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Maxillary sinus floor elevation is usually performed in two different ways: the lateral approach involves the creation of a bony window on the maxillary sinus lateral wall, providing direct access to the sinus cavity for membrane elevation and subsequent graft placement, and the transcrestal approach is considered less invasive. The aim of this article is to describe, based on the literature, how to anticipate, avoid, and manage the intraoperative complications that can occur with both approaches. For both approaches, the most common complication is the sinus membrane perforation. For the lateral approach, an average frequency ranging from 15.7% to 23.1% is reported, but because of the better visibility, their management will be easier compared to the transcrestal approach. Mean perforation rate reported for the transcrestal approach is lower (3.1%–6.4%), but it should be noted that a significant number of perforations cannot be detected and managed given the blind nature of this technique. Anatomical parameters such as sinus width and buccal wall thickness may be a risk factor for one approach and not the other. As it is impossible to assess the resistance of the Schneiderian membrane, the transcrestal approach is more likely to lead to infectious complications in the event of perforation. Others, such as the risk of vascular damage, are encountered only with the lateral approach, which can be prevented easily by dissecting the alveolo‐antral artery. For both approaches, prevention is essential and consists in analyzing the anatomy, mastering the surgical technique, and collaborating with the ENT to manage the essentially infectious consequences of intraoperative complications. [ABSTRACT FROM AUTHOR]

This work presents a novel approach for detecting underlying pulsatile structures with laparoscopic tools by using proximal vibroacoustic sensing. This new method could detect pulsations at a depth of up to 1.5 cm. The outcome of this work indicates the potential of identifying deep-seated pulsatile structures during robot-assisted laparoscopy, where haptic feedback is highly limited, to help surgeons prevent vascular damage that may lead to injuries. [ABSTRACT FROM AUTHOR]

There is a relative scarcity of large-scale population studies investigating the relationship between the insulin resistance index of homeostasis model assessment (HOMA-IR) and vascular damage. Therefore, we assessed the association between HOMA-IR and vascular damage in adults aged 18 years and older in China. A total of 17,985 research subjects were included. Vascular damage markers and relevant laboratory tests were measured. HOMA-IR was calculated as (fasting insulin * fasting blood glucose)/22.5. Vascular damage included arteriosclerosis (ba-PWV > 1800 cm/s), peripheral artery disease (ABI < 0.9), and microalbuminuria (UACR > 30 mg/g). The relationship between HOMA-IR and vascular damage was analyzed using the RCS. The restricted cubic spline (RCS) analysis suggested that HOMA-IR was nonlinearly associated with arteriosclerosis (P for no-liner < 0.01), peripheral artery disease (P for no-liner < 0.01), and microalbuminuria (P for no-liner < 0.01). Further segmented regression analyses revealed that in study subjects with HOMA-IR < 5, we found that HOMA-IR was associated with an increased OR for arteriosclerosis (OR: 1.36, 95% CI (1.28, 1.45), P < 0.01), peripheral artery disease (OR: 1.33, 95% CI (1.10, 1.60), P < 0.01) and microalbuminuria (OR: 1.59, 95% CI (1.49, 1.70), P < 0.01). HOMA-IR is an independent risk factor for vascular damage, both macrovascular and microvascular. The phenomenon of saturation of HOMA-IR with vascular damage needs further investigation. [ABSTRACT FROM AUTHOR]

Abstract This study aimed to characterize the role of female sex in the pathogenesis of diabetic retinopathy. In the retinae of female Ins2Akita-diabetic mice (F-IA), ovariectomized female Ins2Akita-diabetic mice (F-IA/OVX), male Ins2Akita-diabetic mice (M-IA), and female STZ-diabetic mice (F-STZ), the formation of reactive metabolites and post-translational modifications, damage to the neurovascular unit, and expression of cellular stress response genes were analyzed. Compared to the male diabetic retina, the concentrations of the glycation adduct fructosyl-lysine, the Maillard product 3-deoxyglucosone, and the reactive metabolite methylglyoxal were significantly reduced in females. In females, there was also less evidence of diabetic damage to the neurovascular unit, as shown by decreased pericyte loss and reduced microglial activation. In the male diabetic retina, the expression of several members of the crystallin gene family (Cryab, Cryaa, Crybb2, Crybb1, and Cryba4) was increased. Clinical data from type 1 diabetic females showed that premenopausal women had a significantly lower prevalence of diabetic retinopathy compared to postmenopausal women stratified for disease duration and glycemic control. These data emphasize the importance of estradiol in protecting the diabetic retina and highlight the pathogenic relevance of sex in diabetic retinopathy.

The search for new biomarkers for the early diagnosis of systemic lupus erythematosus (SLE) is a crucial task. Objective: a comparative study of concentrations of conservative protein nucleobindin 1 (NUCB1) in the blood serum of patients with SLE and healthy donors and assessment of correlation of NUCB1 level with clinical and serological manifestations of the disease.Material and methods. The study included 21 patients with SLE who fulfilled SLICC criteria and 23 healthy donors. SLEDAI-2K index was used to assess SLE activity. Organ damage was assessed using SLICC damage index. Standard laboratory markers of SLE were analyzed in all patients. Concentration of NUCB1 in blood serum was determined using the enzyme immunoassay method. Results and discussion. The group of SLE patients included 20 women and 1 man (median age 33 [27; 40] years, disease duration 5 [3; 10] years), mainly with high disease activity (median SLEDAI-2K 8.5 [6.0; 14.0]). Kidney involvement was found in 52% of cases (nephritis), involvement of joints – in 67% (arthritis), vessels – in 33%, skin – in 67%, pericarditis – in 29%, hematological abnormalities – in 71%, antinuclear factor – in 76% and antibodies against double-stranded DNA – in 71%. An increase in the mean NUCB1 level to 3881 ng/ml was found in the blood serum of SLE patients compared to the control group (2766 ng/ml; p=0.048). Correlations of NUCB1 levels with vascular damage (r=0.653; p

Abstract There is a relative scarcity of large-scale population studies investigating the relationship between the insulin resistance index of homeostasis model assessment (HOMA-IR) and vascular damage. Therefore, we assessed the association between HOMA-IR and vascular damage in adults aged 18 years and older in China. A total of 17,985 research subjects were included. Vascular damage markers and relevant laboratory tests were measured. HOMA-IR was calculated as (fasting insulin * fasting blood glucose)/22.5. Vascular damage included arteriosclerosis (ba-PWV > 1800 cm/s), peripheral artery disease (ABI 30 mg/g). The relationship between HOMA-IR and vascular damage was analyzed using the RCS. The restricted cubic spline (RCS) analysis suggested that HOMA-IR was nonlinearly associated with arteriosclerosis (P for no-liner

