Circulating lncRNA IFNG‐AS1 expression correlates with increased disease risk,higher disease severity and elevated inflammation in patients with coronary artery disease

Background

This study aimed to investigate the associations of circulating long, non‐coding (lncRNA) IFNG‐AS1, lncRNA ANRIL and lncRNA ITSN1 relative expressions with disease risk, severity and inflammatory cytokines levels in coronary artery disease (CAD) patients.

Methods

One hundred and ninety‐one patients suspected of CAD who underwent coronary angiography were consecutively enrolled in this casecontrol study, and divided into CAD patients (N = 102) and controls (N = 89) according to coronary angiographic results. Blood samples of all participants were collected. Plasma lncRNA IFNG‐AS1, lncRNA ANRIL and lncRNA ITSN1 expressions were detected using quantitative polymerase chain reaction (qPCR). Serum tumor necrosis factor‐α (TNF‐α), interleukin (IL)‐1β (IL‐1β), IL‐6, IL‐8, IL‐10, and IL‐17 were assessed using enzyme‐linked immunosorbent assay (ELISA). Gensini Score was used to evaluate the disease severity of CAD patients.

Results

LncRNA IFNG‐AS1 relative expression in CAD patients was upregulated compared with that in controls (P < .001), and the receiver operating characteristic (ROC) curve showed that the area under curve (AUC) of lncRNA‐IFNG‐AS1 for predicting the risk of CAD was 0.755 (95% CI: 0.688‐0.821). lncRNA IFNG‐AS1 relative expression was remarkably associated with Gensini Score (r = .259, P = .009). Additionally, lncRNA IFNG‐AS1 relative expression was positively associated with high‐sensitivity C‐reactive protein (hs‐CRP) (r = .283, P = .004), TNF‐α (r = .269, P = .006), and IL‐6 levels (r = .425, P < .001), while it was negatively correlated with IL‐10 level (r = −.263, P = .008). lncRNA ANRIL or lncRNA ITSN1 was not correlated with CA D risk, Gensini Score, hs‐CRP, ESR, TNF‐α, IL‐1β, IL‐6, IL‐8, IL‐10, or IL‐17 levels (all P > .05).

Conclusion

Circulating lncRNA IFNG‐AS1 expression correlates with increased disease risk, higher disease severity and elevated inflammation in CAD patients.

     

Genetic analysis of interleukin 18 gene polymorphisms in alopecia areata

Background

Alopecia areata (AA), which appears as nonscarring hair shedding on any hair‐bearing area, is a common organ‐specific autoimmune condition. Cytokines have important roles in the development of AA. Interleukin (IL) 18 is a significant proinflammatory cytokine that was found higher in the patients with AA. We aimed to investigate whether the IL‐18 (rs187238 and rs1946518) single nucleotide polymorphisms (SNPs) may be associated with AA and/or clinical outcome of patients with AA in Turkish population.

Methods

Genotyping of rs187238 and rs1946518 SNPs were detected using sequence‐specific primer‐polymerase chain reaction (SSP‐PCR) method in 200 patients with AA and 200 control subjects.

Results

The genotype distribution of rs1946518 (−607C>A) SNP was found to be statistically significantly different among patients with AA and controls (P = .0008). Distribution of CC+CA genotypes and frequency of −607/allele C of rs1946518 SNP were higher in patients with AA (P = .001, P = .001, respectively). The genotype distribution of rs187238 (−137G>C) SNP was found to be statistically significantly different among patients with AA and control subjects (P = .0014). Distribution of GG genotype and frequency of −137/allele G of rs187238 SNP were higher in patients with AA (P = .0003, P = .001, respectively).

Conclusion

The rs1946518 (−607C>A) and rs187238 (−137G>C) polymorphisms were found associated with alopecia areata disease. The study suggests that IL‐18 rs187238 and rs1946518 SNPs may be the cause of the AA susceptibility.

