The Placental Protein Syncytin-1 Impairs Antiviral Responses and Exaggerates Inflammatory Responses to Influenza

Background

Pregnancy increases susceptibility to influenza. The placenta releases an immunosuppressive endogenous retroviral protein syncytin-1. We hypothesised that exposure of peripheral monocytes (PBMCs) to syncytin-1 would impair responses to H1N1pdm09 influenza.

Methods and Findings

Recombinant syncytin-1 was produced. PBMCs from non-pregnant women (n=10) were exposed to H1N1pdm09 in the presence and absence of syncytin-1 and compared to responses of PBMCs from pregnant women (n=12). PBMCs were characterised using flow cytometry, release of interferon (IFN)-α, IFN-λ, IFN-γ, IL-10, IL-2, IL-6 and IL-1β were measured by cytometric bead array or ELISA. Exposure of PBMCs to H1N1pdm09 resulted in the release of IFN-α, (14,787 pg/mL, 95% CI 7311-22,264 pg/mL) IFN-λ (1486 pg/mL, 95% CI 756-2216 pg/mL) and IFN-γ (852 pg/mL, 95% CI 193-1511 pg/mL) after 48 hours. This was significantly impaired in pregnant women (IFN-α; p<0.0001 and IFN-λ; p<0.001). Furthermore, in the presence of syncytin-1, PBMCs demonstrated marked reductions in IFN-α and IFN-λ, while enhanced release of IL-10 as well as IL-6 and IL-1β.

Conclusions

Our data indicates that a placental derived protein, syncytin-1 may be responsible for the heightened vulnerability of pregnant women to influenza.     

Soluble α-Klotho as a Novel Biomarker in the Early Stage of Nephropathy in Patients with Type 2 Diabetes

Objective

Although α-klotho is known as an anti-aging, antioxidant, and cardio-renal protective protein, the clinical implications of soluble α-klotho levels in patients with diabetes have not been evaluated. Therefore, this study evaluated whether plasma and urinary α-klotho levels are associated with albuminuria in kidney disease in diabetes.

Research Design and Methods

A total of 147 patients with type 2 diabetes and 25 healthy control subjects were enrolled. The plasma and urine concentrations of α-klotho were analyzed by enzyme-linked immunosorbent assay.

Results

Plasma α-klotho (572.4 pg/mL [95% CI, 541.9–604.6 pg/mL] vs. 476.9 pg/mL [95% CI, 416.9–545.5 pg/mL]) and urinary α-klotho levels (59.8 pg/mg creatinine [95% CI, 43.6–82.0 pg/mg creatinine] vs. 21.0 pg/mg creatinine [95% CI, 9.7–45.6 pg/mg creatinine]) were significantly higher in diabetic patients than non-diabetic controls. Among diabetic patients, plasma α-klotho concentration was inversely associated with albuminuria stages (normoalbuminuria, 612.6 pg/mL [95% CI, 568.9–659.6 pg/mL], microalbuminuria, 551.8 pg/mL [95% CI, 500.5–608.3 pg/mL], and macroalbuminuria, 505.7 pg/mL [95% CI, 439.7–581.7 pg/mL] (p for trend  = 0.0081), while urinary α-klotho levels were remained constantly high with increasing urinary albumin excretion.

Conclusions

Soluble α-klotho levels in plasma and urine may be novel and useful early markers of diabetic renal injury.     

Serum γ-glutamyl Transferase Levels,Insulin Resistance and Liver Fibrosis in Patients with Chronic Liver Diseases

Background and Aims

Serum levels of γ-glutamyl-transpeptidase(γ-GT) were associated with liver disease severity and metabolic alterations, which in turn are able to affect hepatic damage. In patients with nonalcoholic fatty liver disease (NAFLD), genotype 1 chronic hepatitis C (G1CHC) and chronic hepatitis B (CHB), we assessed the link between liver fibrosis and γ-GT serum levels, and we evaluated if normal or high γ-GT serum levels affect the association between insulin resistance (IR) and severity of liver fibrosis.

Methods

843 consecutive patients with chronic liver disease (CLD)(193 NAFLD, 481 G1CHC, 169 CHB) were evaluated by liver biopsy (Kleiner and Scheuer scores) and clinical and metabolic measurements. IR was diagnosed if HOMA>3. A serum γ-GT concentration of >36 IU/L in females and >61 IU/L in males was considered the threshold value for identifying high levels of γ-GT.

