The significance of Syndecan 1, a new marker for endothelial dysfunction, in cases of fetal growth retardation.

PROBLEM: In the current study we aimed to investigate Syndecan 1 (SDC1) levels in pregnant women diagnosed with fetal growth restriction (FGR) and the relationship between SDC1 levels and clinical and doppler parameters in FGR cases associated with endothelial dysfunction, angiogenesis and uteroplacental insufficiency METHOD OF STUDY: A total of 90 pregnant women included in the study, (45 with FGR, 45 healthy control) matched by week of gestation and maternal age. Venous blood samples were collected and plasma concentrations of SDC1 were determined by a specific immunoassay. Doppler examination was performed to evaluate the relationship between the SDC1 levels and placental blood supply. RESULTS: Doppler parameters; mean UtA-PI (p < .001), CPR (p = .002) and CPUR (p < .001) were different between the groups, however MCA PI, umbilical artery PI and umbilical artery S/D were not (p > .05). While gestational age at delivery, birth weight, APGAR score at 1 and 5 min were significantly lower (all, p < .001) in the study group, non-reassure fetal heart rate tracing (p = .09) and NICU admission (p = .02) were significantly higher. SDC 1 level was 2,00 ± 1,47 ng/mL and 2,34 ± 1,12 ng/mL in the FGR and control groups, respectively (p = .008). In the study group SDC 1 level was 1,69 ± 2,00 in those with gestational age below 32 weeks and 2,13 ± 1,18 in those with gestational age above 32 weeks and there was a statistically significant difference between the groups (p = .015). Plasma SDC 1 concentration of 2,1850 ng/mL or less had a sensitivity of 70%, a specificity of 72%, area under the ROC curve .65 (p < .005). CONCLUSIONS: Low maternal plasma SDC1 level may be associated with placental insufficiency and FGR. Low levels of SDC1 may be helpful as a predictor for the development of FGR during gestation.

Perioperative serum syndecan-1 concentrations in patients who underwent cardiovascular surgery with cardiopulmonary bypass and its association with the occurrence of postoperative acute kidney injury: a retrospective observational study.

BACKGROUND: Various factors can cause vascular endothelial damage during cardiovascular surgery (CVS) with cardiopulmonary bypass (CPB), which has been suggested to be associated with postoperative complications. However, few studies have specifically investigated the relationship between the degree of vascular endothelial damage and postoperative acute kidney injury (pAKI). The objectives of this study were to measure perioperative serum syndecan-1 concentrations in patients who underwent CVS with CPB, evaluate their trends, and determine their association with pAKI. METHODS: This was a descriptive and case‒control study conducted at the National University Hospital. Adult patients who underwent CVS with CPB at a national university hospital between March 15, 2016, and August 31, 2020, were included. Patients who were undergoing preoperative dialysis, had preoperative serum creatinine concentrations greater than 2.0 mg dl-1, who were undergoing surgery involving the descending aorta were excluded. The perioperative serum syndecan-1 concentration was measured, and its association with pAKI was investigated. RESULTS: Fifty-two patients were included. pAKI occurred in 18 (34.6%) of those patients. The serum syndecan-1 concentration increased after CPB initiation and exhibited bimodal peak values. The serum syndecan-1 concentration at all time points was significantly elevated compared to that after the induction of anesthesia. The serum syndecan-1 concentration at 30 min after weaning from CPB and on postoperative day 1 was associated with the occurrence of pAKI (OR = 1.10 [1.01 to 1.21], P = 0.03]; OR = 1.16 [1.01 to 1.34], P = 0.04]; and the cutoff values of the serum syndecan-1 concentration that resulted in pAKI were 101.0 ng ml-1 (sensitivity = 0.71, specificity = 0.62, area under the curve (AUC) = 0.67 (0.51 to 0.83)) and 57.1 ng ml-1 (sensitivity = 0.82, specificity = 0.56, AUC = 0.71 (0.57 to 0.86)). Multivariate logistic regression analysis revealed that the serum syndecan-1 concentration on postoperative day 1 was associated with the occurrence of pAKI (OR = 1.02 [1.00 to 1.03]; P = 0.03). CONCLUSION: The serum syndecan-1 concentration at all time points was significantly greater than that after the induction of anesthesia. The serum syndecan-1 concentration on postoperative day 1 was significantly associated with the occurrence of pAKI. TRIAL REGISTRATION: This study is not a clinical trial and is not registered with the registry.

Peripheral blood syndecan-1 levels after mechanical thrombectomy can predict the clinical prognosis of patients with acute ischemic stroke.