     

Plasma CXCL1 levels and TRAF3IP2 variants in patients with myocardial infarction

Background

IL‐17A plays an important role in inflammatory responses in myocardial infarction (MI). IL‐17A signals through its receptor, for which, Act1 (TRAF3IP2) functions as a key upstream adaptor in the pathway.

Aim

To compare frequencies of functional polymorphisms of TRAF3IP2 (rs13210247, rs33980500) between patients with MI and healthy controls.

Methods

The selected SNPs were studied in 201 Iranian MI patients and 201 healthy blood donors from Fars Province by PCR‐RFLP in association with clinicopathologic criteria of patients. CXCL1 plasma levels in 126 MI patients and 50 normal subjects were measured by ELISA.

Results

A significant increase in the mutant (T) allele of TRAF3IP2 rs33980500 in patients with diastolic dysfunction of the heart (P = .01) was observed. The highest correlation, however, was observed between the TRAF3IP2 rs33980500 TT genotype and T allele with left main coronary artery stenosis (P = .01, P < .001; OR = 31.03). T allele of TRAF3IP2 rs33980500 was also associated with female gender, family history of cardiovascular disease, and mechanical complications of heart (P = .04, P = .02, and P = .01, respectively). Moreover, TRAF3IP2 rs13210247 (G) correlated with mechanical complications of the heart (P = .01). A significant increase in the plasma levels of CXCL1 chemokine in patients (P = .0006) associated with TT genotype of TRAF3IP2 (rs33980500) was observed (P = .04).

Conclusion

The gene variants of Act1 adaptor are associated with correlates of poor outcome in patients with MI and plasma CXCL1 levels.

     

Variants in the Toll-interacting protein gene are associated with susceptibility to sepsis in the Chinese Han population

Introduction  

Deregulated or excessive host immune responses contribute to the pathogenesis of sepsis. Toll-like receptor (TLR) signaling pathways and their negative regulators play a pivotal role in the modulation of host immune responses and the development of sepsis. The objective of this study was to investigate the association of variants in the TLR signaling pathway genes and their negative regulator genes with susceptibility to sepsis in the Chinese Han population.     

The correlation between SNPs within the gene of adrenergic receptor and neuropeptide Y and risk of cervical vertigo

Background

The current investigation was aimed to explore the potential associations of SNPs within ADRB2, ADRB1, NPY, and ADRA1A with risk and prognosis of cervical vertigo.

Methods

Altogether 216 patients with cervical vertigo and 204 healthy controls were gathered, and their DNAs were extracted utilizing the whole‐blood DNA extraction kit. Besides, the PCR reactions were conducted using the TaqMan^R single nucleotide polymorphism (SNP) genotyping assays, and the SNPs were detected on the 7900HT real‐time fluorogenic quantitative polymerase chain reaction (PCR) instrument. Finally, the severity of cervical vertigo was classified according to the JOA scoring, and the recovery rate (RR) of cervical vertigo was calculated in light of the formula as:

Results

The SNPs within ADRA1A [rs1048101 (T>C) and rs3802241 (C>T)], NPY [rs16476 (A>C), rs16148 (T>C), and rs5574 (C>T)], ADRB1 [rs28365031 (A>G)] and ADRB2 [rs2053044 (A>G)] were all significantly associated with regulated risk of cervical vertigo (all P < .05). Haplotypes of ADRA1A [CT and TC] and NPY [CCT and ATT] were also suggested as the susceptible factors of cervical vertigo in comparison with other haplotypes. Furthermore, the SNPs within ADRA1A [rs1048101 (T>C)], NPY [rs16476 (A>C), rs16148 (T>C)], as well as ADRB1 [rs28365031 (A>G)] all appeared to predict the prognosis of cervical vertigo in a relatively accurate way (all P < .05). Ultimately, the haplotypes of ADRA1A (CC) and NPY (CCT) tended to decrease the RR.

Conclusions

The SNPs within ADRB2, ADRB1, NPY, and ADRA1A might act as the diagnostic biomarkers and treatment targets for cervical vertigo.