Results

By multivariate logistic regression analysis, abnormal γ-GT serum levels were independently linked to severe liver fibrosis in patients with NAFLD (OR2.711,CI1.120–6.564,p = 0.02), G1CHC (OR3.461,CI2.138–5.603,p<0.001) and CHB (OR2.778,CI1.042–7.414,p = 0.04), together with IR and liver necroinflammation, and with a negative predictive value>80%. Interestingly, among patients with high or normal γ-GT values, even if IR prevalence was significantly higher in patients with severe fibrosis compared to those without, IR remained significantly associated with severe fibrosis in patients with abnormal γ-GT values only (OR4.150,CI1.079–15.970,p = 0.03 for NAFLD; OR2.250,CI1.211–4.181,p = 0.01 for G1CHC; OR3.096,CI2.050–34.220,p = 0.01 for CHB).

Conclusions

In patients with CLD, IR is independently linked to liver fibrosis only in patients with abnormal γ-GT values, without differences according to liver disease etiology, and suggesting a role of γ-GT as a marker of metabolic-induced liver damage. These data could be useful for the clinical and pharmacologic management of patients with CLD.     

Mechanical Ventilation Drives Inflammation in Severe Viral Bronchiolitis

Introduction

Respiratory insufficiency due to severe respiratory syncytial virus (RSV) infection is the most frequent cause of paediatric intensive care unit admission in infants during the winter season. Previous studies have shown increased levels of inflammatory mediators in airways of mechanically ventilated children compared to spontaneous breathing children with viral bronchiolitis. In this prospective observational multi-center study we aimed to investigate whether this increase was related to disease severity or caused by mechanical ventilation.

Materials and Methods

Nasopharyngeal aspirates were collected <1 hour before intubation and 24 hours later in RSV bronchiolitis patients with respiratory failure (n = 18) and non-ventilated RSV bronchiolitis controls (n = 18). Concentrations of the following cytokines were measured: interleukin (IL)-1α, IL-1β, IL-6, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α.

Results

Baseline cytokine levels were comparable between ventilated and non-ventilated infants. After 24 hours of mechanical ventilation mean cytokine levels, except for MIP-1α, were elevated compared to non-ventilated infected controls: IL-1α (159 versus 4 pg/ml, p<0.01), IL-1β (1068 versus 99 pg/ml, p<0.01), IL-6 (2343 versus 958 pg/ml, p<0.05) and MCP-1 (174 versus 26 pg/ml, p<0.05).

Conclusions

Using pre- and post-intubation observations, this study suggests that endotracheal intubation and subsequent mechanical ventilation cause a robust pulmonary inflammation in infants with RSV bronchiolitis.     

Precedent Fluctuation of Serum hs-CRP to Albumin Ratios and Mortality Risk of Clinically Stable Hemodialysis Patients

Background

A high sensitivity C-reactive protein to albumin ratio (hs-CRP/Alb) predicts mortality risk in patients with acute kidney injury. However, it varies dynamically. This study was conducted to evaluate whether a variation of this marker was associated with long-term outcome in clinically stable hemodialysis (HD) patients.

Methods

hs-CRP/Alb was checked bimonthly in 284 clinically stable HD outpatients throughout all of 2008. Based on the “slope” of trend equation derived from 5–6 hs-CRP/alb ratios for each patient, the total number of patients was divided into quartiles—Group 1: β≦ −0.13, n = 71; group 2: β>-0.13≦0.003; n = 71, group 3: β>0.003≦0.20; and group 4: β>0.20, n = 71. The observation period was from January 1, 2009 to August 31, 2012.

Results

Group 1+4 showed a worse long-term survival (p = 0.04) and a longer 5-year hospitalization stay than Group 2+3 (38.7±44.4 vs. 16.7±22.4 days, p<0.001). Group 1+4 were associated with older age (OR = 1.03, 95% CI = 1.01–1.05) and a high prevalence of congestive heart failure (OR = 2.02, 95% CI = 1.00–4.11). Standard deviation (SD) of hs-CRP/Alb was associated with male sex (β = 0.17, p = 0.003), higher Davies co-morbidity score (β = 0.16, p = 0.03), and baseline hs-CRP (β = 0.39, p<0.001). Patients with lower baseline and stable trend of hs-CRP/Alb had a better prognosis. By multivariate Cox proportional methods, SD of hs-CRP/alb (HR: 1.05, 95% CI: 1.01–1.08) rather than baseline hs-CRP/Alb was an independent predictive factor for long-term mortality after adjusting for sex and HD vintage.

Conclusion

Clinically stable HD patients with a fluctuating variation of hs-CRP/Alb are characterized by old age, and more co-morbidity, and they tend to have longer subsequent hospitalization stay and higher mortality risk.     

