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Background: The coronavirus disease 2019 (COVID-19) pandemic in Iran has led to a lack of intensive care unit (ICU) facilities. This study examines C-reactive protein (CRP), D-dimer, erythrocyte sedimentation rate (ESR), and troponin in ICU patients with COVID-19 in comparison to COVID-19 patients admitted to the wards in Iran., Materials and Methods: In a case-control study, troponin, CRP, ESR, and D-dimer were compared in the case samples of 109 COVID-19 patients admitted to the ICU, and in the control group, 140 COVID-19 patients admitted to the wards., Results: The mean of CRP ( P < 0.001) and D-dimer ( P < 0.001) was higher, whereas troponin ( P < 0.001) was lower in patients admitted to the ICU, but no significant difference was observed between the values of ESR ( P = 0.292) in the two groups., Conclusion: This study showed that the values of CRP and D-dimer were higher in patients admitted to the ICU, but no significant difference was observed between the values of ESR in the two groups., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Research in Medical Sciences.)

Signal transducer and activator of transcription 3 (STAT3) has been introduced as one of the critical genetic factors in the pathogenesis of rheumatoid arthritis (RA). Single nucleotide polymorphisms (SNPs) in microRNA binding sites, known as miRSNPs, are a class of common variants in the 3' untranslated regions of genes targeted by miRNAs. miRSNPs unbalance gene expression by disrupting the binding regions of microRNAs. In this study, we intended to evaluate the association of two miRSNPs with the risk of RA development and its clinical features. We studied 120 Iranian patients with RA and 125 non-RA subjects as controls. The genotypes and alleles of rs1053005 and rs1053023 in each individual were assessed by the high-resolution melting method. The distribution of STAT3 variants did not differ markedly in RA patients compared to healthy controls. Stratification analysis revealed that rs1053005 was linked with a higher concentration of C-reactive protein and an increased erythrocyte sedimentation rate, two indicators of inflammation and disease activity in RA patients. The rs1053023 variant was correlated with higher levels of creatinine as an indicator of renal involvement. Our data demonstrate an association between STAT3 variants and clinical characteristics of RA, such as disease activity and probably kidney impairment.  However, we did not observe a significant relationship between the two targeted variants and a predisposition to RA.

Background: The role of anti-phospholipid antibodies (aPLs) in the prognosis of COVID-19 patients is controversial. In order to prove the role of this factor, the necessary measures such as early initiation of anticoagulants should be started even in the early stages of the disease and in outpatients or the use of other drugs in addition to anticoagulants. We decided to investigate the role of these antibodies in ICU admission outcomes in critically ill COVID-19 patients., Methods: The case-control study was carried out in Isfahan, Iran, from March to September 2021. One hundred nine patients in the case group were selected, including patients admitted to the ICU with a COVID-19 diagnosis. The 140 patients in the control group were selected from hospitalized and outpatients with COVID-19 with PCR + and pulmonary involvement, similar to the case group without the need for ICU hospitalization. The anti B2GP1 (IgM, IgG) and anti-cardiolipin (IgM, IgG)) were compared in two groups., Results: The frequency percentage of patients in the abnormal group of anti-phospholipid antibodies was about 10% in total. No statistically significant difference in these aPLs in continued measures was observed between the two groups of patients admitted to the ICU and those outside the ICU. Also, in the logistics regression analysis, no significant association was observed., Conclusions: Therefore, the cause of coagulation in patients admitted to the ICU is not related to these aPLs. This means that aPLs could not be a good predictor of patient admission to the ICU., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 International Journal of Preventive Medicine.)

Introduction/objectives: MiRSNPs may interfere with mRNA stability through effects on microRNAs (miRNAs)-mRNA interactions via direct changes in miRNA binding site or effect on the secondary structure of this region and changes in accessibility of this region to miRNAs. Studies have confirmed that an elevated level of interleukin-15 receptor alpha (IL-15RA) has an important role in the pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In the present study, for the first time, we aimed to evaluate the possible correlation between a miRSNP, rs2296135, in IL-15RA gene with the risk of SLE and RA., Methods: In this case-control study, 100 SLE patients, 100 RA patients, and 110 healthy participants were enrolled to assess rs2296135 genotypes with real-time PCR high-resolution melting method., Results: According to our findings, AA genotype and A allele of rs2296135 were considerably associated with enhanced risk of RA (for AA genotype, OR = 2.29; 95% CI [1.06-5.02]; for A allele, OR = 1.65; 95% CI [1.10-2.48]). However, this common variant was not significantly correlated with SLE risk in population under study. Stratification analysis in the RA group verified that patients with the A allele had considerably higher serum concentrations of C-reactive protein (CRP) (P < 0.001). In SLE subjects, the frequency of arthritis (P: 0.021) and renal involvement (P: 0.025) in patients with A allele was significantly higher than in other SLE individuals., Conclusion: The current study proposes a substantial association between rs2296135 polymorphism in IL-15RA gene with augmented risk of RA and some clinical characteristics in RA and SLE patients., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Background: Recently, genome-wide association studies (GWAS) have discovered several single nucleotide polymorphisms (SNPs) and loci associated with the risk of systemic lupus erythematosus (SLE). rs6445975 (T>G; intronic variant) polymorphism in the PXK gene is one of these loci. However, there was an inconsistency between the results of replicative studies on European and Asia ancestry. This study aimed to assess the possible association between rs6445975 polymorphism with SLE risk in the Iranian population., Methods: Genotype and allele distribution of rs6445975 polymorphism were investigated in 110 patients with SLE and 115 healthy controls in Isfahan University of Medical Sciences, Isfahan, Iran in 2019 via real-time PCR high resolution melting method (HRM)., Results: GG and TG genotypes, but not TT genotype, were associated with increased risk of SLE (GG vs TT; OR= 7.538; 95%CI [3.47, 17.066] and TG vs TT; OR=2.21; 95%CI [1.06, 4.72]). Inheritance analysis revealed that TG + GG was correlated with the increased risk of SLE disease in the dominant model (OR=3.928; 95%CI [2.056, 7.74]). Moreover, subjects with the G allele were more frequently affected with SLE than individuals with the T allele (OR= 3.55; 95%CI [2.37, 5.36]). The G allele in patients was correlated with serum concentration of CRP, ESR, anti-dsDNA antibody, C3, and C4 and presentation of some clinical manifestations such as kidney involvements and skin lesions ( P <0.05)., Conclusion: Our findings suggest a substantial association between rs6445975 polymorphism in the PXK gene with susceptibility and clinical characteristics of SLE in the Iranian population., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest., (Copyright © 2022 Karimifar et al. Published by Tehran University of Medical Sciences.)