Abstract Background Traditional biomarkers of chronic kidney disease (CKD) detect the disease in its late stages and hardly predict associated vascular damage. Integrin-linked kinase (ILK) is a scaffolding protein and a serine/threonine protein kinase that plays multiple roles in several pathophysiological processes during renal damage. However, the involvement of ILK as a biomarker of CKD and its associated vascular problems remains to be fully elucidated. Methods CKD was induced by an adenine-rich diet for 6 weeks in mice. We used an inducible ILK knockdown mice (cKD-ILK) model to decrease ILK expression. ILK content in mice's peripheral blood mononuclear cells (PBMCs) was determined and correlated with renal function parameters and with the expression of ILK and fibrosis and inflammation markers in renal and aortic tissues. Also, the expression of five miRNAs that target ILK was analyzed in whole blood of mice. Results The adenine diet increased ILK expression in PBMCs, renal cortex, and aortas, and creatinine and urea nitrogen concentrations in the plasma of WT mice, while these increases were not observed in cKD-ILK mice. Furthermore, ILK content in PBMCs directly correlated with renal function parameters and with the expression of renal and vascular ILK and fibrosis and inflammation markers. Finally, the expression of the five miRNAs increased in the whole blood of adenine-fed mice, although only four correlated with plasma urea nitrogen, and of those, three were downregulated in cKD-ILK mice. Conclusions ILK, in circulating mononuclear cells, could be a potential biomarker of CKD and CKD-associated renal and vascular damage. Graphical Abstract ILK content in circulating mononuclear cells reflects renal and vascular damage in a CKD experimental model.

BACKGROUND Findings regarding the association between Cardio-Ankle Vascular Index (CAVI) and cardiac hypertension-mediated organ damage (HMOD), such as left ventricular hypertrophy (LVH) assessed by echocardiography, in elderly hypertensive patients are scanty. We sought to investigate this issue in the hypertensive fraction of the general population treated with anti-hypertensive drugs enrolled in the Pressioni Monitorate E Loro Associazioni (PAMELA) study. METHODS The study included 239 out of 562 participants who attended the second and third surveys of the PAMELA study performed after 10 and 25 years from the initial evaluation. Data collection included medical history, anthropometric parameters, office, home, ambulatory blood pressure (BP), blood examinations, echocardiography, and CAVI measurements. RESULTS In the whole study sample (age 69 ± 9 years, 54% males), CAVI was positively correlated with age, office, home, ambulatory systolic BP, LV mass (LVM) index, and negatively associated with body mass index (BMI). In multivariate analysis, CAVI was associated with the LVM index (P  < 0.05) independently of major confounders. The participants with LVH exhibited significantly higher CAVI (10.6 ± 2.8 vs. 9.2 ± 1.8 m/s P  < 0.001), larger left atrial diameter, and lower LV ejection fraction values than their counterparts without it. The CAVI value of 9.4 m/s was the best cut-off for prediction of LVH in the whole sample. CONCLUSIONS Our study provides new evidence of an independent association between CAVI and LVH in treated elderly hypertensive patients and suggests that the use of this metric of arterial stiffness could not only be used to evaluate vascular damage but also to stratify the risk of LVH. [ABSTRACT FROM AUTHOR]

Background: Traditional biomarkers of chronic kidney disease (CKD) detect the disease in its late stages and hardly predict associated vascular damage. Integrin-linked kinase (ILK) is a scaffolding protein and a serine/threonine protein kinase that plays multiple roles in several pathophysiological processes during renal damage. However, the involvement of ILK as a biomarker of CKD and its associated vascular problems remains to be fully elucidated. Methods: CKD was induced by an adenine-rich diet for 6 weeks in mice. We used an inducible ILK knockdown mice (cKD-ILK) model to decrease ILK expression. ILK content in mice's peripheral blood mononuclear cells (PBMCs) was determined and correlated with renal function parameters and with the expression of ILK and fibrosis and inflammation markers in renal and aortic tissues. Also, the expression of five miRNAs that target ILK was analyzed in whole blood of mice. Results: The adenine diet increased ILK expression in PBMCs, renal cortex, and aortas, and creatinine and urea nitrogen concentrations in the plasma of WT mice, while these increases were not observed in cKD-ILK mice. Furthermore, ILK content in PBMCs directly correlated with renal function parameters and with the expression of renal and vascular ILK and fibrosis and inflammation markers. Finally, the expression of the five miRNAs increased in the whole blood of adenine-fed mice, although only four correlated with plasma urea nitrogen, and of those, three were downregulated in cKD-ILK mice. Conclusions: ILK, in circulating mononuclear cells, could be a potential biomarker of CKD and CKD-associated renal and vascular damage. ILK content in circulating mononuclear cells reflects renal and vascular damage in a CKD experimental model. [ABSTRACT FROM AUTHOR]

Thymic epithelial tumors (TET) patients are at high risk of autoimmune and hypoimmune complications. Limited evidence is available on the potential risk of immune-related and inflammatory reactions induced by SARS-Cov-2 vaccine in this patient population. In order to identify subjects at higher risk for vaccine complications, we prospectively evaluated a panel of serum biomarkers related to inflammation (TNF-α, IL-1β, −6, −10, −12, and −17A, IFN-α, β and γ, MPO, MMP-9), and vascular damage (E- and P-selectin, VEGF-A, P-ANCA and MCP-1) in 44 TET patients and in 30 healthy controls along the whole SARS-Cov-2 vaccine cycle. About 50 % of subjects (either TET and controls) showed an increase of serum biochemical markers of inflammation and endothelial damage with a large heterogeneity of values. Such increase appeared early, after the first dose in control subjects and later, after the second dose in TET patients (in which we observed mainly an increase of inflammatory biomarkers). The values normalized after about 3 months and did not increase after the third, booster dose. No autoimmune or vascular complications were observed in the study subjects and no difference was observed in terms of vaccine response among subjects showing serum biomarkers increase and those who experienced no changes. Our data highlight the relevance of Sars-Cov-2 vaccine in TET patients, as it resulted safe and prevented severe COVID-19. However, further studies are awaited to explore the mechanisms and the potential consequences of the observed increase of serum inflammatory and vascular damage biomarkers. [ABSTRACT FROM AUTHOR]

Aim. To evaluate the association of the triglyceride-glucose index (TGI) with micro- and macrovascular changes in patients with moderate, high and very high cardiovascular risk (CVR).Material and methods. The study included 134 men and 129 women aged 40 to 65 years with a SCORE2 ten-year risk of adverse cardiovascular events of 2,5% or more. Based on a detailed survey, a comprehensive physical and paraclinical examination, the relationship between TGI and CVR factors was assessed using Pearson correlation analysis, followed by a linear correlation strength assessment using the Chaddock scale. Modeling of the TGI association with macro- and microvascular damage in patients with moderate CVD was performed using multivariate logistic regression.Results. According to regression analysis, increased TGI was associated with an increased risk of both macrovascular and microvascular changes. Similar results were obtained using multivariate logistic regression with model adjustment for age, sex, body mass index, waist circumference, smoking, hypertension, family history of premature cardiovascular disease, lipid-lowering therapy, and glucose-lowering therapy. An increased level of TGI was associated with an increase in the odds ratio (OR) of carotid atherosclerosis (OR 1,73, 95% confidence interval 1,27-2,36, P for trend

Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease. Vascular damage is one of the important features of SSc, which affects the progression and prognosis of the disease. MiR‐126‐3p is an important microRNA (miRNA) that regulates vascular structure and function, which can be transported through exosomes. However, the role of miR‐126‐3p in vascular damage in SSc is still unclear. Therefore, we focused on the connection between miR‐126‐3p and vascular damage in SSc, as well as investigated the potential role of miR‐126‐3p in vascular damage in SSc. First, this study successfully extracted extracellular vesicles from clinical plasma samples and characterized the exosomes within them. Then, we predicted and screened the target pathway mammalian/mechanistic target of rapamycin (mTOR) and the target gene SLC7A5 of miR‐126‐3p through online databases. Next, we constructed SSc mice for in vivo studies. The results showed that the expression of miR‐126‐3p was decreased in the plasma exosomes, while the SLC7A5 expression, autophagy, and lipid peroxidation were increased in the aorta. Luciferase reporter gene assays demonstrated that miR‐126‐3p can bind to SLC7A5, resulting in a decrease in its expression. In vitro experiments have shown that exosomal miR‐126‐3p can be internalized by human umbilical vein endothelial cells (HUVECs). The miR‐126‐3p group exhibited enhanced cell viability and tube formation ability, along with increased expression of the vascular formation marker CD31. Additionally, miR‐126‐3p downregulated the protein expression of SLC7A5 and LC3 in HUVECs, while upregulating the protein expression of mTOR, P62, PPARγ, and CPT‐1. However, the effects of miR‐126‐3p on HUVECs were counteracted by mTOR inhibitors and enhanced by mTOR activators. The results indicated that exosomal miR‐126‐3p has the potential to protect against vascular injury in SSc by regulating the SLC7A5/mTOR signalling pathway in HUVECs. [ABSTRACT FROM AUTHOR]

Hyperhomocysteinemia (HHcy) a significant risk factor for vascular disease, often emerges in epilepsy with the use of antiepileptic drugs. In this relationship, our study investigates the combined effects of HHcy and antiepileptics on vascular function using a rat model.

Our previous work indicated the greater magnitude of damage to the thoracic aorta at 6 months after starting 5 Gy irradiation in descending order of exposure to X-rays in 25 fractions > acute X-rays > acute γ-rays > X-rays in 100 fractions ≫ chronic γ-rays, in which the limitations of the study included a lack of data for fractionated γ-ray exposure. To better understand effects of dose protraction and radiation quality, the present study examined changes after exposure to γ-rays in 25 fractions, and compared its biological effectiveness with five other irradiation regimens. Male C57BL/6J mice received 5 Gy of 137Cs γ-rays delivered in 25 fractions spread over six weeks. At 6 months after starting irradiation, mice were subjected to echocardiography, followed by tissue sampling. The descending thoracic aorta underwent scanning electron microscopy, immunofluorescence staining and histochemical staining. The integrative analysis of multiple aortic endpoints was conducted for inter-regimen comparisons. Exposure to γ-rays in 25 fractions induced vascular damage (evidenced by increases in endothelial detachment and vascular endothelial cell death, decreases in endothelial waviness, CD31, endothelial nitric oxide synthase and vascular endothelial cadherin), inflammation (evidenced by increases in tumor necrosis factor α, CD68 and F4/80) and fibrosis (evidenced by increases in transforming growth factor β1, alanine blue stain and intima-media thickness). The integrative analysis revealed biological effectiveness in descending order of exposure to X-rays in 25 fractions > acute X-rays > γ-rays in 25 fractions > acute γ-rays > X-rays in 100 fractions ≫ chronic γ-rays. The results suggest that dose protraction effects on aortic damage depend on radiation quality, and are not a simple function of dose rate and the number of fractions. [ABSTRACT FROM AUTHOR]

Hyperbaric oxygen (HBO) treatment aims to restore tissue oxygenation by inhaling 100% oxygen in pressure rooms. Although beneficial effects have been reported with regard to re-oxygenated ischemic tissues, conflicting findings have been presented concerning the paradoxical tissue response following reperfusion and/or the different responses of non-ischemic normal tissues to increased oxygen exposure. The present study sought to experimentally investigate the impact of continuous HBO treatments on normal aortic tissue. New Zealand rabbits were placed in pressure rooms for 90 minutes per day under 2.5 atmospheric pressure and exposed to HBO for 28 days. Normal structural histology was obtained in the control group. Foam cells were detected in the aortic intimae, thickening and undulation were visualized in the endothelium, and localized separations were observed in the tunica media in the study group compared with the control group. Moreover, salient vasa vasorum was detected in the study group via histopathology. These findings suggest that continuous HBO exposures disrupt the normal vascular structure of a healthy aorta. [ABSTRACT FROM AUTHOR]

Background: The aims of this study were to analyze prevalence and severity of vascular risk factors in older patients referred to our clinic due to onset of Very Late-Onset Schizophrenia-Like Psychosis (VLOSLP) and to create a specific phenotype based on pathophysiological insight rather than age of onset. Methods: In a longitudinal study, 103 (M = 39, F = 64; mean age of 80.32 ± 7.65 years) patients were evaluated with cognitive, neuropsychiatric, and functional assessment scales. Blood concentration of hemoglobin (Hb), mean corpuscular volume (MCV), platelets, total protein test (TPT), creatinine, azotemia, glycemia, total cholesterol (TC), triglycerides (TG), uric acid (UA), sodium (Na), potassium (K), chlorine (Cl), calcium (Ca), folate, vitamin B12 (Vit-B12), and homocysteine were measured. Presence/absence of tobacco use, alcohol consumption, psychoactive substance use, hypertension, hyperlipidemia, diabetes mellitus, and history of vascular disease were collected. Results: Females were more apathetic than males (NPI-Apathy: p = 0.040). Males had a significantly higher level of Hb (p = 0.019) and UA (p = 0.001), and a lower level of platelets (p = 0.004) and Ca (p = 0.003), and used more tobacco (p = 0.046) and alcohol (p = 0.024) than females. Comparing patients < 80 and ≥80 years, we found differences in frequency of vascular risk factors among men (p = 0.027). In total, 102 patients were treated for psychosis (59.16% of them were using atypical antipsychotics). Conclusions: The results of this study could be useful for a progressive demonstration of the causal relationship between cardiac and cerebral vascular events and VLOSLP. [ABSTRACT FROM AUTHOR]

A growing body of evidence suggests that the gut microbiota affects the cardiovascular system directly and indirectly via biologically active molecules. TMAO, a key metabolite produced by gut bacteria is implicated in atherosclerosis and chronic endothelial dysfunction, but with an unclear effect on vascular tone, oxidative stress, and inflammation. Our study aimed to evaluate the acute effects of TMAO on vascular contractility in relation with oxidative stress markers and inflammation. Aortic rings were harvested from laboratory rats and placed in a tissue bath system containing TMAO in concentrations of 300, 100, 10 µM, and control. Vascular tone under the influence of vasoconstrictor phenylephrine and non-endothelial-dependent vasodilator sodium nitroprusside was assessed using force transducers connected to a computer-based acquisition system. Oxidative stress and inflammation were quantified by vascular assessment of the activity of NF-κB, NRF2, SOD1, and iNOS by western-blotting and MDA by spectrofluorimetry. After the incubation of the aortic rings in TMAO solutions for 1 h, there was no difference in vasoconstrictor and non-endothelial vasodilator response between the studied doses. TMAO acutely induced oxidative stress and inflammation, significantly increasing levels of MDA and the expression of NF-κB, NRF2, SOD1, and iNOS, mostly in a dose-dependent manner. Our study showed the lack of a short-term effect of studied TMAO doses on vascular contractility, but demonstrated an acute prooxidative effect and activation of major inflammatory pathways, which can partially explain the detrimental effects of TMAO in cardiovascular disease. [ABSTRACT FROM AUTHOR]