Modulation of Early Inflammatory Response by Different Balanced and Non-Balanced Colloids and Crystalloids in a Rodent Model of Endotoxemia

The use of hydroxyethyl starch (HES) in sepsis has been shown to increase mortality and acute kidney injury. However, the knowledge of the exact mechanism by which several fluids, especially starch preparations may impair end-organ function particularly in the kidney, is still missing. The aim of this study was to measure the influence of different crystalloid and colloid fluid compositions on the inflammatory response in the kidney, the liver and the lung using a rodent model of acute endotoxemia. Rats were anesthetized and mechanically ventilated. Lipopolysaccharide (5 mg/kg) was administered intravenously. After one hour crystalloids [lactate-buffered (RLac) or acetate-buffered (RAc)] were infused i.v. (30 ml/kg) in all groups. At 2 hours rats either received different crystalloids (75 ml/kg of RLac or RAc) or colloids (25 ml/kg of HES in saline or HES in RAc or gelatin in saline). Expression of messenger RNA for cytokine-induced neutrophil chemoattractant-1 (CINC-1), monocyte chemotactic protein-1 (MCP-1), necrosis factor α (TNFα) and intercellular adhesion molecule 1 (ICAM-1) was assessed in kidney, liver and lung tissue by real-time PCR after 4 hours. The use of acetate-buffered solutions was associated with a significantly higher expression of CINC-1 and TNFα mRNA in the liver, in the kidney and in the lung. Only marginal effects of gelatin and hydroxyethyl starch on mRNA expression of inflammatory mediators were observed. The study provides evidence that the type of buffering agent of different colloidal and crystalloid solutions might be a crucial factor determining the extent of early end-organ inflammatory response in sepsis.     

Magnetic Resonance Imaging Determined Visceral Fat Reduction Associates with Enhanced IL-10 Plasma Levels in Calorie Restricted Obese Subjects

Background

Obesity is characterized by a low grade chronic inflammation state. Indeed circulating pro-inflammatory cytokines, such as TNF-α and IL-6, are elevated in obese subjects, while anti-inflammatory cytokines, such as IL-10, appear to be reduced. Cytokines profile improves after weight loss, but how visceral or subcutaneous fat loss respectively affect pro- or anti-inflammatory cytokines plasma levels has not been precisely assessed. Therefore in the present study we correlated changes in circulating cytokine profile with quantitative changes in visceral and subcutaneous adipose tissue depots measured by an ad hoc Magnetic Resonance Imaging (MRI) protocol before and after weight loss.

Materials and Methods

In 14 obese subjects, MRI determination of visceral and subcutaneous fat and plasma glucose, insulin, TNF-α IL-6, and IL-10 measurements were performed before and after a caloric restriction induced weight loss of at least 5% of the original body weight.

Results

Weight loss improved insulin sensitivity (QUICKI Index: 0.35±0.03 vs 0.37±0.04; P<0.05), increased IL-10 (3.4±1.9 vs 4.6±1.0 pg/mL; P<0.03), and reduced TNF-α and IL-6 plasma levels (2.5±1.3 vs 1.6±1.5 pg/mL, P<0.0015, 2.3±0.4 vs 1.6±0.6 pg/mL, P<0.02 respectively). A significant correlation was observed between the amount of visceral fat loss and the percentage reduction in both TNF-α (r = 0.56, p<0.05) and IL-6 (r = 0.19 p<0.05) plasma levels. In a multiple regression analysis, the amount of visceral fat loss independently correlated with the increase in IL-10 plasma levels.

Conclusion

The reduction in visceral adipose tissue is the main driver of the improved inflammatory profile induced by weight loss.     

Relationship between Blood Myostatin Levels and Kidney Function:Shimane CoHRE Study

Objectives

Myostatin (MSTN), a member of TGF-β superfamily, is produced in the skeletal muscle to inhibit myocyte differentiation. MSTN expression is increased in the skeletal muscle in patients with chronic kidney disease (CKD), which may play a role in the pathogenesis of sarcopenia or in the protein energy wasting (PEW). This observation implies that the plasma MSTN level may be correlated with kidney function. Thus, we conducted a cross-sectional study to evaluate the association between the plasma MSTN concentration and the estimated glomerular filtration rate (eGFR).

Subjects and Methods

Subjects were 781 participants of a health examination performed in a rural area in Japan. Among them, 124 subjects were selected by stratified random sampling according to eGFR. Creatinine clearance (ClCr) by the Cockcroft-Gault equation was used as a measure of kidney function. Plasma concentration of MSTN was determined by ELISA.