Introduction: /objectives. Single nucleotide polymorphisms (SNPs) located at the 3'-UTR region of the target genes of microRNAs (miRNAs) can dysregulate their expression via disrupting the binding site of miRNAs. Interleukin-16 (IL-16) is involved in the pathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In the current study, we assessed the possible association between rs1131445 polymorphism in IL-16 gene with risk and clinical characteristics of RA and SLE in the Iranian population., Methods: In this case-control study, 120 patients with RA, 120 patients with SLE, and 120 unrelated healthy subjects were collected to estimate rs1131445 (T > C) polymorphism in IL-16 gene using real-time PCR high-resolution melting (HRM) method., Results: Our results demonstrated considerable associations between TC genotype and C allele of rs1131445 with enhanced risk of RA (OR for TC genotype  = 3.01; 95%CI [1.667-5.526], P < 0.001; OR for C allele  = 1.96; 95%CI [1.314-2.941], P < 0.001). Besides, there was a marginal association between CC genotype and increased risk of RA (P: 0.031). However, there was an insignificant correlation between genotypes and allele frequencies of rs1131445 with incidence risk of SLE (P > 0.05). Moreover, stratification analysis indicated that the C allele in rs1131445 was linked with disease activity-associated laboratory parameters such as CRP and ESR in both RA and SLE patients, as well as the higher incidence of neurological symptoms in SLE subjects (P < 0.05)., Conclusion: These results proposed a significant association between IL-16 polymorphism and augmented risk of RA and clinical characteristics of RA and SLE., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Objective: Over the past decades, TNIP1 has been identified as a strong risk locus in multiple genome-wide association studies (GWAS), spanning multiple populations and various autoimmune diseases. TNIP1 is a polyubiquitin-binding protein that works as a physiological inhibitor of NF-κB and maintains immune homeostasis. Some studies have confirmed that TNIP1 is downregulated in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In the current study, for the first time, we evaluated the possible association between rs6889239 polymorphism in the TNIP1 gene with the risk and clinical characteristics of RA and SLE in the Iranian population., Method: In this case-control study, 115 patients with RA, 115 patients with SLE, and 115 unrelated healthy subjects were enrolled to estimate rs6889239 genotypes with real-time PCR high resolution melting (HRM) method., Results: Our results demonstrated considerable associations between CC genotype and C allele of rs6889239 with augmented risk of SLE (OR for CC genotype= 2.23; 95%CI [1.175-4.307], OR for C allele= 1.84; 95%CI [1.254-2.720]). However, there was an insignificant association between genotypes and allele frequencies of rs6889239 with the occurrence risk of RA in the population under study ( p > 0.05). Additionally, stratification analysis specified that the C allele in rs6889239 was linked with the incidence of renal involvement in SLE patients and lower age of onset in the RA group ( p < 0.05)., Conclusion: These findings propose a significant association between TNIP1 polymorphism and higher risk of SLE and some clinical characteristics of RA and SLE.

Background: Rheumatoid Arthritis (RA) has multifactorial etiology and numerous genetic and environmental factors have been related to an increased risk of RA. Recently, Genome-Wide Association Studies (GWAS) suggested a large number of Single Nucleotide Polymorphisms (SNPs) loci affecting the susceptibility to RA. One of these loci is rs6859219 (C>A), a functional polymorphism in the ANKRD55 gene which was associated with the expression of ANKRD55 and IL6ST . In the current study, we evaluated the possible association between rs6859219 (intronic variant) in the ANKRD55 gene with RA risk in the Iranian population., Methods: A case-control study using 118 RA patients and 115 healthy counterparts was undertaken in order to determine rs6859219 genotypes using real-time polymerase chain reaction High-Resolution Melting (HRM) method., Results: There was a significant difference in the genotype and allele frequencies of rs6859219 between patients and controls (p<0.001). Logistic regression analysis demonstrates that CC genotype and C allele increased the risk of RA (OR for CC genotype = 7.12; 95%CI [3.51-15.05]/OR for C allele =4.16; 95%CI [2.78-6.28]). Furthermore, regarding the dominant and recessive model of inheritance, RA patients indicated obvious association of the rs6859219 variant compared to healthy controls (p<0.001). Moreover, in the patient group, there was a significant correlation between C-Reactive Protein (CRP) concentration with rs6859219 polymorphism (p<0.001)., Conclusion: Our findings propose a substantial correlation between rs6859219 polymorphism and RA risk and clinical characteristics of this disease in the Iranian population., Competing Interests: Conflict of Interest None declared., (Copyright© 2022 Avicenna Research Institute.)