BACKGROUND: Previously, we revealed noticeable dynamic fluctuations in syndecan-1 levels in the peripheral blood of post-stroke patients. We further investigated the clinical prognostic value of syndecan-1 as a biomarker of glycoprotein damage in patients with acute ischaemic stroke (AIS). METHODS: We examined 105 patients with acute large vessel occlusion in the anterior circulation, all of whom underwent mechanical thrombectomy (MT). Peripheral blood syndecan-1 levels were measured 1 day after MT, and patients were categorised into favourable and unfavourable prognostic groups based on the 90-day modified Rankin Scale (mRS) score. Additionally, we compared the clinical outcomes between groups with high and low syndecan-1 concentrations. RESULTS: The findings revealed a significantly lower syndecan-1 level in the group with an unfavourable prognosis compared to those with a favourable prognosis (p < 0.01). In the multivariable logistic regression analysis, lower syndecan-1 levels were identified as a predictor of unfavourable prognosis (odds ratio (OR) = 0.965, p = 0.001). Patients displaying low syndecan-1 expression in the peripheral blood (< 29.51 ng/mL) experienced a > twofold increase in the rates of unfavourable prognosis and mortality. CONCLUSIONS: Our study demonstrates that syndecan-1, as an emerging, easily detectable stroke biomarker, can predict the clinical outcomes of patients with AIS. After MT, low levels of syndecan-1 in the peripheral blood on the first day emerged as an independent risk factor for an unfavourable prognosis, suggesting that lower syndecan-1 levels might signify worse clinical presentation and outcomes in stroke patients undergoing this procedure.

Association of Preoperative and Postoperative Plasma Syndecan-1 and Colorectal Cancer Outcome.

BACKGROUND/AIM: A three-dimensional network constructed using glycocalyx (GCX) extends throughout the cancer cell nest in human colorectal cancer (CRC). GCX was found to be closely related to cancer. We examined the prognostic correlation and potential of syndecan-1 (SDC1), a representative proteoglycan of GCX, as a biomarker. PATIENTS AND METHODS: We analyzed SDC1 in the transcriptomic profiles of a major publicly available CRC cohort from The Cancer Genome Atlas (TCGA) using a computational algorithm. We investigated serum SDC1 levels preoperatively and on postoperative day seven in 48 patients with stage I-III CRC who underwent surgery during July-December 2019 at Gifu University Hospital. RESULTS: For TCGA, no significant differences existed between the high and low SDC1 expression groups regarding disease-free, disease-specific, and overall survival for stage I-III, and only overall survival for stage IV was significantly different. In our study, among the 48 patients, 17 (no recurrence), 13 (1 recurrence), and 18 (10 recurrences) had stage I-III, respectively. Preoperative and postoperative day 7 SDC1 levels for patients with stage I-III were 10.7±2.3 and 9.9±3.1 ng/ml (p=0.40), 11.1±1.7 and 10.1±0.8 ng/ml (p=0.07), and 10.3±2.0 and 9.5±1.4 ng/ml (p=0.15), respectively. In stage II and III, patients were divided into two groups according to differences between preoperative and postoperative SDC1 levels (SDC1pre-pro). SDC1pre-pro ≤0 group significantly prolonged disease-free survival compared with SDC1pre-pro >0 group (p=0.048). CONCLUSION: Dynamic change in serum SDC1 levels serves as a prognostic biomarker for stage II and III colorectal cancer.

Doxycycline can reduce glycocalyx shedding by inhibiting matrix metalloproteinases in patients undergoing cardiopulmonary bypass: A randomized controlled trial.

BACKGROUND: Cardiopulmonary bypass (CPB) leads to shedding of the glycocalyx of endothelial cells, resulting in a series of complications such as tissue edema and coagulatory and microcirculatory dysfunctions. Matrix metalloproteinases (MMPs) can cause glycocalyx shedding in a variety of pathological processes, but their role in the process of CPB is still unclear. We hypothesized that the MMPs inhibitor doxycycline would reduce glycocalyx shedding by inhibiting MMPs during CPB. METHODS: Thirty-six patients were randomized to receive either 100 mg oral doxycycline (an MMPs inhibitor) or a matching placebo pill twice a day for three days before CPB. The primary outcome was the concentration of plasma syndecan-1. Secondary outcomes included heparan sulphate, MMP-2, MMP-9, ratio of urinary albumin to creatinine, and short-term clinical outcomes. In order to further prove that MMPs in plasma caused the glycocalyx shedding, human umbilical vein endothelial cells were cultured with plasma obtained from cardiac surgery patients before or after CPB (with or without MMPs inhibitor GM6001). The change in glycocalyx content was detected by immunofluorescence. RESULTS: CPB resulted in an increase of MMPs and shedding of the glycocalyx. Plasma syndecan-1 was higher in the control group than in the doxycycline group (median difference:15.04 µg/L; 95% CI: 9.14-20.94 µg/L; P < 0.001). Similar to syndecan-1, plasma heparan sulphate, MMP-2, and MMP-9 concentrations in the doxycycline group were significantly lower than those in the control group during CPB. Doxycycline was also correlated with a reduction in the ratio of urinary albumin to creatinine and improved the short-term clinical outcomes of patients. Endothelial cells cultured with plasma from patients after CPB showed significant shedding of syndecan-1 and heparan sulphate (post-CPB group vs pre-CPB group, P < 0.001). GM6001 was shown to reduce shedding of syndecan-1 and heparan sulphate by inhibiting MMPs (post-CPB + GM6001 group vs post-CPB group, P < 0.001). CONCLUSION: Doxycycline can reduce glycocalyx shedding by inhibiting MMPs during CPB.