Results

The plasma MSTN level was not different between men (3.42±1.61 ng/mL) and women (3.27±1.43 ng/mL). In a simple regression analysis, the MSTN level was significantly correlated with eGFR (r = -0.25, p<0.01) and ClCr (r = -0.20, p<0.05) but not with age and BMI. In a multiple linear regression analysis, the MSTN level showed a negative correlation with eGFR (standardized β = -0.31, p<0.01) and ClCr (standardized β = -0.35, p<0.01) under the adjustment with age, sex, BMI and LDL-C. Weak correlation was observed between the MSTN level and BMI / the serum LDL-C level. When the subjects were stratified into 4 groups according to eGFR, MSTN was significantly greater in the groups with the lowest and the 2^nd lowest eGFR (3.55±1.79 and 3.76±1.75 ng/mL, respectively) than the level in the group with the highest eGFR (2.77±0.85 ng/mL).

Conclusion

Plasma MSTN level was elevated in an early stage of CKD, which could be involved in the progression of sarcopenia.     

Association between Inflammation and Cardiac Geometry in Chronic Kidney Disease: Findings from the CRIC Study

Background

Left ventricular hypertrophy (LVH) and myocardial contractile dysfunction are independent predictors of mortality in patients with chronic kidney disease (CKD). The association between inflammatory biomarkers and cardiac geometry has not yet been studied in a large cohort of CKD patients with a wide range of kidney function.

Methods

Plasma levels of interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, high-sensitivity C-Reactive protein (hs-CRP), fibrinogen and serum albumin were measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Echocardiography was performed according to the recommendations of the American Society of Echocardiography and interpreted at a centralized core laboratory.

Results

LVH, systolic dysfunction and diastolic dysfunction were present in 52.3%, 11.8% and 76.3% of the study subjects, respectively. In logistic regression analysis adjusted for age, sex, race/ethnicity, diabetic status, current smoking status, systolic blood pressure, urinary albumin- creatinine ratio and estimated glomerular filtration rate, hs-CRP (OR 1.26 [95% CI 1.16, 1.37], p<0.001), IL-1RA (1.23 [1.13, 1.34], p<0.0001), IL-6 (1.25 [1.14, 1.36], p<0.001) and TNF-α (1.14 [1.04, 1.25], p = 0.004) were associated with LVH. The odds for systolic dysfunction were greater for subjects with elevated levels of hs-CRP (1.32 [1.18, 1.48], p<0.001) and IL-6 (1.34 [1.21, 1.49], p<0.001). Only hs-CRP was associated with diastolic dysfunction (1.14 [1.04, 1.26], p = 0.005).

Conclusion

In patients with CKD, elevated plasma levels of hs-CRP and IL-6 are associated with LVH and systolic dysfunction.     

Adult Non-Cystic Fibrosis Bronchiectasis Is Characterised by Airway Luminal Th17 Pathway Activation

Background

Non-cystic fibrosis (CF) bronchiectasis is characterised by chronic airway infection and neutrophilic inflammation, which we hypothesised would be associated with Th17 pathway activation.

Methods

Th17 pathway cytokines were quantified in bronchoalveolar lavage fluid (BALF), and gene expression of IL-17A, IL-1β, IL-8 and IL-23 determined from endobronchial biopsies (EBx) in 41 stable bronchiectasis subjects and 20 healthy controls. Relationships between IL-17A levels and infection status, important clinical measures and subsequent Pseudomonas aeruginosa infection were determined.

Results

BALF levels of all Th17 cytokines (median (IQR) pg/mL) were significantly higher in bronchiectasis than control subjects, including IL-17A (1.73 (1.19, 3.23) vs. 0.27 (0.24, 0.35), 95% CI 1.05 to 2.21, p<0.0001) and IL-23 (9.48 (4.79, 15.75) vs. 0.70 (0.43, 1.79), 95% CI 4.68 to 11.21, p<0.0001). However, BALF IL-17A levels were not associated with clinical measures or airway microbiology, nor predictive of subsequent P. aeruginosa infection. Furthermore, gene expression of IL-17A in bronchiectasis EBx did not differ from control. In contrast, gene expression (relative to medians of controls) in bronchiectasis EBx was significantly higher than control for IL1β (4.12 (1.24, 8.05) vs 1 (0.13, 2.95), 95% CI 0.05 to 4.07, p = 0.04) and IL-8 (3.75 (1.64, 11.27) vs 1 (0.54, 3.89), 95% CI 0.32 to 4.87, p = 0.02) and BALF IL-8 and IL-1α levels showed significant relationships with clinical measures and airway microbiology. P. aeruginosa infection was associated with increased levels of IL-8 while Haemophilus influenzae was associated with increased IL-1α.

Conclusions and Clinical Relevance

Established adult non-CF bronchiectasis is characterised by luminal Th17 pathway activation, however this pathway may be relatively less important than activation of non-antigen-specific innate neutrophilic immunity.     