The number of stentriever passes during endovascular thrombectomy impacts clinical outcomes in acute ischemic stroke. Previous studies suggest that the simultaneous double stent retriever technique (DSRT) could improve the efficacy and reduce the number of passes. We aim to analyze the degree of vessel wall injury according to the number of passes and technique (single vs. simultaneous devices). Histological changes were evaluated in renal arteries (RAs) of swine models after thrombectomy (1, 2, or 3 passes) with single stent (SSRT) and DSRT. Thrombectomy passes were performed in 12 RA: 3 samples from each artery were studied by optical microscopy to assess a vascular damage score. All thirty-six samples showed endothelial denudation and different degrees of damage in the deepest layers of the arterial wall; however, all arteries remained patent by the time of assessment. In all cases, the degree of vascular injury increased with the number of passes. Compared with a SSRT, DSRT showed a higher severity of histological damage corresponding to the damage caused by 1.4 SSRT passes. However, in distal arteries, vascular damage was relatively similar when comparing SSRT with multiple passes and DSRT with one pass. The degree of vessel injury increases with the number of passes. Even though histological damage per pass was 1.4 higher with DSRT than SSRT, short-term vessel patency was not compromised after up to 3 DSRT passes. Further studies are needed to characterize the risk–benefit ratio of the DSRT in routine clinical practice. [ABSTRACT FROM AUTHOR]

Pericyte loss and deficient vascular platelet-derived growth factor receptor-β (PDGFRβ) signaling are prominent features of the blood-brain barrier breakdown described in Alzheimer's disease (AD) that can predict cognitive decline yet have never been studied in the retina. Recent reports using noninvasive retinal amyloid imaging, optical coherence tomography angiography, and histological examinations support the existence of vascular-structural abnormalities and vascular amyloid β-protein (Aβ) deposits in retinas of AD patients. However, the cellular and molecular mechanisms of such retinal vascular pathology were not previously explored. Here, by modifying a method of enzymatically clearing non-vascular retinal tissue and fluorescent immunolabeling of the isolated blood vessel network, we identified substantial pericyte loss together with significant Aβ deposition in retinal microvasculature and pericytes in AD. Evaluation of postmortem retinas from a cohort of 56 human donors revealed an early and progressive decrease in vascular PDGFRβ in mild cognitive impairment (MCI) and AD compared to cognitively normal controls. Retinal PDGFRβ loss significantly associated with increased retinal vascular Aβ40 and Aβ42 burden. Decreased vascular LRP-1 and early apoptosis of pericytes in AD retina were also detected. Mapping of PDGFRβ and Aβ40 levels in pre-defined retinal subregions indicated that certain geometrical and cellular layers are more susceptible to AD pathology. Further, correlations were identified between retinal vascular abnormalities and cerebral Aβ burden, cerebral amyloid angiopathy (CAA), and clinical status. Overall, the identification of pericyte and PDGFRβ loss accompanying increased vascular amyloidosis in Alzheimer's retina implies compromised blood-retinal barrier integrity and provides new targets for AD diagnosis and therapy.

Abstract Single cell RNA sequencing studies identified novel neurodegeneration-associated microglial (MGnD/DAM) subtypes activated around cerebral amyloid plaques. Micro-RNA (miR)-155 of the TREM2-APOE pathway was shown to be a key transcriptional regulator of MGnD microglial phenotype. Despite growing interest in studying manifestations of Alzheimer’s disease (AD) in the retina, a CNS organ accessible to noninvasive high-resolution imaging, to date MGnD microglia have not been studied in the AD retina. Here, we discovered the presence and increased populations of Clec7a+ and Galectin-3+ MGnD microglia in retinas of transgenic APPSWE/PS1L166P AD-model mice. Conditionally targeting MGnD microglia by miR-155 ablation via the tamoxifen-inducible CreERT2 system in APPSWE/PS1L166P mice diminished retinal Clec7a+ and Galectin-3+ microglial populations while increasing homeostatic P2ry12+ microglia. Retinal MGnD microglia were often adhering to microvessels; their depletion protected the inner blood-retina barrier and reduced vascular amyloidosis. Microglial miR-155 depletion further limits retinal inflammation. Mass spectrometry analysis revealed enhanced retinal PI3K-Akt signaling and predicted IL-8 and Spp1 decreases in mice with microglia-specific miR-155 knockout. Overall, this study identified MGnD microglia in APPSWE/PS1L166P mouse retina. Transcriptional regulation of these dysfunctional microglia mitigated retinal inflammation and vasculopathy. The protective effects of microglial miR-155 ablation should shed light on potential treatments for retinal inflammation and vascular damage during AD and other ocular diseases.

ABSTRACT In this review, I summarise the circumstances leading to the collaboration between London and Örebro on the basic research performed to study potential mechanisms underlying the improved patency of saphenous veins harvested by the no-touch technique. Histological studies reveal various forms of vascular damage to saphenous vein grafts harvested in conventional coronary artery bypass grafting (CABG) whereas no-touch grafts retain a normal architecture. The perivascular fat that remains intact on no-touch saphenous vein grafts seems to play a particularly important role as the “protector” of all layers of the graft. In addition, the perivascular fat is a source of adipose cell-derived factors that may contribute to the success of the no-touch technique. While a number of trials have compared no-touch with conventional grafts following CABG, these have generally been limited to short follow-up periods, low patient numbers, and inadequate histological data. When handling no-touch saphenous vein at harvesting, there is no direct contact of the vein by surgical instruments, spasm does not occur, and high-pressure intraluminal distension is not required. While damage to both endothelial and vascular smooth muscle cells are evident at the microscopic and ultrastructural level in conventional saphenous vein grafts, their structure in no-touch grafts is preserved. Also, in no-touch veins, the vasa vasorum remains intact and transmural blood supply is maintained. This microvascular network is disrupted during conventional harvesting, a situation likely to stimulate processes involved in graft occlusion. The use of excess graft material for histology is to be encouraged for the assessment of vascular damage and even surgeon competence. If you don’t look, you don’t find.