     

Enteral nutrition with eicosapentaenoic acid, γ-linolenic acid and antioxidants in the early treatment of sepsis: results from a multicenter, prospective, randomized, double-blinded, controlled study: the INTERSEPT study

Introduction  

Enteral nutrition (EN) with eicosapentaenoic acid (EPA)/γ-linolenic acid (GLA) is recommended for mechanically ventilated patients with severe lung injury. EPA/GLA has anti-inflammatory benefits, as evidenced by its association with reduction in pulmonary inflammation, improvement in oxygenation and improved clinical outcomes in patients with severe forms of acute lung injury. This study was a prospective, multicenter, randomized, double-blinded, controlled trial designed to investigate whether EPA/GLA could have an effective role in the treatment of patients with early sepsis (systemic inflammatory response syndrome with confirmed or presumed infection and without any organ dysfunction) by reducing the progression of the disease to severe sepsis (sepsis associated with at least one organ failure) or septic shock (sepsis associated with hypotension despite adequate fluid resuscitation). Secondary outcomes included the development of individual organ failure, increased ICU and hospital length of stay, need for mechanical ventilation and 28-day all-cause mortality.     

Discriminative value of inflammatory biomarkers for suspected sepsis

Background

Circulating biomarkers can facilitate sepsis diagnosis, enabling early management and improved outcomes. Procalcitonin (PCT) has been suggested to have superior diagnostic utility compared to other biomarkers.

Study Objectives

To define the discriminative value of PCT, interleukin-6 (IL-6), and C-reactive protein (CRP) for suspected sepsis.

Methods

PCT, CRP, and IL-6 were correlated with infection likelihood, sepsis severity, and septicemia. Multivariable models were constructed for length-of-stay and discharge to a higher level of care.

Results

Of 336 enrolled subjects, 60% had definite infection, 13% possible infection, and 27% no infection. Of those with infection, 202 presented with sepsis, 28 with severe sepsis, and 17 with septic shock. Overall, 21% of subjects were septicemic. PCT, IL6, and CRP levels were higher in septicemia (median PCT 2.3 vs. 0.2 ng/mL; IL-6 178 vs. 72 pg/mL; CRP 106 vs. 62 mg/dL; p < 0.001). Biomarker concentrations increased with likelihood of infection and sepsis severity. Using receiver operating characteristic analysis, PCT best predicted septicemia (0.78 vs. IL-6 0.70 and CRP 0.67), but CRP better identified clinical infection (0.75 vs. PCT 0.71 and IL-6 0.69). A PCT cutoff of 0.5 ng/mL had 72.6% sensitivity and 69.5% specificity for bacteremia, as well as 40.7% sensitivity and 87.2% specificity for diagnosing infection. A combined clinical-biomarker model revealed that CRP was marginally associated with length of stay (p = 0.015), but no biomarker independently predicted discharge to a higher level of care.

Conclusions

In adult emergency department patients with suspected sepsis, PCT, IL-6, and CRP highly correlate with several infection parameters, but are inadequately discriminating to be used independently as diagnostic tools.     

Cytokine responses,microbial aetiology and short‐term outcome in community‐acquired pneumonia

Background

The inflammatory response to community‐acquired pneumonia (CAP) is orchestrated through activation of cytokine networks and the complement system. We examined the association of multiple cytokines and the terminal complement complex (TCC) with microbial aetiology, disease severity and short‐term outcome.

Materials and methods

Plasma levels of 27 cytokines and TCC were analysed in blood samples obtained at hospital admission, clinical stabilization and 6‐week follow‐up from 247 hospitalized adults with CAP. Fourteen mediators were included in final analyses. Adverse short‐term outcome was defined as intensive care unit (ICU) admission and 30‐day mortality.

Results

Cytokine and TCC levels were dynamic in the clinical course of CAP, with highest levels seen at admission for most mediators. Admission levels of cytokines and TCC did not differ between groups of microbial aetiology. High admission levels of IL‐6 (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.18‐1.84, P = .001), IL‐8 (OR 1.79, 95% CI 1.26‐2.55, P = .001) and MIP‐1β (OR 2.28, 95% CI 1.36‐3.81, P = .002) were associated with a CURB‐65 severity score of ≥3, while IL‐6 (OR 1.37, 95% CI 1.07‐1.74, P = .011) and MIP‐1β (OR 1.86, 95% CI 1.03‐3.36, P = .040) were associated with a high risk of an adverse short‐term outcome.

