than 30% of epilepsies remain intractable and characterization of the molecular mechanisms involved in BBB dysfunction is essential to the identification of new thera-peutic strategies. In this work, we induced status epilepticus in rats by injection of the proconvul-sant drug pilocarpine that leads to TLE. Using RT-qPCR, double immunohistochemistry and con-focal imaging, we studied at different time points of epileptogenesis (latent phase, 3, 7, 14 days; chronic phase, 1 and 3 months) the regulation of reactive glia and vascular markers. In the hippo-campus, increased expression of mRNA encoding the glial proteins GFAP and Iba1 confirmed neu-roinflammatory status. We report for the first time the concomitant induction in endothelial cells, pericytes and basement membrane of the BBB of specific proteins CD31, PDGFR and ColIV, that peaks at the same time points as inflammation. The altered expression of these proteins occurs ear-ly in TLE, during the latent phase, suggesting that they could be associated with early rupture and pathogenicity of the BBB that will contribute to the chronic phase of epilepsy.

Here, we review findings and trends in sleep research in 2020-2021 demonstrating how COVID-19 and sleep disorders can induce the BBB leakage via neuroinflammation, which might contribute to the 'coronasomnia' phenomenon. The new studies suggest that the controlling of sleep hygiene and quality should be incorporated into the rehabilitation of COVID-19 patients. We also discuss perspective strategies for prevention of COVID-19-related BBB disorders. We demonstrate that sleep might be a novel biomarker of the BBB leakage and the analysis of sleep EEG patterns can be a breakthrough non-invasive technology for diagnosis of the COVID-19-caused BBB disruption.

The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical for the development of autoimmune inflammation in the central nervous system (CNS). TNF-a or IL-17 stimulation is known to enhance the adherence of Th17 cells to the brain endothelium. The brain endothelial cells (bEnd.3) express VCAM-1, the receptor responsible for inflammatory cell adhesion, which binds VLA-4 on migrating effector lymphocytes at the early stage of brain inflammation. The present study examines the effect of the pro-inflammatory cytokines TNF-a and IL-17 on the adherence of Th17 cells to bEnd.3 The bEnd.3 cells were found to increase production of CCL2 and CXCL1 after stimulation by pro-inflammatory cytokines, while CCL2, CCL5, CCL20 and IL17 induced Th17 cell migration through a bEnd.3 monolayer. This interaction between Th17 cells and the brain endothelium appears to be mediated by VCAM-1 and some chemotactic cytokines. This observation may suggest potential therapeutic targets for the prevention of autoimmune neuroinflammation development in the CNS.

Magnetic Nanoparticles (MNPs) is a promising technique to cure brain diseases. On the one hand, by serving as drug carriers, they can bypass the blood-brain barrier and deliver drug molecules to the brain parenchyma; on the other hand, their transport trajectory can be manipulated by applying an external magnetic field. However, due to the complex microstructure of brain tissues, e.g. the anisotropy of white matter (WM), how to achieve desired drug distribution patterns, e.g. uniform distribution, by tuning the drug delivery system is largely unknown. Here, in this study, by adopting a mathematical model capable of capturing the diffusion trajectories of MNPs in the microstructures, we systematically investigated the effects of key parameters in the MNPs delivery system on the equivalent diffusion coefficient of MNPs in the microenvironment of brain WM. The results show that uniform distribution of MNPs in anisotropic tissues can be achieved by adjusting the particle size and magnetic field. We have not only obtained a deeper understanding on how to optimise the MNPs delivery system, it can also be anticipated that an improved mathematical model could even help to achieve complex drug distribution patterns in the complicated brain environment by designing an appropriate combination of the key parameters.

Background: Mounting evidence supports the role of the endocannabinoid system in neurophysiology, includ-ing blood-brain barrier (BBB) function. Recent work has demonstrated that activation of endocannabinoid re-ceptors can mitigate insults to the BBB during neurological disorders, like traumatic brain injury, cortical spreading depression and stroke. As alterations to the BBB are associated with worsening clinical outcomes in these conditions, studies herein sought to examine the impact of endocannabinoid depletion on BBB integrity. Methods: Barrier integrity was investigated in vitro via bEnd.3 cell monolayers to assess endocannabinoid syn-thesis, barrier function, calcium influx, junctional protein expression, and proteome-wide changes. Results: In-hibition of 2-AG synthesis using DAGLα inhibition and siRNA inhibition of DAGLα led to loss of barrier in-tegrity via altered expression of VE-cadherin, which could be partially rescued by exogenous application of 2-AG. Moreover, the deleterious effects of DAGLα inhibition on BBB integrity showed both calcium and PKC (protein kinase C)-dependency. Conclusions: These data indicate that disruption of 2-AG homeostasis in brain endothelial cells, in the absence of insult, is sufficient to disrupt BBB integrity thus supporting the role of the endocannabinoid system in neurovascular disorders.

Insulin receptors are internalized by endothelial cells; however, the impact of hyperinsulinemia on this process is not known. Thus, the aim of this study is to determine the role of hyperinsulinemia on insulin receptor function and internalization, as well as the potential impact of protein tyrosine phosphatase 1B (PTP1B). To this end, hippocampal microvessels were isolated from male C57Bl/6J mice on either a control or high-fat diet and assessed for insulin receptor signaling. Cell surface insulin receptors in brain microvascular endothelial cells were labelled with biotin to assess the role hyperinsulinemia plays on receptor internalization in response to stimulation, with and without Claramine treatment, a potent PTP1B antagonist. Our results indicated that insulin receptor levels increased in tandem with insulin receptor dysfunction in the high-fat diet mouse hippocampal microvessels. Hyperinsulinemic cell-receptors demonstrate a shift in splice variation towards decreased IR-A/IR-B ratios and demonstrate a higher membrane-localized proportion. This corresponded with decreased autophosphorylation at sites critical for receptor internalization and signaling, however, Claramine restored signaling and receptor internalization in hyperinsulinemic cells. In conclusion, hyperinsulinemia negatively impacts brain microvascular endothelial cell insulin receptor function and internalization, likely through both alternative splicing and increased negative feedback from PTP1B.

Pathologies of the blood brain barrier (BBB) have been linked to a multitude of CNS disorders whose pathology is poorly understood. Cortical spreading depression (CSD) has long been postulated to be involved in the underlying mechanisms of these disease states, yet full understanding remains elusive. This study utilized an in vitro model of the BBB with b.End3 murine endothelial cells to investigate the role of CSD in BBB pathology by characterizing effects of the release of major pronociceptive substances on BBB functional integrity using TEER screening, transcellular uptake, and immunoreactive methods in concert with global proteome and phospho-proteomic approaches. Findings demonstrated relocalization and functional alteration to proteins associated with the cytoskeleton and endothelial tight junctions. Pathologic mechanisms induced by individual substances released during CSD were found to have unique phosphorylation signatures in phospho-proteome analysis, identifying Zona Occludens 1 as a possible pathologic “checkpoint” of the BBB. Utilizing these phosphorylation signatures, possible novel diagnostic methods may be developed for neurological diseases and warrants further investigation.

Malignant gliomas are the most common primary brain tumors in adults up to an extent of 78% of all primary malignant brain tumors. However, total surgical resection is almost unachievable due to considerable infiltrative ability of glial cells. The efficacy of current multimodal therapeutic strategies is, furthermore, limited by the lack of specific therapies against malignant cells, and, therefore, the prognosis these in patients is still very unfavorable. The limitation of conventional therapies, which may result from inefficient delivery of the therapeutic or contrast agent to brain tumors are major reasons for this unsolved clinical problem. The major problem in brain drug delivery is the presence of the blood brain barrier which limits the delivery of many chemotherapeutic agents. Nanoparticles, thanks to their chemical configuration, are able to go through the blood-brain barrier carrying drugs or genes targeted against gliomas. Carbon nanomaterials show distinct properties including electronic properties, penetrating capability on the cell membrane, high drug-loading and pH-dependent therapeutic unloading capacities, thermal properties, large surface area and easy modification with molecules, which render them as a suitable candidate to deliver drugs. In this review we will focus on the potential effectiveness of the use of carbon nanomaterials in the treatment of malignant gliomas discussing the current progress of in vitro and in vivo researches of carbon nanomaterials-based drug delivery to brain.

Brain death (BD) concept has been increasingly widely accepted beginning since the late 1950s, but several controversies have appeared when intracranial pathology is localized to the posterior fossa. In the presence of a primary supratentorial brain lesion, a severe forebrain lesion is combined with either the subsequent gradual loss of brainstem function, due to rostrocaudal transtentorial brain herniation. In secondary brain lesions (i.e., cerebral hypoxia), the brainstem is also affected like the forebrain. However, a minority of patients with a primary infratentorial brain lesion (i.e., basilar artery thrombosis or brainstem or cerebellar bleeds) may retain cerebral blood flow and EEG activity. In this article I discuss that if a brainstem lesion does not provoke a massive increase of intracranial pressure there may be no complete cerebral circulatory arrest, explaining the preservation of EEG activity, evoked potentials, and autonomic function. I also discuss the case of Jahi McMath who was declared brain-dead, but ancillary tests, performed 9 months after initial brain insult, showed conservation of intracranial structures, EEG activity, and autonomic reactivity to “Mother Talks” stimulus, rejecting the diagnosis of BD. Jahi McMath’s MRI study demonstrated a huge lesion in the pons. Some authors have argued that in patients with primary brainstem lesions it might be possible to find a in some cases partial recover of consciousness, even fulfilling clinical BD criteria. This was the case in Jahi McMath. Further research and discussion are necessary about the use of ancillary tests in BD diagnosis in primary posterior fossa lesions.