Both progression from the early pathogenic events to clinically manifest cardiovascular diseases (CVD) and cancer impact the integrity of the vascular system. Pathological vascular modifications are affected by interplay between endothelial cells and their microenvironment. Soluble factors, extracellular matrix molecules and extracellular vesicles (EVs) are emerging determinants of this network that trigger specific signals in target cells. EVs have gained attention as package of molecules with epigenetic reversible activity causing functional vascular changes, but their mechanisms are not well understood. Valuable insights have been provided by recent clinical studies, including the investigation of EVs as potential biomarkers of these diseases. In this paper, we review the role and the mechanism of exosomal epigenetic molecules during the vascular remodeling in coronary heart disease as well as in cancer-associated neoangiogenesis. [ABSTRACT FROM AUTHOR]

Summary: The term "vasculitis" refers to a group of rare immune‐mediated diseases characterized by the dysregulated immune system attacking blood vessels located in any organ of the body, including the skin, lungs, and kidneys. Vasculitides are classified according to the size of the vessel that is affected. Although this observation is not specific to small‐, medium‐, or large‐vessel vasculitides, patients show a high circulating neutrophil‐to‐lymphocyte ratio, suggesting the direct or indirect involvement of neutrophils in these diseases. As first responders to infection or inflammation, neutrophils release cytotoxic mediators, including reactive oxygen species, proteases, and neutrophil extracellular traps. If not controlled, this dangerous arsenal can injure the vascular system, which acts as the main transport route for neutrophils, thereby amplifying the initial inflammatory stimulus and the recruitment of immune cells. This review highlights the ability of neutrophils to "set the tone" for immune cells and other cells in the vessel wall. Considering both their long‐established and newly described roles, we extend their functions far beyond their direct host‐damaging potential. We also review the roles of neutrophils in various types of primary vasculitis, including immune complex vasculitis, anti‐neutrophil cytoplasmic antibody‐associated vasculitis, polyarteritis nodosa, Kawasaki disease, giant cell arteritis, Takayasu arteritis, and Behçet's disease. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc, scleroderma) is a multifaceted rare connective tissue disease whose pathogenesis is dominated by immune dysregulation, small vessel vasculopathy, impaired angiogenesis, and both cutaneous and visceral fibrosis. Microvascular impairment represents the initial event of the disease, preceding fibrosis by months or years and accounting for the main disabling and/or life-threatening clinical manifestations, including telangiectasias, pitting scars, periungual microvascular abnormalities (e.g., giant capillaries, hemorrhages, avascular areas, ramified/bushy capillaries) clinically detectable by nailfold videocapillaroscopy, ischemic digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. Despite a variety of available treatment options, treatment of SSc-related vascular disease remains problematic, even considering SSc etherogenity and the quite narrow therapeutic window. In this context, plenty of studies have highlighted the great usefulness in clinical practice of vascular biomarkers allowing clinicians to assess the evolution of the pathological process affecting the vessels, as well as to predict the prognosis and the response to therapy. The current narrative review provides an up-to-date overview of the main candidate vascular biomarkers that have been proposed for SSc, focusing on their main reported associations with characteristic clinical vascular features of the disease. [ABSTRACT FROM AUTHOR]

Tobacco smoking is strongly linked to vascular damage contributing to the development of hypertension, atherosclerosis, as well as increasing the risk for neurodegeneration. Still, the involvement of the innate immune system in the development of vascular damage upon chronic tobacco use before the onset of clinical symptoms is not fully characterized. Our data provide evidence that a single acute exposure to tobacco elicits the secretion of extracellular vesicles expressing CD105 and CD49e from endothelial cells, granting further recognition of early preclinical biomarkers of vascular damage. Furthermore, we investigated the effects of smoking on the immune system of healthy asymptomatic chronic smokers compared to never-smokers, focusing on the innate immune system. Our data reveal a distinct immune landscape representative for early stages of vascular damage in clinically asymptomatic chronic smokers, before tobacco smoking related diseases develop. These results indicate a dysregulated immuno-vascular axis in chronic tobacco smokers that are otherwise considered as healthy individuals. The distinct alterations are characterized by increased CD36 expression by the blood monocyte subsets, neutrophilia and increased plasma IL-18 and reduced levels of IL-33, IL-10 and IL-8. Additionally, reduced levels of circulating BDNF and elevated sTREM2, which are associated with neurodegeneration, suggest a considerable impact of tobacco smoking on CNS function in clinically healthy individuals. These findings provide profound insight into the initial and ongoing effects of tobacco smoking and the potential vascular damage contributing to neurodegenerative disorders, specifically cerebrovascular dysfunction and dementia.

Background: The global burden of hypertension is constantly increasing with adverse cardiovascular and ocular sequelae. The association between elevated blood pressure and choroidal thickness (CT), as assessed via optical coherence tomography (OCT), is poorly understood. Objectives and Design: Studies including hypertensive adults and normotensive controls undergoing OCT were evaluated for inclusion in this meta-analysis. The primary endpoint was CT difference between hypertensive and normotensive adults. Data Sources and Methods: We conducted a systematic review and after searching 1011 results from MEDLINE, ClinicalTrials.gov, medRxiv and Cochrane Library, six studies were deemed eligible and were pooled according to a random-effect model. Results: A statistically significant reduction in choroidal thickness was found in hypertensive adults (n = 454) as compared with normotensive controls (n = 365) [mean difference: −0.77; 95% confidence intervals: (−1.20, −0.34); p = 0.0004]. The main limitations of this meta-analysis are the relatively small population included and the high statistical heterogeneity (I 2 = 87%) among the various studies. Of note, after excluding one study the heterogeneity was markedly reduced. Conclusion: Choroidal thickness is reduced among hypertensive subjects compared with normotensive controls. This finding mandates further examination in the context of long-term clinical outcomes. [ABSTRACT FROM AUTHOR]

Introduction: The occurrence of vascular injury during drilling is a rare but severe complication. Unfortunately, drilling protection systems are not available in all hospitals. Thanks to the development of 3D printing in recent years, sharing devices and materials to solve surgical problems has become easy and inexpensive. The objective of our work is to evaluate a universal, freely accessible, 3D-printable drilling protection device. Materials and methods: A prospective, randomized, and triple-blind evaluation of excess drilling was evaluated in expert surgeons and resident surgeons without the use of the protection device. Subsequently, excess drilling was assessed using the device in both groups. The differences in drilling lengths between both groups with and without the device were analyzed to establish the reduction of excess drilling in both groups. Results: The drilling in the expert surgeon without device group was 3.03 mm (SD 1.69 95% CI 2.40–3.66 p value = 9.89e−11), while the resident surgeon with device group performed excess drilling of 1.76 mm (SD 0.89 CI 95% 1.43–2.10). Results showed better results in the resident surgeon with device group than in the expert surgeons with device group (p value ˂ 0.01). The device improved drilling in both resident surgeons (5.77 mm) and expert surgeons (1.17 mm). Conclusions: The device improves drilling in both expert surgeons and resident surgeons, showing greater benefits in the latter. The device is printable with any 3D printer, making it universally accessible, inexpensive, and effective, allowing expert surgeons to improve precision in high-risk situations and resident surgeons to improve their technique without increasing risk to the patient. [ABSTRACT FROM AUTHOR]