Conclusions

In this CAP cohort, admission levels of IL‐6, IL‐8 and MIP‐1β were associated with disease severity and/or adverse short‐term outcome. Still, for most mediators, only nonsignificant variations in inflammatory responses were observed for groups of microbial aetiology, disease severity and short‐term outcome.     

A comparison of high-mobility group-box 1 protein,lipopolysaccharide-binding protein and procalcitonin in severe community-acquired infections and bacteraemia: a prospective study

Introduction  

High-mobility group box-1 protein (HMGB1) has been known as a chromosomal protein for many years. HMGB1 has recently been shown to be a proinflammatory cytokine with a role in the immunopathogenesis of sepsis. Lipopolysaccharide-binding protein (LBP) has a central role in the innate immune response when the host is challenged by bacterial pathogens. Procalcitonin (PCT) has been suggested as a marker of severe bacterial infections and sepsis. The aim of the present study was to investigate levels of HMGB1, LBP and PCT in a well-characterised sepsis cohort. The study plan included analysis of the levels of the inflammatory markers in relation to the severity of infection, to the prognosis and to the ability to identify patients with bacteraemia.     

The change and effect of endothelial progenitor cells in pig with multiple organ dysfunction syndromes

Introduction  

The dysfunction and decrease of endothelial progenitor cells (EPCs) may play a very important role in the initiation of organ dysfunction caused by trauma or severe sepsis. We aim to measure the number and function of EPCs in the progression of multiple organ dysfunction syndromes (MODS) caused by severe sepsis, which may help to understand the pathogenesis of MODS by the changing of EPCs.     

A placebo-controlled,double-blind,dose-escalation study to assess the safety,tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock

Introduction  

Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters.     

Challenges in assessing the burden of sepsis and understanding the inequalities of sepsis outcomes between National Health Systems: secular trends in sepsis and infection incidence and mortality in Germany

Purpose

Sepsis contributes considerably to global morbidity and mortality, while reasons for its increasing incidence remain unclear. We assessed risk adjusted secular trends in sepsis and infection epidemiology in Germany.

Methods

Retrospective cohort study using nationwide German hospital discharge data. We assessed incidence, outcomes and trends of hospital-treated sepsis and infections between 2010 and 2015. Sepsis was identified by explicit ICD-10 sepsis codes. As sensitivity analysis, results were compared with sepsis cases identified by implicit sepsis coding (combined infection and organ dysfunction codes).

Results

Among 18 664 877 hospital admissions in 2015, 4 213 116 (22.6%) patients had at least one infection code. There were 320 198 patients that had explicit sepsis codes including 136 542 patients with severe sepsis and septic shock; 183 656 patients were coded as sepsis without organ dysfunction. For patients with explicitly coded sepsis (including severe sepsis), or with severe sepsis alone, mortality rates over the period 2010–2015 decreased from 26.6 to 23.5%, and from 47.8 to 41.7%, respectively.

Conclusions

Sepsis and infection remain significant causes of hospital admission and death in Germany. Sepsis-related mortality is higher and has declined to a lesser degree than in other high-income countries. Although infection rates steadily increased, the observed annual increase of sepsis cases seems to result, to a considerable degree, from improved coding of sepsis.

     

Evaluation of vitamin D receptor gene polymorphisms (Fok‐I and Bsm‐I) in T1DM Saudi children

Background

Vitamin D deficiency conferred strongest susceptibility to pathogenesis of type 1 diabetes mellitus (T1DM). Altered gene expression and function have strong effect on VDR gene polymorphism.

Objectives

We aimed to check for the association of two single nucleotide polymorphisms (SNPs) in VDR gene (Fok‐I and Bsm‐I) with T1DM in Saudi children.