The knowledge of the optical properties of biological tissues in a wide spectral range is highly important for the development of noninvasive diagnostic or treatment procedures. The absorption coefficient is one of those properties, from which various information about tissue components can be retrieved. Using transmittance and reflectance spectral measurements acquired from ex vivo rabbit brain cortex samples, allowed to calculate its optical properties in the ultraviolet to the near infrared spectral range. Melanin and lipofuscin, the two pigments that are related to the ageing of tissues and cells were identified in the cortex absorption. By subtracting the absorption of these pigments from the absorption of the brain cortex, it was possible to evaluate the true ratios for the DNA/RNA and hemoglobin bands in the cortex – 12.33 fold (at 260 nm), 12.02 fold (at 411 nm) and 4.47 fold (at 555 nm). Due to the fact that the accumulation of melanin and lipofuscin increases with the ageing of the brain tissues and are related to the degeneration of neurons and their death, further studies should be performed to evaluate the evolution of pigment accumulation in the brain to prevent the development of Alzheimer, Parkinson and stroke pathologies in the brain.

Abstract: The brain endothelial cell (BEC) glycocalyx (ecGCx) is a BEC surface coating consisting of a complex interwoven polysaccharide (sweet husk) mesh-like network of membrane-bound proteoglycans, glycoproteins, and glycosaminoglycans (GAGs) covering the apical luminal layer of the brain endothelial cells. The ecGCx may considered as the 1st barrier of a tripartite blood-brain barrier (BBB) consisting of 1) ecGCx; 2) BECs; (3) extravascular compartment of pericytes, extracellular matrix, and perivascular astrocytes, Perturbations of this barrier allow for increased permeability in the postcapillary venule that will be permissive to both fluids, solutes, and proinflammatory peripherally-derived leukocytes into the perivascular spaces (PVS) to result in enlargement as well as increased neuroinflammation. The ecGCx is known to have multiple functions, which include its physical and charge barrier, mechanical transduction, regulation of vascular permeability, modulation of inflammatory response, and anticoagulation functions. This review discusses each of the listed functions in detail and utilizes multiple transmission electron micrographs and illustrations to allow for a better understanding of the ecGCx structural and functional roles as it relates to enlarged perivascular spaces (EPVS). This is the 5th review of a series quintet that discuss the importance of EPVS from the perspective of the cells of brain barriers. Attenuation and/or loss of the ecGCx results in brain barrier disruption with increased permeability to proinflammatory leukocytes, fluids and solutes, which accumulate in the postcapillary venule perivascular spaces. This accumulation results in obstruction and results in EPVS with impaired waste removal of the recently recognized glymphatic system. Importantly, EPVS are progressively being regarded as a marker of cerebrovascular and neurodegenerative pathology.

The Neurovascular Unit (NVU), comprised of glia (astrocytes, oligodendrocytes, microglia), neurons, pericytes and endothelial cells, is a dynamic interface ensuring physiological functioning of the central nervous system (CNS), that gets affected and contributes to the pathology of several neurodegenerative diseases. Neuroinflammation is a common feature of neurodegenerative diseases and is primarily related to the activation state of perivascular microglia and astrocytes, which constitute two of its major cellular components. Our studies focus on monitoring in real time the morphological changes of perivascular astrocytes and microglia, as well as their dynamic interactions with the brain vasculature, under physiological conditions and following systemic neuroinflammation triggering both microgliosis and astrogliosis. To this end, we performed 2-photon laser scanning microscopy (2P-LSM) for intravital imaging of the cortex of transgenic mice visualizing the dynamics of microglia and astroglia following neuroinflammation induced by systemic administration of the endotoxin lipopolysaccharide (LPS). Our results indicate that following neuroinflammation the end-feet of activated perivascular astrocytes lose their close proximity and physiological crosstalk with vasculature, an event that most possibly contributes to a loss of blood-brain-barrier (BBB) integrity. At the same time, microglial cells get activated with more frequent contacts of the blood vessels. These dynamic responses of perivascular astrocytes and microglial are peaking at 4 days following LPS administration, however they still persist at a lower level 8 days after LPS, revealing incomplete reversal of inflammation affecting the glial properties and interactions with the NVU.

Emerging evidence demonstrated that using a new manufacturing technology to produce γ-aminobutyric acid (GABA)-fortified oolong (GO) tea could relieve human stress and exert versatile physiological benefits. The purpose of this human research aims to investigate therapeutic effects of daily GO tea consumption on the improvement of blood pressure, relaxation-related brain waves and quality of life (QOL) during a period of 28 consecutive days. Total polyphenols, major catechins and free amino acids were analyzed via HPLC assay. Changes of heart rate, blood pressure, α-brain wave (index of relaxation) and eight-item QOL score were investigated on day 0, 7, 14, 21 and 28, respectively. The chemical analysis results showed that GO tea contained the most abundant amino acids and GABA, contributing to the relaxation activity. Among all study participants, daily drinking GO tea could reduce systolic blood pressure on day 21 and diastolic blood pressure on day 28 (p &lt; 0.05, respectively). For participants with pre-hypertension, GO tea could effectively reduce heart rate, systolic and diastolic blood pressure on day 28 (p &lt; 0.05). At the end of the study, incremental changes in alpha-brain wave and QOL scores were also demonstrated (p &lt; 0.05, respectively). This study recommended that GO tea might potentially serve as a natural source of alternative therapy to benefit blood pressure, stress-relief and QOL.

Focal cerebral ischemia can lead to blood-brain barrier (BBB) breakdown, which is implicated in neuroinflammation and elevation of matrix metalloproteinases (MMPs). The role of the anti-inflammatory protein, monocyte chemotactic protein–induced protein 1 (MCPIP1) plays in the injury of BBB in stroke has not yet been reported. This study was conducted to identify and characterize the role MCPIP1 plays in BBB breakdown. Transient middle cerebral artery occlusion (MCAO) is induced in both wild-type and Mcpip1^-/- mice for 2 hours of occlusion periods followed by reperfusion for 24 or 48 hours. BBB permeability was measured by FITC-dextran extravasation, MMP-9/3 expression was analyzed by western blot, and claudin-5 and zonula occludens-1 (ZO-1) were analyzed by immunohistochemistry and western blot. After MCAO in wild type mouse is induced, there is significantly increase in MCPIP1 mRNA and protein levels. Absence of MCPIP1 leaded to significant increase in FITC-dextran leakage in peri-infarct brain, significant upregulation of MMP-9, MMP-3 and reduced levels of tight junction components, claudin-5 and ZO-1 in the brain after MCAO. Our data demonstrate that absence of MCPIP1 exacerbates ischemia-induced blood-brain barrier disruption by enhancing the expression of matrix metalloproteinases and degradation of tight junction proteins. Overall data indicate that MCPIP1 is important protective role against BBB disruption in cerebral ischemia.

A frequent co-morbidity of cerebrovascular pathology and Alzheimer's disease pathology has been observed over past decades. Accordingly, much evidence has been reported which indicates that microvascular endothelial dysfunction, due to cerebrovascular risk factors (e.g., atherosclerosis, obesity, diabetes, smoking, hypertension, aging), precedes cognitive decline in Alzheimer's disease and contributes to its pathogenesis. By incorporating appropriate drug(s) into biomimetic (lipid cubic phase) nanocarriers, one obtains a multitasking combination therapeutic which targets certain cell-surface scavenger receptors, mainly class B type I (i.e., SR-BI), and crosses the blood-brain barrier (BBB). Such targeting allows for various Alzheimer's-related cell types to be simultaneously searched out, in vivo, for localized drug treatment. This in vivo targeting advantage may be particularly important for repurposing an FDA-approved drug, especially one which has shown the added ability to restore some cognitive functions in certain animal models of Alzheimer's disease (e.g., the anticancer drug bexarotene); this (candidate repurposing) drug up to now, by itself (i.e, without nanocarrier), displayed poor CNS penetration in human subjects.

The importance of PAs for CNS functions are well known. Less clear is, however, where PAs in the brain are derived from. Principally, there are three possibilities: (i) intake by nutrition, release into the bloodstream, and subsequent uptake from CNS capillaries, (ii) products of parenchymatous organs as the liver, and again uptake from CNS capillaries, and (iii) uptake of precursors such as arginine from the blood and subsequent local biosynthesis of polyamines within the CNS.The present investigation aimed to unequivocally answer the question, whether PAs, especially the higher ones like SPD and SPM can or cannot be taken up into the brain from the bloodstream. For this purpose a biotin-labelled analogue of SPM was synthesized, characterized, and used to visualize its uptake into brain cells subsequent to application to surviving brain slices, to the intraventricular space, or to the bloodstream.In surviving slices uptake of B-X-SPM is massive into protoplasmic and absent in fibrous type astrocytes. It is also taken up by neurons but to a lesser degree. Under in-vivo conditions astrocyte uptake of biotinylated SPM also is massive from the brain interstitial fluid subsequent to intraventricular application. In contrast, following intracardial injection there is no uptake from the bloodstream, indicating that the brain is completely dependent on the local synthesis of polyamines.