Blockade of Thrombopoietin Reduces Organ Damage in Experimental Endotoxemia and Polymicrobial Sepsis

Background and Purpose

Thrombopoietin (TPO), a growth factor primarily involved in thrombopoiesis may also have a role in the pathophysiology of sepsis. In patients with sepsis, indeed, TPO levels are markedly increased, with disease severity being the major independent determinant of TPO concentrations. Moreover, TPO increases and correlates with ex vivo indices of platelet activation in patients with burn injury upon sepsis development, and may contribute to depress cardiac contractility in septic shock. Still, the role of TPO in sepsis pathophysiology remains controversial, given the protective role of TPO in other experimental disease models, for instance in doxorubicin-induced cardiotoxicity and myocardial ischemia/reperfusion injury. The aim of our study was to define the contribution of TPO in the development of organ damage induced by endotoxemia or sepsis, and to investigate the effects of inhibiting TPO in these conditions.

Methods

We synthesized a chimeric protein able to inhibit TPO, mTPOR-MBP, and studied its effect in two murine experimental models, acute endotoxemia and cecal ligation and puncture (CLP) model.

Results

In both models, TPO levels markedly increased, from 289.80±27.87 pg/mL to 465.60±45.92 pg/mL at 3 hours in the LPS model (P<0.01), and from 265.00±26.02 pg/mL to 373.70±26.20 pg/mL in the CLP model (P<0.05), respectively. Paralleling TPO levels, also platelet-monocyte aggregates increased, from 32.86±2.48% to 46.13±1.39% at 3 hours in the LPS model (P<0.01), and from 43.68±1.69% to 56.52±4.66% in the CLP model (P<0.05). Blockade of TPO by mTPOR-MBP administration reduced histological damage in target organs, namely lung, liver, and gut. In particular, neutrophil infiltration and lung septal thickening were reduced from a score of 1.86±0.34 to 0.60±0.27 (P<0.01) and from 1.43±0.37 to 0.40±0.16 (P<0.05), respectively, in the LPS model at 3 hours, and from a score of 1.75±0.37 to 0.38±0.18 (P<0.01) and from 1.25±0.31 to 0.13±0.13 (P<0.001), respectively, in the CLP model. Similarly, the number of hepatic microabscesses was decreased from 14.14±1.41 to 3.64±0.56 in the LPS model at 3 hours (P<0.001), and from 1.71±0.29 to 0.13±0.13 in the CLP model (P<0.001). Finally, the diameter of intestinal villi decreased from 90.69±3.95 μm to 70.74±3.60 μm in the LPS model at 3 hours (P<0.01), and from 74.29±4.29 μm to 57.50±1.89 μm in the CLP model (P<0.01). This protective effect was associated with the blunting of the increase in platelet-monocyte adhesion, and, on the contrary, with increased platelet-neutrophil aggregates in the circulation, which may be related to decreased neutrophil sequestration into the inflamed tissues. Conversely, circulating cytokine levels were not significantly changed, in both models, by mTPOR-MBP administration.

Conclusion

Our results demonstrate that TPO participates in the development of organ damage induced by experimental endotoxemia or polymicrobial sepsis via a mechanism involving increased platelet-leukocyte adhesion, but not cytokine release, and suggest that blocking TPO may be useful in preventing organ damage in patients affected by systemic inflammatory response or sepsis.     

Haematuria Increases Progression of Advanced Proteinuric Kidney Disease

Background

Haematuria has been traditionally considered as a benign hallmark of some glomerular diseases; however new studies show that haematuria may decrease renal function.

Objective

To determine the influence of haematuria on the rate of chronic kidney disease (CKD) progression in 71 proteinuric patients with advanced CKD (baseline eGFR <30 mL/min) during 12 months of follow-up.

Results

The mean rate of decline in eGFR was higher in patients with both haematuria and proteinuria (haemoproteinuria, HP, n=31) than in patients with proteinuria alone (P patients, n=40) (-3.8±8.9 vs 0.9±9.5 mL/min/1.73m2/year, p<0.05, respectively). The deleterious effect of haematuria on rate of decline in eGFR was observed in patients <65 years (-6.8±9.9 (HP) vs. 0.1±11.7 (P) mL/min/1.73m2/year, p<0.05), but not in patients >65 years (-1.2±6.8 (HP) vs. 1.5±7.7 (P) mL/min/1.73m2/year). Furthermore, the harmful effect of haematuria on eGFR slope was found patients with proteinuria >0.5 g/24 h (-5.8±6.4 (HP) vs. -1.37± 7.9 (P) mL/min/1.73m2/year, p<0.05), whereas no significant differences were found in patients with proteinuria < 0.5 g/24 h (-0.62±7.4 (HP) vs. 3.4±11.1 (P) mL/min/1.73m2/year). Multivariate analysis reported that presence of haematuria was significantly and independently associated with eGFR deterioration after adjusting for traditional risk factors, including age, serum phosphate, mean proteinuria and mean serum PTH (β=-4.316, p=0.025).