Single cell RNA sequencing studies identified novel neurodegeneration-associated microglial (MGnD/DAM) subtypes activated around cerebral amyloid plaques. Micro-RNA (miR)-155 of the TREM2-APOE pathway was shown to be a key transcriptional regulator of MGnD microglial phenotype. Despite growing interest in studying manifestations of Alzheimer's disease (AD) in the retina, a CNS organ accessible to noninvasive high-resolution imaging, to date MGnD microglia have not been studied in the AD retina. Here, we discovered the presence and increased populations of Clec7a+ and Galectin-3+ MGnD microglia in retinas of transgenic APPSWE/PS1L166P AD-model mice. Conditionally targeting MGnD microglia by miR-155 ablation via the tamoxifen-inducible CreERT2 system in APPSWE/PS1L166P mice diminished retinal Clec7a+ and Galectin-3+ microglial populations while increasing homeostatic P2ry12+ microglia. Retinal MGnD microglia were often adhering to microvessels; their depletion protected the inner blood-retina barrier and reduced vascular amyloidosis. Microglial miR-155 depletion further limits retinal inflammation. Mass spectrometry analysis revealed enhanced retinal PI3K-Akt signaling and predicted IL-8 and Spp1 decreases in mice with microglia-specific miR-155 knockout. Overall, this study identified MGnD microglia in APPSWE/PS1L166P mouse retina. Transcriptional regulation of these dysfunctional microglia mitigated retinal inflammation and vasculopathy. The protective effects of microglial miR-155 ablation should shed light on potential treatments for retinal inflammation and vascular damage during AD and other ocular diseases. [ABSTRACT FROM AUTHOR]

Introduction: The psychiatric disorders and obesity comorbidity is related to neurocognitive impairment and inflammation. Exercise is crucial to improve and maintain healthy lifestyles. This randomized controlled trial tested the efficacy of aerobic exercise as promoter of neurocognitive improvement across psychiatric disorders with comorbid obesity (OB)., Methods: Patients with major depressive disorder, bipolar disorder and, schizophrenia and with comorbid OB (n = 29) received brief healthy lifestyle counseling and were randomized into two groups: guided physical activity group (GPAG) (n = 10) which included 12 weeks of guided-exercise of moderate intensity and frequency, and incentive of autonomous physical activity proposals by the specialist. Standard physical activity group (SPAG) (n = 19) continue with their usual daily physical activity, without guidance or incentives, over 12 weeks. Peripheral blood biomarkers of inflammation, oxidative stress, vascular mechanisms, and metabolic activity, as well as neurocognitive and functional performance were assessed twice, before and after intervention. Mixed one-way analysis of variance and linear regression analyses were performed., Results: Individuals in GPAG showed better neurocognitive and functional performance than individuals in SPAG after physical activity training (p < 0.05; η²p = 0.14 to 0.15). A significant improvement in cognition before and after the physical activity training in the GPAG group was found (p < 0.0001; η²p = 0.29). In all cases, the effect size was from moderate to large. Inflammatory activity (interleukin [IL-6]), oxidative (mitochondrial reactive oxygen species [mROS] and mitochondrial membrane potential [ΔΨm]) and inter cellular adhesion molecule 1 [ICAM1], leukocyte-endothelium adhesion [LEPMN], and p-selectin [PSEL]) levels, and cardio-metabolic (low-density lipoprotein [LDL], systolic blood pressure [SBP], and insulin) processes were significant predicting neurocognitive improve of individuals with psychiatric disorders and comorbid OB., Conclusions: Physical activity programs may have positive impact on neurocognitive and functional performance in individuals with psychiatric disorders and OB. Exercise influences inflammatory, oxidative, vascular, and cardio-metabolic pathways, and modulate cognition. These findings may have a potential translational utility for early intervention in these disorders., Competing Interests: Declaration of competing interest Dr. V. Balanzá-Martínez has received honoraria from Angelini over the last 3 years unrelated to the present work., (Copyright © 2024. Published by Elsevier B.V.)

Background and Purpose: Prior observational studies have suggested a strong correlation between sarcopenia and stroke, but the causal link between them remains uncertain. This study aims to investigate the associations between genetically predicted sarcopenia-related traits and stroke using a two-step Mendelian randomization (MR) approach., Methods: Genome-wide association study (GWAS) summary data for sarcopenia-related traits were acquired from the UK Biobank. Genetic associations for ischemic stroke (IS) and its subtypes were selected from the MEGASTROKE consortium comprising European ancestry participants. GWAS summary data for cerebral hemorrhage were obtained from the FinnGen consortium, including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). MR estimates were calculated using the inverse-variance weighted (IVW) method. The robustness of results was assessed for heterogeneity and pleiotropy of individual single nucleotide polymorphisms (SNPs)., Results: Higher appendicular lean mass (ALM) exhibited a potential causal association with a reduced incidence of large artery atherosclerosis (LAA) (odds ratio [OR] = 0.81, 95% confidence interval [CI]:0.71-0.93; P = 0.003) and small vessel disease (SVD) (OR = 0.83, 95% CI:0.74-0.94; P = 0.002). The associations of ALM with IS and ICH were compromised after adjusting for body fat and physical activity with multivariable MR. Two-step MR mediation analysis explored 33 candidate mediators, among which hypertension and SBP accounted for more than 10% of the mediation proportion in the relationship between ALM and stroke and its subtypes., Conclusion: Our research findings indicate that lower ALM is associated with a increased risk of stroke . It is necessary to explore the specific protective mechanisms of higher ALM for preventing stroke occurrence., Competing Interests: Declaration of competing interest The authors declared that there were no potential conflicts of interest regarding this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Synopsis: This study describes a rare case of a prenatal spontaneous abdominal wall hematoma that occurred in a pregnant woman with severe pre‐eclampsia and upper respiratory tract infection. [ABSTRACT FROM AUTHOR]

To replace kidney function, peritoneal dialysis (PD) utilizes hyperosmotic PD fluids with specific physico-chemical properties. Their composition induces progressive damage of the peritoneum, leading to vasculopathies, decline of membrane function, and PD technique failure. Clinically used PD fluids differ in their composition but still remain bioincompatible. We mapped the molecular pathomechanisms in human endothelial cells induced by the different characteristics of widely used PD fluids by proteomics. Of 7894 identified proteins, 3871 were regulated at least by 1 and 49 by all tested PD fluids. The latter subset was enriched for cell junction-associated proteins. The different PD fluids individually perturbed proteins commonly related to cell stress, survival, and immune function pathways. Modeling two major bioincompatibility factors of PD fluids, acidosis, and glucose degradation products (GDPs) revealed distinct effects on endothelial cell function and regulation of cellular stress responses. Proteins and pathways most strongly affected were members of the oxidative stress response. Addition of the antioxidant and cytoprotective additive, alanyl-glutamine (AlaGln), to PD fluids led to upregulation of thioredoxin reductase-1, an antioxidant protein, potentially explaining the cytoprotective effect of AlaGln. In conclusion, we mapped out the molecular response of endothelial cells to PD fluids, and provided new evidence for their specific pathomechanisms, crucial for improvement of PD therapies. [ABSTRACT FROM AUTHOR]

