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To evaluate the plasma levels of angiopoietin-1 and vascular endothelial growth factor (VEGF) and their association with macular neovascularization (MNV) in patients with chronic central serous chorioretinopathy (cCSC). Correlations between plasma cytokine levels, CSC duration, and mean choroidal thickness (CT) were also investigated. Of the 59 patients with cCSC, 10 patients with MNV secondary to cCSC and 10 patients with cCSC without MNV were enrolled in the study. The control group included 15 healthy volunteers matched for age, sex, smoking status, and comorbidities. Chronic CSC was diagnosed based on typical findings on swept-source optical coherence tomography (OCT), fundus fluorescein angiography, and indocyanine green angiography. Additionally, all patients underwent OCT angiography to help detect MNV. Plasma angiopoietin-1 and VEGF levels were assessed using multiplex immunoassay. The plasma angiopoietin-1 levels differed between the 3 groups ( p = 0.005). The angiopoietin-1 levels were lower in patients with cCSC with MNV than in controls ( p = 0.006). There were no differences in the plasma VEGF levels between all the 3 groups ( p = 0.329). The VEGF levels were negatively correlated with mean CT in cCSC patients with MNV (rho = -0.683, p = 0.042) but correlated positively with disease duration in patients with cCSC without MNV (rho = 0.886, p = 0.003). Our study confirms that MNV is a common complication of cCSC and provides new insights into the role of angiopoietin-1 in cCSC and MNV. Reduced angiopoietin-1 levels in cCSC patients, regardless of MNV status, highlight the importance of the Ang-Tie2 pathway in disease pathogenesis and may point to new therapeutic targets and future novel treatments to improve the management of these patients.

Background: In addition to their fundamental roles in preserving vascular integrity, platelets also contribute to tumor angiogenesis and metastasis. However, despite being a reservoir for angiogenic and metastatic cytokines, platelets also harbor negative regulators of tumor progression. Angpt1 (angiopoietin-1) is a cytokine essential for developmental angiogenesis that also protects against tumor cell metastasis through an undefined mechanism. Although activated platelets release Angpt1 from α-granules into circulation, the contributions of platelet Angpt1 to tumor growth, angiogenesis, and metastasis have not been investigated., Methods: Using cytokine arrays and ELISAs, we first compared platelet Angpt1 levels in breast and melanoma mouse tumor models to tumor-free controls. We then assessed tumor growth and metastasis in mice lacking megakaryocyte and platelet Angpt1 (Angpt1 Plt KO ). The spontaneous metastasis of mammary-injected tumor cells to the lungs was quantified using RT-PCR (reverse transcription-polymerase chain reaction). The lung colonization of intravenously injected tumor cells and tumor cell extravasation were determined using fluorescent microscopy and flow cytometry., Results: Platelet Angpt1 is selectively upregulated in the PyMT (polyoma middle tumor antigen) breast cancer mouse model, and platelets are the principal source of Angpt1 in blood circulation. While primary tumor growth and angiogenesis were unaffected, Angpt1 Plt KO mice had both increased spontaneous lung metastasis and tumor cell lung colonization following mammary or intravenous injection, respectively. Although platelet Angpt1 did not affect initial tumor cell entrapment in the lungs, Angpt1 Plt KO mice had increased tumor cell retention and extravasation. Serum from Angpt1 Plt KO mice increased endothelial permeability and reduced VE (vascular endothelial)-cadherin expression at endothelial junctions compared with serum from control mice (Angpt1 WT )., Conclusions: Platelets provide an intravascular source of Angpt1 that restrains tumor metastasis by preserving the lung microvasculature to limit tumor cell extravasation., Competing Interests: None.

Introduction: Our objective was to examine the factors associated with the serum angiopoietin-2/angiopoietin-1 (Angpt-2/Angpt-1) ratio in peritoneal dialysis (PD) patients and to investigate the association between Angpt-2/Angpt-1 ratio and cardiovascular and all-cause mortality., Methods: Patients on PD who were prevalent between January 2014 and April 2015 in the center of Renji Hospital were enrolled. At the time of enrollment, serum and dialysate samples were collected to detect biochemical parameters, serum angiopoietin-2 and angiopoietin-1 levels. Patients were dichotomized into two groups according to a median of Angpt-2/Angpt-1 ratio and followed up prospectively until the end of the study., Results: A total of 325 patients were enrolled, including 168 males (51.7%) with a mean age of 56.9 ± 14.2 years and a median PD duration of 32.4 (9.8-55.9) months. Multiple linear regression showed pulse pressure (β = 0.206, p  < .001) and high-sensitivity C-reactive protein (hs-CRP) (β = 0.149, p  = .011) were positively correlated with serum Angpt-2/Angpt-1 ratio, while residual renal function (RRF) (β= -0.219, p  < .001) was negatively correlated with serum Angpt-2/Angpt-1 ratio. Multivariate Cox regression analysis showed the high serum Angpt-2/Angpt-1 ratio was an independent predictor of cardiovascular mortality (hazard ratio (HR)=2.467, 95% confidence interval (CI) 1.243-4.895, p  = .010) and all-cause mortality (HR = 1.486, 95%CI 1.038-2.127, p  = .031). In further subgroup analysis by gender, a significant association was shown in high Angpt-2/Angpt-1 ratio with all-cause mortality in male ( p  < .05), but not in female patients ( p >.05)., Conclusions: High Angpt-2/Angpt-1 ratio is an independent risk factor for cardiovascular and all-cause mortality in PD patients.

Dengue virus (DENV) infection is associated with plasma leakage, which may progress to shock. The angiopoietin (Ang)-tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (Tie-2) axis regulates endothelial permeability. We examined the clinical utility of Ang-1, Ang-2, and the Ang-2-to-Ang-1 ratio for prediction of progression to severe DENV in a prospective cohort study of children and young adults (age 1 to <26 years) with DENV infection. Ang-1, Ang-2, Tie-2 were measured at presentation to an outpatient clinic in the Philippines from stored plasma by multiplex Luminex® assay. Patients were followed prospectively to document the clinical course (hospitalization, length of stay, intravenous fluid resuscitation, and transfer to a higher level facility). We included 244 patients (median age 9 years, 40% female). At presentation, 63 patients (26%) had uncomplicated dengue, 179 (73%) had dengue with warning signs, and 2 (0.82%) had severe dengue. One hundred eighty-one patients (74%) were hospitalized. Ang-1 levels were lower and Ang-2 higher in patients who required hospitalization. Ang-2-to-Ang-1 ratio >1 was associated with a relative risk of hospitalization of 1.20 (95% CI: 1.03-1.36, P = 0.016). A higher Ang-2-to-Ang-1 ratio was associated with longer length of hospital stay, higher frequency of transfer to a higher level facility, larger intravenous fluid requirement, hemoconcentration, and thrombocytopenia. Angiopoietin-2 was correlated with procalcitonin (Kendall's τ = 0.17, P = 0.00012), a marker of systemic inflammation, as well as soluble vascular cell adhesion molecule-1 (τ = 0.22, P <0.0001) and Endoglin (τ = 0.14, P = 0.0017), markers of endothelial activation. In conclusion, altered Ang-2-to-Ang-1 ratio can be detected early in the course of DENV infection and predicts clinically meaningful events (hospitalization, length of stay, and fluid resuscitation).

Background: To investigate the relationship between cord blood levels of Angiopoietin-1 (Ang-1) and S-endoglin (sCD105) and bronchopulmonary dysplasia (BPD) in preterm infants., Methods: Sixty-one preterm infants admitted to the neonatal intensive care unit of the study hospital between July 2021 and September 2022 were included. Cord blood was collected after the birth of premature infants. Ang-1 and sCD105 levels were quantified using the vascular endothelial growth factor enzyme-linked immunosorbent assay. Preterm infants were divided into BPD and non-BPD groups, and differences in Ang-1 and sCD105 levels between the two groups were compared. A binary logistic model was used to assess the association between low and high levels Ang-1 and BPD in preterm infants., Results: In the study, there were 20 preterm infants with BPD (32.8%) and 41 preterm infants with non-BPD (67.2%). Ang-1 concentration levels were lower in the BPD group than in the non-BPD group (7105.43 (5617.01-8523.00) pg/ml vs. 10488.03 (7946.19-15962.77) pg/ml, P = 0.027). However, the sCD105 concentration levels were not significantly different between the BPD and non-BPD groups (P = 0.246). A median Ang-1 concentration of 8800.40 pg/ml was calculated. Logistic regression analysis showed that after adjusting for gestational age, birth weight, and maternal prenatal steroid hormone application, the odds ratio (OR) was 8.577 for the risk of BPD in preterm infants with Ang-1 concentrations of ≤ 8800.40 pg/ml compared to those with Ang-1 concentrations of > 8800.40 pg/ml (OR: 8.577, 95% confidence interval: 1.265-58.155, P = 0.028)., Conclusion: Our study indicated that Ang-1 levels in the cord blood of preterm infants may be associated the risk of BPD. In the future, we will continue to conduct study with large samples., (© 2024. The Author(s).)