Background: The high heritability of Rheumatoid Arthritis (RA) has been estimated from different studies. Recently, Genome-Wide Association Studies (GWAS) show a large number of Single Nucleotide Polymorphisms (SNPs) loci affecting susceptibility to RA. The rs934734 polymorphism in the SPRED2 gene is one of these loci. Studies have shown that the SPRED2 gene is involved in the regulation of inflammatory response, leukocyte infiltration, and local chemokine production. In the current study, the possible association between SNP rs934734 (intronic variant) in the SPRED2 gene with RA risk in the Iranian population was evaluated., Methods: One hundred fourteen RA patients and 120 healthy counterparts were recruited in this case-control study to evaluate rs934734 genotypes using the real-time PCR High Resolution Melting method (HRM)., Results: Logistic regression analysis demonstrated that GG and AG genotypes compared with AA genotype increase the risk of RA (GG vs . AA; OR=4.61; 95%CI [2.21-9.35]; p<0.001 and AG vs . AA; OR=2.54; 95%CI [1.36-4.76]; p=0.004). Furthermore, subjects with allele G were more frequently affected with RA than subjects with A allele (OR=2.33; 95%CI [1.61-3.38]; p<0.001). Besides, in the patient group, there was a significant correlation between Erythrocyte Sedimentation Rate (ESR) and C-reactive protein (CRP) concentration with rs934734 polymorphism (p<0.05)., Conclusion: Our findings suggest that rs934734 in SPRED2 strongly underlies RA development and is associated with clinicopathological characteristics of this disease., (Copyright© 2022 Avicenna Research Institute.)

Background: Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are multisystemic autoimmune diseases with multifactorial nature. Considering the limitations of the current conventional serological tests for the diagnosis of these diseases, researchers strive to find more new valid biomarkers., Methods: Sixty-nine patients with SLE, 63 patients with RA, and 71 healthy controls were recruited to evaluate the methylation level of interferon-induced protein 44-like (IFI44L) promoter. Quantitative methylation of the promoter region of the IFI44L gene was measured in extracted DNA of peripheral blood mononuclear cells (PBMCs) with methylation-quantification endonuclease-resistant DNA (MethyQESD) method., Results: Our findings unveiled a drastic hypomethylation of IFI44L promoter in SLE and RA patients compared with healthy volunteers (mean: 40.23% ± 64.54%, 35.19% ± 24.09%, and 71.98% ± 23.83%, respectively; P < 0.001 for both SLE and RA). In comparison between SLE and RA patients with the control group, IFI44L promoter methylation had a sensitivity of 81.15% and 84.12%, respectively, and specificity was 76.05%. The promoter methylation level was not meaningfully different between SLE and RA patients (P = 0.267). Moreover, our analysis revealed that the methylation level of the IFI44L promoter was not significantly different between SLE disease activity and renal involvements (P > 0.05). While RA patients with a higher concentration of CRP had a lower DNA methylation level (P = 0.023)., Conclusion: The methylation level of IFI44L promoter was lower in PBMCs of Iranian patients with SLE and RA than that in the control group. Furthermore, DNA methylation level of the IFI44L promoter had a negative correlation with RA disease activity. However, there was not a significant association with the clinical characteristics of SLE., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Signal transducer and activator of transcription 3 (STAT3) is a major regulator of immune response and chronic inflammatory conditions acting through regulation of B cells, T-helper 17 (Th17) cells, and IL-17 production. Previous studies have demonstrated that dysregulation of STAT3 is crucial for SLE pathogenesis and disease severity. It is believed that single nucleotide polymorphisms (SNPs) located at the 3'-UTR sequence of the target genes could dysregulate their expression by disrupting the binding site of miRNAs. In the present study, we assessed the possible association between rs1053005 and rs1053023 SNPs at miRNA binding sites in the STAT3 gene and the risk of SLE in the Iranian population for the first time., Methods: 112 SLE cases and 120 healthy controls were genotyped for rs1053005 (A>G) and rs1053023 (A>G) polymorphisms in STAT3 using real-time PCR high resolution melting method (HRM)., Results: Our results revealed substantial associations between GG genotype and G allele of rs1053023 with enhanced risk of SLE (OR for GG genotype= 3.13; 95%CI [1.61-6.1], OR for G allele = 2.22; 95%CI [1.51-3.25]). However, no important correlations have been found between rs1053005 polymorphism and SLE susceptibility in this population ( p >0.05). Moreover, stratification analysis showed that these polymorphisms are correlated with parameters indicating disease activity and more severe course of the disease. These factors include some laboratory test results and clinical manifestations such as renal involvements., Conclusion: The current study suggests a significant association between STAT3 polymorphisms and augmented risk of SLE, clinical symptoms, disease activity, and severity.

Introduction/objectives: Systemic lupus erythematosus (SLE) is a multifactorial systemic autoimmune disease, in which genetic susceptibility plays a pivotal role. The nucleotide oligomerization domain 2 (NOD2) gene is one of the main regulators of chronic inflammatory conditions and could be involved in SLE pathogenesis. Single nucleotide polymorphisms (SNPs) in miRNA binding sites which are located in 3'UTR of the NOD2 gene could be associated with SLE risk by dysregulation of NOD2 expression. In the present study, we assessed the possible association between SNPs rs3135500 and rs3135499 in the NOD2 gene with SLE risk in the Iranian population., Methods: A case-control study using 110 SLE patients and 120 control subjects was undertaken to estimate rs3135500 (G > A) and rs3135499 (A > C) genotypes via real-time PCR high-resolution melting method (HRM)., Results: No significant association was observed between allele and genotype frequencies of rs3135500 and rs3135499 polymorphisms and SLE risk in this population (P > 0.05). However, there was an obvious association between rs3135500 (A allele) with laboratory factors that are associated with disease activity (P < 0.05) and some clinical manifestations that are associated with disease severity such as neurological symptoms, skin manifestations, renal involvements, and higher serum concentration of creatinine (P < 0.05). Besides, rs3135499 (C allele) was correlated with renal involvement and also the concentration of creatinine (P < 0.05). Moreover, in the patients group, the risk alleles in these polymorphisms were associated with lower age of onset (P < 0.05)., Conclusions: Our results suggest a substantial association between NOD2 polymorphisms with clinicopathological characteristics and SLE disease activity. Key Points • Single nucleotide polymorphisms (SNPs) in miRNA binding sites which are located in 3'UTR of the NOD2 gene could be associated with SLE risk by dysregulation of NOD2 expression. • Our results suggested that two miRSNPs (rs3135500 and rs3135499) in the NOD2 gene were meaningfully correlated with clinicopathological characteristics and disease activity of SLE., (© 2021. International League of Associations for Rheumatology (ILAR).)

