• Users Online: 814
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 31  |  Issue : 3  |  Page : 360-367

Serum salusin-β levels as predictors of coronary artery disease in obese Egyptian women


1 Department of Internal Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Physiology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
3 Department of Cardiology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Submission27-Dec-2019
Date of Acceptance14-Feb-2019
Date of Web Publication27-Aug-2019

Correspondence Address:
Nearmeen M Rashad
Department of Internal Medicine, Faculty of Medicine, Zagazig University, 44519
Egypt
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejim.ejim_123_18

Rights and Permissions
  Abstract 


Background Obesity is a growing health concern that has become an epidemic all over the world. Obesity is associated with coronary artery disease (CAD). Salusin-β is an endogenous bioactive peptide that accelerates inflammatory responses in vascular endothelial cells and increases oxidative stress. The objective of this study was to explore the potential roles of salusin-β in endothelial dysfunction in CAD. Also, we aimed to evaluate the association between salusin-β with severity of CAD in obese Egyptian women.
Patients and methods This cross-sectional study enrolled 95 obese women who were classified into two groups: 58 patients without CAD and 37 patients without CAD. All patients were investigated using a 12-lead standard ECG, echocardiography, and coronary arteriography. Salusin-β levels were measured by enzyme-linked immunosorbent assay.
Results Salusin-β levels were significantly higher in obese patients with CAD compared with patients without CAD. Salusin-β levels were positively correlated with cardiometabolic risks and severity of coronary occlusion. Serum salusin-β levels, high-sensitivity C-reactive protein, and BMI were independently correlated with CAD and BMI. Homeostatic model assessment of insulin resistance, high-sensitivity C-reactive protein, and uric acid were the main associated variables of serum salusin-β levels among other clinical and laboratory biomarkers. The diagnostic power of serum salusin-β levels in differentiating CAD from obese patients without CAD was highly sensitive (97.2%) and the specificity was 98.3%.
Conclusion The higher levels of salusin-β levels in obesity, as well as CAD, were positively correlated with cardiometabolic risk factors and severity of coronary occlusion. Therefore, salusin-β levels seem to be a noninvasive biomarker of CAD.

Keywords: coronary artery disease, endothelial dysfunction, obesity, oxidative stress, salusin-β


How to cite this article:
Rashad NM, Ashour WM, Samir GM, Abomandour HG. Serum salusin-β levels as predictors of coronary artery disease in obese Egyptian women. Egypt J Intern Med 2019;31:360-7

How to cite this URL:
Rashad NM, Ashour WM, Samir GM, Abomandour HG. Serum salusin-β levels as predictors of coronary artery disease in obese Egyptian women. Egypt J Intern Med [serial online] 2019 [cited 2019 Sep 17];31:360-7. Available from: http://www.esim.eg.net/text.asp?2019/31/3/360/265429




  Introduction Top


Despite attempts to increase awareness of the deleterious health consequences associated with obesity, there continues to be a significant increase in the obese population worldwide. A preponderance of evidence suggests that cardiovascular disease represents the most important complication associated with obesity. The development of endothelial dysfunction combined with vascular remodeling are the earliest manifestations of an altered vascular homeostasis, involved in the initiation, evolution, and complications of cardiovascular disorders [1].

Endothelial dysfunction, which is an early manifestation of altered vascular homeostasis due to exposure to cardiovascular risk factors, is a predictive index of cardiovascular events in high-risk patients. Indeed; endothelial dysfunction is generally characterized by an increased level of vascular wall oxidative stress, supported mainly by the reactive oxygen species [2].

Salusin-β is an endogenous bioactive peptide with 20 amino acid residues [3]. It stimulates the proliferation, migration of vascular smooth muscle cells, and foam cell formation [4],[5]. Salusin-β blockade ameliorates endothelial inflammation to improve pulmonary arterial hypertension [6] and pulmonary vascular remodeling [7]. Substantial evidence implicates the high salusin-β levels with hyperglycemia [8].