People who suffer a mild traumatic brain injury (mTBI) have heterogeneous symptoms and disease trajectories, which make it difficult to precisely diagnose and assess complications long-term. Insufficient information is available regarding how to precisely diagnose and assess mTBI. This study identified and compared deficits in cognitive, psychosocial, visual functions, and balance performance between college students with and without histories of mTBI. Global DNA methylation ratio (5-mC%) in blood was also compared as a peripheral epigenetic marker. Twenty-five volunteers participated in this pilot study, including 11 mTBI cases (27.3% females; mean age of 28.7 years, SD=5.92) and 14 healthy controls (64.3% females; mean age of 22.0, SD=4.13). All the participants were assessed for cognitive (by NIH toolbox—executive function, memory, and processing speed), psychological (by PROMIS—depression, anxiety, and sleep disturbances), visual function (by King-Devick and binocular accommodative tests), postural balance performance (by a force plate), and blood 5-mC% (global methylation) levels. Students with mTBI reported significantly poorer episodic memory, severe anxiety, and more sleep disturbance problems. They also had higher blood 5-mC% level (all p’s<.05). No significant differences were found in visual function and postural balance. These findings validate changes in cognitive, psychosocial, and global DNA methylation long after mTBI.

Survivors of severe brain injury may require care in a neurointensive care unit (neuro-ICU), where the brain is vulnerable to secondary brain injury. Thus, there is a need for noninvasive, bedside, continuous cerebral blood flow monitoring approaches in the neuro-ICU. Our goal is to address this need through combined measurements of EEG and functional optical spectroscopy (EEG-Optical) instrumentation and analysis to provide a complementary fusion of data about brain activity and function. The present case demonstrates in a patient with traumatic brain injury, noninvasive cerebral blood flow transients can be recorded that correlate with gold-standard invasive measurements and with the frequency content changes in the EEG data during clinical care.

Background: Several kinds of research say that adjuvant blood glucose and blood pressure are usual, but an efficient solution for medical application count remains. This review analyzes the pandemic blood pressure and blood glucose to identify the publications which tell about the clinical practices and research gaps in systematic research.Methods: A study guides to identify the research of Blood Pressure (BP) and Blood Glucose. In order to analyze the recent innovations and research on BP and Blood glucose, the relevant publications and literature from journals were identified.Results: Co-morbidity of BP and Blood glucose is reported as very high. The commonness of blood pressure is thrice as high in type I diabetes patients and almost two times higher in type II diabetes patients when compared to others without Diabetes. The pervasiveness of getting depression is more in the female when compared with men. A detailed study about the linkage of BP and blood glucose tells that the relationship between them is not exactly clear.Limitations: Nearly all reviews providing the linkage of BP and blood glucose are with some limitations and they are not providing any clear conclusion.Conclusions: Present research tells that people having high blood glucose will have a greater chance of getting high blood pressure. More research is needed to state the linkage between BP, blood glucose, and the growth of diabetes mellitus issues and to provide support for managing Diabetes.

Following traumatic brain injury (TBI), secondary brain damage due to chronic inflammation is the most predominant cause of the delayed onset of mood and memory disorders. Currently no therapeutic approach is available to effectively mitigate secondary brain injury after TBI. One reason is the blood-brain barrier (BBB), which prevents passage of most therapeutic agents into the brain. Peptides have been among the leading candidates for CNS therapy due to their low immunogenicity and toxicity, bioavailability, and ease of modification. In this study, we demonstrated that non-invasive intranasal administration of KAFAK, a cell penetrating anti-inflammatory peptide, traversed the BBB in a murine model of diffuse, moderate TBI. Notably, KAFAK treatment reduced the production of pro-inflammatory cytokines that contribute to secondary injury. Furthermore, behavioral tests showed improved or restored neurological, memory, and locomotor performance in KAFAK-treated mice. This study demonstrates KAFAK's ability to cross the blood-brain barrier, to lower pro-inflammatory cytokine levels in vivo, and to restore function after a moderate TBI.

Background: High blood pressure (BP) has been implicated as a major risk factor for cardiovascular diseases in several global populations, including in individuals of African ancestry. Despite the elevated burden of high BP-induced cardiovascular diseases in Africa and other global populations with African ancestry, limited genetic studies have been carried out to explore the genetic machinery driving this phenomenon. Methods: We performed univariate and multivariate analyses using Genome-wide association studies (GWAS) and summary statistics data of 77,850 individuals of African ancestry for systolic (SBP) and diastolic blood pressure (DBP) traits. The six independent cohorts used included individuals derived from the African Partnership for Chronic Disease Research (APCDR), the UK Biobank, and the Million Veteran Program (MVP). Subsequently, we annotated, prioritized, visualized, and interpreted our meta-analyses results using FUMA, to gain further insight into the molecular mechanism(s) that contribute to the genetics of BP traits. Finally, loci attaining genome-wide significance, GWS (p<5x10-8) were also followed up with Bayesian fine-mapping to identify potential causal variants. Results: Our meta-analyses altogether identified 350 GWAS SNPs for SBP (166 SNPs) and DBP (184 SNPs, including two novel loci) whilst our multivariate GWAS method identified 166 SNPs (including three novel loci). Interestingly, in FUMA there was significant tissue enrichment of up-regulated differentially expressed genes (DEGs) in the sigmoid and transverse colon for SBP, as well as 10 significant gene sets from MAGMA gene set analyses, However, for DBP, no significant DEGs nor gene sets in MAGMA were found; instead, in DBP for gene property analysis for tissue specificity nine candidates were found to be significant and all nine were in different brain regions. Finally, Bayesian fine-mapping revealed that only 11 variants from the lead SNPs had >50% posterior probability (PP) of being causal and they included novel variant rs562545 (MOBP, PP = 77%) and 10 other previously published variants. Conclusion: Our results demonstrate the importance of performing GWAS in large sample sizes of global populations of African ancestry, including continental Africans; which yield novel insights, from novel loci to novel pathways/tissue expression candidates. Large-scale genomic datasets are required to enhance further discovery and fine-mapping of high-risk loci/variants in highly susceptible groups for cardiovascular disease and other related traits. Our study highlights the need for diversity in genetic research and the importance of expanding large GWASs to include ancestrally diverse populations.

The study aimed to showcase how implementing a patient blood management (PBM) program effectively cut unnecessary red blood cell (RBC) transfusions in a New York City urban community teaching hospital. Analyzing seven years from 2013 to 2019, a retrospective review of RBC transfusions was conducted. Following PBM introduction, considerable improvements were observed annually. These included a drop in mean pretransfusion hemoglobin levels from 7.26g/dL (2013) to 6.58g/dL (2019), a 34% reduction in yearly RBC unit transfusions, and fewer units given to patients with pre-Hgb levels ≥7g/dL (1210 units in 2013 to 310 units in 2019). Furthermore, the study noted a decline in two-unit RBC orders when Hgb levels were ≥7g/dL from 65 orders in 2013 to merely 3 in 2019. The estimated total cost-savings attributed to the six-year PBM program duration after full implementation in 2014 amounted to $2.1 million US dollars. Overall, PBM implementation significantly decreased RBC transfusions and enhanced transfusion practices. The findings emphasize that successful PBM strategies don't always necessitate extensive resources or increased budgets but instead rely on the application of intuitive methods, as evidenced by this study.

The signs and symptoms of Long COVID can be explained by a shortage of blood in the body and a resulting deficient blood flow through nearly all organs. This shortage arose during the acute phase of COVID19 by an increased breakdown of haematocytes, to which the liver responds by reducing the production of plasma, in order to prevent a too large decrease in haematocrit. In order to ensure the perfusion of organs that are directly necessary for survival, the body takes the emergency measure of diverting blood from other organs and tissues. The perfusion of the blood-producing organs is also affected by this distribution measure, which hinders the smooth recovery of the total blood volume. The body is stuck in this vicious circle: a shortage of circulating blood hinders the recovery of blood production. This explains the long duration of Long COVID. My proposed treatment of Long COVID focuses on the recovery of the correct volume of blood in the body of the right composition by the intravenous administration of donor blood products, starting with albumin concentrate. A trial treatment can be performed in any hospital without much additional preparations, and has a lower associated risk for the patient than analysing the total blood. A diagnosis ex juvantibus, by therapeutic response, is therefore preferable. I suspect that we will find a haematocrit value at the high extreme of the reference range, and an albumin value at the low extreme of the reference range in most Long COVID patients before the start of the treatment, because the liver can not keep up with the recovery of the red bone marrow.