Background: Rheumatoid arthritis (RA) is a complex systemic autoimmune disorder with multifactorial nature. Numerous previous studies have shown that several genes are involved in the pathogenesis and increased risk of RA. The Nod-like receptor pyrin domain containing 3 (NLRP3) is involved in the regulation of innate immunity and its upregulation has previously been reported in RA., Objective: To evaluate the correlation between 3 functional polymorphisms of NLRP3 and its gene expression and RA risk., Method: One hundred and fourteen patients with RA and 120 healthy participants were recruited to this case-control study. Genotyping of rs4612666 (intronic variant), rs10754558 (3UTR variant), and rs6672995 (downstream variant) were performed applying the real‑time polymerase chain reaction high‑resolution melting (HRM) method., Results: Based on logistic regression analysis, subjects with CC genotype and C allele in rs4612666 had increased risk of RA (OR for CC genotype= 3.10; 95%CI [1.78-8.26]/ OR for C allele= 2.00; 95%CI [1.45-3.10]). Furthermore, in the patient groups, there was a significant relationship between the concentration of C-reactive protein (CRP) and rs4612666 and rs10754558 polymorphism (p < 0.05). Besides, our results revealed no significant association between the genotype and allele frequency of rs10754558 and rs6672995 and the risk of RA (P> 0.05)., Conclusion: Our findings propose a significant association between rs4612666 polymorphism and increased risk of RA in the Iranian population. Moreover, rs4612666 and rs10754558 were correlated with disease activity.

Competing Interests: Conflict of interest The authors declare that there is no conflict of interest.

Objective: Nod-like receptor pyrin domain containing 3 ( NLRP3 ) gene encodes an intracellular receptor whose dysregulation in systemic lupus erythematosus (SLE) has been reported in multiple studies. Activation of NLRP3 inflammasome leads to the induction of inflammatory response via cleaving and producing of specific cytokines. In the present study, we assessed the possible association between three functional polymorphisms in this gene and SLE risk in the Iranian population. These variants include two gain of function (rs4612666 and rs10754558) and one loss of function (rs6672995) which are correlated with modulation of expression of NLRP3 ., Methods: A case-control study involving 110 SLE patients and 116 control subjects was undertaken to estimate the frequency of rs4612666, rs10754558, and rs6672995 genotypes using real-time PCR high resolution melting method (HRM)., Results: Our findings revealed significant associations between GG genotype and G allele of rs10754558 with increased risk of SLE (OR for GG genotype = 2.82; 95%CI [1.45-5.46]/OR for G allele = 1.97; 95%CI [1.36-2.87]). Although, no significant associations were recognized between allele and genotype frequencies of rs4612666 and rs6672995 polymorphisms with SLE risk ( P  > 0.05). Also, our analysis revealed that the C allele in rs4612666 and G allele in rs10754558 was correlated with the severity of disease activity (P < 0.001). Moreover, these common variants were associated with lower age of onset and some clinical symptoms in the patient group, such as skin manifestation, neurological symptom and, renal involvement (P < 0.05)., Conclusion: This study demonstrates a substantial association between NLRP3 polymorphisms with increased risk, clinical symptoms, and the severity of disease activity of SLE.

Background: Rheumatoid Arthritis (RA) is a progressive, heterogeneous, and common multifactorial autoimmune disease. Several Genome-Wide Association Studies (GWASs) have revealed more than 100 risk loci for RA. One of these loci is a functional single nucleotide polymorphism (rs874040; G>C) near the recombination signal-binding protein for the immunoglobulin kappa J region ( RBPJ ) gene. RBPJ can convert into a transcriptional activator upon activation of the canonical Notch pathway. Notch signaling has recently emerged as an important regulator of immune responses in inflammation and autoimmune diseases. In the present study, the possible association between SNP rs874040 (G>C) upstream of the RBPJ gene with RA risk was assessed in Iranian population., Methods: A case-control study including 60 RA patients and 44 control subjects was conducted to estimate rs874040 genotypes using real-time polymerase chain reaction High Resolution Melting (HRM) method., Results: Logistic regression analysis indicated that homozygous CC and heterozygous GC genotypes increase the risk of RA compared with GG genotype (CC vs. GG; OR=11.36; 95% CI [3.93-33.33] and CG vs. GG; OR=3.78; 95% CI [1.30-10. 98]). Besides, subjects with C allele were more frequently affected with RA than subjects with G allele (OR=10.42; 95% CI [5.21-20.83]). Furthermore, in the patient group, a significant correlation was found between C-reactive protein concentrations and rs874040 polymorphism (p<0.05)., Conclusion: Our findings propose a substantial correlation between rs874040 polymorphism and RA risk in Iranian population., Competing Interests: Conflict of Interest There is no conflict of interest to declare., (Copyright© 2021 Avicenna Research Institute.)