Obesity reflects a generalized proinflammatory state with high risk for metabolic comorbidities, such as coronary artery disease (CAD). Endothelial dysfunction is a systemic manifestation and is associated with CAD and mortality. Effective preventive strategies for high-risk patients with severe endothelial dysfunction are important to improve the prognosis. Thus, the objective of this study was to explore the potential roles of salusin-β in endothelial dysfunction in CAD. Also, we aimed to evaluate the association between salusin-β with severity of CAD in obese Egyptian women.


  Patients and methods Top


Patients

This study included 95 obese women, having BMI more than 30 who were recruited from the Diabetes and Endocrinology outpatient clinic of Internal Medicine Department, Zagazig University Hospitals. They were classified into two groups: 58 patients without CAD and 37 patients with CAD. The diagnosis of CAD was based on the combination of clinical presentation and ECG. Patients with diabetes, decompensated liver disease, rheumatic valvular heart diseases, decompensated heart failure, previous myocardial infarction, or recent cerebrovascular events (such as brain infarction or hemorrhage) within the prior 6 months were excluded from the study. All patients were subjected to thorough history taking and full clinical assessment including blood pressure and anthropometric variables. BMI was calculated as weight (kg)/height (m2). The patients underwent elective coronary angiography for disease in the Cardiology Department of Zagazig University Hospitals. All patients were investigated using a 12-lead standard ECG, echocardiography. Coronary arteriography was performed to all patients by the Judkins technique for assessment of lesions’ distribution and description. Severity of atherosclerotic CAD was assessed by using SYNTAX score which is based on the baseline diagnostic angiogram. The total SYNTAX score was calculated from the summation of the individual scorings for each separate lesion by using a SYNTAX score algorithm available on the SYNTAX website (http://www.syntaxscore.com). CAD was considered significant if there was at least a 0% diameter stenosis in at least one coronary artery.

The ethics committee of the Faculty of Medicine, Zagazig University approved our study protocol, and all participants signed a written informed consent to participate in the study.

Collection of blood and biochemical analysis

Venous blood samples were collected from patients after an overnight fasting for the determination of total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and triglyceride (TG). Also, fasting plasma glucose (FPG) level and fasting serum insulin (FSI) levels were determined by high-sensitivity enzyme-linked immunosorbent assay kit provided by Biosource Europe S.A. (Nivelles, Belgium). Homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. Serum TC, HDL cholesterol, and TG concentrations were determined calorimetrically by kits purchased from Stanbio Laboratory (Boerne, Texas, USA). Serum low-density lipoprotein (LDL) cholesterol was calculated according to the Friedewald formula [9]. C-reactive protein was measured using immunoturbidimetric assay on Roche/Hitachi Cobas system (c501) autoanalyzer (Roche Diagnostics, Mannheim, Germany). Serum salusin-β levels were measured by commercial enzyme-linked immunosorbent assay kits (Uscn Life Science, Houston, Texas, USA).

Statistical analysis

Categorical variables were presented as frequencies and percentages and compared using the χ2-test. Shapiro–Wilk’s testing was conducted to determine the normal distribution of quantitative variables. Variables with normal distribution were compared using Student’s t-test. Non-normally distributed variables were tested using the Mann–Whitney U-test. Correlations between continuous variables were determined by Pearson’s correlation test. Logistic regression was conducted to evaluate the association between salusin-β levels and other correlated variables. Linear regression analysis tested the influence of the main independent variables against salusin-β. A receiver operating characteristic (ROC) curve was generated for serum levels of salusin-β. A P-value of less than 0.05 was considered statistically significant.