The purpose of this work was to evaluate a novel methodology developed by Digital Blood Corporation (DBC) to calculate critical blood values using four non-invasive measured values as input. The values obtained using a point-of-care testing (POCT) device were utilized for comparison and reference. Radial arterial blood was collected for the POCT comparator analysis using the Abbott i-STAT^® device. The non-invasive methodology from DBC requires four parameters to be directly measured: temperature, hemoglobin, pO2, and pCO2. Subsequently, sodium, potassium, chloride, ionized calcium, total carbon dioxide, pH, bicarbonate, and oxygen saturation are calculated using an algorithm. The agreement between the POCT and DBC’s methodology was analyzed using Bland-Altman difference plots. For a second data set, pO2 and pCO2 values collected with the POCT were used as input for DBC’s algorithm to test its robustness. Data from 37 healthy ambulatory individuals, mean age: 42.4 + 13 years; range: 18-64 years, were included in the primary analysis. In the case of the non-invasive gained four input values the greatest variation between POCT and DBC’s approach was observed for pO2 and consequently for algorithm values that depend upon pO2 precision. Replacing transcutaneous pO2 and pCO2 with POCT values demonstrates the principal ability of DBC’s algorithm to predict the additional 8 blood values in sufficient agreement with a standard POCT device in healthy patients. The algorithm developed by DBC appears to be robust in the case of healthy patients but does need the four measured input values with preciseness comparable to a POCT device to give reliable and clinically relevant results. The present study thus serves as a proof of concept to facilitate future study and further development of this methodology into a non-invasive device.

(1) Background: This study aimed to evaluate whether the implementation of a modified blood sampling protocol, which focused on need-based laboratory testing and minimized venous sampling by replacing it with point-of-care testing (POCT) via capillary puncture, successfully reduced iatrogenic blood loss, incidence of anemia, and frequency of blood transfusion in extremely low birth weight infants (ELBWIs) without negatively affecting neonatal outcomes. (2) Methods: A retrospective analysis was conducted on 313 ELBWIs of gestational age (GA) between 23 and 28 weeks, born between 2013 and 2019. The infants were divided into two groups: before (period I) and after (period II) the implementation of the modified blood sampling protocol in January 2016. Propensity score matching was conducted to minimize selection bias. Clinical data, including the frequency and amount of blood sampling, frequency and volume of blood transfusion, and clinical characteristics, such as gestational age, birth weight, and neonatal outcome data, were collected and compared between the two groups. (3) Results: No significant differences in the GA or birth weight between the two periods were observed. The total sampling volume during a month after birth (16.7 ± 4.1 mL vs. 15.6 ± 4.4 mL, P=0.03) and total sampling volume during hospital days (51.4 ± 29.7 mL vs. 44.3 ± 27.5 mL, P=0.04) in period II were significantly lower than that in period I. There were no differences in the mortality or morbidity between the two periods. Although the transfusion frequency and amount did not have significant differences between the periods, we observed a positive correlation between the transfusion frequency and sampling volume (coefficient: 0.09, 95% CI: 0.08–0.11). (4) Conclusions: The modified blood sampling protocol effectively reduced the iatrogenic blood loss without negatively affecting the neonatal outcomes.

BACKGROUND Detecting total cholesterol in dried blood spots could aid in identifying individuals with a high likelihood of familial hypercholesterolemia and could be used as a screening measure. This study aims to assess the diagnostic accuracy of dried blood spots on Whatman 903 paper cards using a manual enzymatic technique. METHODS A total of 394 samples collected as serum and dried blood spots were compared. Cholesterol was determined in serum using the automated reference method, while cholesterol on paper was measured using a manual enzymatic method. Within- and between-day diagnostic variability were analyzed. The correlation between both methods was assessed using Passing-Bablok regression and Bland-Altman plot. Internal validation of our correlation formula was performed on 149 samples, along with external validation of the formula proposed by Corso et al. RESULTS The within- and between-day coefficient of variation was found to be lower than 10.14% and 14.09%, respectively. Method comparison yielded an area under the curve of 0.976, with a standard error of 0.009. Passing-Bablok regression indicated a precision of 0.803 and an accuracy of 0.96. Internal validation precision was measured at 0.716. Regarding internal validation, calculated cholesterol with our regression line did not differ from serum cholesterol analysis, while significant differences were observed in calculated cholesterol levels using the external formula. CONCLUSIONS Total cholesterol analysis in dot blood spots demonstrates high precision and reproducibility. This method reliably enables the incorporation of this biological marker into neonatal screening for familial hypercholesterolemia detection.

Combined radiation with hemorrhage (combined injury, CI), exacerbates hematopoietic acute radiation syndrome and mortality compared to radiation alone (RI). We evaluated the effects of RI or CI on blood cell depletion as a biomarker to differentiate the two. Male CD2F1 mice were exposed to 8.75 Gy γ- radiation (60Co). Within 2 h of RI, animals were bled under anesthesia 0% (RI) or 20% (CI) of total blood volume. Blood samples were collected at 4-5 h and days 1, 2, 3, 7, and 15 after RI. CI decreased WBC at 4-5 h and continued to decrease them until day 3; counts then stayed at the nadir up to day 15. CI decreased neutrophils, lymphocytes, monocytes, eosinophils and basophils more than RI on day 1 or day 2. CI decreased RBCs, hemoglobin and hematocrit on days 7 and 15 compared to RI, whereas Hemorrhage alone returned to the baseline on days 7 and 15. RBCs depleted after CI faster than post RI. Hemorrhage alone increased platelet counts on days 2, 3, and 7, which returned to the baseline on day 15. Our data suggest that WBC depletion may be a biomarker within 2 days post-CI and RBC depletion after 3 days post-CI.

The problem of blood delivery has been a critical concern in past decades. However, the unsteady behavior of blood donors, along with the uncertainties associated with demands in a crisis imposes several challenges for resource management. In this research work, we analyze the blood delivery behavior in a crisis modeled by coupled queues of patients and blood sources. Using Markovian modeling and results associated with G-network, we derive two critical probabilities, namely lack of unit of blood (unit of donations) or not having any storage capacity left to accept new donors' blood. We propose a closed-form solution to calculate the optimal blood storage size, and also we suggest sufficient conditions that guarantee the feasibility of the model. Finally, we conduct a sensitivity analysis to investigate the impact of model parameters on storage size and the proportion of time that storage is full.

Glycosylation is a complex post-translational modification that conveys functional diversity to glycoconjugates. Cell surface glycosylation mediates several biological activities such as induction of intracellular signaling pathway and pathogen recognition. Red blood cell (RBC) membrane N-glycans determine blood type and influence cell lifespan. Although several proteomic studies were carried out, glycosylation of RBC membrane proteins has not been systematically investigated. This work aims at exploring the human RBC N-glycome by high-sensitivity MALDI-MS techniques to outline a fingerprint of RBC N-glycans. To this purpose, MALDI-TOF spectra of healthy subjects harboring different blood groups were acquired. Results showed the predominant occurrence of neutral and sialylated complex N-glycans with bisected N-acetylglucosamine, core- and/or an-tennary fucosylation. In the higher mass region these species presented with multiple N-acetyllactosamine repeating units. Amongst the detected glycoforms, the presence of glycans bearing ABO(H) antigens allowed us to define a distinctive spectrum for each blood group. For the first time, advanced glycomic techniques have been applied to a comprehensive exploration of human RBC N-glycosylation, providing a new tool for the early detection of distinct glycome changes associated with disease conditions as well as to understand pathogens molecular recognition.

This study explored the effects of a comprehensive health care program (CHCP) on blood pressure, blood glucose, body composition, and depression in older adults living alone. We used a quasi-experimental, two-group, pre-posttest design. The CHCP consisted of open lectures, health counseling, exercise classes, nutrition counseling, and self-help group meetings at a local senior welfare center. Fifty-eight subjects participated in this study, with thirty subjects in the experimental group and twenty-eight subjects in the control group. Data were analyzed using the descriptive statistics, χ²-test, and t-test. Comparisons of the pretest and posttest systolic blood pressure (t = - 2.530, p < .016) and blood glucose (t = 3.089, p < .004) between the experimental and control groups showed significant differences. In both the experimental (t = 3.949, p < .001) and control groups (t = 3.816, p < .002), depression symptoms showed a significant decrease post-test, compared with pre-test. Our findings infer that older adults require physical and psychosocial healthcare and that more efforts must be made to improve the general health and wellbeing of this population group.

Background/Objectives: Determining the outcome of epilepsy is crucial for making proactive and timely treatment decisions, as well as for counseling patients. Recent research efforts have focused on using various imaging techniques and EEG for prognostication; however, there is insufficient evidence regarding the role of blood parameters. Our study aimed to investigate the additional prognostic value of routine blood parameters in predicting epilepsy outcomes. Methods: We analyzed data from 1,782 patients who underwent routine blood tests within 90 days of their first visit and had a minimum follow-up duration of three years. The etiological types were structural (35.1%), genetic (14.2%), immune (4.7%), infectious (2.9%), and unknown (42.6%). The outcome was defined as the presence of seizures in the last year. Results: Initially, a multivariate analysis was conducted based on clinical variables, MRI, and EEG data. This analysis revealed that sex, age of onset, epileptiform discharge, structural etiology, and the number of antiseizure medications were related to the outcome, with an area under curve (AUC) of 0.708. Among the blood parameters, fibrinogen, bilirubin, uric acid, and aPTT were significant, with AUCs of 0.602, 0.597, 0.455, and 0.549, respectively. Including these blood parameters in the analysis slightly improved the AUC to 0.713. Conclusions: Some blood parameters were found to be related to the final outcome, potentially paving the way to understanding the mechanisms of epileptogenesis and drug resistance.