Background: Obstructive sleep apnea (OSA) is increasingly recognized as a common condition in the general population and causes significant OSA-associated morbidities including cardiovascular and cerebrovascular events such as cerebral small vessel disease (CSVD) and stroke., Methods: In this study, using sensitive ELISA immunoassays, we measured subset of endothelial/vascular and inflammatory biomarkers as well as neurofilament light chain (NfL), a sensitive marker for neuroaxonal injury, using plasma from OSA patients post-stroke (Acute Cerebral Infarction (ACI), N = 26) to determine their usefulness as potential prognostic markers in disease progression., Results: Our results showed significantly increased plasma TNFα and NfL concentrations and decreased concentrations of platelet derived growth factor (PDGF-AA) in post-stroke OSA patients with more severe white matter hyperintensities (WMHs). And after separating the patients based on sex, compared to females, male post-stroke OSA patients with severe WMHs have increased circulating levels of inflammatory chemokine CXCL10 and cytokine Interleukin-10 (IL-10) and significantly decreased levels of Angiopoietin-1 (Ang-1) an important protein responsible for endothelial/vascular integrity functions. Importantly, in a subset of newly diagnosed OSA patients (without prior history of stroke), significantly increased plasma CXCL10 levels and decreased plasma Ang-1 levels were also readily observed when compared to healthy controls, indicating possible altered endothelial integrity and ongoing vascular inflammation in these newly diagnosed OSA patients., Conclusions: In summary, our study has identified a novel set of plasma biomarkers including PDGF-AA, CXCL10 and Ang-1 for their potential prognostic value for disease outcomes pre- and post-stroke in OSA patients and use as surrogate markers to measure efficacy of treatment modalities., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The poor remodeling of placental spiral arteries seen in preeclampsia is also discussed to contribute to recurrent pregnancy loss (RPL) preceded by abnormal angiogenesis and excessive complement activation. Low levels of Mannose-binding-lectin (MBL), a pattern recognition molecule (PRM) of the lectin pathway, have been found in women with RPL. We propose that pregnancy loss is connected to defective angiogenesis with reperfusion damage in the placenta and decreased levels of PRM in the lectin pathway in women with RPL. In this cohort study, we investigate the angiogenic factors and the lectin complement pathway in early pregnancy and their time-dependent relationship with pregnancy outcomes in 76 women with secondary RPL (sRPL) who have at least four prior pregnancy losses and a live birth. We evaluated levels of Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Vascular Endothelial Growth Factor (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PRMs, MBL, ficolin-1, -2, -3 and an additional soluble PRM, Pentraxin-3, during the 5th, 6th, and 7th gestational weeks. Our results showed that, compared to live births, pregnancies that ended in loss were associated with elevated VEGF levels and decreased levels of the Ang-2/Ang-1 ratio. Also, increasing levels of ficolin-2 were significantly associated with pregnancy loss, with MBL showing no association. Our research suggests that women with sRPL may have inadequate placentation with impaired angiogenesis in pregnancies ending in a loss., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here provide the mechanistic evidence in support of the relevance for these observations. Angiopoetin-1 (Ang-1), which promotes vascular integrity, was decreased in blood plasma of human and murine septic newborns. In preclinical models, administration of Ang-1 provided prophylactic protection from septic death. Arachidonic acid metabolism appears to be functionally connected to Ang-1 via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Strengthening this intersection via oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death while also increasing plasma Ang-1 levels among septic newborns. Our data highlight that targeting angiogenesis-associated pathways with interventions that increase Ang-1 activity directly or indirectly through ROS/eNOS provide promising avenues to prevent and/or treat severe neonatal sepsis., (© 2024. The Author(s).)

Objective: To evaluate the relationships between the severity of myxomatous mitral valve disease (MMVD) and pulmonary hypertension (PH) and serum angiopoietin (Ang)-1 and Ang-2 concentrations in dogs with MMVD., Animals: 74 dogs (control, n = 12; MMVD, n = 62) were included., Methods: Serum Ang-1 and Ang-2 concentrations were estimated using the canine-specific ELISA kit. The concentrations were compared between dogs with MMVD and healthy dogs, and they were analyzed according to the severity of MMVD and PH., Results: The median serum Ang-1 concentration did not differ among the study groups. The median serum Ang-2 concentration was higher in dogs with stage B2 MMVD (P = .041) and acute congestive heart failure (P = .002) than in control dogs. In addition, the median serum Ang-2 concentration was higher in MMVD dogs with PH than in those without PH (P = .031). Serum Ang-2 concentration was correlated with vertebral heart score (rs = 0.36, P = .004) and vertebral left atrial score (r = 0.50, P < .001) in dogs with MMVD, and correlated with vertebral heart score (r = 0.63, P = .01), maximum E wave amplitude of the diastolic transmitral flow (rs = 0.61, P = .018), ejection fraction (rs = -0.77, P < .001) and fractional shortening (rs = -0.56, P = .032) in dogs with acute congestive heart failure., Clinical Relevance: Circulating Ang-2 levels increase in dogs with the severity of MMVD and the presence of PH.

Introduction: Renal injury is among the leading causes of morbidity and mortality; however, there are no reliable indicators for determining the likelihood of developing chronic kidney disease (CKD), CKD progression, or AKI events. Vascular growth factors called angiopoietins have a role in endothelial function, vascular remodeling, tissue stabilization, and inflammation and have been implicated as prognostic and predictive markers in AKI., Methods: Although the exact mechanism of the relationship between kidney injury and angiopoietins is unknown, this review demonstrates that AKI patients have higher angiopoietin-2 levels and that higher angiopoietin-1 to angiopoietin-2 ratio may potentially be linked with a reduced risk of the CKD progression., Results: This review therefore emphasizes the importance of angiopoietin-2 and proposes that it could be an important predictor of AKI in clinical settings., Conclusion: There is a need for further large-scale randomized clinical trials in order to have a better understanding of the significance of angiopoietin-2 and for the determination of its potential clinical implications., (© 2024 S. Karger AG, Basel.)

Introduction: Kidney transplant recipients (KTRs) have increased risk of cardiovascular disease (CVD) mortality. We investigated vascular biomarkers, angiopoietin-1, and angiopoietin-2 (angpt-1, -2), in CVD development in KTRs., Methods: This ancillary study from the FAVORIT evaluates the associations of baseline plasma angpt-1, -2 levels in CVD development (primary outcome) and graft failure (GF) and death (secondary outcomes) in 2000 deceased donor KTRs. We used Cox regression to analyze the association of biomarker quartiles with outcomes. We adjusted for demographic; CVD- and transplant-related variables; medications; urine albumin-to-creatinine ratio; and randomization status. We calculated areas under the curves (AUCs) to predict CVD or death, and GF or death by incorporating biomarkers alongside clinical variables., Results: Participants' median age was 52 IQR [45, 59] years: with 37% women and 73% identifying as white. Median time from transplantation was 3.99 IQR [1.58, 7.93] years and to CVD development was 2.54 IQR [1.11-3.80] years. Quartiles of angpt-1 were not associated with outcomes. Whereas higher levels of angpt-2 (quartile 4) were associated with about 2 times the risk of CVD, GF, and death (aHR 1.85 [1.25-2.73], p &lt; 0.01; 2.24 [1.36-3.70)], p &lt; 0.01; 2.30 [1.48-3.58], p &lt; 0.01, respectively) as compared to quartile 1. Adding angiopoietins to preexisting clinical variables improved prediction of CVD or death (AUC improved from 0.70 to 0.72, p = 0.005) and GF or death (AUC improved from 0.68 to 0.70, p = 0.005). Angpt-2 may partially explain the increased risk of future CVD in KTRs. Further research is needed to assess the utility of using angiopoietins in the clinical care of KTRs., Conclusion: Angpt-2 may be a useful prognostic tool for future CVD in KTRs. Combining angiopoietins with clinical markers may tailor follow-up to mitigate CVD risk., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Diagnosing patients with giant cell arteritis (GCA) remains difficult. Due to its non-specific symptoms, it is challenging to identify GCA in patients presenting with symptoms of polymyalgia rheumatica (PMR), which is a more common disease. Also, commonly used acute-phase markers CRP and ESR fail to discriminate GCA patients from PMR and (infectious) mimicry patients. Therefore, we investigated biomarkers reflecting vessel wall inflammation for their utility in the accurate diagnosis of GCA in two international cohorts., Methods: Treatment-naïve GCA patients participated in the Aarhus AGP cohort (N = 52) and the Groningen GPS cohort (N = 48). The AGP and GPS biomarker levels and symptoms were compared to patients presenting phenotypically as isolated PMR, infectious mimicry controls and healthy controls (HCs). Serum/plasma levels of 12 biomarkers were measured by ELISA or Luminex., Results: In both the AGP and the GPS cohort, we found that weight loss, elevated erythrocyte sedimentation rate (ESR) and higher angiopoietin-2/-1 ratios but lower matrix metalloproteinase (MMP)-3 levels identify concomitant GCA in PMR patients. In addition, we confirmed that elevated platelet counts are characteristic of GCA but not of GCA mimicry controls and that low MMP-3 and proteinase 3 (PR3) levels may help to discriminate GCA from infections., Conclusion: This study, performed in two independent international cohorts, consistently shows the potential of angiopoietin-2/-1 ratios and MMP-3 levels to identify GCA in patients presenting with PMR. These biomarkers may be used to select which PMR patients require further diagnostic workup. Platelet counts may be used to discriminate GCA from GCA look-alike patients., (© 2022. The Author(s).)