Serum Syndecan-1: A Novel Biomarker for Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: Syndecan-1 (SDC1) has multiple functions in tumorigenesis in general and specifically in pancreatic cancer. We aimed to evaluate SDC1 as a diagnostic and prognostic biomarker in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: In this case-control study, patients newly diagnosed with a biopsy-proven PDAC were enrolled alongside healthy individuals in a derivation-validation cohort design. Serum SDC1 was measured by enzyme-linked immunoassay. The diagnostic accuracy of SDC1 levels for diagnosing PDAC was computed. A unified cohort enriched with additional early-stage patients with PDAC was used to evaluate the association of SDC1 with survival outcomes and patient characteristics. RESULTS: In the derivation cohort, serum SDC1 levels were significantly higher in patients with PDAC (n = 39) compared with healthy controls (n = 20) (40.1 ng/mL, interquartile range 29.8-95.3 vs 25.6 ng/mL, interquartile range 17.1-29.8, respectively; P < 0.001). The receiver operating characteristic analysis area under the curve was 0.847 (95% confidence interval 0.747-0.947, P < 0.001). These results were replicated in a separate age-matched validation cohort (n = 38 PDAC, n = 38 controls; area under the curve 0.844, 95% confidence interval 0.757-0.932, P < 0.001). In the combined-enriched PDAC cohort (n = 110), using a cutoff of 35 ng/mL, the median overall 5-year survival between patients below and above this cutoff was not significantly different, although a trend for better survival after 1 year was found in the lower level group (P = 0.06). There were 12 of the 110 patients with PDAC (11%) who had normal CA 19-9 in the presence of elevated SDC1. DISCUSSION: These findings suggest serum SDC1 as a promising novel biomarker for early blood-based diagnosis of pancreatic cancer.

Dexmedetomidine suppresses serum syndecan-1 elevation and improves survival in a rat hemorrhagic shock model.

Hemorrhagic shock causes vascular endothelial glycocalyx (EGCX) damage and systemic inflammation. Dexmedetomidine (DEX) has anti-inflammatory and EGCX-protective effects, but its effect on hemorrhagic shock has not been investigated. Therefore, we investigated whether DEX reduces inflammation and protects EGCX during hemorrhagic shock. Anesthetized Sprague-Dawley rats were randomly assigned to five groups (n=7 per group): no shock (SHAM), hemorrhagic shock (HS), hemorrhagic shock with DEX (HS+DEX), hemorrhagic shock with DEX and the α7 nicotinic type acetylcholine receptor antagonist methyllycaconitine citrate (HS+DEX/MLA), and hemorrhagic shock with MLA (HS+MLA). HS was induced by shedding blood to a mean blood pressure of 25-30 mmHg, which was maintained for 30 min, after which rats were resuscitated with Ringer's lactate solution at three times the bleeding volume. The survival rate was assessed up to 3 h after the start of fluid resuscitation. Serum tumor necrosis factor-alpha (TNF-α) and syndecan-1 concentrations, and wet-to-dry ratio of the heart were measured 90 min after the start of fluid resuscitation. The survival rate after 3 h was significantly higher in the HS+DEX group than in the HS group. Serum TNF-α and syndecan-1 concentrations, and the wet-to-dry ratio of heart were elevated by HS, but significantly decreased by DEX. These effects were antagonized by MLA. DEX suppressed the inflammatory response and serum syndecan-1 elevation, and prolonged survival in rats with HS.

Association between plasma glycocalyx component levels and poor prognosis in severe influenza type A (H1N1).