  Results Top


Clinical, anthropometric, and laboratory characteristics of the studied patients

Among the obese groups, patients with CAD (n=37) had significantly higher values of systolic blood pressure, MI, waist/hip ratio as well as lipid profile (TG, TC and LDL) compared with women without CAD. Furthermore, there were significantly higher values of FPG, FSI, and HOMA-IR in obese patients with CAD compared with obese women without CAD. In addition, nontraditional risk factors such as serum uric acid and high-sensitivity C-reactive protein (hs-CRP) levels were significantly higher in obese group patients with CAD compared with women without CAD (P<0.001) ([Table 1]).
Table 1 Clinical, anthropometric, and laboratory characteristics of obese groups

Click here to view


Comparison of salusin-β levels in different studied groups

Our results showed statistically significant higher values of salusin-β levels in obese patients with CAD (418.4±79.35) compared with obese women without CAD (250.9±61.46) (P<0.001) ([Figure 1]a).
Figure 1 (a) Comparison of salusin-β (pg/ml) levels in obese groups. (b) Comparison of salusin-β (pg/ml) levels in the coronary artery disease group. (c) Comparison of SYNTAX score in different obese groups. CAD, coronary artery disease.

Click here to view


Salusin-β levels in obese women with coronary artery disease stratified according to the number of coronary arteries occlusion

Among patients with CAD (n=37), patients with multivessel occlusion (n=12) had statistically significant higher values of salusin-β levels (626.2±134.5) compared with patients with two-vessel occlusion (n=15,451.5±84.4) and patients with single-vessel occlusion (n=10, 349.1±23.7) (P<0.001) ([Figure 1]b).

The severity of coronary artery disease using the SYNTAX score

We estimated the severity of CAD according to coronary angiography findings and we used the SYNTAX score. The mean value of SYNTAX score in CAD patients was 30.12±5.365, whereas in women without CAD it was 11.12±4.365 (P<0.001) ([Figure 1]c).

Correlation between salusin-β levels and severity of coronary artery disease using the SYNTAX score

In the CAD subgroup (n=37), there were significant positive correlations between salusin-β levels and Syntax score (P<0.05) ([Figure 2]a).
Figure 2 (a) Correlation between salusin-β (pg/ml) levels and SYNTAX. (b) Correlation between salusin-β (pg/ml) levels and BMI. (c) Correlation between SYNTAX values and BMI.

Click here to view


Correlation between BMI and severity of coronary artery disease using the SYNTAX score

There were significant positive correlations between BMI and SYNTAX score (P<0.05) ([Figure 2]c).

Pearson’s correlation between salusin-β levels with clinical and laboratory parameters among type 2 diabetes mellitus patients

Our results showed that there were significant positive correlations between salusin-β levels and SBP, BMI ([Figure 2]b), TC, TG, LDL, FSI, FPG, HOMA-IR, hs-CRP, and uric acid. In contrast, salusin-β levels were significantly negatively correlated with ejection fraction (P<0.05) ([Table 2]).
Table 2 Correlation between salusin-β levels with cardiometabolic risk factors among obese patients

Click here to view


Linear regression analysis in obese groups

Our results found that BMI, HOMA-IR, hs-CRP, and uric acid were the main associated variables with salusin-β levels among other clinical and laboratory biomarkers (P<0.05) ([Table 3]).
Table 3 Linear regression analysis test used to explore the influence of the main independent variables against salusin-β (dependent variable) in obese patients

Click here to view


Logistic regression analysis test was used to evaluate the association of salusin-β, with the severity of coronary artery disease among obese groups

Our study showed that the only variables associated with severity of CAD among obese patients were salusin-β [odds ratio=1.054, 95% confidence interval (CI)=1.022–1.086], hs-CRP (odds ratio=0.184, 95% CI=0.046–0.727), and BMI (odds ratio=1.303, 95% CI=1.014–1.674) (P<0.001) ([Table 4]).
Table 4 Logistic regression analysis test used to evaluate the association of salusin-β with severity of coronary artery disease among obese patients

Click here to view


The accuracy of circulating salusin-β levels in the diagnosis of coronary artery disease by receiver operating characteristic analysis

The power of salusin-β level to diagnose CAD among the studied patients was evaluated using the ROC analysis. The area under the curve was 0.982 (95% CI=0.953–1.000) with a sensitivity of 97.2%, specificity of 98.3%, and the cutoff values was found to be 345.3 ([Figure 3]).
Figure 3 Receiver operating characteristic curve for salusin-β, as diagnostic biomarkers for the diagnosis of coronary artery disease among obese women. AUC, area under the curve.