Blood cancers, including leukemia, lymphoma, and myeloma, pose significant diagnostic challenges due to their diverse and complex nature. Detecting these cancers early and accurately is crucial for timely intervention and improved patient outcomes. This review explores current and emerging detection methods for human blood cancers, focusing on their principles, advantages, limitations, and potential clinical applications.

product transfusions, but clinical practices vary widely. Many very low birth weight (VLBW) infants receive packed red blood cell (RBC) or platelet transfusions during their initial NICU stay, with incidence inversely proportional to gestational age at birth ^1,2. Many critically ill infants are also transfused with plasma or cryoprecipitate to promote coagulation ^3,4. These blood product transfusions are most often prophylactic, with clinical decisions made in response to numerical blood count values, as opposed to therapeutic transfusions in the context of active bleeding.Emerging evidence has shown that some transfusion practices are harmful for certain NICU patients, such as platelet transfusions in preterm infants ^5,6. More broadly, transfusion reactions can occur with virtually all blood products ⁷ and these reactions are likely under-diagnosed, under-estimated, and under-reported in pediatric patients ³. Our intention was to establish optimal transfusion guidelines for our division and neonatal network, including 19 hospitals, based on a review of currently available literature.

Blood has certain significant physical properties, which the authors investigated. This paper provides values of surface tension and viscosity of blood at 37 °C, as well as relationship between them plotted on a cross-plot. By applying Hagen- Poiseuille equation and Jurin's law to the experimentally obtained data, the authors calculated with great accuracy viscosity and surface tension of blood. Evaluating both of the properties using described methods required from the authors to know the density of investigated liquid, which was found to be on average $\rho=1063,56 \frac{kg}{m^3}$. The authors took blood samples from 30 healthy subjects and determined aforementioned physical properties. There has been made a distinction in regard of a sex of the blood donor. Results indicate that both surface tension and viscosity are independent from sex of a subject, as well as indicate that there is no correlation between viscosity and surface tension of blood at 37\degree C. Average values of surface tension and viscosity were found to be $\sigma=5,241\pm 0,262 \cdot 10^{-2}\frac{J}{m^2}$ and $\eta=3,352\pm0,360 \cdot 10^{-3} Pa \cdot s$, respectively.

Blood glucose (BG) monitoring is an important issue for critically ill patients. Previous studies reported that poor sugar control was associated with increased mortality in admitted patients. However, repeated blood glucose monitoring can be resource-consuming and cause a healthcare burden in clinical practice. In this study, we aimed to develop a personalized machine-learning model to predict dysglycemia based on electrocardiogram (ECG) findings. The study included patients with more than 20 ECG records during single hospital admission in the Medical Information Mart for Intensive Care III database, focusing on the lead II recordings, along with the corresponding blood sugar data. We processed the data and used ECG features from each heartbeat as inputs to develop a one-class support vector machine (SVM) algorithm to predict dysglycemia. The model prediction for dysglycemia using a single heartbeat had an AUC level of 0.92 ± 0.09, with a sensitivity of 0.92 ± 0.10 and specificity of 0.84 ± 0.04. Based on 10 s majority voting, the model prediction for dysglycemia improved to an AUC of 0.97 ± 0.06. In this study, we found that a personalized machine-learning algorithm could accurately detect dysglycemia using a single-lead ECG.

Exposure to traffic-related air pollution is linked with acute alterations in blood pressure (BP). We examined the cumulative short-term effect of black carbon (BC) exposure on systolic (SBP) and diastolic (DBP) BP and assessed effect modification by participant characteristics. SBP and DBP were repeatedly measured on 152 traffic enforcers. Using a linear mixed-effects model with random intercepts, quadratic (QCDL) and cubic (CCDL) constrained distributed lag models were fitted to estimate the cumulative effect of BC concentration on SBP and DBP during the 10-hours (daily exposure) and 7-days (weekly exposure) before the BP measurement. Ambient BC was related to increased BP with QCDL models. An interquartile range change in BC cumulative during the 7-days before the BP measurement was associated with increased BP [1.2% change in mean SBP, 95% confidence interval (CI), 0.1 to 2.3; and 0.5% change in mean DBP, 95% CI, –0.8 to 1.7]. Moreover, the association between the 10-hours cumulative BC exposure and SBP was stronger for females (4.0% change, 95% CI: 2.1–5.9) versus males, and for obese (2.9% change, 95% CI: 1.0–4.8) vs. non-obese traffic enforcers. Short-term cumulative exposure to ambient traffic-related BC could bring about cardiovascular diseases through mechanisms involving increased BP.

Cardiotonic steroids (CTS) are a group of steroid compounds derived from certain plants and animals. CTS are selective inhibitors of Na,K-ATPase, so for a long time they were widely used for medical purposes to treat heart failure and some other diseases. However, over time, doctors gradually began to refuse this group of drugs due to their narrow therapeutic range and a number of serious side effects. However, in parallel with the rise and fall of interest in CTS as a drug, interest in them as a single class of high-affinity Na,K-ATPase inhibitors has only increased. Numerous data on the effect of CTS on signaling cascades and cell viability made impelling a search for a rationale for the existence of such a subtle biological regulator. A large number of studies devoted to the potential use of CTS in the treatment of neurodegenerative, oncological, immune and other diseases "revitalized" the already "written off" group of the drugs. If initially the role of exogenous (mainly plant origin) CTS was studied, then by the 90s of the XX century the study of the role of endogenous CTS and their regulatory effects became a popular trend in biology and physiology. The role of endogenous CTS was studied in details in the pathogenesis of cardiovascular diseases [1]. A large number of researchers have unanimously stated that endogenous CTS are very complex regulators of the development of pathological processes; however, the exact cause-and-effect relationship that would unambiguously explain the processes of synthesis, utilization, and the role of endogenous CTS has not yet been established. The effects of CTS in the frame of various regulatory schemes have been described, but the predominant number of studies was devoted to arterial hypertension, heart and renal failure, cancer [2–4], aging [5,6], and neuroinflammation. The effects of both endo- and exogenous CTS on blood cells and have been studied to a much lesser extent.

There is no well-defined threshold for intra-operative blood transfusion (BT) in advanced epithelial ovarian cancer (EOC) surgery. We developed a Machine Learning (ML)-driven prediction algorithm to trigger and explain a communication alert for BT based on anticipated peri-operative events irrespective of BT policies. We analysed prospectively collected data from 403 EOC patients who underwent cytoreductive surgery between 2014 and 2019. We calculated the estimated blood volume (EBV) using the formula EBV = weight x 80 and set off 10%EBV as threshold for individual intervention. Based on the known estimated blood loss (EBL) we identified two groups. We employed Receiver operating characteristic (ROC) curves for performance metrics. The model performance for the above threshold prediction was satisfactory (AUC 0.823, 95% CI 0.76-0.88). The top feature commonly shared between interrogators was operative time (OT). Intra-operative blood loss of at least 10%EBV was associated with OT&gt;250 minutes, primary surgery, serous histology, performance status 0, R2 resection and surgical complexity score &gt;4. Large bowel resection, stoma formation, ileocecal resection/right hemicolectomy, mesenteric resection, bladder and upper abdominal peritonectomy were amongst sub-procedures clearly associated with increased intervention risk. Precise prediction of blood requirements is not possible unless a rough estimate of OT is known in advance.

Circulating miRNA-451a has recently emerged as an important biomolecule with potential clinical values as a diagnostic marker for several diseases. However, to be used as such, it is critical to accurately assay miRNA-451a in the clinic. Yet, pre-analytical factors that can affect such an error-free clinical assay of miRNA-451a have not been explored. This study aimed at investigating several of these pre-analytical factors that may affect the accurate quantification of miRNA-451a in human blood samples. We initially evaluated miRNA-451a levels in red blood cells (RBCs), white blood cells (WBCs), platelets, and plasma by droplet digital PCR (ddPCR). Next, we quantified miRNA-451a levels in whole blood or plasma stored at different temperatures for different time periods by ddPCR and used hemolyzed plasma samples to study the effects of hemolysis on plasma miRNA-451a concentration. We found that WBCs and platelets contain trace amounts of miRNA-451a and that about 99.9% of miRNA-451a in the blood are localized in RBCs. Hemolyzed plasma showed 58.5-fold increase in miRNA-451 concentration as compared to non-hemolyzed plasma. Importantly, plasma stored at room temperature (RT) or 4ºC showed a steady statistically significant decrease in miRNA-451a levels over a 7-day period whereas plasma samples stored at -20 or -80ºC for up to 7 days showed stable miRNA-451a levels. Together, our data indicate that hemolysis and blood storage at RT or 4ºC may have significant negative effects on the levels of circulating miRNA-451a.