Conclusions

The presence of haematuria is closely associated with a faster decrease in renal function in advanced proteinuric CKD patients, especially in younger CKD patients with high proteinuria levels; therefore this high risk subgroup of patients would benefit of intensive medical surveillance and treatment.     

Chronic Medical Conditions and Risk of Sepsis

Background

We sought to determine the associations between baseline chronic medical conditions and future risk of sepsis.

Methods

Longitudinal cohort study using the 30,239 community-dwelling participants of the REGARDS cohort. We determined associations between baseline chronic medical conditions and incident sepsis episodes, defined as hospitalization for an infection with the presence of infection plus two or more systemic inflammatory response syndrome criteria.

Results

Over the mean observation time of 4.6 years (February 5, 2003 through October 14, 2011), there were 975 incident cases of sepsis. Incident sepsis episodes were associated with older age (p<0.001), white race (HR 1.39; 95% CI: 1.22–1.59), lower education (p<0.001) and income (p<0.001), tobacco use (p<0.001), and alcohol use (p = 0.02). Incident sepsis episodes were associated with baseline chronic lung disease (adjusted HR 2.43; 95% CI: 2.05–2.86), peripheral artery disease (2.16; 1.58–2.95), chronic kidney disease (1.99; 1.73–2.29), myocardial infarction 1.79 (1.49–2.15), diabetes 1.78 (1.53–2.07), stroke 1.67 (1.34–2.07), deep vein thrombosis 1.63 (1.29–2.06), coronary artery disease 1.61 (1.38–1.87), hypertension 1.49 (1.29–1.74), atrial fibrillation 1.48 (1.21–1.81) and dyslipidemia 1.16 (1.01–1.34). Sepsis risk increased with the number of chronic medical conditions (p<0.001).

Conclusions

Individuals with chronic medical conditions are at increased risk of future sepsis events.     

Early Vascular Aging in Young and Middle-Aged Ischemic Stroke Patients: The Norwegian Stroke in the Young Study

Background

Ischemic stroke survivors have high risk of cardiovascular morbidity and mortality even at young age, suggesting that early arterial aging is common among such patients.

Methods

We measured aortic stiffness by carotid-femoral pulse wave velocity (PWV) in 205 patients (69% men) aged 15–60 years with acute ischemic stroke in the prospective Norwegian Stroke in the Young Study. High for age carotid-femoral PWV was identified in the reference normogram.

Results

Patients were on average 49±10 years old, 34% had a history of hypertension and 37% had metabolic syndrome (MetS). In the total study population, higher PWV was associated with history of hypertension (β = 0.18), higher age (β = 0.34), systolic blood pressure (BP) (β = 0.28) and serum creatinine (β = 0.18) and lower high-density lipoprotein (HDL) cholesterol (β = –0.10, all p<0.01) in multivariate linear regression analysis (multiple R² = 0.42, p<0.001). High for age PWV was found in 18% of patients. In univariate analyses, known hypertension was associated with a 6-fold, MetS with a 4-fold and presence of carotid plaque with a 3.7-fold higher risk for high for age PWV (all p<0.01). In multiple logistic regression analysis higher systolic BP (odds ratio [OR] 1.04; 95% confidence interval [CI] 1.02–1.06; p<0.01), history of hypertension (OR 3.59; 95% CI 1.52–8.51; p<0.01), low HDL cholesterol (OR 3.03; 95% CI 1.00–9.09; p = 0.05) and higher serum creatinine (OR 1.04; 95% CI 1.01–1.06; p<0.01) were associated with high for age PWV.

Conclusions

Higher PWV is common in younger and middle-aged ischemic stroke patients and associated with a clustering of classical cardiovascular risk factors.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01597453","term_id":"NCT01597453"}}NCT01597453     

Obstructive Sleep Apnoea Syndrome,Endothelial Function and Markers of Endothelialization. Changes after CPAP

Study objectives

This study tries to assess the endothelial function in vivo using flow-mediated dilatation (FMD) and several biomarkers of endothelium formation/restoration and damage in patients with obstructive sleep apnoea (OSA) syndrome at baseline and after three months with CPAP therapy.

Design

Observational study, before and after CPAP therapy.