Click here to view



  Discussion Top


Obesity is a challenge for global public health, particularly with regard for its effects on several comorbid diseases including CAD [10]. Many recent studies proposed that obesity is associated with endothelial dysfunction [11]. Extensive data support a major role of perivascular adipose tissue on vascular tone through the secretion of a variety of proinflammatory cytokines that lead to oxidative stress and endothelial dysfunction [12],[13].

Mounting evidence indicates that salusin-β levels are higher in patients with diabetes than healthy controls [7]. Even more importantly, it has been observed that the inhibition of salusin-β improves oxidative stress, inflammation, and cardiac dysfunction [14].

Conflicting data have been reported regarding the association between body weight and cardiovascular risk factors. Obesity is associated with advanced cardiovascular disease and a higher mortality rate [15]. Weight loss has been associated with improvement in preexisting cardiovascular risk factors including hypertension, diabetes, and dyslipidemia and mortality [16]. Therefore, we aimed to explore the potential roles of salusin-β in endothelial dysfunction in CAD. Also, we aimed to evaluate the association between salusin-β with severity of CAD in obese Egyptian women.

As expected, our finding adds to the growing body of evidence implicating that obesity is associated with cardiometabolic disease [17],[18]. According to our cross-sectional study, about 37 (38.9%) women had CAD documented by the result of coronary angiography. Obese patients with CAD had significantly higher cardiovascular risk factors. Interestingly, there were significant positive correlations between BMI and severity of coronary artery occlusion by the SYNTAX score.

Similar results were observed in the study by Flegal et al. [15]; the researchers observed a high-mortality rate in obese patients with CAD than lean patients with CAD.

In contrast, a study by Niraj et al. [19] did not find a correlation between obesity and severity of CAD after adjustment for confounders suggesting that younger age may influence the obesity paradox. Also, in contrast to our findings, a study by Parsa and Jahanshahi [20] reported an inverse relationship between BMI and severity of CAD in a cross-sectional, prospective study of 414 patients with suspected CAD.

Previous studies have indeed demonstrated a clear association between salusin peptides as endogenous modulators of atherogenesis [8] and atherosclerosis [21]. Moreover, emerging data have demonstrated that atherosclerosis is a complex and multifactorial disease whose pathogenesis is associated with inflammatory responses [22],[23].

Accumulating studies have reported that the endogenous salusin-β excessively produced in vascular lesions could contribute to the development of atherosclerosis [24]. In this respect, salusin-β is released from human monocytes/macrophage, suggesting a possible autocrine/paracrine role in the development and progression of atherosclerosis [25].

The results presented here are innovative, as this study was the first Egyptian study that investigated the serum levels of salusin-β in the obese group as well as patients with CAD. Our results showed statistically significant higher values of salusin-β levels in the obese group in particular obese patients with CAD.

In agreement with our results, a study conducted by Kołakowska et al. [26] found higher salusin-β plasma levels in obese children than lean ones.

Similar to our result, a study conducted by Sato et al. [25] found circulating salusin-β levels increased in patients with CAD.

Our findings are in concordance with Liu et al. [27] who detected that serum salusin-β levels were significantly higher in patients undergoing coronary artery graft than those in healthy controls. Among patients undergoing coronary artery graft, patients with CAD had significantly higher serum salusin-β levels compared with patients without CAD [27].

Our results showed that there were significant positive correlations between serum salusin-β levels and SBP, BMI, TG, LDL, HOMA-IR, FSI, FPG, hs-CRP, and uric acid. In addition, serum salusin-β levels, hs-CRP, and BMI were independently correlated with CAD after adjusting other cofactors and BMI, HOMA-IR, hs-CRP, and uric acid were the main associated variables of serum salusin-β levels among other clinical and laboratory biomarkers.