Objectives: Raynaud's phenomenon (RP) is a peripheral vascular disorder that frequently occurs in systemic sclerosis (SSc). Although therapeutic heating seems reasonable given that RP is elicited by cold stimuli, the effects of heating are still unclear. We examined the effects of heating applied on various body parts in SSc patients with RP of fingers., Methods: Fourteen SSc patients heated their neck, elbows, and wrists with disposable heating pads for 1 week each. The visual analogue scale (VAS) for RP during each heating period was compared with that of each 1-week pre-treatment interval. On the day after the expiration of each heating period, their finger temperature, the finger blood flow, and angiogenesis-related factors (vascular endothelial growth factor, endostatin, angiopoietin-1, and angiopoietin-2) obtained from the cubital vein and fingertip were measured., Results: The mean VAS was significantly reduced during the heating of the neck and elbows. Fingertip blood samples showed significantly increased angiopoietin-1 after each of the heating periods and increased endostatin after wrist heating. After the termination of heating, changes in finger temperature or blood flow could not be detected., Conclusions: Heating the neck or elbows can alleviate RP in SSc. The heat up-regulates angiopoietin-1 in the fingers., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Long noncoding RNAs (lncRNAs) have been recently recognized as key players of gene expression in cerebral pathogenesis. Thus, their potential use in stroke diagnosis, prognosis, and therapy is actively pursued. Due to the complexity of the disease, identifying stroke-specific lncRNAs remains a challenge. This study investigated the expression of lncRNAs HIF1A-AS2 and LINK-A, and their target gene hypoxia-inducible factor-1 (HIF-1) in Egyptian stroke patients. It also aimed to determine the molecular mechanism implicated in the disease. A total of 75 stroke patients were divided into three clinical subgroups, besides 25 healthy controls of age-matched and sex-matched. Remarkable upregulation of lncRNA HIF1A-AS2 and HIF1-α along with a downregulation of lncRNA LINK-A was noticed in all stroke groups relative to controls. Serum levels of phosphatidylinositol 3-kinase (PI3K), phosphorylated-Akt (p-Akt), vascular endothelial growth factor (VEGF), and angiopoietin-1 (ANG1) as well as their receptors, malondialdehyde (MDA), and total antioxidant capacity (TAC) were significantly increased, whereas brain-derived neurotrophic factor (BDNF) levels were significantly decreased particularly in hemorrhagic stroke versus ischemic groups. Eventually, these findings support the role of lncRNAs HIF1A-AS2 and LINK-A as well as HIF1-α in activation of angiogenesis, neovascularization, and better prognosis of stroke, especially the hemorrhagic type., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Several biomarkers for detecting pulmonary hypertension (PH) have been reported. However, these biomarkers are deemed insufficient to detect PH in its early stages. We evaluated the utility of serum angiopoietin (ANGP), a glycoprotein related to angiogenesis, as a diagnostic and prognostic biomarker of PH. Patients with PH who underwent right-heart catheterization, were retrospectively studied. Serum concentrations of ANGP-1 and ANGP-2 were measured using an enzyme-linked immunosorbent assay in patients with PH (n = 32), those with idiopathic pulmonary fibrosis (IPF) without PH (as a disease control, n = 75), and age-matched healthy controls (HC, n = 60). Nineteen patients (59.4%) with PH had World Health Organization group 3 PH. Serum ANGP-2 concentration, but not ANGP-1, in patients with PH was significantly higher compared with that in HC (p = 0.025) and in patients with IPF without PH (p = 0.008). Serum ANGP-2 concentration in patients with PH positively and significantly correlated with N-terminal pro-B-type natriuretic peptide (r = 0.769, p < 0.001), right ventricular diameter on echocardiography (r = 0.565, p = 0.035), and mean pulmonary arterial pressure (r = 0.449, p = 0.032) and pulmonary vascular resistance (r = 0.451, p = 0.031) on right-heart catheterization. ANGP-1 and ANGP-2 were expressed on lung vascular endothelial cells, as shown by immunohistochemistry. Patients with PH with higher ANGP-2 concentration (≥ 2.48 ng/mL) had significantly worse survival (p = 0.022). Higher ANGP-2 concentration was a significant worse prognostic factor (hazard ratio = 6.063, p = 0.037), while serum ANGP-1 concentration was not. In conclusion, serum ANGP-2 may be a useful diagnostic and prognostic biomarker in patients with PH, especially in patients with group 3 PH., (© 2021. The Author(s).)

Acute kidney injury (AKI) is a frequent and potentially fatal complication of snakebites. In the setting of snakebites, endothelial biomarkers may be used to predict disease severity and can play a major role in AKI pathophysiology. The aim of this study was to investigate the potential role of endothelial biomarkers in predicting AKI in Bothrops envenoming. Therefore, blood and urine samples were collected from 26 patients admitted to the emergency department after Bothrops envenoming at 3 different post-bite points in time: on admission (up to 8 h post-bite), 12-16 h, and 24-28 h post-bite, to investigate the time course of endothelial biomarkers in AKI following Bothrops snakebites. The diagnostic performance of injury biomarkers in Bothrops envenomation was evaluated. AKI was diagnosed using the Kidney Disease Improving Global Outcomes (KDIGO) criteria. There was an association between endothelial injury and increased risk for AKI in bothropic envenoming. Angiopoietin- 1 (Ang-1) and Vascular cell adhesion protein-1 (VCAM-1) were useful biomarkers to predict mild AKI [AUC-ROC: Ang-1 0.82, VCAM-1 0.76] within the interval of 8-16 h post Bothrops snakebites. The use of endothelial biomarkers VCAM-1 e Ang-1 within 12-16 h post-bite may be useful in the early stage of mild AKI related to Bothrops envenoming and might have an effect on the early intervention for renal protection in less severe Bothrops-related AKI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Angiopoietin (Ang), a ligand of the endothelium-specific receptor Tie-2 system, is associated with tumor growth and progression that depend on angiogenesis. The present study aimed to investigate the predictive potential of angiopoietin factors in incurable stage IV colorectal cancer (CRC) patients who have undergone primary tumor resection., Methods: The study included 40 consecutive patients with incurable stage IV CRC who underwent primary tumor resection at our hospital between 2011 and 2015. Patients were divided into subgroups of low and high Ang-1, Ang-2, and Tie-2. Patient age and sex, tumor location, TNM stages, vascular invasion, chemotherapy, and overall survival were assessed., Results: The cut-off values of Ang-1, Ang-2, and Tie-2 were 0.4, 1.8, and 15.0 ng/mL, respectively. Overall survival was significantly longer in the low Ang-2 group than in the high Ang-2 group. High Ang-2 levels were associated with age, N stage, and chemotherapy. Immunofluorescent staining of Ang-2 revealed that endothelial cells and cancer cells expressed Ang-2 in each case., Conclusions: Our findings suggest that the serum Ang-2 level is associated with disease progression and is an important predictor of mortality in incurable stage IV CRC patients. Thus, it may be a useful prognostic biomarker in these patients.

Traumatic injury and hemorrhagic shock result in endothelial cell activation and vascular dysfunction that, if not corrected, can propagate multiorgan failure. Angiopoietin-1 and angiopoietin-2 are important regulators of endothelial cell function, and the ratio of plasma angiopoietin-2-to-1 is a useful indicator of overall vascular health. We therefore characterized plasma angiopoietin-2/-1 ratios over time after trauma in adults in an effort to gain insight into the pathophysiology that may drive post-traumatic vasculopathy and organ injury. We performed a single-center prospective observational study to measure plasma angiopoietin-1 and -2 levels and determine angiopoietin-2/-1 ratios in adult trauma patients upon hospital arrival and after 12, 24, and 48 h. Compared with levels in healthy adults, angiopoietin-1 levels were significantly elevated at hospital arrival, and angiopoietin-2 levels were significantly elevated at 12, 24, and 48 h. These kinetics translated in angiopoietin-2/-1 ratios that were significantly greater than controls at 24 and 48 h. After regression analysis, elevated angiopoietin-2 levels were independently associated with blunt injuries at admission, with coagulopathy at admission and 12 h, and with hemorrhagic shock at 24 and 48 h. Significant correlations were observed between both angiopoietins and 24-h transfusion requirements. Angiopoietin-2/-1 ratios correlated with mechanical ventilation duration and intensive care unit and hospital lengths of stay. In this study, we demonstrate novel temporal associations between angiopoietin dysregulation and blunt injuries, acute coagulopathy, and hemorrhagic shock. Moreover, our findings highlight the presence of endothelial activation following traumatic insults in adults that may contribute to worse clinical outcomes.

Objectives: We investigated whether platelet count associated with biomarkers of endothelial function, and additionally sought to identify novel predictors of outcomes in a cohort of patients with severe sepsis at a quaternary care academic medical center., Design: Prospective, observational cohort., Patients: Eighty-six sepsis patients admitted into intensive care units were prospectively enrolled into an on-site sepsis registry and biobank., Interventions: None., Measurements and Main Results: Platelet count, mean platelet volume, platelet mass, plasma angiopoietin-1 and angiopoietin-2, syndecan-1, platelet factor 4, sCD40L concentrations, and plasma autotaxin activity were determined for each patient at enrollment. Patient mortality was recorded up to 30 days following hospital discharge. Platelet count and plasma sCD40L was significantly lower in patients who did not survive up to 30 days following hospital discharge. Angiopoietin-2 and the angiopoietin-2/1 ratio were significantly higher in patients who did not survive up to 30 days following discharge. Furthermore, plasma autotaxin activity was significantly higher in patients who did not survive up to 30 days. Interestingly, autotaxin activity correlated with platelet count and the ratio of angiopoietin-2/1 across our population., Conclusions: Platelet count, the ratio of angiopoietin-2/1, and autotaxin activity all predicted 30-day mortality. Autotaxin activity within the plasma correlates with both platelet counts and vascular dysfunction biomarkers across both survivors and non-survivors indicating a possible involvement of autotaxin within sepsis.

Background: Malaria could affect people of all ages, most especially young children. The study evaluated the levels of serum angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) which are critical regulators of endothelial activation and integrity with some hematological parameters (total white blood cell counts (WBC), total red blood cell counts (RBC), platelet counts, and malaria parasite density) in malaria-infected children., Method: A total of 92 blood samples from children between the ages of 6 months to 15 years were analyzed. The samples consisted of 30 cases of severe malaria, 40 cases of uncomplicated malaria, and 22 apparently healthy subjects served as control. Serum Ang-1 and -2 levels were determined using the enzyme-linked immunosorbent assay technique. The hematological parameters were determined using the WHO standard., Results: There was significant decrease ( p < 0.05) in serum Ang-1 of uncomplicated malaria and severe malaria compared with the control, while significant increase ( p < 0.05) was observed in Ang-2 and Ang-2/Ang-1 ratio in uncomplicated malaria and severe malaria compared with the control. RBC and platelet showed significant decrease, while WBC showed significant increase in severe malaria compared with uncomplicated malaria and control., Conclusion: This study showed that subjects with malaria infection had a significant increase of Ang-2 and Ang-2 : Ang-1 ratio but presented with a significant decrease of Ang-1. Ang-1 and Ang-2 may be used to determine the severity of malaria infection since their levels differ significantly in malaria subjects compared with the control., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2020 A. O. Oluboyo et al.)