Influenza A virus infection causes a series of diseases, but the factors associated with disease severity are not fully understood. Disruption of the endothelial glycocalyx contributes to acute lung injury in sepsis, but has not been well studied in H1N1 influenza. We aim to determine whether the plasma glycocalyx components levels are predictive of disease severity in H1N1 influenza. This prospective observational study included 53 patients with influenza A (H1N1) during the influenza season, and 30 healthy controls in our hospital. Patients were grouped by severity and survival. We collected clinical data and blood samples at admission. Inflammatory factors (tumor necrosis factor-α, interleukin-6, interleukin-10) and endothelial glycocalyx components (syndecan-1, hyaluronan, heparan sulfate) were measured. The plasma levels of syndecan-1, hyaluronan, and heparan sulfate were significantly higher in patients with severe influenza A (H1N1) than in mild cases. Syndecan-1 and hyaluronan were positively correlated with disease severity, which was indicated by the APACHE II and SOFA scores and lactate levels, and negatively correlated with albumin levels. At a cutoff point ≥ 173.9 ng/mL, syndecan-1 had a 81.3% sensitivity and 70.3% specificity for predicting of 28-day mortality. Kaplan-Meier analysis demonstrated a strong association between syndecan-1 levels and 28-day mortality (log-rank 11.04, P = 0.001). Elevated plasma levels of syndecan-1 has a potential role in systemic organ dysfunction and may be indicative of disease severity in patients with influenza A (H1N1).

Suppressing Syndecan-1 Shedding to Protect Against Renal Ischemia/Reperfusion Injury by Maintaining Polarity of Tubular Epithelial Cells.

ABSTRACT: Syndecan-1 (SDC-1), a type of heparan sulfate proteoglycan on the surface of epithelial cells, is involved in maintaining cell morphology. Loss of cell polarity constitutes the early stage of ischemic acute kidney injury (AKI). This study investigated the role of SDC-1 shedding in I/R-induced AKI and the underlying mechanisms. Levels of the shed SDC-1 in the serum were measured with ELISA 12 and 24 h after reperfusion in renal I/R model mice. Na+/K+-ATPase-α1 expression was evaluated using western blotting in vivo and immunofluorescence in hypoxia/reoxygenation (H/R) cysts. Renal tubular epithelial cell apoptosis was measured using TUNEL in vivo and flow cytometry in vitro. Furthermore, plasma syndecan-1 (pSDC-1) levels were measured in patients at the time of anesthesia resuscitation after cardiac surgery. We found that shed SDC-1 levels increased and Na+/K+-ATPase-α1 expression decreased after H/R in the three-dimensional (3D) tubular model, and this state was exacerbated with extended period of hypoxia. After the inhibition of SDC-1 shedding by GM6001, SDC-1 and Na+/K+-ATPase-α1 expression was restored, while H/R-induced apoptosis was decreased. In vivo, SDC-1 shedding was induced by renal I/R and was accompanied with a loss of renal tubular epithelial cell polarity and increased apoptosis. GM6001 pretreatment protected against I/R injury by alleviating the disruption of cell polarity and apoptosis. pSDC-1 levels were significantly higher in AKI patients than in non-AKI patients. ROC curve showed that the accuracy of pSDC-1 for AKI prediction was 0.769. In conclusion, inhibition of I/R-induced SDC-1 shedding could contribute to renal protection by restoring the loss of cell polarity and alleviating apoptosis in tubular epithelial cells.

Shock-Induced Endothelial Dysfunction is Present in Patients With Occult Hypoperfusion After Trauma.

BACKGROUND: Shock-induced endothelial dysfunction, evidenced by elevated soluble thrombomodulin (sTM) and syndecan-1 (Syn-1), is associated with poor outcomes after trauma. The association of endothelial dysfunction and overt shock has been demonstrated; it is unknown if hypoperfusion in the setting of normal vital signs (occult hypoperfusion [OH]) is associated with endothelial dysfunction. We hypothesized that sTM and Syn-1 would be elevated in patients with OH when compared to patients with normal perfusion. METHODS: A single-center study of patients requiring highest-level trauma activation (2012-2016) was performed. Trauma bay arrival plasma Syn-1 and sTM were measured by enzyme-linked immunosorbent assay. Shock was defined as systolic blood pressure (SBP) <90 mm Hg or heart rate (HR) ≥120 bpm. OH was defined as SBP ≥ 90, HR < 120, and base excess (BE) ≤-3. Normal perfusion was assigned to all others. Univariate and multivariable analyses were performed. RESULTS: Of 520 patients, 35% presented with OH and 26% with shock. Demographics were similar between groups. Patients with normal perfusion had the lowest Syn-1 and sTM, while patients with OH and shock had elevated levels. OH was associated with increased sTM by 0.97 ng/mL (95% CI 0.39-1.57, p = 0.001) and Syn-1 by 14.3 ng/mL (95% CI -1.5 to 30.2, p = 0.08). Furthermore, shock was associated with increased sTM by 0.64 (95% CI 0.02-1.30, p = 0.04) and with increased Syn-1 by 23.6 ng/mL (95% CI 6.2-41.1, p = 0.008). CONCLUSIONS: Arrival OH was associated with elevated sTM and Syn-1, indicating endothelial dysfunction. Treatments aiming to stabilize the endothelium may be beneficial for injured patients with evidence of hypoperfusion, regardless of vital signs.