Setting and Patients

We studied 30 patients with apnoea/hypopnoea index (AHI) >15/h that were compared with themselves after three months of CPAP therapy. FMD was assessed non-invasively in vivo using the Laser-Doppler flowmetry. Circulating cell-free DNA (cf-DNA) and microparticles (MPs) were measured as markers of endothelial damage and the vascular endothelial growth factor (VEGF) was determined as a marker of endothelial restoration process.

Measurements and results

After three month with CPAP, FMD significantly increased (1072.26 ± 483.21 vs. 1604.38 ± 915.69 PU, p< 0.005) cf-DNA and MPs significantly decreased (187.93 ± 115.81 vs. 121.28 ± 78.98 pg/ml, p<0.01, and 69.60 ± 62.60 vs. 39.82 ± 22.14 U/μL, p<0.05, respectively) and VEGF levels increased (585.02 ± 246.06 vs. 641.11 ± 212.69 pg/ml, p<0.05). These changes were higher in patients with more severe disease. There was a relationship between markers of damage (r = -0.53, p<0.005) but not between markers of damage and restoration, thus suggesting that both types of markers should be measured together.

Conclusions

CPAP therapy improves FMD. This improvement may be related to an increase of endothelial restoration process and a decrease of endothelial damage.     

Placenta Growth Factor in Eyes with Neovascular Glaucoma Is Decreased after Intravitreal Ranibizumab Injection

Purpose

To evaluate changes in the concentrations of placental growth factor (PlGF) and vascular endothelial growth factor-A (VEGF-A) in aqueous humor of patients with neovascular glaucoma (NVG) before and after an intravitreal injection of ranibizumab (IVR) and to determine the underlying correlation between the levels.

Methods

The prospective interventional comparative study involved 20 eyes of 20 patients with surgery-required advanced NVG and 20 control subjects from January 2013 to November 2013. The NVG eyes received the IVR treatment before glaucoma surgery. Aqueous humor was collected at the time of the IVR injection (pre- IVR) and at the time of antiglaucomatous surgery (post-IVR). Aqueous humor was also collected at the time of cataract surgery in normal control. Aqueous humor and plasma VEGF-A and PlGF levels were measured with an enzyme-linked immunosorbent assay methods, respectively.

Results

The mean aqueous humor PlGF and VEGF-A concentrations in the pre-IVR eyes were significantly higher than in those of the control subjects (p<0.001), whereas the plasma levels showed no significant difference. There was a statistically significant correlation between the aqueous humor PlGF and the VEGF-A concentration (r = 0.612, p = 0.003). The mean aqueous humor PlGF in the post-IVR eyes dramatically decreased from 1078.36 ± 755.83 to 177.64 ± 151.73 pg/mL (p<0.001). The VEGF-A level showed a similar trend from 3697.64 ± 2104.47 pg/mL to 183.54 ± 130.35 pg/mL (p<0.001).

Conclusions

Aqueous humor concentrations of VEGF-A and PlGF were significantly elevated in the eyes with NVG, and there was a positive correlation between the levels. After an IVR treatment, VEGF-A and PlGF were significantly decreased in NVG eyes.     

Identifying Adult Dengue Patients at Low Risk for Clinically Significant Bleeding

Background

Clinically significant bleeding is important for subsequent optimal case management in dengue patients, but most studies have focused on dengue severity as an outcome. Our study objective was to identify differences in admission parameters between patients who developed clinically significant bleeding and those that did not. We sought to develop a model for discriminating between these patients.

Methods

We conducted a retrospective study of 4,383 adults aged >18 years who were hospitalized with dengue infection at Tan Tock Seng Hospital, Singapore from 2005 to 2008. Patients were divided into those with clinically significant bleeding (n = 188), and those without (n = 4,195). Demographic, clinical, and laboratory variables on admission were compared between groups to determine factors associated with clinically significant bleeding during hospitalization.

Results

On admission, female gender (p<0.001); temperature >38°C (p<0.001); nausea/vomiting (p = 0.009) and abdominal pain/tenderness (p = 0.005); lower systolic blood pressure (p<0.001); higher pulse rate (p<0.001); increased absolute neutrophil count (ANC; p<0.001); reduced absolute lymphocyte count (ALC; p<0.001), haematocrit percentage (p<0.001) and platelet count (p = 0.04), and increased prothrombin time (p = 0.003) were significantly associated with clinically significant bleeding on univariate analysis. Multivariate analysis showed that independent variables in the final model were female gender (aOR 2.85; 95% CI: 1.9–4.33); temperature >38°C (aOR 1.81; 95% CI: 1.27–2.61), nausea/vomiting (aOR 1.39; 95% CI: 0.94–2.12), ANC (aOR 1.3; 95% CI: 1.15–1.46), ALC (aOR 0.4; 95% CI: 0.25–0.64), hematocrit percentage (aOR 0.96; 95% CI: 0.92–1.002) and platelet count (aOR 0.993; 95% CI: 0.988–0.998). At the cutoff of -3.919, the model achieved an AUC of 0.758 (sensitivity:0.87, specificity: 0.38, PPV: 0.06, NPV: 0.98).