Background: We aimed to investigate the role of angiopoietin (Angpt) as a predictive biomarker for sepsis by evaluating associations between plasma Angpt and various inflammatory cytokines and mortality in critically ill patients with sepsis., Methods: This study was a retrospective cohort study of the prospectively collected samples and clinical data of 145 patients with sepsis who were admitted to the medical intensive care unit (ICU) of a 2000-bed university tertiary referral hospital in South Korea. We collected plasma within 24 h of medical ICU admission, and several biomarkers (Angpt-1 and -2, Tie2, vascular endothelial growth factor, interleukin (IL)-1β, IL-10, IL-18, IL-6, interferon gamma-induced protein-10, and tumor necrosis factor-α) were measured using a Human Magnetic Luminex Screening Assay kit., Results: Plasma Angpt-2 was correlated with IL-6 (r s  = 0.555) and tumor necrosis factor-α (r s  = 0.559). Plasma Angpt-2 (r s  = 0.530) and Angpt-2/1 (r s  = 0.562) were correlated with the Sequential Organ Failure Assessment (SOFA) score. The area under the curve (AUC) for the 28-day mortality prediction for the plasma Angpt-2/1 ratio was 0.736; AUCs for the Acute Physiology and Chronic Health Evaluation II (APACHE II) and SOFA scores were 0.659 and 0.745, respectively. Using multivariate Cox proportional hazard regression analysis for 28-day mortality, we found that acute respiratory distress syndrome (hazard ratio (HR) = 2.235, 95% CI = 1.163-4.296,p = 0.016), APACHE II score (HR = 1.127, 95% CI = 1.037-1.224,p = 0.005), and Angpt-2/1 > 3.2 (HR = 2.522, 95% CI = 1.205-5.278,p = 0.014) were risk factors for 28-day mortality., Conclusions: Plasma Angpt-2 was related to cytokines, but Angpt-2/1 ratio was a good predictor of 28-day mortality in patients with sepsis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Severe malaria is mostly caused by Plasmodium falciparum, resulting in considerable, systemic inflammation and pronounced endothelial activation. The endothelium forms an interface between blood and tissue, and vasculopathy has previously been linked with malaria severity. We studied the extent to which the endothelial glycocalyx that normally maintains endothelial function is involved in falciparum malaria pathogenesis by using incident dark-field imaging in the buccal mucosa. This enabled calculation of the perfused boundary region, which indicates to what extent erythrocytes can permeate the endothelial glycocalyx. The perfused boundary region was significantly increased in severe malaria patients and mirrored by an increase of soluble glycocalyx components in plasma. This is suggestive of a substantial endothelial glycocalyx loss. Patients with severe malaria had significantly higher plasma levels of sulfated glycosaminoglycans than patients with uncomplicated malaria, whereas other measured glycocalyx markers were raised to a comparable extent in both groups. In severe malaria, the plasma level of the glycosaminoglycan hyaluronic acid was positively correlated with the perfused boundary region in the buccal cavity. Plasma hyaluronic acid and heparan sulfate were particularly high in severe malaria patients with a low Blantyre coma score, suggesting involvement in its pathogenesis. In vivo imaging also detected perivascular hemorrhages and sequestering late-stage parasites. In line with this, plasma angiopoietin-1 was decreased while angiopoietin-2 was increased, suggesting vascular instability. The density of hemorrhages correlated negatively with plasma levels of angiopoietin-1. Our findings indicate that as with experimental malaria, the loss of endothelial glycocalyx is associated with vascular dysfunction in human malaria and is related to severity., (Copyright © 2020 American Society for Microbiology.)

Malaria in pregnancy causes adverse birth outcomes due to sequestration of Plasmodium falciparum -infected erythrocytes in the placenta. Angiopoietins are critical regulators of vascular development and formation of placental villous vasculature. Angiopoietin-1 and Angiopoietin-2 concentrations were measured in peripheral and placental plasma samples from 70 malaria-infected and 216 control women using commercially available DuoSet ELISA development kit. Angiopoietins increased in placental plasma (ANG1-5833.5 pg/ml and ANG2-9580.6 pg/ml) as compared to peripheral plasma (ANG1-2293.1 pg/ml and ANG2-1198.9 pg/ml, p < 0.0001). The concentration of placental and peripheral ANG1 (6099.23 pg/ml and 2320.5 pg/ml) was significantly lower (5013.5 pg/ml, 2208.5 pg/ml), and ANG2 (9553.3 pg/ml, 1180.92 pg/ml) was significantly higher (9664.6 pg/ml, 1254.4 pg/ml) in malaria-positive cases as compared to malaria-negative ( p < 0.0001). The association of dysregulated angiopoietins in malaria with adverse birth outcomes showed that the peripheral and placental ANG1 concentration was lower and ANG2 concentration was higher in low-birth-weight baby and stillbirth birth outcome as compared to normal deliveries among malaria-positive group. Therefore, ANG1 and ANG2 could be considered a biomarker for adverse outcome during malaria in pregnancy., Competing Interests: The authors declare that there was no competing financial interest., (Copyright © 2020 Puspendra P. Singh et al.)

Hereditary angioedema is a disabling, life-threatening condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) leading to bradykinin accumulation and recurrent episodes of edema attack. Vascular leakage is a complex process sustained by the coordinated production of several permeabilizing factors including vascular endothelial growth factors (VEGFs), angiopoietins (ANGPTs) and phospholipase A 2 enzymes (PLA 2 ). We previously reported that patients with C1-INH-HAE in remission have increased plasma levels of VEGFs, ANGPTs and secreted PLA 2 . In this study, we sought to analyze plasma levels of these mediators in 15 patients with C1-INH-HAE during the acute attack compared to remission. Plasma concentrations of VEGF-A, VEGF-C and VEGF-D were not altered during attack compared to remission. Moreover, VEGF-D concentrations were not altered also in remission phase compared to controls. Concentrations of ANGPT1, a vascular stabilizer, were increased during attacks compared to symptoms-free periods, whereas ANGPT2 levels were not altered. The ANGPT2/ANGPT1 ratio was decreased during angioedema attacks. Platelet activating factor acetylhydrolase activity was increased in patients with C1-INH-HAE in remission compared to controls and was decreased during angioedema attacks. Our results emphasize the complexity by which several vasoactive mediators are involved not only in the pathophysiology of C1-INH-HAE, but also during angioedema attacks and its resolution., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Angiotensin-converting enzyme inhibitor-associated angioedema (ACEI-AAE) affects 0.1%-0.7% of patients treated with ACEIs. While previous research suggests that angioedema attacks result from increased vascular permeability, the pathogenesis is not completely understood. Objective: This study aimed to describe the clinical, genetic, and laboratory parameters of ACEI-AAE patients and to investigate the role of vascular endothelial growth factors A and C (VEGF-A and VEGF-C), angiopoietins 1 and 2 (Ang1/Ang2), and secretory phospholipase A2 (sPLA2) in the pathogenesis of ACEI-AAE., Methods: The clinical and laboratory data of ACEI-AAE patients were collected from 2 angioedema reference centers. Healthy volunteers and ACEI-treated patients without angioedema were enrolled to compare laboratory parameters. Genetic analyses to detect mutations in the genes SERPING1, ANGPT1, PLG, and F12 were performed in a subset of patients., Results: A total of 51 patients (57% male) were diagnosed with ACEI-AAE. The average time to onset of symptoms from the start of ACEI therapy was 3 years (range, 30 days-20 years). The most commonly affected sites were the lips (74.5%), tongue (51.9%), and face (41.2%). Switching from ACEIs to sartans was not associated with an increased risk of angioedema in patients with a history of ACEIAAE. VEGF-A, VEGF-C, and sPLA2 plasma levels were higher in ACEI-AAE patients than in the controls. Ang1/2 concentrations remained unchanged. No mutations were detected in the genes analyzed., Conclusions: Our data suggest that sartans are a safe therapeutic alternative in ACEI-AAE patients. Increased concentrations of VEGF-A, VEGF-C, and sPLA2 in ACEI-AAE patients suggest a possible role of these mediators in the pathogenesis of ACEI-AAE.

Background: In patients with chronic stable coronary artery disease (CAD), well‑developed coronary collateral circulation (CCC) is known to reduce long‑term mortality., Aims: The objective of this study was to determine the relationship of serum calprotectin (S100A8 / S100A9), angiopoietin‑1 (Ang‑1) and angiopoietin‑2 (Ang‑2) concentrations with CCC in patients with stable CAD., Methods: This prospective cross‑sectional study included 147 patients with stable angina pectoris. The Cohen-Rentrop classification was used to assess CCC. Patients were divided into 2 groups: with poor CCC (Cohen-Rentrop score, 0-1; n = 79) and with good CCC (Cohen-Rentrop score, 2-3; n = 68). Serum calprotectin, Ang‑1, and Ang‑2 concentrations were compated between groups., Results: Compared with the group with good CCC, serum calprotectin and Ang‑1 levels were higher (P <0.01 and P <0.001, respectively), while serum Ang‑2 levels were lower (P <0.01) in the poor‑CCC group. C‑reactive protein levels showed a moderate positive correlation with calprotectin levels (r = 0.359; P <0.001). In a multivariate regression analysis, only calprotectin (P <0.05) and Ang‑1 (P <0.05) were found to be independent predictors of good and poor CCC., Conclusions: Our study showed that Ang‑2 levels were lower, while serum calprotectin and Ang‑1 levels were higher, in patients with stable CAD and poor CCC regardless of the complexity and severity of coronary arteriosclerosis. If these results are confirmed in future studies, calprotectin may be considered a useful biomarker for guiding anti‑ischemic treatment.