MicroRNA-124 (miR-124) is known as an important regulator of the immune system and inflammatory response. Studies have reported that this miRNA is dysregulated in autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). A functional analysis demonstrated that rs531564 (C>G) affects the biogenesis of primary microRNA transcript-124 (pri-miR-124) and changes the expression of mature miR-124. In the present study, for the first time, we intended to evaluate the possible association between rs531564 polymorphism with SLE and RA risk.  In this case-control study, 110 patients with SLE, 115 patients with RA, and 120 healthy subjects were enrolled to evaluate rs531564 genotypes with real-time polymerase chain reaction (PCR) high resolution melting method. Our findings demonstrated that frequency of GC genotype and G allele were considerably higher in the control group than RA patients, demonstrating that that GC genotype and G allele have a protective effect for healthy individuals (GC vs CC; OR: 0.29; 95%CI [0.12,0.67] and G vs C; OR: 0.42; 95%CI [0.23,0.78]). However, no significant correlation was confirmed between allele and genotype frequencies of rs531564 with SLE risk (p>0.05). However, the G allele in rs531564 polymorphism was associated with serum level of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-dsDNA antibody, C3, C4, and creatinine, and frequency of renal involvements in SLE patients (p<0.05). Moreover, in RA patients, the G was correlated with lower concentration ESR and CRP (p<0.001).  Our findings propose a considerable association between rs531564 polymorphism in the pri-miR-124 gene with susceptibility and clinical characteristics of RA and SLE in the Iranian population.

The nucleotide-binding oligomerization domain 2 (NOD2) is the key regulator of inflammatory responses and has been involved in the pathogenesis of rheumatoid arthritis (RA). Laboratory and in silico evaluations have demonstrated that some polymorphisms in 3'UTR of NOD2 gene could influence the secondary structure of this region and similarly thermodynamic features of hybridization site and finally deregulate the expression of NOD2. In the current study, for the first time, we evaluated the possible association between single nucleotide polymorphisms (SNPs) rs3135500 and rs3135499 in the NOD2 gene with RA risk in the Iranian population. One hundred and fifteen patients with RA and 120 healthy subjects were recruited in this case-control study. Genotyping of rs3135500 and rs3135499 polymorphisms were accomplished using the real‑time polymerase chain reaction high resolution melting (HRM) method. We found a substantial association of AA and AG genotypes in rs3135500 with the risk of RA (AA vs GG; OR=5.547; 95%CI [2.564-11.999]; p<0.001 and AG vs GG; OR=2.179; 95%CI [1.145-4.147]; p=0.017). Moreover, in the patient group, there was a significant relationship between the increased concentration of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) with rs3135500 (A allele) (p<0.05). However, there were no important associations between rs3135499 with the risk of RA (p>0.05). However, we found a noteworthy association of the C allele in rs3135499 with an increased level of CRP in patients (p>0.05). Our findings propose a considerable association between NOD2 polymorphisms with increased risk of RA and disease activity.

Disruption in DNA methylation processes can lead to alteration in gene expression and function that would ultimately result in malignant transformation. In this way, studies have shown that, in cancers, methylation-associated silencing inactivates tumor suppressor genes, as effectively as mutations. DNA methylation machinery is composed of several genes, including those with DNA methyltransferases activity, proteins that bind to methylated cytosine in the promoter region, and enzymes with demethylase activity. Based on a prominent body of evidence, DNA methylation machinery could be regulated by microRNAs (miRNAs) called epi-miRNAs. Numerous studies demonstrated that dysregulation in DNA methylation regulators like upstream epi-miRNAs is indispensable for carcinogenesis; consequently, the malignant capacity of these cells could be reversed by restoring of this regulatory system in cancer. Conceivably, recognition of these epi-miRNAs in cancer cells could not only reveal novel molecular entities in carcinogenesis, but also render promising targets for cancer therapy. In this review, at first, we have an overview of the methylation alteration in cancers, and the effect of this phenomenon in miRNAs expression and after that, we conduct an in-depth discussion about the regulation of DNA methylation regulators by epi-miRNAs in cancer cells.

Background: Rheumatoid arthritis (RA) is a progressive and common autoimmune disease with multifactorial etiology. Several pieces of research show that genetic factors play a major role in the incidence of RA. Several genome-wide association studies (GWAS) have identified the tumor necrosis factor alpha inducible protein 3 (TNFAIP3) genes as one of the candidate loci. The TNFAIP3 gene encoding ubiquitin-editing protein A20 witch restricts B cell survival and prevents autoimmunity. Previous studies have indicated that single nucleotide polymorphisms (SNPs) in the TNFAIP3 gene are correlated with several autoimmune disorders. In the present study, we assessed the possible association between SNP rs5029937 (intronic variant) in the TNFAIP3 gene with RA risk in the Iranian population. Methods: A case-control study using 50 RA patients and 50 control subjects was undertaken to evaluate rs5029937 (G>T) genotypes using real-time PCR high resolution melting method (HRM). The SPSS22 was used for statistical analyses and the significance level was set at P<0.05. Results: Logistic regression analysis demonstrates that homozygous TT + heterozygous TG genotypes compared with GG genotype increase the risk of RA (TT+TG vs GG; P= 0.004, OR= 3.46; 95%CI [1.492-8.075]). Also, individuals with allele T were more frequently affected with RA than subjects with G allele (T vs G; P= 0.004, OR= 2.61; 95%CI [1.382-4.919]). Conclusion: Our findings propose a substantial correlation between rs5029937 (G>T) polymorphism and RA risk in Iranian population., Competing Interests: Conflicts of Interest: None declared, (© 2021 Iran University of Medical Sciences.)

Deregulation of microRNAs, as key elements in colorectal cancer (CRC) pathogenesis, is correlated with various stages of this cancer. miR-196 is involved in the initiation and progression of a verity of malignances, especially CRC. miR-196 in CRC cells could target different types of genes with oncogenic and/or tumor suppressor function such as HOX genes, GATA6, SOCS1, SOCS3, ANXA1, DFFA, PDCD4, ZG16 and ING5. Therefore, these genes could be up or down-regulated in cells and subsequently change the capacity of CRC cells in terms of tumor development, progression and, response to therapy. Comprehension of miR-196-associated aberrations underlying the CRC pathogenesis might introduce promising targets for therapy. Additionally, it seems that miR-196 expression profiling, especially circulatory exosomal miR-196, might be useful for diagnosis and prognosis determination of the CRC patients. In this review, at first, we summarize the roles of miR-196 in different types of cancers. After that, a detailed discussion about this miRNA and also their targets in CRC pathogenesis, progression, and response to treatment are represented. Moreover, we highlight the potential utilization of miR-196 and its targets as therapeutic targets and novel biomarkers in early detection and prediction of prognosis in CRC patients.