Objective: To explore three novel fasting blood glucose (FBG)-based novel indicators, including FBG-to-albumin ratio (FAR), FBG-to-lymphocytes ratio (FLR), and FBG-to-hemoglobin ratio (FHR), in predicting prognosis and detecting metastasis for patients with pancreatic neuroendocrine neoplasms after resection. Materials and methods: A total of 178 pNEN patients underwent surgical resection were included in this study. Receiver operating characteristic (ROC) curves were used to evaluate the diagnosis values of FAR, FLR, and FHR, and the cut-off values were obtained for further analyses. Univariate and multivariate analyses were conducted to determine the independent predictors. The Kaplan-Meier method was used to evaluate the progression-free survival (PFS) and overall survival (OS) of the pNEN patients. Results: The optimal cut-off values of FAR, FLR, and FHR were 0.17, 2.85, and 0.028, respectively. As for PFS, the area under the curve (AUC) was 0.693 for FAR, 0.690 for FLR, and 0.661 for FHR, respectively. The AUC was 0.770, 0.692, and 0.715 accordingly for OS. The groups with lower FAR, FLR, and FHR were significantly associated with prolonged PFS and OS (p < 0.05). In patients with metastasis, the lower FAR group was correlated with significantly longer PFS and OS (p = 0.022 and 0.002, respectively). The FLR was an independent predictor of PFS in pNEN patients, and the FAR was a predictor of OS. FAR was an independent indicator of PFS in patients with metastasis. Conclusion: Preoperative FAR, FLR, and FHR are effective in predicting the prognosis of pNEN patients and detecting the synchronous metastases.

This study presents, for the first time, the development of fibers with favorable properties for biodegradable wound dressings made from the Ecovio® (EC) polymer blend, composed of poly(lactic acid) (PLA) and poly(butylene adipate-co-terephthalate) (PBAT), incorporated with tea tree essential oil (TTE). TTE presented antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus, achieving minimal inhibitory concentrations of 15 and 7.5 mg/mL, respectively. The TTE was mixed with EC in a binary chloroform and formic acid (85/15 v/v) mixture, leading to homogeneous and wettable fibers by electrospinning. The EC/TTE fibers were characterized confirming the TTE in the fibers. The tests showed that TTE (0.5, 1.0 or 1.5 mL) improved the polymer blend electrospinnability. TTE (1.5 mL or 75 w% concerning the EC) lead to homogeneous fibers with an average diameter of 278 nm. TTE (75 w%) increased the wettability of the EC fibers from 120±2° to 69±1°. Preliminary bacterial adhesion and proliferation assays demonstrated that the EC/TTE fibers have anti-adhesive activity e seems to be more toxic against P. aeruginosa compared to S. aureus after 24 hours of incubation. Compatibility tests with human blood indicated that the EC/TTE fibers accelerate blood coagulation. The EC/TTE fibers exhibit promising chemical and biological properties (in vitro) for the development of wound dressings.

Background: Orthostatic hypotension (OH) is associated with higher risk of mortality in general population however not studied in cancer population. The study aimed to assess the prevalence of OH in cancer patients compared to the non-cancer population. Methods: A total of 411 patients (mean age 63.5 ± 10.6 years) were recruited: patients with active cancer (n = 223) and patients hospitalized for other reasons but without cancer diagnosis (n = 188). Medical history was collected and an orthostatic challenge test was performed. OH was defined as blood pressure (BP) decrease on standing ≥ 20 mmHg for systolic or ≥ 10 mmHg for diastolic BP in 1 or 3 minutes; or systolic BP decrease &lt; 90 mmHg. Results: The prevalence of OH in cancer was significantly higher than in subjects without cancer- 28.7% vs. 16.5%, respectively, P = 0.003). OH was the most common in lung cancer, 57.5%. In single variable analysis, the predictors of OH were: cancer presence, age ≥ 65 years, and body mass index (BMI) ≥ 30 kg/m2. In the multivariable model, the strongest independent predictor of OH was cancer status doubling the risk of OH; BMI ≥ 30 kg/m2 and diabetes. Conclusions: Cancer patients are characterized by a high prevalence of OH. In this population, the recommendation of routine orthostatic challenge tests should be considered.

This study was conducted to determine the role of pre-operative 2 weeks use of Finasteride in reducing intra-operative blood loss in patients undergoing monopolar TURP. Number of enrolled patients were 120, on the basis of inclusion criteria. Patients who were candidates of monopolar TURP were given 5mg Finasteride for 2 weeks before the surgery. On the 13th day of medicine, they got admitted in ward and prepared for surgery. During surgery intra-operative irrigation fluid was measured and gathered, then tested for Hemoglobin and the blood loss was calculated with equation formula. Blood loss evaluation was done on the basis of irrigation fluid, hemoglobin in irrigation fluid, preoperative hemoglobin and resected tissue weight. Significant reduction in blood loss was observed in interventional group as compared to the control group. Mean blood loss was 296ml in Group-A and 370ml in Group-B while blood loss per gram was 11.7ml/g in Group-A and 14.7 ml/g in Group-B. Mean operative time was measured 42 minutes in Group-A and 49 minutes in Group-B. This research proclaims a clear-cut supremacy of pre-operative use of Finasteride for two weeks. It significantly reduces intraoperative blood loss and blood loss per gram in patients undergoing monopolar TURP.

The likelihood of pre-hypertensive young adults developing hypertension has been steadily increasing over the past few years. Despite the fact that aerobic exercise training (AET) has demonstrated positive results in lowering high blood pressure, the efficacy of different types of AET among pre-hypertensive young adults has not been well-established. The objective of this study was to evaluate the effectiveness of high-intensity interval training (HIIT) and continuous moderate-intensity training (CMT) on blood pressure (BP) of physically inactive pre-hypertensive young adults. 32 adults (age 20.0±1.1 years and BMI 21.5±1.8) were randomly assigned into 3 groups: HIIT, CMT and control (CON). HIIT and CMT groups participated in 5 weeks of AET; while the CON group followed a DASH diet plan only. The HIIT protocol consisted of 1:4 minute work to rest ratio of participants 80%-85% heart rate reserve (HR-reserve) and 40%-60% HR-reserve respectively for 20-minutes, CMT group exercised at 40%-60% of HR-reserve continuously for 20-minutes. In both HIIT and CMT groups, systolic blood pressure (SBP) (3.8±2.8 mmHg, P=0.002 VS 1.6±1.5 mmHg, P=0.011) was significantly reduced. While, significant reductions in the diastolic blood pressure (DBP) (2.9±2.2 mmHg, P=0.002) and mean arterial pressure (MAP) (3.1±1.6mmHg, P<0.0005) were noted only in the HIIT group. No significant differences in SBP (-0.4±3.7 mmHg, P=0.718), DBP (0.4±3.4 mmHg, P=0.714), or MAP (0.1±2.5mmHg, P= 0.892) were observed in the CON group. Both HIIT and CMT decreased the BP in physically inactive pre-hypertensive young adults; however, HIIT yielded more beneficial results in terms of reducing the SPB, DBP and MAP.

Background:The association between ABO and Rh blood groups and diseases is an intriguing topic that continues to be studied. However, how mandibular symmetry may vary by blood group has not been investigated. This study explored the relationship between these blood groups and mandibular condyle and ramal asymmetries in the Turkish adult population. Methods:The study included 149 adult patients (67 males and 82 females) without systemic diseases or temporomandibular disorder complaints. Asymmetry was assessed in panoramic radiographic images using a formula developed in a previous study. The chi-square and Kruskal-Wallis tests were used to analyze differences among ABO groups while the Mann-Whitney U test was used for Rh groups. Results:There were no statistically significant differences among the ABO blood groups, nor the Rh groups, in terms of sex, Rh factor, and age distribution. However, a comparison of the ABO and Rh blood groups revealed that condylar asymmetries were significantly more common in the AB group. Conclusions:These results suggest that mandibular asymmetry may be associated with the ABO blood group. These findings may guide future research to gain a deeper understanding of the relationship between mandibular asymmetry and blood groups.

Background: for patients with endocarditis, guidelines recommend repeating blood cultures until they become negative, but with very limited evidence. Methods: a literature review was done on the incidence and duration of persistent bacteremia and persistent fever in endocarditis patients, compared to their associations with persistent infection at day 7. Results: persistent bacteremia and persistent fever are common in the first few days after starting antibiotic therapy, a normal duration for either at or around < 3-7 days. Persistent bacteremia is more prevalent and longer lasting in Staphylococcus (especially MRSA) and Enterococcus species than in Streptococcus species. In one study the risk for persistent infection at day 7 was 50% in those with positive blood cultures at 48-72 hours while it was 32% in those with negativization of blood cultures. Both persistent bacteremia at 48-72 hours and persistent infection at day 7 are predictive of in-hospital mortality. Conclusion: persistent bacteremia after treatment for endocarditis is common and often accompanied by persistent fever. Persistent infection at 7 days (as indication for urgent surgery) cannot be reliably predicted by positive or negative blood cultures at 48-72 hours. The recommendation of performing survey blood cultures in all patients therefore needs to be reconsidered.