High-grade astrocytomas are some of the most common and aggressive brain cancers, whose signs and symptoms are initially non-specific. Up to the present date, there are no diagnostic tools to observe the early onset of the disease. Here, we analyzed the combination of blood serum proteins, which may play key roles in the tumorigenesis and the progression of glial tumors. Fifty-nine astrocytoma patients and 43 control serums were analyzed using Custom Human Protein Antibody Arrays, including ten targets: ANGPT1, AREG, IGF1, IP10, MMP2, NCAM1, OPN, PAI1, TGFβ1, and TIMP1. The decision tree analysis indicates that serums ANGPT1, TIMP1, IP10, and TGFβ1 are promising combinations of targets for glioma diagnostic applications. The accuracy of the decision tree algorithm was 73.5% (75/102), which correctly classified 79.7% (47/59) astrocytomas and 65.1% (28/43) healthy controls. The analysis revealed that the relative value of osteopontin (OPN) protein level alone predicted the 12-month survival of glioblastoma (GBM) patients with the specificity of 84%, while the inclusion of the IP10 protein increased model predictability to 92.3%. In conclusion, the serum protein profiles of ANGPT1, TIMP1, IP10, and TGFβ1 were associated with the presence of astrocytoma independent of its malignancy grade, while OPN and IP10 were associated with GBM patient survival., Competing Interests: The authors declare no conflict of interest.

Objectives: Cell-based therapy has emerged as a promising strategy for the treatment of patients with heart failure. Increasing evidence supports the hypothesis that paracrine mechanisms mediated by soluble factors released by the cells play a predominate role in reparative processes. The aim of our study was to analyze which cytokines are released by CD34 + enriched cell products intended for autologous transendocardial CD34 + cell transplantation in patients with cardiomyopathy., Material and Methods: The peripheral blood CD34 + cells from 12 patients were mobilized with granulocyte colony-stimulating factor, collected via apheresis and enriched by immunoselection., Results: In CD34 + enriched cell population, hematopoietic, but not mesenchymal or endothelial, progenitors were detected. Except for angiopoietin-1, other measured cytokines (FGF1, FGF2, VEGF, PDGF, IL-6, HGH, SDF-1α/CXCL12, NRG1) were not released by CD34 + cells. The average concentration of angiopoietin-1 released by 5×10 6 CD34 + cells grown in neutral DMEM medium was 213.6±130.0pg/mL (range: 74-448pg/mL). Angiopoietin-1 secretion correlated well with CD34 + cell's capacity for generating colonies derived from hematopoietic progenitors (Pearson's correlation=0.964; P<0.001)., Conclusion: Our study presents angiopoietin-1 as an interesting candidate and suggests future studies to explore how its release by CD34 + cells might impact the success of autologous CD34 + cell transplantation., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Objectives: To determine whether biomarkers of endothelial activation and inflammation provide added value for prediction of in-hospital mortality within 28 days when combined with physician judgment in critically ill emergency department patients., Design: Prospective, observational study., Setting: Two urban, academic emergency departments, with ≈80,000 combined annual visits, between June 2016 and December 2017., Patients: Admitted patients, greater than 17 years old, with two systemic inflammatory response syndrome criteria and organ dysfunction, systolic blood pressure less than 90 mm Hg, or lactate greater than 4.0 mmol/L. Patients with trauma, intracranial hemorrhage known prior to arrival, or without available blood samples were excluded., Interventions: Emergency department physicians reported likelihood of in-hospital mortality (0-100%) by survey at hospital admission. Remnant EDTA blood samples, drawn during the emergency department stay, were used to measure angiopoietin-1, angiopoietin-2, tumor necrosis factor receptor-1, interleukin-6, and interleukin-8., Measurements and Main Results: We screened 421 patients and enrolled 314. The primary outcome of in-hospital mortality within 28 days occurred in 31 (9.9%). When predicting the primary outcome, the best biomarker model included angiopoietin-2 and interleukin-6 and performed moderately well (area under the curve, 0.72; 95% CI, 0.69-0.75), as did physician judgment (area under the curve, 0.78; 95% CI, 0.74-0.82). Combining physician judgment and biomarker models improved performance (area under the curve, 0.85; 95% CI, 0.82-0.87), with area under the curve change of 0.06 (95% CI, 0.04-0.09; p < 0.01) compared with physician judgment alone., Conclusions: Predicting in-hospital mortality within 28 days among critically ill emergency department patients may be improved by including biomarkers of endothelial activation and inflammation in combination with emergency department physician judgment.

Background/purpose: Endothelium is a key element in the regulation of vascular homeostasis and its alteration can lead to the development of vascular diseases. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with potential extensive vascular lesions, involving skin vessels, renal glomeruli, cardiovascular system, brain, lung alveoli, gastrointestinal tract vessels and more. We aimed to assess endothelial dysregulation related biomarkers in pediatric-onset SLE (pSLE) patient serum and elucidate its correlation with their clinical features, laboratory parameters, and the overall disease activity., Methods: Disease activities were evaluated by SLE disease activity index (SLEDAI). Patient characteristics were obtained by retrospective chart review. Six biomarkers associated with endothelial dysregulation, including Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Tie2, Vascular endothelial growth factor (VEGF), thrombomodulin, and a disintegrin-like and metalloprotease with thrombospondin type 1 motif (ADAMTS13) were tested through enzyme-linked immunosorbent assay (ELISA) measurement., Results: This study comprised 118 pSLE patients. Data from 40 age-matched healthy controls were also obtained. The mean diagnostic age was 13 ± 4.12 years-old and 90.7% are females. Serum levels of VEGF, Tie2, thrombomodulin were significantly higher while serum ADAMTS13 was lower in active pSLE patients when compared to those with inactive diseases (all p < 0.05). In organ specific association, serum thrombomodulin level was higher in pSLE patient with renal involvement, and serum ADAMTS13 levels was negatively associated with neurological involvement (p < 0.05). A cutoff of thrombomodulin at 3333.6 pg/ml best correlated renal involvement. (AUC = 0.752, p < 0.01)., Conclusion: Endothelial dysregulation associating proteins seems to be potent biomarkers for pSLE activity as well as organ involvement in pSLE patients. These biomarkers may be beneficial in understanding of the vascular pathogenesis and disease monitoring.

The aim of this study was to determine the association of dietary folate and cobalamin with plasma levels of Angiopoietins (ANG), vascular endothelial growth factor-C (VEGF-C) and tyrosine kinase receptor-2 (Tie-2) of primary breast cancer patients. Women (n = 177), aged 30 to 75 years diagnosed with breast cancer were recruited from an ongoing case series study. Dietary intake of nutrients was estimated by using a validated food frequency questionnaire. Enzyme-linked immunosorbent assay was applied to measure biomarkers. MCF-7 cell cultures were supplemented with folic acid (0-40 μM) for 24 h to measure cell viability and fold change of expression by the real-time reverse transcriptase-polymerase chain reaction. Structural equation modeling was applied to analyze the structural relationships between the measured variables of nutrients and Angiopoietins. Dietary intake of folate and cobalamin showed a significant inverse correlation with plasma ANG-1 and ANG-2 (P < 0.05), particularly in subjects with estrogen-receptor positive tumors or low plasma VEGF-C. Plasma folate was positively associated with the ratio of ANG-1/ANG-2 (P < 0.05). Residual intake levels of total cobalamin were inversely associated with plasma ANG-1 when plasma stratum of VEGF-C was high (P < 0.05). Structural equation modeling identified a significant inverse contribution of folate profiles on the latent variable of Angiopoietins (coefficient β = -0.99, P < 0.05). Folic acid treatment resulted in dose-dependent down-regulations on ANGPT1 and ANGPT1/ANGPT2 ratio but VEGF and ANGPT2/VEGF were upregulated at folic acid >20 μM. Studying the contributing role of dietary folate to pro-angiogenic biomarkers in breast cancer patients can infer the preventive role of folate in the ANGs/VEGF-C-dependent cascade of tumor metastasis. By contrast, high concentrations of folic acid in vitro supported VEGF-C-dependent ANGPT2 overexpression might potentiate micro-lymphatic vessel development to support malignant cell dissemination.

Background: Angiopoietin-1 (Agpt-1) and Agpt-2 are cytokine regulators of vascular endothelial integrity. Elevated plasma Agpt-2 levels and ratios of Agpt-2:Agpt-1 are associated with adverse outcomes in adult trauma and pediatric sepsis populations. However, the behavior of the angiopoietins after pediatric trauma has not been characterized, and their relationship to endothelial glycocalyx damage, indicated by plasma syndecan-1 (Syn-1) levels, has not been established., Methods: We performed a secondary analysis of prospectively collected data from 52 pediatric trauma patients and 12 control patients at a level one pediatric trauma center from 2013 to 2016. We measured Agpt-1, Agpt-2, and Syn-1 levels from plasma taken upon hospital arrival and 24 h after admission. Angiopoietin levels were compared to controls, and the correlation between Agpt-2 and Syn-1 was assessed., Results: Plasma Agpt-1 and Agpt-2 levels are elevated immediately after pediatric trauma compared with controls. At 24 h, trauma patients demonstrated significantly elevated plasma Agpt-2:Agpt-1 ratios relative to controls due to decline of Agpt-1 levels to near that of controls. Higher 24-h Agpt-2 levels are associated with more hypoperfusion, and elevated 24-h Agpt-2:Agpt-1 ratios are associated with adverse clinical outcomes. Significant positive correlations between Agpt-2 and Syn-1 upon admission and at 24 h after injury were identified., Conclusion: Our findings suggest dysregulation of circulating angiopoietins after pediatric trauma that may be linked to endothelial glycocalyx injury. Larger prospective studies are needed to validate these findings and determine the relationship of Agpt-2 with other markers of endotheliopathy.