Similarly, Liu et al. [27] detected that there was positive correlation between serum salusin-β levels and coronary atherosclerosis index score. Salusin-β acts as a potential proatherogenic factor via promoting macrophage foam cell formation [28].

In agreement with our results, a study conducted by Kołakowska et al. [26] derived a positive correlation between serum salusin-β level and the TG/HDL ratio.

To better elucidate the diagnostic power of serum salusin-β, we tested our findings by using an ROC test which revealed that the diagnostic power of serum salusin-β level in differentiating CAD from obese patients without CAD was highly sensitive (97.2%) and the specificity was 98.3%.


  Conclusion Top


Our results showed statistically significant higher values of serum salusin-β levels in the obese patients with CAD than those without CAD. The higher levels of serum salusin-β levels were strongly correlated with cardiometabolic risk factors and severity of coronary occlusion. Therefore, serum salusin-β might be considered to be a noninvasive biomarker of CAD.

Acknowledgements

The authors acknowledge all the participants of this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Lu Y, Hajifathalian K, Ezzati M, Woodward M, Rimm EB, Danaei G. Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1.8 million participants. Lancet 2014; 383:970–983.  Back to cited text no. 1
    
2.
Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation 2005; 111:363–368.  Back to cited text no. 2
    
3.
Shichiri M, Ishimaru S, Ota T, Nishikawa T, Isogai T, Hirata Y. Salusins: newly identified bioactive peptides with hemodynamic and mitogenic activities. Nat Med 2003; 9:1166–1172.  Back to cited text no. 3
    
4.
Sun HJ, Liu TY, Zhang F, Xiong XQ, Wang JJ, Chen Q et al. Salusin-β contributes to vascular remodeling associated with hypertension via promoting vascular smooth muscle cell proliferation and vascular fibrosis. Biochim Biophys Acta 2015; 1852:1709–1718.  Back to cited text no. 4
    
5.
Sun HJ, Zhao MX, Liu TY, Ren XS, Chen Q, Li YH et al. Salusin-β induces foam cell formation and monocyte adhesion in human vascular smooth muscle cells via miR155/NOX2/NFκB pathway. Sci Rep 2016; 6:23596.  Back to cited text no. 5
    
6.
Xu T, Zhang Z, Liu T, Zhang W, Liu J, Wang W et al. Salusin-β contributes to vascular inflammation associated with pulmonary arterial hypertension in rats. J Thorac Cardiovasc Surg 2016; 152:1177–1187.  Back to cited text no. 6
    
7.
Fujimoto K, Hayashi A, Kamata Y, Ogawa A, Watanabe T, Ichikawa R et al. Circulating levels of human salusin-beta, a potent hemodynamic and atherogenesis regulator. PLoS ONE 2013; 8:e76714.  Back to cited text no. 7
    
8.
Zhao MX, Zhou B, Ling L, Xiong XQ, Zhang F, Chen Q et al. Salusin-β contributes to oxidative stress and inflammation in diabetic cardiomyopathy. Cell Death Dis 2017; 8:e2690.  Back to cited text no. 8
    
9.
Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18:499–502.  Back to cited text no. 9
    
10.
Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss. Arterioscler ThrombVasc Biol 2006; 26:968–976.  Back to cited text no. 10
    
11.
Virdis A, Santini F, Colucci R, Duranti E, Salvetti G, Rugani I et al. Vascular generation of tumor necrosis factor-α reduces nitric oxide availability in small arteries from visceral fat of obese patients. J Am Coll Cardiol 2011; 58:238–247.  Back to cited text no. 11
    
12.
Virdis A. Endothelial dysfunction in obesity: role of inflammation. High Blood Press Cardiovasc Prev 2016; 23:83–85.  Back to cited text no. 12
    