Atherosclerosis continues to be a major cause of death in patients with cardiovascular diseases. The cooperative role of immunity has been recently considered in atherosclerotic plaque inflammation, especially adaptive immune response by T cells. In this review, we examine the possible role of T cells in atherosclerosis-mediated inflammation and conceivable therapeutic strategies that can ameliorate complications of atherosclerosis. The cytokines secreted by T-lymphocyte subsets, different pathophysiological profiles of microRNAs (miRs), and the growth factor/receptor axis have diverse effects on the inflammatory cycle of atherosclerosis. Manipulation of miRNA expression and prominent growth factor receptors involved in inflammatory cytokine secretion in atherosclerosis can be considered diagnostic biomarkers in the induction of anergy and blockade of atherosclerotic development. This manuscript reviews immunomodulation of T cells responses in atherosclerosis anergy., (© American Society for Clinical Pathology 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with multifactorial etiology. Several studies show that genetic factors have an important part in the incidence of SLE. The C1QTNF4 gene is involved in the regulation of the inflammatory pathways by pro-inflammatory function. In the present study, we have evaluated the association between C1QTNF4 gene p.His198Gln mutation and risk of SLE., Methods: Forty SLE patients and 40 control subjects were recruited in this case-control study. Genotyping of C1QTNF4 p.His198Gln mutation was performed using real-time polymerase chain reaction high resolution melting method., Results: We found a significant association between this mutation (GG + GC) with the risk of SLE (odds ratio = 6.33, 95% CI = 1.28-31.11). Furthermore, we observed that in the patient group, this mutation leads to early-onset SLE (19.7 ± 4.34 years for mutation carriers compared to 27.7 ± 11.4 years for wild type carriers; P = .003)., Conclusion: Our results suggest that this mutation (p.His198Gln) potentially has an important role in SLE risk in the Iranian population., (© 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: The objectives of this study were to compare the interferon-induced protein 44-like (IFI44L) promoter methylation level between systemic lupus erythematosus (SLE) patients and healthy controls and to evaluate its diagnostic value in SLE., Materials and Methods: The IFI44L promoter methylation level was measured in 49 patients with SLE and 50 healthy controls. Quantitative analysis of promoter methylation IFI44L gene in genomic DNA samples extracted from peripheral blood mononuclear cells was examined in SLE patients and healthy controls. The level of DNA methylation was compared between SLE patients and healthy controls as well as within SLE patient groups based on the presence of renal involvement. Moreover, diagnostic values of IFI44L were calculated., Results: The IFI44L promoter methylation level in SLE patients was significantly lower than healthy controls (median, 43.8 vs. 57, respectively; P = 0.008). The level of IFI44L promoter methylation was not significantly different between SLE patients with renal involvement and SLE patients without renal involvement (84.6% vs. 92.7%, respectively; P = 0.774). The IFI44L promoter methylation level ≤94.3% was the best cutoff point with a sensitivity of 91.8% and a specificity of 38% to distinguish patients with SLE from healthy individuals., Conclusion: The level of IFI44L promoter methylation from whole peripheral blood in Iranian SLE patients was significantly lower than healthy controls. Furthermore, the DNA methylation level of IFI44L promoter was not associated with renal damage in patients with SLE., Competing Interests: There are no conflicts of interest., (Copyright: © 2019 Journal of Research in Medical Sciences.)

Objectives: Calprotectin (S100A8/A9) appears to function as a tumor suppressor in head and neck squamous cell carcinoma (HNSCC) and expression in the carcinoma cells and patient survival rates are directly related. We seek to characterize the suppressive role of calprotectin in HNSCC., Aims: (1) Investigate changes in S100A8/A9 expression as oral carcinogenesis progresses and (2) determine whether intracellular calprotectin can regulate epidermal growth factor receptor (EGFR), a negative prognostic factor, in HNSCC., Materials and Methods: Using immunohistochemistry (IHC), S100A8/A9 was analyzed in HNSCC specimens (N = 46), including well-differentiated (WD, N = 19), moderately-differentiated (MD, N = 14), poorly-differentiated (PD, N = 5) and non-keratinizing/basaloid (NK/BAS, N = 8), and premalignant epithelial dysplasias (PED, N = 16). Similarly, EGFR was analyzed in HNSCCs (N = 21). To determine whether calprotectin and EGFR expression are mechanistically linked, TR146 HNSCC cells that are S100A8/A9-expressing or silenced (shRNA) were compared for EGFR levels and caspase-3/7 activity using western blotting and immunofluorescence microscopy., Results: In normal oral mucosal epithelium, S100A8/A9 stained strongly in the cytoplasm and nucleus of suprabasal cells; basal cells were consistently S100A8/A9 negative. In PED and HNSCC, S100A8/A9 expression was lower than in adjacent normal epithelial tissues (NAT) and declined progressively in WD, MD, PD and NK/BAS HNSCCs. S100A8/A9 and EGFR levels appeared inversely related, which was simulated in vitro when S100A8/A9 was silenced in TR146 cells. Silencing S100A8/A9 significantly reduced caspase-3/7 activity, whereas EGFR levels increased., Conclusions: In HNSCC, S100A8/A9 is directly associated with cellular differentiation and appears to promote caspase-3/7-mediated cleavage of EGFR, which could explain why patients with S100A8/A9-high tumors survive longer., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Rheumatoid arthritis (RA) is a rheumatic disease that could be disabling if not treated. The aim of RA therapy is to resolve tenderness and swelling in the joints. The present study was conducted to compare two methods of RA treatment with disease-modifying anti-rheumatic drugs (DMARDs) and DMARDs with biologic drugs in two groups of patients., Materials and Methods: The present study was a nonrandomized clinical trial which was conducted from July to September 2017 on 110 patients who were selected based on the American College of Rheumatology (2010) criteria for RA. Patients were divided into two groups of 55: Groups A and B. For the treatment of Group A, prednisolone along with one or two drugs from the DMARDs combinations was used. Group B received one biologic drug besides with the drugs of the group A. T -test and covariance analysis was used to compare the outcomes of both groups., Results: Disease activity score (DAS-28) at the beginning of the study was 4.23 (0.81) in Group A and 4.51 (0.7) in Group B ( P = 0.05). At the end of the study, DAS-28 was 3.52 (0.79) in Group A and 3.75 (0.85) in Group B ( P = 0.1). DAS-28 activity index had a significant difference between both two groups at the beginning of the study ( P = 0.05), but at the end of the study, the difference was not statistically significant ( P = 0.1)., Conclusions: Simultaneous use of DMARDs and biologic drugs in RA patients could lead to improvement the disease symptoms and decrease the severity and activity of the disease., Competing Interests: There are no conflicts of interest.