Introduction and Aim: Microangiopathy is a hallmark of systemic sclerosis (SSc). It is a progressive process from an early inflammatory and proangiogenic environment to insufficient microvascular repair with loss of microvessels. The exact underlying mechanisms remain ill-defined. Aim of the study was to investigate whether imbalanced angiopoietins/VEGF serum profile should be related in SSc to the altered microvascular reactivity characterized by aberrant angiogenesis and avascularity., Materials and Methods: Serum levels of Angiopoietin-1 (Ang1), Angiopoietin-2 (Ang2) and VEGF were measured by ELISA in 47 SSc patients and 27 healthy controls. Microvascular alterations were assessed by nailfold videocapillaroscopy (NVC)., Results: Serum concentrations of Ang1 were significantly lower [mean (S.D.): 21516.04 (11,441.035) pg/ml], and Ang2 significantly increased [25,89.55 (934.225) pg/ml] in SSc as compared with the control group [Ang1: 28,457.08 (10,431.905) pg/ml; Ang2: 1556.23 (481.255) pg/ml, p < 0.01, respectively], whereas VEGF did not differ significantly. The ratios of Ang1/Ang2 and Ang1/VEGF were significantly lower in SSc patients (8.346 ± 4.523 and 95.17 ± 75.0, respectively) than in healthy subjects (17.612 ± 6.731 p < 0.000001 and 183.11 ± 137.73; p = 0.004]. Formation of giant capillaries with vascular leakage and collapse was associated with significant increase in VEGF and concomitant Ang1 deficiency. Capillary loss was related to significant increase in VEGF with respect to those with preserved capillary number (395.12 ± 256.27 pg/mL vs. 254.80 ± 213.61 pg/mL) whereas elevated Ang2 levels induced more advanced capillary damage as indicated by the presence of the "Late" NVC pattern., Conclusions: We found that serum levels of Ang1, Ang2 and VEGF are differentially expressed in SSc and altered Ang1/Ang2 profile might underlay the aberrant angiogenesis in SSc despite increase in VEGF. For the first time we identified that significant deficiency of Ang1 might be involved in early capillary enlargement, followed by collapse and lack of stable newly-formed vessels in VEGF-enriched environment, whereas Ang2 levels seem to increase later in disease progression and advanced microvascular damage ("Late" NVC pattern)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Context: Vascular dysfunction is a common feature in end-organ complications of type 2 diabetes mellitus (T2DM). The endothelium-specific receptor tyrosine kinase Tie2 and its ligand, angiopoietin-1 (Ang1), participate in the processes of vessel repair, renewal, and maturation. However, their dysregulation in T2DM has seldom been investigated., Objectives: To examine the relationship between angiogenic Tie2-expressing monocytes (TEMs) and Ang1, and their pharmacological modulation by the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil, in T2DM and in db/db mouse model., Design and Setting: Randomized, double-blind, placebo-controlled study., Patients and Intervention: db/db male mice were randomly assigned to receive 8 weeks of sildenafil or vehicle. Diabetic men were randomly assigned to receive 4 weeks of sildenafil or placebo., Main Outcomes and Measures: Peripheral blood cells were investigated by flow cytometry to quantify inflammatory myeloid CD11b+ Gr1+ cells and proangiogenic TEMs in mice and classical CD14++CD16neg monocytes and proangiogenic TEMs in humans at baseline and after treatment. In vitro human tube formation assay was used to test serum angiogenic potential., Results: We show that TEMs and Ang1 are defective in mouse and human models of diabetes and are normalized by PDE5i treatment. Serum angiogenic properties are impaired in diabetes because they do not support the in vitro formation of capillary-like structures, but they are reestablished by in vivo PDE5i treatment., Conclusions: Restoring a more physiological Tie2-Ang1 axis with sildenafil reestablishes serum angiogenic properties in diabetes, promoting angiogenic homeostasis., (Copyright © 2019 Endocrine Society.)

Background & Aims: In a phase 3 trial (RESORCE), regorafenib increased overall survival compared with placebo in patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. In an exploratory study, we analyzed plasma and tumor samples from study participants to identify genetic, microRNA (miRNA), and protein biomarkers associated with response to regorafenib., Methods: We obtained archived tumor tissues and baseline plasma samples from patients with HCC given regorafenib in the RESORCE trial. Baseline plasma samples from 499 patients were analyzed for expression of 294 proteins (DiscoveryMAP) and plasma samples from 349 patients were analyzed for levels of 750 miRNAs (miRCURY miRNA PCR). Tumor tissues from 7 responders and 10 patients who did not respond (progressors) were analyzed by next-generation sequencing (FoundationOne). Forty-six tumor tissues were analyzed for expression patterns of 770 genes involved in oncogenic and inflammatory pathways (PanCancer Immune Profiling). Associations between plasma levels of proteins and miRNAs and response to treatment (overall survival and time to progression) were evaluated using a Cox proportional hazards model., Results: Decreased baseline plasma concentrations of 5 of 266 evaluable proteins (angiopoietin 1, cystatin B, the latency-associated peptide of transforming growth factor beta 1, oxidized low-density lipoprotein receptor 1, and C-C motif chemokine ligand 3; adjusted P ≤ .05) were significantly associated with increased overall survival time after regorafenib treatment. Levels of these 5 proteins, which have roles in inflammation and/or HCC pathogenesis, were not associated with survival independently of treatment. Only 20 of 499 patients had high levels and a reduced survival time. Plasma levels of α-fetoprotein and c-MET were associated with poor outcome (overall survival) independently of regorafenib treatment only. We identified 9 plasma miRNAs (MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645) whose levels significantly associated with overall survival time with regorafenib (adjusted P ≤ .05). Functional analyses of these miRNAs indicated that their expression level associated with increased overall survival of patients with tumors of the Hoshida S3 subtype. Next-generation sequencing analyses of tumor tissues revealed 49 variants in 27 oncogenes or tumor suppressor genes. Mutations in CTNNB1 were detected in 3 of 10 progressors and VEGFA amplification in 1 of 7 responders., Conclusion: We identified expression patterns of plasma proteins and miRNAs that associated with increased overall survival times of patients with HCC following treatment with regorafenib in the RESORCE trial. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with HCC most likely to respond to regorafenib. ClinicalTrials.gov number NCT01774344. NCBI GEO accession numbers: mRNA data (NanoString): GSE119220; miRNA data (Exiqon): GSE119221., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Systemic inflammation, platelet dysfunction, and endothelial activation persist in people living with HIV despite sustained virologic suppression (SVS) with combined antiretroviral therapy (cART) and may lead to complications such as atherosclerosis and cardiovascular disease. Angiopoietin-1 (Ang-1) is a key regulator of angiogenesis and endothelial activation and has been studied as an objective biomarker in disease states such as atherosclerosis, sepsis, and severe malaria., Setting: Eight pediatric HIV care centers across Canada., Methods: Cross-sectional study of 61 children living with vertically acquired HIV on cART with undetectable RNA viral load. Plasma levels of Ang-1 were measured by ELISA and analyzed in relation to clinical characteristics abstracted from medical records., Results: Ang-1 levels were directly correlated with clinical indices of virologic control: cumulative proportion of life on effective cART (ρ = +0.35, P = 0.0078) and cumulative proportion of life with SVS (ρ = +0.36, P = 0.0049). Furthermore, higher Ang-1 levels were associated with younger age at SVS (ρ = -0.56, P < 0.0001). These associations remained statistically significant in multivariable linear regression models adjusting for potential confounders (P < 0.05 for all associations)., Conclusions: Early effective cART and SVS were associated with higher Ang-1 levels in children living with vertically acquired HIV-1.

Background: Endothelial hyperpermeability following cardiopulmonary bypass (CPB) contributes to microcirculatory perfusion disturbances and postoperative complications after cardiac surgery. We investigated the postoperative course of renal and pulmonary endothelial barrier function and the association with microcirculatory perfusion and angiopoietin-2 levels in patients after CPB., Methods: Clinical data, sublingual microcirculatory data, and plasma samples were collected from patients undergoing coronary artery bypass graft surgery with CPB (n = 17) before and at several time points up to 72 h after CPB. Renal and pulmonary microvascular endothelial cells were incubated with patient plasma, and in vitro endothelial barrier function was assessed using electric cell-substrate impedance sensing. Plasma levels of angiopoietin-1,-2, and soluble Tie2 were measured, and the association with in vitro endothelial barrier function and in vivo microcirculatory perfusion was determined., Results: A plasma-induced reduction of renal and pulmonary endothelial barrier function was observed in all samples taken within the first three postoperative days (P < 0.001 for all time points vs. pre-CPB). Angiopoietin-2 and soluble Tie2 levels increased within 72 h after CPB (5.7 ± 4.4 vs. 1.7 ± 0.4 ng/ml, P < 0.0001; 16.3 ± 4.7 vs. 11.9 ± 1.9 ng/ml, P = 0.018, vs. pre-CPB), whereas angiopoietin-1 remained stable. Interestingly, reduced in vitro renal and pulmonary endothelial barrier moderately correlated with reduced in vivo microcirculatory perfusion after CPB (r = 0.47, P = 0.005; r = 0.79, P < 0.001). In addition, increased angiopoietin-2 levels moderately correlated with reduced in vitro renal and pulmonary endothelial barrier (r = - 0.46, P < 0.001; r = - 0.40, P = 0.005) and reduced in vivo microcirculatory perfusion (r = - 0.43, P = 0.01; r = - 0.41, P = 0.03)., Conclusions: CPB is associated with an impairment of in vitro endothelial barrier function that continues in the first postoperative days and correlates with reduced postoperative microcirculatory perfusion and increased circulating angiopoietin-2 levels. These results suggest that angiopoietin-2 is a biomarker for postoperative endothelial hyperpermeability, which may contribute to delayed recovery of microcirculatory perfusion after CPB., Trial Registration: NTR4212 .