Conclusion

Clinical risk factors associated with clinically significant bleeding were identified. This model may be useful to complement clinical judgement in triaging adult dengue patients given the dynamic nature of acute dengue, particularly in pre-identifying those less likely to develop clinically significant bleeding.     

Pentraxin 3 (PTX3) Is Associated with Severe Sepsis and Fatal Disease in Emergency Room Patients with Suspected Infection: A Prospective Cohort Study

Background

Early diagnostic and prognostic stratification of patients with suspected infection is a difficult clinical challenge. We studied plasma pentraxin 3 (PTX3) upon admission to the emergency department in patients with suspected infection.

Methods

The study comprised 537 emergency room patients with suspected infection: 59 with no systemic inflammatory response syndrome (SIRS) and without bacterial infection (group 1), 67 with bacterial infection without SIRS (group 2), 54 with SIRS without bacterial infection (group 3), 308 with sepsis (SIRS and bacterial infection) without organ failure (group 4) and 49 with severe sepsis (group 5). Plasma PTX3 was measured on admission using a commercial solid-phase enzyme-linked immunosorbent assay (ELISA).

Results

The median PTX3 levels in groups 1–5 were 2.6 ng/ml, 4.4 ng/ml, 5.0 ng/ml, 6.1 ng/ml and 16.7 ng/ml, respectively (p<0.001). The median PTX3 concentration was higher in severe sepsis patients compared to others (16.7 vs. 4.9 ng/ml, p<0.001) and in non-survivors (day 28 case fatality) compared to survivors (14.1 vs. 5.1 ng/ml, p<0.001). A high PTX3 level predicted the need for ICU stay (p<0.001) and hypotension (p<0.001). AUC^ROC in the prediction of severe sepsis was 0.73 (95% CI 0.66–0.81, p<0.001) and 0.69 in case fatality (95% CI 0.58–0.79, p<0.001). PTX3 at a cut-off level for 14.1 ng/ml (optimal cut-off value for severe sepsis) showed 63% sensitivity and 80% specificity. At a cut-off level 7.7 ng/ml (optimal cut-off value for case fatality) showed 70% sensitivity and 63% specificity in predicting case fatality on day 28.In multivariate models, high PTX3 remained an independent predictor of severe sepsis and case fatality after adjusting for potential confounders.

Conclusions

A high PTX3 level on hospital admission predicts severe sepsis and case fatality in patients with suspected infection.     

Serum Trimethylamine-N-Oxide Is Strongly Related to Renal Function and Predicts Outcome in Chronic Kidney Disease

Background

The microbial metabolite Trimethylamine-N-oxide (TMAO) has been linked to adverse cardiovascular outcome and mortality in the general population.

Objective

To assess the contribution of TMAO to inflammation and mortality in chronic kidney disease (CKD) patients ranging from mild-moderate to end-stage disease and 1) associations with glomerular filtration rate (GFR) 2) effect of dialysis and renal transplantation (Rtx) 3) association with inflammatory biomarkers and 4) its predictive value for all-cause mortality.

Methods

Levels of metabolites were quantified by a novel liquid chromatography/tandem mass spectrometry-based method in fasting plasma samples from 80 controls and 179 CKD 3–5 patients. Comorbidities, nutritional status, biomarkers of inflammation and GFR were assessed.

Results

GFR was the dominant variable affecting TMAO (β = -0.41; p<0.001), choline (β = -0.38; p<0.001), and betaine (β = 0.45; p<0.001) levels. A longitudinal study of 74 CKD 5 patients starting renal replacement therapy demonstrated that whereas dialysis treatment did not affect TMAO, Rtx reduced levels of TMAO to that of controls (p<0.001). Following Rtx choline and betaine levels continued to increase. In CKD 3–5, TMAO levels were associated with IL-6 (Rho = 0.42; p<0.0001), fibrinogen (Rho = 0.43; p<0.0001) and hsCRP (Rho = 0.17; p = 0.022). Higher TMAO levels were associated with an increased risk for all-cause mortality that remained significant after multivariate adjustment (HR 4.32, 95% CI 1.32–14.2; p = 0.016).

Conclusion

Elevated TMAO levels are strongly associated with degree of renal function in CKD and normalize after renal transplantation. TMAO levels correlates with increased systemic inflammation and is an independent predictor of mortality in CKD 3–5 patients.