Kawasaki disease and increased cardiovascular risk: Is there a link to circulating glycocalyx biomarkers?

AIMS: Kawasaki disease (KD) is an acute systemic vasculitis with possible long-term impact of general cardio-vascular health. An endothelial glycocalyx disorder during the disease's acute phase might predispose to long-term vascular anomalies leading to endothelial dysfunction and atherosclerosis. To investigate any association between increased cardiovascular risk and endothelial glycocalyx, we assessed circulating glycocalyx components in patients with a KD history, and analysed their association with acute-phase clinical features and more importantly, with patients' current cardiovascular risk factors. METHODS: This prospective observational cohort study included 51 subjects: 31 patients with a history of KD, and 20 healthy subjects matched for age and sex. We analysed serum syndecan-1 and hyaluronan via ELISA. We assessed features reported during the acute phase of KD such as blood counts, C-reactive protein (CRP) levels and coronary artery aneurysms (CAA), and their current blood pressure and lipid markers in relation to measured glycocalyx components. RESULTS: Our multivariate analysis revealed that hyaluronan and syndecan-1 levels were not associated with KD. However, the latter exhibited a significant association with acute-phase blood count alterations in patients with KD. Furthermore, significant interactions of hyaluronan and syndecan-1 with certain cardiovascular risk factors like blood lipids and blood pressure were only present in KD patients. CONCLUSION: Vasculitis during KD's acute phase might predispose to a long-term endothelial glycocalyx alteration, influenced by other factors having a vascular impact such as blood pressure and circulating lipids. CLINICAL TRIAL REGISTRATION: German Clinical Trials Register on 25th February 2016, DRKS00010071 https://www.drks.de/drks_web/.

Syndecan-1, an indicator of endothelial glycocalyx degradation, predicts outcome of patients admitted to an ICU with COVID-19.

BACKGROUND: We investigated the feasibility of two biomarkers of endothelial damage (Syndecan-1 and thrombomodulin) in coronavirus disease 2019 (COVID-19), and their association with inflammation, coagulopathy, and mortality. METHODS: The records of 49 COVID-19 patients who were admitted to an intensive care unit (ICU) in Wuhan, China between February and April 2020 were examined. Demographic, clinical, and laboratory data, and outcomes were compared between survivors and non-survivors COVID-19 patients, and between patients with high and low serum Syndecan-1 levels. The dynamics of serum Syndecan-1 levels were also analyzed. RESULTS: The levels of Syndecan-1 were significantly higher in non-survivor group compared with survivor group (median 1031.4 versus 504.0 ng/mL, P = 0.002), and the levels of thrombomodulin were not significantly different between these two groups (median 4534.0 versus 3780.0 ng/mL, P = 0.070). Kaplan-Meier survival analysis showed that the group with high Syndecan-1 levels had worse overall survival (log-rank test: P = 0.023). Patients with high Syndecan-1 levels also had significantly higher levels of thrombomodulin, interleukin-6, and tumor necrosis factor-α. Data on the dynamics of Syndecan-1 levels indicated much greater variations in non-survivors than survivors. CONCLUSIONS: COVID-19 patients with high levels of Syndecan-1 develop more serious endothelial damage and inflammatory reactions, and have increased mortality. Syndecan-1 has potential for use as a marker for progression or severity of COVID-19. Protecting the glycocalyx from destruction is a potential treatment for COVID-19.

Serum syndecan-1 concentration in hospitalized patients with heart failure may predict readmission-free survival.