Background and Objective: Angiopoietin-2 (AGPT2) has been proposed as a key mediator of organ dysfunction, mainly in acute respiratory distress syndrome (ARDS). It has also been associated with acute kidney injury (AKI). We aimed to investigate the role of AGPT2 in patients with and without ARDS., Methods: In a cohort study with critically ill patients, AGPT1 and AGPT2 were assayed in plasma collected within the first 24 h after admission to intensive care unit (ICU). Severe AKI and the need for dialysis were outcome measures from comparative analysis with clinical characteristics useful for AKI risk stratification., Results: Among 283 patients (50.2% males), 109 (38.5%) had ARDS. AGPT2 levels at admission were higher in patients with ARDS. Although overall AGPT2 and AGPT2/AGPT1 levels were associated with severe AKI, this association was not significant in patients without ARDS; however, it remained strongly significant in ARDS patients. In patients without ARDS, AGPT2 showed only a weak discriminatory capacity to predict severe AKI (area under the curve (AUC): 0.64 vs 0.81 in the ARDS group). The continuous net reclassification improvement (NRI) in the ARDS group resulting from AGPT2 inclusion was 64.1% (P < 0.001) and the integrated discrimination improvement (IDI) index was 0.057 (P = 0.003). There was no significant difference in NRI in the no-ARDS group., Conclusion: AGPT2 and AGPT2/AGPT1 ratio are associated with severe AKI and there was only a need of renal replacement therapy (RRT) in patients with or at risk of ARDS, not in other critically ill patients. Adding AGPT2 to a clinical model resulted in a significant improvement in the capacity to predict severe AKI specifically in ARDS patients., (© 2019 Asian Pacific Society of Respirology.)

Introduction: Preeclampsia affects 3-5% of pregnancies worldwide and is the primary cause of maternal-fetal and neonatal mortality. Previous studies show that alterations in maternal concentrations of angiogenic factors, such as PlGF, PDGF AA, ANG-1, and ANG-2, may play fundamental roles in the pathophysiology of the disease., Objective: Determine whether the PlGF, PDGF AA, ANG-1, and ANG-2 are predictors of preeclampsia occurrence in a prenatal cohort study., Patients and Methods: This is a case-control study associated with a prospective cohort of pregnant women, with gestational ages between 20 and 25 weeks, composed of 30 pregnant women with preeclampsia (PE) and 90 healthy pregnant women (HP). The plasma concentrations of the markers were determined using the ELISA method. The comparison between the case and control groups was performed using the t test on the SAS® 9.4 software. Also, ROC curves were constructed to evaluate the predictive potential of the biomarkers., Results: Differences in the concentrations of PlGF, PDGF AA, ANG-1 and ANG-2, and the ANG-1/ANG-2 ratio were not observed between the PE and the HP groups. The predictive capacity of the biomarkers was assessed using ROC curves, in which the area under the curve for PlGF AUC = 0.55; PDGF AA AUC = 0.55; ANG-1 AUC = 0.47; ANG-2 AUC = 0.51, and the ANG-1/ANG-2 ratio AUC = 0.57., Conclusion: In pregnant women, with gestational ages between 20 and 25 weeks significant differences in biomarker concentrations between groups PE and HP were not observed. The ROC curves showed that the biomarkers were ineffective as preeclampsia predictors in the analyzed cohort., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Angiopoietins are postulated diagnostic biomarkers in children and adults with severe sepsis and septic shock. The diagnostic value of angiopoietins in children less than 5 years old has not been established, nor has their effect on permeability in the capillary microvasculature. We aim to determine if levels of angiopoietin-1 or -2 (angpt-1, -2) are diagnostic for severe sepsis/shock in young children and whether they affect the permeability of cultured human dermal microvascular endothelial cells (HDMEC)., Design: Prospective observational study of children < 5 years old. Patients were classified as non-systemic inflammatory response syndrome (SIRS), SIRS/sepsis and severe sepsis/septic shock., Setting: Tertiary care pediatric hospitals., Patients: Critically ill children., Interventions: None., Measurements: Plasma angpt-1 and -2 levels were measured with enzyme-linked immunoassays. Expression of angpt-2 in endothelial cells was assessed with quantitative polymerase chain reaction. Permeability changes in cultured HDMECs were assessed with transendothelial electrical resistance measurements., Results: Angpt-1 levels were significantly higher in younger children compared with levels found in previous study of older children across disease severity (all P < 0.001). Angpt-2 was significantly higher in this cohort with severe sepsis/septic shock compared with children without SIRS and SIRS/sepsis (all P < 0.003). Angpt-2/1 ratio was also elevated in children with severe sepsis/septic shock but an order of magnitude less than older children (P < 0.02, P = 0.002). Angpt-1 and -2 did not affect basal HDMEC permeability or modulate leak in isolation or in the presence of tumor necrosis factor (TNF)., Conclusions: Angpt-2 levels and the angpt-2/1 ratio are appropriate diagnostic biomarkers of severe sepsis/septic shock in children less than 5 years old. Neither angpt-1 nor -2 affects basal HDMEC permeability alone or modulates TNF induced capillary leak.

Purpose: There are currently no biomarkers that are associated with cognitive impairment (CI) in patients with obstructive sleep apnea syndrome (OSAS). This pilot study performed an exploratory plasma proteomic analysis to discover potential biomarkers and explore proteomic pathways that differentiate OSAS subjects with and without CI., Methods: Participants were selected from a cohort of women within 5 years of menopause not on hormone replacement therapy between the ages of 45-60 years. The Berlin questionnaire was used to select OSAS participants who then completed the MCFSI (Mail-In Cognitive Function Screening Instrument) to measure cognition. Six subjects with the highest MCFSI scores (≥ 5 denoting CI) were compared to six with normal scores. Proteomic analysis was done by Myriad RBM using a targeted ELISA for 254 serum proteins. Pathway analysis of differentially expressed proteins was performed using STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) software., Results: Distinct proteomic signatures were seen in OSAS subjects with CI as compared to those without CI. Proteins including insulin, prostasin, angiopoietin-1, plasminogen activator inhibitor 1, and interleukin-1 beta were overexpressed in OSAS subjects with CI. Proteins underexpressed in CI participants included cathepsin B, ceruloplasmin, and adiponectin. Pathway analysis revealed prominence of insulin-regulated vascular disease biomarkers., Conclusions: Proteomic biomarkers in participants with cognitive impairment suggest roles for insulin, and vascular signaling pathways, some of which are similar to findings in Alzheimer's disease. A better understanding of the pathogenic mechanisms of CI in OSAS will help focus clinical trials needed in this patient population.

Background: Angiopoietin-1 and -2 are vascular growth factors that exert opposing effects on endothelial activation and dysfunction. The aim of this study was to assess the association of these biomarkers with outcomes in children with sepsis. Methods: Biomarkers were assayed from the blood collected in an emergency department prior to any intervention. Predictor variables were Ang-1 and Ang-2 levels and the Ang-2/Ang-1 ratio. Outcomes included mortality, length of time on vasopressors, and ICU and hospital lengths of stay. The Pediatric RISk of Mortality III Score was calculated. A vasoactive inotrope score was calculated every 12 hours. Results: Forty-five children with sepsis and 49 with septic shock were analyzed. The median Ang-2 was higher in septic shock. The Ang-2/Ang-1 ratio was approximately 2-fold greater in those with septic shock. The Ang-2/Ang-1 ratio was associated with higher doses of vasoactive agents at 12 hours and longer ICU length of stay. In septic shock, for every 0.35 unit increase in the Ang-2/Ang-1 ratio, the PRISM III score increased by 1. Conclusions: The Ang-2/Ang-1 ratio was higher in children with septic shock. Ang-2/Ang-1 was associated with higher vasoactive agents, longer ICU length of stay, and correlated with the severity of illness score., Competing Interests: Competing Interests: Dr. Liles is listed as an inventor on US patent, ''Biomarkers for Early Determination of a Critical or Life-Threatening Response to Illness and/or Treatment Response.” The remaining authors have no financial relationships relevant to this article to disclose.