Subjects and Methods

Cross‐sectional study included 100 T1DM Saudi children, plus 102 unrelated healthy subjects. PCR technique was used for detection of Fok‐I and Bsm‐I SNPs in VDR gene.

Results

Regarding the Fok‐I polymorphisms, T1DM cases showed a significant increased frequency of the heterozygous genotype (Ff) than controls (33% vs 21%, OR = 1.9, 95% CI = 1.006‐3.587, P = .04). In the meantime, they showed significantly lower frequency of the homozygous (ff) genotype (64% vs 79%, OR = 0.51, 95% CI = 0.28‐0.96, P = .03). Cases showed also a significantly lower frequency of the (f) allele than controls (80.5% vs 87.7%, OR = 0.57, 95% CI = 0.33‐0.995, P = .04). On the other hand, cases showed significantly higher frequency of the Bsm‐I homozygous (bb) and heterozygous (Bb) genotypes (25% vs 11.8%, P = .01, OR = 2.5, 95% CI = 1.18‐5.31) & (45% vs 27.5%, P = .0, OR = 2.1, 95 % CI = 1.20‐3.89, respectively). Cases showed also significantly higher frequency of (b) allele compared to control (47.5% vs 25.5%, P = .0, OR = 2.6, 95% CI = 1.74‐4.02). Haplotype analysis showed an increased risk with the fB and fb haplotypes.

Conclusion

This study emphasizes a positive association between SNPs (Fok‐I and Bsm‐I) and T1DM among Saudi children with increased risk with the Fok‐I F and Bsm‐I b alleles.

     

The influence of <Emphasis Type="Italic">N</Emphasis>-acetyl-L-cystein infusion on cytokine levels and gastric intramucosal pH during severe sepsis

Introduction  

The purpose of the present study was to evaluate the effects of continuously infused N-acetyl-L-cystein (NAC) on serum cytokine levels and gastric intramucosal pH in humans suffering from severe sepsis.     

Impact of invasive fungal infection on outcomes of severe sepsis: a multicenter matched cohort study in critically ill surgical patients

Introduction

Fungal infection is increasingly common in critical illness with severe sepsis, but the influence of invasive fungal infection (IFI) on severe sepsis is not well understood. The aim of this study was to investigate the impact that IFI has on the outcomes of critically ill surgical patients with severe sepsis in China by means of matched cohort analysis; we also evaluated the epidemiologic characteristics of IFI in this population.

Methods

Records for all admissions to 10 university hospital surgical intensive care units (ICUs) from December 2004 to November 2005 were reviewed. Patients who met criteria for severe sepsis were included. IFI was identified using established criteria based on microbiologic or histological evidence. A matched cohort study was conducted to analyze the relationship between IFI and outcomes of severe sepsis.

Results

A total of 318 patients with severe sepsis were enrolled during the study period, of whom 90 (28.3%) were identified as having IFI. A total of 100 strains of fungi (58% Candida albicans) were isolated from these patients. Independent risk factors for IFI in patients with severe sepsis included mechanical ventilation (>3 days), Acute Physiology and Chronic Health Evaluation score, coexisting infection with both Gram-positive and Gram-negative bacteria, and urethral catheterization (>3 days). Compared with the control cohort, IFI was associated with increased hospital mortality (P < 0.001), high hospital costs (P = 0.038), and prolonged stay in the ICU (P < 0.001) and hospital (P = 0.020).

Conclusion

IFI is frequent in patients with severe sepsis in surgical ICUs and is associated with excess risk for hospital mortality, longer ICU and hospital stays, and greater consumption of medical resources.     

Interleukin 1B rs16944 G > A polymorphism was associated with a decreased risk of esophageal cancer in a Chinese population

Objective

Esophageal cancer is the sixth leading cause of cancer-associated deaths worldwide and represents a particularly aggressive type of cancer. Genetic polymorphisms may partly explain individual differences in esophageal cancer susceptibility.