Syndecan-1 is found in the endothelial glycocalyx and is released into the bloodstream during stressed conditions, including severe diseases such as acute kidney injury, chronic kidney disease, and cardiovascular disease. This study investigated the prognostic value of serum syndecan-1 concentration in patients with heart failure upon admission. Serum syndecan-1 concentration was analyzed in 152 patients who were hospitalized for worsening heart failure from September 2017 to June 2018. The primary outcome of the study was readmission-free survival, defined as the time from the first admission to readmission for worsened heart failure or death from any cause, which was assessed at 30 months after discharge from the hospital. The secondary outcome of the study was survival time. Blood samples and echocardiogram data were analyzed. Univariate and multivariable time-dependent Cox regression analyses adjusted for age, creatinine levels, and use of antibiotics were conducted. The serum syndecan-1 concentration was significantly associated with readmission-free survival. Subsequently, the syndecan-1 concentration may have gradually decreased with treatment. The administration of human atrial natriuretic peptide and antibiotics may have modified the relationship between readmission-free survival and serum syndecan-1 concentration (p = 0.01 and 0.008, respectively). Serum syndecan-1 concentrations, which may indicate injury to the endothelial glycocalyx, predict readmission-free survival in patients with heart failure.

Indications of Persistent Glycocalyx Damage in Convalescent COVID-19 Patients: A Prospective Multicenter Study and Hypothesis.

The COVID-19 pandemic is caused by the SARS CoV-2 virus and can lead to severe lung damage and hyperinflammation. In the context of COVID-19 infection, inflammation-induced degradation of the glycocalyx layer in endothelial cells has been demonstrated. Syndecan-1 (SDC-1) is an established parameter for measuring glycocalyx injury. This prospective, multicenter, observational, cross-sectional study analyzed SDC-1 levels in 24 convalescent patients that had been infected with SARS-CoV-2 with mild disease course without need of hospitalization. We included 13 age-matched healthy individuals and 10 age-matched hospitalized COVID-19 patients with acute mild disease course as controls. In convalescent COVID-19 patients, significantly elevated SDC-1 levels were detected after a median of 88 days after symptom onset compared to healthy controls, whereas no difference was found when compared to SDC-1 levels of hospitalized patients undergoing acute disease. This study is the first to demonstrate signs of endothelial damage in non-pre-diseased, convalescent COVID-19 patients after mild disease progression without hospitalization. The data are consistent with studies showing evidence of persistent endothelial damage after severe or critical disease progression. Further work to investigate endothelial damage in convalescent COVID-19 patients should follow.

Circulating CD138 enhances disease progression by augmenting autoreactive antibody production in a mouse model of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a progressive autoimmune disease characterized by high levels of antibodies directed against nuclear antigens. Elevated serum CD138, a heparan sulfate-bearing proteoglycan, correlates with increased disease activity in patients with SLE, but the contribution of CD138 to lupus disease is not known. Corroborating patient data, we detected an increase in serum CD138 in MRL/MpJ-Faslpr/J (MRL/Lpr) mice (a model for SLE disease) parallel to disease activity. Although T-cell receptor ß (TCRß)+CD138+ T cells typically expand in MRL/Lpr mice as the disease progresses, surprisingly, TCRß+CD138- cells were the primary source of circulating CD138, as the transfer of TCRß+CD138- cells, but not TCRß+CD138+ cells, to young MRL/Lpr mice resulted in higher serum CD138 in the recipients. We found that trypsin was able to cleave CD138 from TCRß+CD138+ cells, and that trypsin was highly expressed in TCRß+CD138- cells. Moreover, trypsin inhibitors, the "defined trypsin inhibitor" and leupeptin, increased CD138 expression on TCRß+CD138- cells, suggesting a contribution of cleaved CD138 to the increase in blood CD138 levels. Furthermore, soluble CD138 was able to bind "a proliferation-inducing ligand" (APRIL) and enhance APRIL-mediated plasma cell generation and autoreactive antibody production through the phosphorylation of extracellular signal-regulated kinase in B cells. The APRIL receptor "transmembrane activator, calcium modulator, and cyclophilin ligand interactor" was involved in the enhancement of APRIL activity by CD138, as the synergistic effect of APRIL and CD138 was ablated in transmembrane activator, calcium modulator, and cyclophilin ligand interactor-deficient B cells. These findings indicate a regulatory role for soluble CD138 in B-cell differentiation and autoreactive antibody production in SLE disease.

Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria.

Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. Identifying novel biomarkers may improve detection of pregnancies at risk. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating maternal syndecan-1 was measured in several cohorts; a large prospective cohort collected around 36 weeks' gestation (n = 1206), a case control study from the Manchester Antenatal Vascular service (285 women sampled at 24-34 weeks' gestation); two prospective cohorts collected on the day of delivery (36 + 3-41 + 3 weeks' gestation, n = 562 and n = 405 respectively) and a cohort who delivered for preterm FGR (< 34 weeks). Circulating syndecan-1 was consistently reduced in women destined to deliver growth restricted infants and those delivering for preterm disease. Syndecan-1 secretion was reduced by hypoxia, and its loss impaired proliferation. Matrix metalloproteinases and mitochondrial electron transport chain inhibitors significantly reduced syndecan-1 secretion, an effect that was rescued by coadministration of succinate, a mitochondrial electron transport chain activator. In conclusion, circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses.