Competing Interests: There are no conflicts of interest.

Competing Interests: There are no conflicts of interest.

Background: To date, there is no standard approach to manage and to improve central sleep apnea (CSA). The most applicable therapeutic approaches are positive airway pressure therapy (PAP), bi-level PAP therapy (BIPAP), supplemental O 2 and servo ventilation, or a combination of two approaches. Given the high prevalence of heart disease (HF) and/or concomitants of other diseases and opioid use worldwide; it seemingly requires evaluation of patients' conditions in response to each abovementioned approach to select the most effective approach., Materials and Methods: This longitudinal cross-sectional study included 64 CSA patients who had undergone continuous PAP (CPAP), CPAP + O 2 , and BiPAP. Hence, if a patient was nonresponsive to a treatment, the next was applied. If the patient was nonresponsive to all approaches, oxygen alone was administered. The collected data were analyzed with SPSS., Results: The study of 64 CSA patients showed that frequencies of response to CPAP, CPAP + O 2 , and BiPAP were 42.2%, 20.3%, and 28.1%, respectively. While 9.4% of patients with histories of congestive heart failure (CHF) and ischemic heart disease (IHD) who were older than others and with the highest apnea-hypopnea index, were nonresponsive to all approaches. CPAP therapy showed more appropriate results in patients with CHF and IHD. Furthermore, patients with the history of opioid use showed the most positive results in response to CPAP and BIPAP., Conclusion: The results suggest that CPAP and BIPAP are, respectively, the most effective therapeutic approaches to CSA in patients with the histories of HF and opioid use, but CPAP + O 2 could be reliable in some conditions as well. Therefore, it may require further studies to be clarified., Competing Interests: There are no conflicts of interest.

Background: Hypertension is a major risk factor for premature disability and death and is the leading risk factor for global disease burden. The present study aimed to assess the rates of prevalence, awareness, treatment, and control of hypertension in a sample of teachers, staff, and students at Isfahan University of Medical Sciences (IUMS). Methods: This cross-sectional survey was conducted from January to September 2015 on the staff, teachers, and students at IUMS. A total of 1500 subjects were randomly selected and were invited to participate in the survey. Hypertension was defined as an average of 2 blood pressure measurements of at least 140/90 mmHg. The rate of awareness was determined based on self-reports, treatment was defined as the regular use of blood pressure-lowering medications, and control was defined as the maintenance of blood pressure below 140/90 mmHg. Results: The study population comprised 1317 individuals (45.9% female) at a mean age of 41.4±9.5 years. The prevalence rate of hypertension was 17.5% (231 of 1317 participants), and the rate of awareness was 54.5% (126 of 231 hypertensive patients). Seventy-nine (62.7%) patients were undergoing treatment, and 51.9% (41 of 79) controlled their disease. Institutional position (P<0.017), age (P<0.001), body mass index (P<0.001), education level (P<0.001), smoking status (P<0.001), and history of diabetes mellitus (P<0.001) were the most frequent risk factors associated with hypertension. Conclusion: The percentage of the hypertensive subjects who were aware, treated, and controlled was unacceptably low in our sample at IUMS. Hypertension is, therefore, a major health problem in this state institution.

Background: This study was designed to evaluate the effect of melatonin on nonalcoholic fatty liver disease (NAFLD) in compared to placebo., Materials and Methods: A total of 100 patients with histopathological diagnosis NAFLD in two groups of case and control received oral melatonin or placebo thrice daily for 3 months. Collected data were weight, waist, systolic blood pressure (SBP), diastolic blood pressure (DBP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), high sensitive C-reactive protein (hsCRP), fatty liver grade, and side effects which were measured at baseline and after treatment period using standard clinical chemistry techniques., Results: Before treatment the mean of weight, waist, SBP, DBP, ALT, AST, and hsCRP between cases and controls were similar ( P > 0.5). After treatment, only the differences in the mean of hsCRP in cases was significantly lower than controls ( P = 0.003). In case group, all variables after treatment were significantly decreased compare to baseline ( P > 0.5) and only AST after treatment was similar to before treatment ( P > 0.5). The mean of a decrease in the level of weight, waist, SBP, and ALT were not statistically significant between groups ( P > 0.5). In the case group in compare to control group the level of DBP, AST, and hsCRP significantly more decreased. After treatment fatty, liver grade was statistically improved in more cases than controls ( P = 0.001). Side effects were similar between the two groups., Conclusion: Melatonin significantly decreases liver enzymes, so the use of melatonin in patients with NAFLD can be effective., Competing Interests: There are no conflicts of interest.