Introduction: Endothelial dysfunction plays an essential role in the pathogenesis of sepsis. The study aimed to illustrate the associations between the dynamic change (from day 1 to day 7) in biomarker concentration of endothelial dysfunction and outcomes in severe sepsis and septic shock in the intensive care unit (ICU)., Materials and Methods: We studied 102 patients enrolled in the Beijing Chao-yang Hospital affiliated with the Capital Medical University. A receiver operating characteristic (ROC) curve were used to assess the prognostic values of the circulating adhesion Angiopoietin-2/Angiopoietin-1 ratio (Ang-2/Ang-1) and Angiopoietin-1/Tie-2 ratio (Ang-1/Tie-2), intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and thrombomodulin (TM). Spearman's rank correlation and a multiple regression analysis were used to assess the relationship between the change in sequential organ failure assessment (Δ SOFA) score (SOFA score at day 7 minus SOFA score at day 1) and the levels of Δ Ang-2/Ang-1 and Δ Ang-1/Tie-2 ratios, ΔsICAM-1, ΔsVCAM-1 and Δ sTM., Results: The Ang-2/Ang-1 ratio, sICAM-1, sVCAM-1 and sTM levels significantly increased from day 1 to day 7 (all p = 0.045), and the Ang-1/Tie-2 ratio level markedly decreased from day 1 and day 7 (p = 0.027) in non-survivors. The biomarkers at Days 1 and 7 had significant prognostic value for 90-day mortality in severe sepsis and septic shock in ICU. The difference in biomarkers for endothelial dysfunction were suggested to be effective, independent predictors of changes in Δ SOFA., Conclusions: Endothelial dysfunction may constitute an independent contributor to sepsis-associated outcomes in ICU., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ang1 is a soluble ligand to receptor Tie2, and increasing the circulating Ang1 level may improve vascular stabilization under certain disease conditions. Here, we found that the circulating Ang1 level was significantly increased in cynomolgus monkeys treated with non-neutralizing anti-Ang1 antibodies. Improving the antibodies' pharmacokinetic properties by IgG Fc mutations further increased the circulating Ang1 level. However, the mutations decreased the thermal stability of the molecules, which may limit their use as therapeutic antibodies. Nevertheless, we showed that non-neutralizing antibodies may have therapeutic potential by increasing the level of a target molecule in the circulation.

Objectives: To test the hypothesis that higher blood levels of neurotrophic proteins (proteins that support neuronal survival and function) in the first 2 weeks of life are associated with a lower risk of cognitive impairment at 10 years., Study Design: We evaluated 812 10-year-old children with neonatal blood specimens enrolled in the multicenter prospective Extremely Low Gestational Age Newborn Study, assessing 22 blood proteins collected on 3 days over the first 2 weeks of life. Using latent profile analysis, we derived a cognitive function level based on standardized cognitive and executive function tests. We defined high exposure as the top quartile neurotrophic protein blood level on ≥2 days either for ≥4 proteins or for a specific cluster of neurotrophic proteins (defined by latent class analysis). Multinomial logistic regression analyzed associations between high exposures and cognitive impairment., Results: Controlling for the effects of inflammatory proteins, persistently elevated blood levels of ≥4 neurotrophic proteins were associated with reduced risk of moderate (OR, 0.35; 95% CI, 0.18-0.67) and severe cognitive impairment (OR, 0.22; 95% CI, 0.09-0.53). Children with a cluster of elevated proteins including angiopoietin 1, brain-derived neurotrophic factor, and regulated upon activation, normal T-cell expressed, and secreted had a reduced risk of adverse cognitive outcomes (OR range, 0.31-0.6). The risk for moderate to severe cognitive impairment was least with 0-1 inflammatory and >4 neurotrophic proteins., Conclusions: Persisting elevations of circulating neurotrophic proteins during the first 2 weeks of life are associated with lowered risk of impaired cognition at 10 years of age, controlling for increases in inflammatory proteins., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Fluid restriction in patients with acute respiratory distress syndrome increases ventilator-free days while lowering plasma angiopoietin-2 (Ang-2), a marker of pulmonary endothelial injury. We hypothesised that fluid resuscitation may lead to endothelial injury after cardiac surgery and analysed Ang-2, angiopoietin-1 (Ang-1) and phospholipase A 2 (PLA 2 ) levels and the impact of fluid management on ventilation time., Methods: Patients enrolled in a single-centre, prospectively randomised interventional study of liberal or conservative fluid resuscitation strategy had plasma Ang-2, Ang-1 and PLA 2 levels measured at baseline (pre-operative), 6 and 24 hours after commencement of cardiopulmonary bypass, and analysed by linear mixed models as liberal v conservative (intention to treat) or high v low fluid group (actual treatment, ≥ 3250 mL of fluid administered), and further subclassified as EuroSCORE (European System for Cardiac Operative Risk Evaluation) II ≥ 0.9 or < 0.9., Results: Over 9 months, 144 patients were randomly allocated to either liberal ( n =74) or conservative ( n =70) fluid. Patients in the liberal fluid arm tended to an increased Ang-2 ( P =0.12) and had higher PLA 2 levels ( P =0.03). Based on actual fluid administered, Ang-2 levels were higher, the Ang-1/Ang-2 ratio lower, and the length of mechanical ventilation and intensive care unit (ICU) stay was longer in the high fluid group ( P < 0.001). The highest levels of Ang- 2 and corresponding lowest Ang-1/Ang-2 ratio, along with longest length of mechanical ventilation and ICU stay, were found with both the liberal and high fluid groups in patients with a EuroSCORE II ≥ 0.9 ( P < 0.01)., Conclusion: Liberal fluid resuscitation after cardiac surgery was associated with both pulmonary endothelial injury and prolonged length of mechanical ventilation., Clinical Trial Registration: ACTRN12612000754842.

Background: Until now, there are few studies evaluating serum levels of angiogenic cytokines in dermatomyositis (DM). Therefore, the aims of the present study were: (a) to analyze systematically and simultaneously serum levels of angiogenin (ANG), angiopoietin (ANGPT)-1, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-1 and - 2, platelet derived growth factor (PDGF)-AA and -BB in DM; (b) to correlate the serum level of these cytokines with the DM clinical and laboratory features., Methods: This is a cross sectional study, in which 48 patients with DM aged 18 to 45 years were gender-, age- and ethnicity-matched with 48 healthy individuals (control group). The serum levels of cytokines analyses were performed by multiplex immunoassay. The parameters of DM activity were based on the scores established by the International Myositis Assessment & Clinical Studies Group., Results: The mean ages, gender frequencies and ethnicities were comparable between the patients with DM and the control group. A significantly higher serum FGF-1 and FGF-2 levels (P < 0.001 and P < 0.001, respectively), lower VEGF and PDGF-AA levels (P = 0.009 and P = 0.022), and comparable ANG, ANGPT-1 and PDGF-BB levels were observed in DM patients compared to controls. There was a tendency for cytokines (with the exceptions of VEGF and PDGF-BB) to correlate positively with the DM activity parameters, whereas FGF-2 correlated inversely. Moreover, FGF-1 strongly correlated with DM cutaneous manifestations., Conclusions: The present data provide the relevance of different serum angiogenic cytokines in patients with DM. Additional studies will be needed to validate the data obtained in this work.

Rationale: During pneumonia, pathogen-host interaction evokes inflammation and lung barrier dysfunction. Tie2 activation by angiopoietin-1 reduces, whereas Tie2 blockade by angiopoietin-2 increases, inflammation and permeability during sepsis. The role of angiopoietin-1/-2 in pneumonia remains unidentified., Objectives: To investigate the prognostic and pathogenic impact of angiopoietins in regulating pulmonary vascular barrier function and inflammation in bacterial pneumonia., Methods: Serum angiopoietin levels were quantified in pneumonia patients of two independent cohorts (n = 148, n = 395). Human postmortem lung tissue, pneumolysin- or angiopoietin-2-stimulated endothelial cells, isolated perfused and ventilated mouse lungs, and mice with pneumococcal pneumonia were investigated., Measurements and Main Results: In patients with pneumonia, decreased serum angiopoietin-1 and increased angiopoietin-2 levels were observed as compared with healthy subjects. Higher angiopoietin-2 serum levels were found in patients with community-acquired pneumonia who died within 28 days of diagnosis compared with survivors. Receiver operating characteristic analysis revealed improved prognostic accuracy of CURB-65 for 28-day survival, intensive care treatment, and length of hospital stay if combined with angiopoietin-2 serum levels. In vitro, pneumolysin enhanced endothelial angiopoietin-2 release, angiopoietin-2 increased endothelial permeability, and angiopoietin-1 reduced pneumolysin-evoked endothelial permeability. Ventilated and perfused lungs of mice with angiopoietin-2 knockdown showed reduced permeability on pneumolysin stimulation. Increased pulmonary angiopoietin-2 and reduced angiopoietin-1 mRNA expression were observed in Streptococcus pneumoniae-infected mice. Finally, angiopoietin-1 therapy reduced inflammation and permeability in murine pneumonia., Conclusions: These data suggest a central role of angiopoietin-1/-2 in pneumonia-evoked inflammation and permeability. Increased angiopoietin-2 serum levels predicted mortality and length of hospital stay, and angiopoietin-1 may provide a therapeutic target for severe pneumonia.

Background: Hypertensive disorders, fetal growth restriction and preterm birth are major obstetrical complications and are related to impaired placentation. Early identification of impaired placentation can advance clinical care by preventing or postpone adverse pregnancy outcome., Objectives: Determine whether sonographic assessed placental vascular development and concomitant changes in inflammation- and/or angiogenesis-related serumproteins differ in the first trimester between uncomplicated pregnancies and pregnancies with adverse outcome., Study Design: This prospective longitudinal study defines adverse pregnancy outcome as conditions associated with impaired placentation; fetal growth restriction, hypertensive disorder, preterm birth and placental abruption. The vascularization index, flow index, vascularization flow index and placental volume were determined at 8, 10 and 12 weeks pregnancy from 64 women using 3D power Doppler. Serum levels were analyzed for Angiopoetin-1 and -2, Leptin, VEGF-R, VEGF, and EGF., Results: The vascularization index and vascular flow index increased in uneventful pregnancies with almost 50% between 8 and 12 weeks, resulting in a ∼50% higher vascularization index at 12 weeks compared to women with an adverse pregnancy outcome. Women with an adverse pregnancy outcome (n = 13) had significantly lower indices and placental volumes at all time points measured and these indices did not increase between 8 and 12 weeks. Reduced vascular development was associated with increased Angiopoietin-1 levels at 8 and 12 weeks and increased Leptin levels at 8 weeks., Conclusions: Pregnancies with an adverse outcome caused by conditions associated with impaired placentation differ from uneventful pregnancies in having reduced placental vascularization accompanied by elevated circulating levels of Angiopoietin-1 and Leptin already in the first trimester., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)