A Randomized, Multicenter, Open-Label, Blinded End Point, Phase 2, Feasibility, Efficacy, and Safety Trial of Preoperative Microvascular Protection in Patients Undergoing Major Abdominal Surgery.

BACKGROUND: The endothelial glycocalyx, a carbohydrate-rich layer coating all endothelial surfaces, plays a fundamental role in the function of microcirculation. The primary aim of this study was to evaluate the feasibility of using dexamethasone and albumin to protect the endothelial glycocalyx in patients undergoing abdominal surgery. Secondary and exploratory outcomes included efficacy and safety. METHODS: We conducted a multicenter, open-label, blinded end point, phase 2, randomized trial. Patients undergoing colorectal, pancreas, or liver surgery were recruited and randomized to receive either intravenous dexamethasone (16 mg) and 20% albumin (100 mL) at induction of anesthesia, then 200 mL of 20% albumin with each subsequent 1000 mL of crystalloid administered (dexamethasone and albumin [Dex-Alb] group), or crystalloid fluid only with no dexamethasone (control group). Feasibility end points included patient recruitment and retention, consent rate, and successful study drug administration. The primary efficacy end point was the measurement of plasma syndecan-1 level on postoperative day (POD) 1, and secondary end points were heparan sulfate levels and inflammatory markers measured at 4 perioperative timepoints. Safety end points included errors in administration of the intervention, hyperglycemia, occurrence of postoperative complications, and patient retention. RESULTS: Seventy-two patients were randomized. All feasibility end points were achievable. There were no statistically significant differences observed in median (interquartile range) syndecan-1 levels on POD 1 (39 ng·mL-1 [20-97] in the Dex-Alb group versus 41 ng·mL-1 [19-84] in the control group; difference in medians -2.1, 95% confidence interval [CI], -13 to 8.6; P = .69). The Dex-Alb group had lower POD 1 heparan sulfate levels (319 ng·mL-1 [161-717] in the Dex-Alb group versus 1422 [670-2430] ng·mL-1 in the control group; difference in medians -1085, 95% CI, -1779 to -391) and C-reactive protein (CRP) levels on POD 1 (48 [29-77] mg·L-1 in the Dex-Alb group versus 85 mg·L-1 [49-133] in the control group; difference in medians -48, 95% CI, -75 to -21). Fewer patients had one or more postoperative complication in the Dex-Alb group than in the control group (6 [17%] vs 18 patients [50%]; odds ratio = 0.2, 95% CI, 0.06-0.6). CONCLUSIONS: Intravenous dexamethasone and albumin administration was feasible but did not reduce syndecan-1 on POD 1 in patients undergoing abdominal surgery. Given the clinically important CIs observed between the groups for heparan sulfate, CRP, and postoperative complications, a larger trial assessing the associations between dexamethasone and albumin administration and these outcomes is warranted.

Prophylactic Norepinephrine Infusion Reduces Postoperative Complications and Hospitalization Time in Elderly Patients Undergoing Posterior Lumbar Spinal Fusion.

This single-center prospective randomized controlled trial explores the effect of prophylactic norepinephrine infusion on the incidence of complications and hospitalization time in elderly patients (60-85 years old) undergoing posterior lumbar spinal fusion. In total, 129 elderly patients were randomized into two groups: a group that received norepinephrine during general anesthesia and a control group not receiving norepinephrine. The primary outcomes were in-hospital complications and 90-day postoperative complications and hospitalization time. The results show that in-hospital complications occurred in 24 of 60 patients (40%) in the control group versus 11 of 60 patients (18.3%) in the norepinephrine group (RR, 2.182; 95% CI, 1.177-4.045; P = 0.015). Cardiac events occurred significantly more frequently in the control than in the norepinephrine group. Total number of patients experiencing complications within 90 days postoperatively was lower in the norepinephrine (11 of 60; 18.3%) than in the control group (26 of 60; 43.3%; RR, 2.364; 95% CI, 1.288-4.339; P = 0.005). The median length of hospital stay was 17 days (11-27) in the control group and 15 days (10- 23) in the norepinephrine group (P = 0.01). The secondary outcomes were serum levels of syndecan-1, hyaluronic acid, heparan sulfate, and brain natriuretic peptide. Logistic regression analysis is used to describe the relationship between selected independent variables and in-hospital complications. Intraoperative total fluid, crystalloid, and colloid volumes were significantly higher in the control than in the norepinephrine group. The patients in the norepinephrine group had a higher MAP but a lower heart rate than those in the control group after the induction of anesthesia and intraoperatively. Syndecan-1, hyaluronic acid, and heparan sulfate serum levels showed a different course in the two groups. In conclusion, prophylactic norepinephrine infusion during posterior lumbar spinal fusion is preferable for elderly patients undergoing lumbar spinal fusion under general anesthesia. It can reduce postoperative complications and hospitalization time by reducing the injury to the vascular endothelium. This trial is registered with Clinical Trial Registration http://www.chictr.org.cn/showproj.aspx?proj=33660, identifier ChiCTR-1900021309.