13.
Reho JJ, Rahmouni K. Oxidative and inflammatory signals in obesity-associated vascular abnormalities. Clin Sci 2017; 131:1689–1700.  Back to cited text no. 13
    
14.
Koya T, Miyazaki T, Watanabe T, Shichiri M, Atsumi T, Kim-Kaneyama JR et al. Salusin-β accelerates inflammatory responses in vascular endothelial cells via NF-kappaB signaling in LDL receptor-deficient mice in vivo and HUVECs in vitro. Am J Physiol Heart Circ Physiol 2012; 303: H96–H105.  Back to cited text no. 14
    
15.
Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA 2013; 309:71–82.  Back to cited text no. 15
    
16.
Artham SM, Lavie CJ, Milani RV, Ventura HO. Value of weight reduction in patients with cardiovascular disease. Curr Treat Options Cardiovasc Med 2010; 12:21–35.  Back to cited text no. 16
    
17.
Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease. risk factor, paradox, and impact of weight loss. J Am Coll Cardiol 2009; 53:1925–1932.  Back to cited text no. 17
    
18.
Lavie CJ, Milani RV, Artham SM, Patel DA, Ventura HO. The obesity paradox, weight loss, and coronary disease. Am J Med 2009; 122:1106–1114.  Back to cited text no. 18
    
19.
Niraj A, Pradahan J, Fakhry H, Veeranna V, Afonso L. Severity of coronary artery disease in obese patients undergoing coronary angiography: ‘Obesity Paradox’ revisited. Clin Cardiol 2007; 30:391–396.  Back to cited text no. 19
    
20.
Parsa AFZ, Jahanshahi B. Is the relationship of body mass index to severity of coronary artery disease different from that of waist-to-hip ratio and severity of coronary artery disease? Paradoxical findings. Cardiovasc J Afr 2015; 26:13–16  Back to cited text no. 20
    
21.
Watanabe T, Sato K, Itoh F, Iso Y, Nagashima M, Hirano T et al. The roles of salusins in atherosclerosis and related cardiovascular diseases. J Am Soc Hypertens 2011; 5:359–365.  Back to cited text no. 21
    
22.
Ross R. Atherosclerosis − an inflammatory disease. N Engl J Med 1999; 340:115–126.  Back to cited text no. 22
    
23.
Zhou CH, Liu L, Liu L, Zhang MX, Guo H, Pan J et al. Salusin-β not salusin-α promotes vascular inflammation in ApoE-deficient mice via the I kBa/NF-kB pathway. PLoS ONE 2014; 9:e91468.  Back to cited text no. 23
    
24.
Watanabe T, Nishio K, Kanome T, Matsuyama T, Koba S, Sakai T et al. Impact of salusin-α and −β on human macrophage foam cell formation and coronary atherosclerosis. Circulation 2008; 117:638–648.  Back to cited text no. 24
    
25.
Sato K, Watanabe R, Itoh F, Shichiri M, Watanabe T. Salusins: potential use as a biomarker for atherosclerotic cardiovascular diseases. Int J Hypertens 2013; 2013:965140.  Back to cited text no. 25
    
26.
Kołakowska U, Kuroczycka-Saniutyc E, Wasilewska A, Olański W. Is the serum level of salusin-β associated with hypertension and atherosclerosis in the pediatric population? Pediatr Nephrol 2015; 30:523–531.  Back to cited text no. 26
    
27.
Liu J, Ren YG, Zhang LH, Tong YW, Kang L. Serum salusin-β levels are associated with the presence and severity of coronary artery disease. J Investig Med 2015; 63:4.  Back to cited text no. 27
    
28.
Niepolski L, Grzegorzewska AE. Salusins and adropin: new peptides potentially involved in lipid metabolism and atherosclerosis. Adv Med Sci 2016; 61:282–287.  Back to cited text no. 28
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Patients and methods
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed49    
    Printed0    
    Emailed0    
    PDF Downloaded13    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]