Sphingolipids are well-recognized critical components in several biological processes. Ceramides constitute a class of sphingolipid metabolites that are involved in important signal transduction pathways that play key roles in determining the fate of cells to survive or die. Ceramide accumulated in cells causes apoptosis; however, ceramide metabolized to sphingosine promotes cell survival and angiogenesis. Studies suggest that vascular-targeted therapies increase endothelial cell ceramide resulting in apoptosis that leads to tumour cure. Specifically, ultrasound-stimulated microbubbles (USMB) used as vascular disrupting agents can perturb endothelial cells, eliciting acid sphingomyelinase (ASMase) activation accompanied by ceramide release. This phenomenon results in endothelial cell death and vascular collapse and is synergistic with other antitumour treatments such as radiation. In contrast, blocking the generation of ceramide using multiple approaches, including the conversion of ceramide to sphingosine-1-phosphate (S1P), abrogates this process. The ceramide-based cell survival "rheostat" between these opposing signalling metabolites is essential in the mechanotransductive vascular targeting following USMB treatment. In this review, we aim to summarize the past and latest findings on ceramide-based vascular-targeted strategies, including novel mechanotransductive methodologies. [ABSTRACT FROM AUTHOR]

Study Design: A controlled laboratory study.Objective: The aim of this study was to examine bone damage caused by irradiation to spinal vertebrae in rats.Summary Of Background Data: Radiotherapy is widely used in the treatment of malignant spine tumors. However, a few studies have reported vertebral fractures following radiotherapy as an adverse reaction. There are no reports on irradiation- induced changes in bone fragility, mechanical and structural changes focusing on the spine, and the mechanism of irradiation-induced bone osteoporosis.Methods: Eighty-four female Wistar rats were randomly allocated to the 20 Gy irradiated or the nonirradiated (control) group. The lumbar vertebrae were irradiated with an external focal radiation dose of 20 Gy. Biomechanical, structural, and histological analyses were performed at 0, 2, 4, 6, 8, 12, and 24 weeks after irradiation. Structural analysis and bone density measurement of vertebral trabecular bone were performed by μCT. Histopathological evaluation was performed by hematoxylin and eosin staining and immunostaining.Results: The bone strength at 2 weeks after irradiation (311 ± 23 N) was 22% lower than that before irradiation (398 ± 34 N) (P  < 0.05). The trabecular spacing increased, and trabecular connectivity and width decreased significantly in the irradiated group compared with those in the non-irradiated group. The three-dimensional structure model became coarse, and the trabecular structure continued to thin and disrupt after irradiation. There was no significant change in the bone mineral density in both groups.Conclusion: A decrease in bone strength was observed 2 weeks after irradiation. Bone mineral density remained unaltered, whereas the microstructure of trabecular bone changed, suggesting bone damage by irradiation.Level of Evidence: N/A. [ABSTRACT FROM AUTHOR]

Severe vascular damage and complications are often observed in cancer patients during treatment with chemotherapeutic drugs such as cisplatin. Thus, development of potential options to ameliorate the vascular side effects is urgently needed. In this study, the effects and the underlying mechanisms of far‐infrared radiation (FIR) on cisplatin‐induced vascular injury and endothelial cytotoxicity/dysfunction in mice and human umbilical vein endothelial cells (HUVECs) were investigated. An important finding is that the severe vascular stenosis and poor blood flow seen in cisplatin‐treated mice were greatly mitigated by FIR irradiation (30 minutes/day) for 1‐3 days. Moreover, FIR markedly increased the levels of phosphorylation of PI3K and Akt, and VEGF secretion, as well as the expression and the activity of hypoxia‐inducible factor 1α (HIF‐1α) in cisplatin‐treated HUVECs in a promyelocytic leukemia zinc finger protein (PLZF)‐dependent manner. However, FIR‐stimulated endothelial angiogenesis and VEGF release were significantly diminished by transfection with HIF‐1α siRNA. We also confirmed that HIF‐1α, PI3K, and PLZF contribute to the inhibitory effect of FIR on cisplatin‐induced apoptosis in HUVECs. Notably, FIR did not affect the anticancer activity and the HIF‐1α/VEGF cascade in cisplatin‐treated cancer cells under normoxic or hypoxic condition, indicating that the actions of FIR may specifically target endothelial cells. It is the first study to demonstrate that FIR effectively attenuates cisplatin‐induced vascular damage and impaired angiogenesis through activation of HIF‐1α–dependent processes via regulation of PLZF and PI3K/Akt. Taken together, cotreatment with the noninvasive and easily performed FIR has a therapeutic potential to prevent the pathogenesis of vascular complications in cancer patients during cisplatin treatment. [ABSTRACT FROM AUTHOR]

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In this review, I summarise the circumstances leading to the collaboration between London and Örebro on the basic research performed to study potential mechanisms underlying the improved patency of saphenous veins harvested by the no-touch technique. Histological studies reveal various forms of vascular damage to saphenous vein grafts harvested in conventional coronary artery bypass grafting (CABG) whereas no-touch grafts retain a normal architecture. The perivascular fat that remains intact on no-touch saphenous vein grafts seems to play a particularly important role as the “protector” of all layers of the graft. In addition, the perivascular fat is a source of adipose cell-derived factors that may contribute to the success of the no-touch technique. While a number of trials have compared no-touch with conventional grafts following CABG, these have generally been limited to short follow-up periods, low patient numbers, and inadequate histological data. When handling no-touch saphenous vein at harvesting, there is no direct contact of the vein by surgical instruments, spasm does not occur, and high-pressure intraluminal distension is not required. While damage to both endothelial and vascular smooth muscle cells are evident at the microscopic and ultrastructural level in conventional saphenous vein grafts, their structure in no-touch grafts is preserved. Also, in no-touch veins, the vasa vasorum remains intact and transmural blood supply is maintained. This microvascular network is disrupted during conventional harvesting, a situation likely to stimulate processes involved in graft occlusion. The use of excess graft material for histology is to be encouraged for the assessment of vascular damage and even surgeon competence. If you don’t look, you don’t find. [ABSTRACT FROM AUTHOR]

Oxidative stress is defined as a disturbance in the balance between oxidants and antioxidants in favor of the former, which leads to molecular and cellular damage. Free radicals play an important role in the pathogenesis of a large number of diseases. Thalassemic syndromes are increasingly perceived as diseases associated with oxidative damage. The premature hemolysis of erythroid cells and the oxidative effect of the free iron accumulated in the body due to the regular hemotransfusions are important for the reduced survival of the patients with beta-thalassemia Lipids are the most favored target for free-radical damage because they are easily oxidized. Lipid peroxidation is the main molecular mechnism of free radical toxicity. Malondialdehyde, in its role as an end compound of lipid peroxidation, is widely used as an index of oxidative status, respectively a measure of oxidative damage. It has been proven that the processes for its formation play a major role in the pathogenesis of premature atherosclerosis. In recent years, numerous studies have demonstrated elevated levels of malondialdehyde in transfusion-dependent patients with beta-thalassemia major. In this group of patients, altered vascular elasticity with thickening of the intima of the vascular wall and arterial stiffness are additionally demonstrated. A higher incidence of vascular complications, premature arterial aging and early atherosclerosis was also observed. Therefore, it is necessary to start the follow up and the evaluation of the carotid walls of the patients at an earlier age. [ABSTRACT FROM AUTHOR]