Designs and methods

We conducted a hospital-based case–control study to evaluate the genetic effects of functional single nucleotide polymorphisms (SNPs) in the interleukin 1 (IL1A and IL1B), IL1f7, IL3 and IL7Ra genes on the development of esophageal cancer. A total of 380 esophageal squamous cell carcinoma (ESCC) cases and 380 controls were recruited for this study. The genotypes were determined using a custom-by-design 48-Plex SNPscan™ Kit.

Results

When the IL1B rs16944 GG homozygote genotype was used as the reference group, the GA genotype was associated with a significantly decreased risk of ESCC (GA vs. GG: adjusted OR = 0.69, 95% CI = 0.49–0.99, p = 0.041). However, there were no significant associations between the other five SNPs and ESCC risk. Stratified analyses indicated no significantly different risks of ESCC associated with the IL1B rs16944 G > A polymorphism according to sex, age, smoking status or alcohol consumption. IL3 rs2073506 G > A polymorphism was associated with an increased risk for ESCC higher tumor, nodal, and metastatic (TNM) stages.

Conclusions

These findings indicated that the functional IL1B rs16944 G > A polymorphism might contribute to ESCC susceptibility. IL3 rs2073506 G > A polymorphism was associated with an increased risk for ESCC higher TNM stages. However, the results were based on a limited sample size and larger well-designed studies are warranted to confirm these initial findings.     

4G/5G polymorphism of <Emphasis Type="Italic">PAI-1</Emphasis> gene is associated with multiple organ dysfunction and septic shock in pneumonia induced severe sepsis: prospective,observational, genetic study

Introduction  

Activation of inflammation and coagulation are closely related and mutually interdependent in sepsis. The acute-phase protein, plasminogen activator inhibitor-1 (PAI-1) is a key element in the inhibition of fibrinolysis. Elevated levels of PAI-1 have been related to worse outcome in pneumonia. We aimed to evaluate the effect of functionally relevant 4G/5G polymorphism of PAI-1 gene in pneumonia induced sepsis.     

Early alterations of the innate and adaptive immune statuses in sepsis according to the type of underlying infection

Introduction

Although major changes of the immune system have been described in sepsis, it has never been studied whether these may differ in relation to the type of underlying infection or not. This was studied for the first time.

Methods

The statuses of the innate and adaptive immune systems were prospectively compared in 505 patients. Whole blood was sampled within less than 24 hours of advent of sepsis; white blood cells were stained with monoclonal antibodies and analyzed though a flow cytometer.

Results

Expression of HLA-DR was significantly decreased among patients with severe sepsis/shock due to acute pyelonephritis and intraabdominal infections compared with sepsis. The rate of apoptosis of natural killer (NK) cells differed significantly among patients with severe sepsis/shock due to ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) compared with sepsis. The rate of apoptosis of NKT cells differed significantly among patients with severe sepsis/shock due to acute pyelonephritis, primary bacteremia and VAP/HAP compared with sepsis. Regarding adaptive immunity, absolute counts of CD4-lymphocytes were significantly decreased among patients with severe sepsis/shock due to community-acquired pneumonia (CAP) and intraabdominal infections compared with sepsis. Absolute counts of B-lymphocytes were significantly decreased among patients with severe sepsis/shock due to CAP compared with sepsis.

Conclusions

Major differences of the early statuses of the innate and adaptive immune systems exist between sepsis and severe sepsis/shock in relation to the underlying type of infection. These results may have a major impact on therapeutics.     

Association of <Emphasis Type="Italic">HMGB1</Emphasis> polymorphisms with outcome in patients with systemic inflammatory response syndrome

Introduction  

High mobility group box 1 protein (HMGB1) is a pleiotropic cytokine, recently implicated in the pathophysiology of the systemic inflammatory response syndrome (SIRS) and sepsis. Data from experimental sepsis models show that administration of anti-HMGB1 antibodies significantly decreased mortality, even when administration was delayed for 24 hours, providing a window of opportunity for therapeutic intervention if transferred into a clinical setting. Whether genetic variation in the human HMGB1 gene is associated with disease susceptibility is unknown.