The tambaqui Colossoma macropomum is the main species of edible fish originating from fish farming in the Amazon region. This study aimed to determine and compare the hematological and biochemical parameters of tambaqui from fish farms in municipalities in the Metropolitan Region of Manaus, Amazonas, Brazil. Two fish farms were sampled in a semi-excavated pond-type breeding system in each of the five towns investigated (Presidente Figueiredo, Manaus, Iranduba, Manacapuru and Novo Airão), totaling ten breeders. On each farm, ten specimens were captured, totaling 100 animals. Blood was collected by caudal puncture, and hematological and biochemical parameters were determined using the methodology described for teleosts fish. For the erythrogram in the variables of hematocrit, hemoglobin concentration and erythrocytes, significant differences were observed in Iranduba and Novo Airão, demonstrating indications of anemic processes and dehydration. For plasma biochemistry, low levels were observed in fish from Iranduba and Novo Airão. High values in lipid compounds were found in tambaqui from Manacapuru. High intraspecific variation was found in the leukogram and thrombogram, which determined similarities between tambaqui from different farms and municipalities. On the other hand, fish from Manacapuru have an inappropriate diet, indicated by the high levels of cholesterol and triglycerides found in the blood.

Adenosine is a multifunctional nucleoside with several roles across various levels in organisms. Beyond its intracellular involvement in cellular metabolism, extracellular adenosine potently influences both physiological and pathological processes. In relation to its blood level, adenosine impacts the cardiovascular system, such as heart beating rate and vasodilation. To exploit the adenosine levels in the blood, we employed the liquid chromatography method coupled with mass spectrometry (LC-MS). Immediately after the collection, a blood sample mixed with acetonitrile solution that is either enriched with 13C-labeled adenosine or a newly generated mixture is transferred into the tubes containing the defined amount of 13C-labeled adenosine. The 13C-enriched isotopic adenosine is used as an internal standard, allowing for more accurate quantification of adenosine. This novel protocol for LC-MS-based estimation of adenosine delivers a rapid, highly sensitive, and reproducible means for quantitative estimation of total adenosine in blood. The method also allows quantification of a few catabolites of adenosine, i.e., inosine, hypoxanthine, and xanthine. This advancement provides the analytical tool that has the potential to enhance our understanding of adenosine's systemic impact and pave the way for further investigations into its intricate regulatory mechanisms.

. Cucurbiturils are a family of macrocyclic oligomers capable of forming host-guest complexes with various molecules. Due to noncovalent binding to drug molecules and low toxicity, cucurbiturils has been extensively investigated as a potential carrier for drug delivery. However, the immune system interactions with different drug carriers, including cucurbiturils, are still under investigation. In this study, we focused on cucurbiturils immunosafety and immunomodulation properties in vivo. We measured blood counts, lymphocyte subpopulations in blood, spleen, and bone marrow, and assessed in vivo toxicity to spleen and bone marrow cells after intraperitoneal administration to mice. We also evaluated the effect of cucurbiturils on cellular and humoral immune responses. Cucurbiturils in high concentrations effect on the immune system in vivo. The action of various cucurbiturils differs in different homologues, which, apparently, is associated with different interactions in the internal environment of the body.

Haemosporidian parasites, including Haemoproteus, Plasmodium, and Leucocytozoon, are intracellular parasites found in the blood and tissues of birds worldwide. The prevalence of these parasites varies depending on bird species and habitats. Humidity, influenced by water availability, is one of the factors affecting their prevalence. In this study, we collected 145 blood samples from wild songbirds in the western region of Iran from April to November 2021-2022. Blood smears were prepared using the push-slide method and stained with Giemsa. The stained smears were examined under a light microscope. Among the seven songbird families sampled, blood parasites were detected in 31 individuals from five families. Of these, 23 individuals (15.86%) were from humid areas, while 8 individuals (5.51%) were from dry areas. The highest infection rates were observed in the Paridae (9.65%) and Motacilliidae (4.82%) families, while the lowest infection rates were found in the Corvidae (1.37%) and Acrocephalidae (1.37%) families. We recorded two new hosts for Leucocytozoon spp. (Motacilla flava and Acrocephalus melanopogon) for the first time in the world and four new host records (Motacilla flava, Pica pica, Acrocephalus melanopogon, and Acrocephalus agricola) for blood parasites in the west of Iran. Our findings highlight the high prevalence of avian blood parasites in songbirds inhabiting humid areas, suggesting that these environments provide suitable conditions for the growth and reproduction of invertebrate hosts.

5-Hydroxytryptamine (5-HT) or serotonin plays a crucial role as a neuromodulator and/or neurotransmitter of several nervous system functions. Its actions are complex and depend on multiple factors, including the type of effector or receptor activated. Briefly, 5-HT can activate: (i) metabotropic (G-protein-coupled) receptors to promote inhibition (5-HT1, 5-HT5) or activation (5-HT4, 5-HT6, 5 HT7) of adenylate cyclase, as well as activation (5-HT2) of phospholipase C; and (ii) ionotropic receptors (5-HT3), which form a ligand-gated Na+/K+ channel. Regarding blood pressure regulation (and beyond the intricacy of central 5-HT effects), this monoamine also exerts direct postjunctional (on vascular smooth muscle and endothelium) or indirect prejunctional (on autonomic and sensory perivascular nerves) effects. At the prejunctional level, 5-HT can facilitate or preclude the release of autonomic (e.g., noradrenaline and acetylcholine) or sensory (e.g., calcitonin gene-related peptide) neurotransmitters facilitating hypertensive or hypotensive effects. Hence, we cannot formulate a specific impact of 5-HT on blood pressure level, since an increase or decrease in neurotransmitter release would be favoured depending on the type of prejunctional receptor involved. This review summarizes and discusses the current knowledge on the prejunctional mechanisms involved in blood pressure regulation by 5-HT and its impact on some vascular-related diseases.

Background of the Study: We investigated the link between hypertension and cancer since it has been suggested that hypertension may raise the long-term risk of cancer. Previous large observational cohort studies found that greater blood pressure (BP) was related to a higher risk of cancer. Mendelian randomization (MR) was utilized to produce less confounded blood pressure estimates (BP) on overall and site-specific malignancies. The study aims to draw conclusions on the relationship between high blood pressure and cancer. Methods: Studies on high blood pressure and various malignancies are inconclusive, except for renal cell carcinoma. However, given that most meta-analyses only contained a limited number of trials, some relative risks had small to moderate magnitudes, and several may have been impacted by residual confounding, careful interpretation is necessary. The study was conducted using the meta-analysis technique. Cochran's Q test and I2 test were used to assess statistical heterogeneity between studies in the current investigation for research involving two or more cause and outcome combinations. Results: Positive correlations were also reported between high blood pressure and esophageal adenocarcinoma, squamous cell carcinoma, liver, and squamous cell carcinoma. However, most studies lacked multivariable adjustments. Physical and numerical risk of cardiovascular disease is linked to bowel cancer but no other cancers. According to a meta-analysis, hypertensive persons could also be at increased danger of gastrointestinal and breast cancer. Most meta-analyses comprised several trials with moderate or mild hazard ratios.ConclusionDifferent types of cancers have been noted to be directly caused by hypertension. In addition, some treatments have also been associated with the side effects of cancer treatments to cause hypertension. Women facing hypertension have an increased risk of getting breast cancer. Although some cancers showed a real relationship with hypertension, others had no connection at all.

The two main chronic obstructive diseases are asthma – affecting 1-18% of adult population – and chronic obstructive pulmonary disease (COPD) prevalent in up to 6% of adults. In both cases the treatment depends on diseases’ severity. In management of these conditions, spirometry and complete blood count are two major monitoring tests. Our aim was to compare blood morphology results and spirometry values between patients in groups of different treatment intensity in asthma and COPD. By measuring that, we expected to study whether asthma/COPD patients have a need of stepping-up their treatment steps. Methods A retrospective analysis of patients admitted in 2013-2019 to an outpatient pulmonology clinic in Łódź (Poland). Spirometry values, complete blood count and information on pharmacological treatment were obtained from archival data. Patients were assigned with disease severity according to present GINA/GOLD recommendations. The study included 125 patients – 47 with COPD (22 females) and 78 with asthma (57 females). Results Among patients with asthma, a positive correlation in white blood cell count (WBC) (r=0,236, p=0.038) and ascending GINA treatment steps was found. Significant negative correlations were shown between ascending GINA treatment steps and FEV1, FEV1%, FVC%, MEF50, MEF50, PEF%. In COPD patients, positive correlations between ascending GOLD treatment groups and white blood cell count, neutrophil count, basophil percentage, platelet count (r=0.346; 0.309; 0.321; 0.401 respectively) were found. Negative correlations were shown between ascending GOLD treatment groups and FEV1, FEV1%, FVC, FVC%, MEF50, MEF50%, PEF, PEF% (r=-0.732; -0.575; -0.705; -0.498; -0.632; -0.558; -0.688; -0.597 respectively). Conclusions Negative correlations between ascending GINA and GOLD treatment steps and spirometry values may suggest that asthma and COPD patients may benefit from stepping-up the treatment steps earlier. Potential advantages of that more intensive treatment needs to be examined in the future

Background: Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Also, limited analyses have been conducted in African ancestry and Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed. Methods: To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including N=229 African American and N=381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN, N = 922 European ancestry participants, whole blood). We then performed a transcriptome-wide association study (TWAS) for platelet count, hemoglobin, hematocrit, and white blood cell count in African (N = 27,955) and Hispanic/Latino (N = 28,324) ancestry participants. Results: Our results revealed 24 suggestive signals (p < 1×10^(-4)) that were conditionally distinct from known GWAS identified variants and successfully replicated these signals in European ancestry subjects from UK Biobank. We found modestly improved correlation of predicted and measured gene expression in an independent African American cohort (the Genetic Epidemiology Network of Arteriopathy (GENOA) study (N=802), lymphoblastoid cell lines) using the larger DGN reference panel; however, some genes were well predicted using MESA but not DGN. Conclusions: These analyses demonstrate the importance of performing TWAS and other genetic analyses across diverse populations and of balancing sample size and ancestry background matching when selecting a TWAS reference panel.