Thrombomodulin (TM) is a type-I transmembrane protein that is mainly expressed on endothelial cells and plays important roles in many biological processes. Circulating TM of different forms are also present in biofluids, such as blood and urine. Soluble TM (sTM), comprised of several domains of TM, is the major circulating TM which is generated by either enzymatic or chemical cleavage of the intact protein under different conditions. Under normal conditions, sTM is present in low concentrations (

ABSTRACT Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever acquired by tick bites. Whether mast cells (MCs), the body’s first line of defense against pathogens, might influence immunity or pathogenesis during SFTS virus (SFTSV) infection remained unknown. Here, we found that SFTSV can cause MC infection and degranulation, resulting in the release of the vasoactive mediators, chymase, and tryptase, which can directly act on endothelial cells, break the tight junctions of endothelial cells and threaten the integrity of the microvascular barrier, leading to microvascular hyperpermeability in human microvascular endothelial cells. Local activation of MCs (degranulation) and MC-specific proteases-facilitated endothelial damage were observed in mouse models. When MC-specific proteases were injected subcutaneously into the back skin of mice, signs of capillary leakage were observed in a dose-dependent manner. MC-specific proteases, chymase, and tryptase were tested in the serum collected at the acute phase of SFTS patients, with the higher level significantly correlated with fatal outcomes. By performing receiver operator characteristic curve (ROC) analysis, chymase was determined as a biomarker with the area under the curve value of 0.830 (95% CI = 0.745 to 0.915) for predicting fatal outcomes in SFTS. Our findings highlight the importance of MCs in SFTSV-induced disease progression and outcome. An emerging role for MCs in the clinical prognosis and blocking MC activation as a potential drug target during SFTSV infection was proposed. IMPORTANCE We revealed a pathogenic role for MCs in response to SFTSV infection. The study also identifies potential biomarkers that could differentiate patients at risk of a fatal outcome for SFTS, as well as novel therapeutic targets for the clinical management of SFTS. These findings might shed light on an emerging role for MCs as a potential drug target during infection of other viral hemorrhagic fever diseases with similar host pathology as SFTS.

Fenglei Zheng,* Yijing Tao,* Jingjing Liu, Zhimin Geng, Ying Wang, Yujia Wang, Songling Fu, Wei Wang, Chunhong Xie, Yiying Zhang, Fangqi Gong Department of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fangqi GongDepartment of Cardiology, Children’s Hospital, Zhejiang University School of Medicine; National Clinical Research Center for Child Health, No. 3333, Binsheng Road, Hangzhou, 310052, People’s Republic of ChinaTel/Fax +86-571-86670008Email gongfangqi@zju.edu.cnPurpose: Macrophages-mediated inflammation is linked with endothelial damage of Kawasaki disease (KD). KCa3.1, a calcium-activated potassium channel, modulates inflammation of macrophages. However, little is known about the role of KCa3.1 in inflammation by macrophages involved in KD. Hence, this study is aimed to explore the potential role of KCa3.1 in regulating inflammatory response by macrophages and subsequent vascular injury in an in vitro model of KD.Methods: RAW264.7 cells were stimulated with Lactobacillus casei cell wall extract (LCWE) with or without TRAM-34 or PDTC or AG490. Subsequently, mouse coronary artery endothelial cells (MCAECs) were incubated with RAW264.7 cells-conditioned medium to mimic local inflammatory lesions in KD. CCKi8 assay was used to evaluate cell viability. The mRNA levels of inflammatory mediators were detected by qRT-PCR. Expressions of KCa3.1, MCAECs injury-associated molecules, proteins involved in signal pathways of nuclear factor-κB (NF-κB), signal transducers and activators of transcription (STAT) 3 and p38 were evaluated by Western blot.Results: Our study showed that LCWE increased KCa3.1 protein level in RAW264.7 macrophages and KCa3.1 inhibition by TRAM-34 notably suppressed the expression of pro-inflammatory molecules in LCWE-treated macrophages via blocking the activation of NF-κB and STAT3 pathways. Besides, the inflammation and damage of MCAECs were attenuated in the TRAM-34-treated group compared with the KD model group. This vascular protective role was dependent on the down-regulation of NF-κB and STAT3 signal pathways, which was confirmed by using inhibitors of NF-κB and STAT3.Conclusion: This study demonstrates that KCa3.1 blockade of macrophages suppresses inflammatory reaction leading to mouse coronary artery endothelial cell injury in a cell model of KD by hampering the activation of NF-κB and STAT3 signaling pathway. These findings imply that KCa3.1 may be a potential therapeutic target for KD.Keywords: Kawasaki disease, macrophages, inflammation, KCa3.1, vascular damage

Disruptions in polyamine metabolism have been identified as contributing factors to various central nervous system disorders. Our laboratory has previously highlighted the crucial role of polyamine oxidation in retinal disease models, specifically noting elevated levels of spermine oxidase (SMOX) in inner retinal neurons. Our prior research demonstrated that inhibiting SMOX with MDL 72527 protected against vascular injury and microglial activation induced by hyperoxia in the retina. However, the effects of SMOX inhibition on retinal neovascularization and vascular permeability, along with the underlying molecular mechanisms of vascular protection, remain incompletely understood. In this study, we utilized the oxygen-induced retinopathy (OIR) model to explore the impact of SMOX inhibition on retinal neovascularization, vascular permeability, and the molecular mechanisms underlying MDL 72527-mediated vasoprotection in the OIR retina. Our findings indicate that inhibiting SMOX with MDL 72527 mitigated vaso-obliteration and neovascularization in the OIR retina. Additionally, it reduced OIR-induced vascular permeability and Claudin-5 expression, suppressed acrolein-conjugated protein levels, and downregulated P38/ERK1/2/STAT3 signaling. Furthermore, our results revealed that treatment with BSA-Acrolein conjugates significantly decreased the viability of human retinal endothelial cells (HRECs) and activated P38 signaling. These observations contribute valuable insights into the potential therapeutic benefits of SMOX inhibition by MDL 72527 in ischemic retinopathy. [ABSTRACT FROM AUTHOR]

Both progression from the early pathogenic events to clinically manifest cardiovascular diseases (CVD) and cancer impact the integrity of the vascular system. Pathological vascular modifications are affected by interplay between endothelial cells and their microenvironment. Soluble factors, extracellular matrix molecules and extracellular vesicles (EVs) are emerging determinants of this network that trigger specific signals in target cells. EVs have gained attention as package of molecules with epigenetic reversible activity causing functional vascular changes, but their mechanisms are not well understood. Valuable insights have been provided by recent clinical studies, including the investigation of EVs as potential biomarkers of these diseases. In this paper, we review the role and the mechanism of exosomal epigenetic molecules during the vascular remodeling in coronary heart disease as well as in cancer-associated neoangiogenesis.