A possible pathogenic role of Syndecan-1 in the pathogenesis of coronavirus disease 2019 (COVID-19).

A cell-surface heparan proteoglycan called Syndecan-1 (SDC-1) has multiple roles in healthy and pathogenic conditions, including respiratory viral infection. In this study, we explore the dynamic alternation in the levels of SDC-1 in cases with COVID-19. A total of 120 cases definitely diagnosed with COVID-19 were admitted to the Firoozgar Hospital, Tehran, Iran, from December 1, 2020, to January 29, 2021, and included in our study. Also, 58 healthy subjects (HS) were chosen as the control group. Patients were classified into two groups: 1) ICU patients and (63 cases) 2) non-ICU patients (57 cases). The dynamic changes of serum SCD-1, CRP, IL-6, IL-10, IL-18, and Vit D levels a well as the disease activity were investigated in three-time points (T1-T3). Our results indicated that the COVID-19 patients had significantly increased SCD-1, CRP, IL-6, IL-10, and IL-18 levels than in HS, while the Vit D levels in COVID-19 patients were significantly lower than HS. Further analysis demonstrated that the SCD-1, CRP, IL-6, IL-10, and IL-18 levels in ICU patients were significantly higher than in non-ICU patients. Tracking dynamic changes in the above markers indicated that on the day of admission, the SCD-1, CRP, IL-6, IL-10, and IL-18 levels were gradually increased on day 5 (T2) and then gradually decreased on day 10 (T3). ROC curve analysis suggests that markers mentioned above, SDC-1, IL-6, and IL-18 are valuable indicators in evaluating the activity of COVID-19. All in all, it seems that the serum SDC-1 levels alone or combined with other markers might be a good candidate for disease activity monitoring.

Endothelial glycocalyx during early reperfusion in patients undergoing cardiac surgery.

BACKGROUND: Experimental cardiac ischemia-reperfusion injury causes degradation of the glycocalyx and coronary washout of its components syndecan-1 and heparan sulfate. Systemic elevation of syndecan-1 and heparan sulfate is well described in cardiac surgery. Still, the events during immediate reperfusion after aortic declamping are unknown both in the systemic and in the coronary circulation. METHODS: In thirty patients undergoing aortic valve replacement, arterial concentrations of syndecan-1 and heparan sulfate were measured immediately before and at one, five and ten minutes after aortic declamping (reperfusion). Parallel blood samples were drawn from the coronary sinus to calculate trans-coronary gradients (coronary sinus-artery). RESULTS: Compared with immediately before aortic declamping, arterial syndecan-1 increased by 18% [253.8 (151.6-372.0) ng/ml vs. 299.1 (172.0-713.7) ng/ml, p < 0.001] but arterial heparan sulfate decreased by 14% [148.1 (135.7-161.7) ng/ml vs. 128.0 (119.0-138.2) ng/ml, p < 0.001] at one minute after aortic declamping. There was no coronary washout of syndecan-1 or heparan sulfate during reperfusion. On the contrary, trans-coronary sequestration of syndecan-1 occurred at five [-12.96 ng/ml (-36.38-5.15), p = 0.007] and at ten minutes [-12.37 ng/ml (-31.80-6.62), p = 0.049] after reperfusion. CONCLUSIONS: Aortic declamping resulted in extracardiac syndecan-1 release and extracardiac heparan sulfate sequestration. Syndecan-1 was sequestered in the coronary circulation during early reperfusion. Glycocalyx has been shown to degrade during cardiac surgery. Besides degradation, glycocalyx has propensity for regeneration. The present results of syndecan-1 and heparan sulfate sequestration may reflect endogenous restoration of the damaged glycocalyx in open heart surgery.