Precise association of serum leptin with body mass index (BMI) and blood pressure (BP; both systolic blood pressure (SBP) and diastolic blood pressure (DBP) is not well known for understanding their involvement in health and disease. Hence, the present study was planned to be conducted for investigating the association of BP, BMI and serum leptin levels in young normal weight (NW) and overweight (OW) male Saudi students. The NW (n: 198) and OW male subjects (n: 192) in the age range of 18-20 years were consulted. Blood pressure (BP) was measured with a mercury sphygmomanometer. Leptin Human ELISA Kits were employed for the determination of the serum leptin levels. The mean ± SD values of BMI (kg/m2), serum leptin (ng/ml), SBP (mmHg), and DBP (mmHg) all showed significant difference for young OW vs. NW male university students as: 27.52± 1.42 vs. 21.49± 2.03; 10.70± 4.67 vs. 4.68± 1.91; 121.37±2.59 vs.118.51±1.54 and 81.44±1.97 vs. 78.79±1.44 respectively. All associations (among BMI, leptin, SBP and DBP) showed positive linear and significant correlation except nonsignificant correlation of BMI and SBP for NW group. The present study in the young Saudi male students, presents significant variations for BP and serum leptin levels and significant positive linear association among serum leptin, BMI and BP.

We estimated the risk of blood clots after COVID-19 vaccination accounting for the roles of vaccination in reducing the infection rate, and indirectly lowering the risk of blood clots caused by infection. A self-controlled case series method was used to examine the association between blood clots and COVID-19 vaccination. To deal with the bias due to under-reported infection among non-hospitalized subjects, a case-control study was used to compare the risk of blood clots in infected subjects to control subjects who were hospitalized due to physical injury. We found increased risks of blood clots after vaccination (incidence rate ratio is 1.13, 95% confidence interval (CI): [1.03, 1.24] after the first dose and 1.23, 95% CI: [1.13,1.34] after the second dose). Furthermore, vaccination attenuated the increased risk of blood clots associated with infection (odds ratio (OR) = 2.16, 95% CI: [1.93, 2.42] in unvaccinated versus OR=1.46, 95% CI: [1.25, 1.70] in vaccinated). A causal model was used to explain and weigh up possible risk factors for blood clots after COVID-19 vaccination. After accounting for vaccine efficacy against infection and the protection against infection-associated blood clots, receiving the COVID-19 vaccines decreases the risk of blood clots, especially during high infection rate period.

Blood gas analysis plays a central role in modern medicine. Advances in technology have expanded the range of available parameters and increased the complexity of their interpretation. By applying user-centered design principles, it is possible to reduce the cognitive load associated with interpreting blood gas analysis. In this international, multicenter study, we explored anesthesiologists' perspectives on Visual Blood, a novel visualization technique for presenting blood gas analysis results. We conducted interviews with participants following two computer-based simulation studies: the first utilizing Virtual Reality (VR) (50 participants) and the second without VR (70 participants). Employing the template approach, we identified key themes in the interview responses and formulated six statements, which were rated using Likert scales: from 1 (strongly disagree) to 5 (strongly agree) in an online questionnaire. The most frequently mentioned theme was the positive usability features of Visual Blood. The online survey revealed that participants found Visual Blood to be an intuitive method for interpreting blood gas analysis (median 4, IQR 4-4, p<0.001). Participants noted that minimal training was required to effectively learn how to interpret Visual Blood (median 4, IQR 4-4, p<0.001). However, adjustments are necessary to reduce visual overload (median 4, IQR 2-4, p<0.001). Overall, Visual Blood received a favorable response. The strengths and weaknesses derived from these data will help optimize future versions of Visual Blood to improve the presentation of blood gas analysis results.

Blood image intensity has been used to detect erythrocyte sedimentation rate (ESR). However, it does not give an information on biophysical properties of blood sample under continuous ESR. In this study, three physical properties, including, τ₀, ESR_τ, and AI_I, are suggested to quantify mechanical variations of blood under continuous ESR. To demonstrate the proposed method, blood sample is loaded into a driving syringe. The blood flow rate is set in a periodic on–off pattern. Blood sample is then supplied into a capillary chip, and microscopic blood images are captured at specific intervals. Blood shear stress is quantified from the interface of blood stream in the coflowing channel. Both τ₀ and ESR_τ are then obtained by analyzing the blood shear stress. Simultaneously, the AI_I is evaluated by analyzing the image intensity of blood flow. According to the experimental results, the τ₀ exhibits consistent trends with respect to hematocrit as well as diluent. The ESR_τ and AI_I showed a reciprocal relationship each other. Three suggested properties represented substantial differences for suspended blood samples (i.e., hardened red blood cells, different concentration of dextran solution and fibrinogen). In conclusion, the present method can detect variations of blood sample under continuous ESR effectively.

This prospective single-center study was designed to assess the clinical utility of the FilmArray® blood culture identification (BCID) panel for improving the diagnostic accuracy in neonatal sepsis. Results obtained using the FilmArray® BCID panel were correlated with results of blood culture in all consecutive neonates with suspicion of early-onset (EOS) and late-onset sepsis (LOS) attended in our service over a 2-year period. A total of 102 blood cultures from 92 neonates were included, 69 (67.5%) in cases of EOS and 33 (32.3%) in LOS. The FilmArray® BCID panel was performed in negative culture bottles at a median of 10 hours of blood culture incubation (range 7.5-20 hours), without differences by the type of sepsis. The FilmArray® BCID panel showed a 66.7% sensitivity, 100% specificity, 100% positive predictive value, and 95.7% negative predictive value. There were four false-negative cases, three of which of Streptococcus epidermidis in neonates with LOS and one case of Granulicatella adiacens in one neonate with EOS. We conclude that the use of the FilmArray® BCID panel in negative blood cultures from neonates with clinical suspicion of sepsis is useful in decision-making of starting or early withdrawal of empirical antimicrobials because of the high specificity and negative predictive values of this assay.

BACKGROUND&AIMS: Hepatitis B virus (HBV) infection remains a major public health problem. The interaction between HBV and the host inflammatory response is an important factor contributing to liver damage and disease development. We compared the correlation between the subclinical index and PBMCs concentration in two groups of pregnant women (HBsAg positive), which are different in HBV DNA concentration in Vietnam. METHODS: The Hierarchical cluster analysis (HCA) was run with 20 different clustering methods on data collected from 80 Vietnamese pregnant women and their babies (60/80 cord blood). RESULTS: In the high viral load group (HBV DNA ≥ 5x10^7 copies/ml), a strong correlation between CBMCs with serum maternal Haemoglobin concentration and maternal platelet and maternal ALT. Their R values are: -0.88, 0.82, and 0.84 with p=8.97E-03, 2.41E-02 and 1.75E-01, respectively. CONCLUSIONS: We found a significant correlation shift of subclinical index between the two groups, which may be important in diagnosing pregnant women with chronic hepatitis B virus infection.

Background/Objectives: Infusion pumps are critical in clinical settings, precisely delivering fluids such as medications and blood products. However, maintaining accuracy and preventing hemolysis is essential when administering blood, particularly to neonates. Conventional pumps may cause hemolysis due to pressure variations during transfusion. This study compares the blood transfusion accuracy and hemolysis rate between the conventional pump, Terufusion TE-LM700 (Terufusion) and the novel cylinder-type infusion pump, Anyfusion H-100 (Anyfusion); Methods: The study evaluated six different infusion rates (10-180cc/hr) and conducted 57 transfusion trials, 20 of which used a 1:1 blood-saline dilution. Blood transfusion accuracy was measured using research-grade packed red blood cells, and hemolysis rates were assessed before and after transfusion by chi-square tests and independent sample t-tests; Results: Anyfusion demonstrated an average transfusion error rate of 3.77%, compared to 4.00% for the Terufusion, with no statistically significant difference in hemolysis rates (p=0.697). Bland-Altman plots confirmed equivalent performance, with hemolysis rates of 0.566 ± 0.095% for Anyfusion and 0.518 ± 0.126% for Terufusion; Conclusions: Anyfusion provides accurate and reliable blood transfusion performance comparable to Terufusion, with no significant difference in hemolysis rates. Its integration of syringe and infusion methods shows potential for safer and more efficient transfusion practices, especially in pediatric and emergency settings.