We herein report the case of a 64-year old woman with recurrent attacks of hypokalemic quadriparesis which resulted from distal renal tubular acidosis (dRTA) secondary to Sjögren syndrome. The patient presented with sudden onset quadriparesis. A physical examination showed symmetric weakness of all four limbs. Severe hypokalemia (1.8 mEq/L), accompanied by normal anion gap metabolic acidosis, a positive urine anion gap and an inappropriately high urine pH pointed toward the diagnosis of dRTA. Further investigations disclosed primary Sjögren syndrome, which had not previously been recognized. On the basis of the current report and a review of the literature we suggest investigating the possibility of Sjögren syndrome in all patients with clinically unexplained dRTA.

Background: Increased proteinuria would lead to a larger risk for renal failure in the long term. Therefore, proteinuria requires immediate and thorough evaluation. This study was designed to evaluate the effects of pioglitazone on proteinuria in patients with non-diabetic renal disease., Methods: In this self-controlled clinical trial study, forty four non-diabetic patients aged 18 and more, who had renal disease and a stable proteinuria of over 0.5 g in 24 hour, were studied. All patients received 15 mg of daily pioglitazone for 4 months. Urine protein excretion was measured as a main end point prior to the study, at the end of the 2nd and 4th months of treatment, and 2 and 4 months after the cessation of the active drug. Other evaluated variables included systolic blood pressure, serum creatinine, urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting blood sugar (FBS), blood urea nitrogen (BUN) and glomerular filtration rate (GFR) levels., Results: Proteinuria (mean ± SEM) prior to the study, at the 2nd and 4th months of the treatment, and 2 and 4 months after the cessation of pioglitazone were 1088.6 ± 131.1, 699.9 ± 118.3, 433.9 ± 68.7, 416.1 ± 54.9 and 646.9 ± 89.1, respectively (p < 0.001). In addition, the reduction of 24-hour urine protein was statistically significant for both male and female patients (p < 0.001 for both)., Conclusions: A reduction of proteinuria in patients with non-diabetic renal disease was observed during the 4-month treatment with pioglitazone which continued for 2 months after the cessation of the treatment. However, 4 months after the cessation of the treatment, a little increase was detected in the level of proteinuria.

Background: Chronic hemodialysis patients frequently require vascular access through central venous catheters (CVCs). The most significant complication of these catheters is infection. This risk can be lowered by the use of an antibiotic-Heparin lock. This study focuses on hemodialysis patients using Tunneled-cuffed catheters (TCC), to assess the rate of catheter-related infections (CRI) in catheter-restricted filling with Cefotaxime and Heparin in end stage renal disease patients., Methods: A double-blind randomized study was conducted to compare 5000 U/ml Heparin plus10 mg/ml cefotaxime (CE/HS) as catheter-lock solutions, with Heparin (5000 U/ml) alone. A total of 30 patients with end-stage renal disease and different etiologies, were enrolled for chronic hemodialysis with permanent catheters from December 2009 to March 2010. These patients were randomly assigned to two groups of 15 members. Blood samples were collected for culture, sensitivity, and colony count, from the catheter lumen and the peripheral vein. CRI was considered as the end point., Results: The rate of CRI was significantly lower in the cefotaxime group versus control group (p < 0.001). No exit site infection was occurred in both groups. Infection-free survival rates at 180 days were 100% for the CE/HS group, and 56% for the HS group., Conclusions: Antibiotic lock therapy using cefotaxime reduces the risk of CRI in hemodialysis patients.

The persistence at birth of the omphalomesenteric (vitelline) duct may result in life-threatening consequences. Early identification of this congenital anomaly is essential for prompt surgical treatment to eliminate the risk of prolapse and herniation. A neonatal umbilical polyp may indicate the presence of an omphalomesenteric duct remnant. We describe the diagnosis and surgical treatment of an infant with an umbilical polyp. We also present an overview of the diagnosis and treatment of vitelline duct remnants and their associated anomalies.

Background & Aims: Intraductal papillary-mucinous tumor (IPMT) of the pancreatic ducts is increasingly recognized. This study investigated if clinical, imaging, or, histological features predicated outcome, formulated a treatment algorithm, and clarified relationships among IPMT, mucinous cystic neoplasms of the pancreas (MCN), and chronic pancreatitis., Methods: The medical records, radiographs, and pathological specimens of 15 patients with IPMT (dilated main pancreatic duct or branch ducts with mucin overproduction) who were evaluated between October 1983 and January 1994 were reviewed., Results: One patient had hepatic metastases. Fourteen underwent an operation (6 distal pancreatectomy, 4 total pancreatectomy, and 4 pancreaticoduodenectomy); all had dysplastic intraductal epithelium and chronic pancreatitis, whereas 3 had invasive adenocarcinoma. After a median of 25 months, 10 patients were alive; 3 of 4 with malignant and 2 of 11 with benign IPMT died (P < 0.05). Patients with or without carcinoma had similar clinical and radiographic features. A clinical diagnosis of chronic pancreatitis had been made in 9 patients with benign IMPT and in none with malignant IPMT (P < 0.05)., Conclusions: IPMT is a dysplastic and likely precancerous lesion that is frequently diagnosed as chronic pancreatitis and is separate from MCN. Because it is not possible to distinguish noninvasive from invasive IPMT preoperatively, complete surgical excision of the dysplastic process is our treatment of choice whenever appropriate.

The so-called hairy or teratoid polyp is a rare lesion of bigerminal origin that comprises elements derived from both ectodermal and mesodermal cell lines. In this article we report the presence of meningothelial elements in a hairy polyp, a previously undescribed component of this entity. The lesion was characterized by a pedunculated outgrowth from the hard palate. The surface of the outgrowth was covered by squamous epithelium and a central core of fibroadipose tissue, pilosebaceous glands, cleftlike pseudovascular spaces, and groups of epithelioid cells. These reticulated and cellular foci had the immunohistochemical and ultrastructural features of meningothelial tissue.