houshang rafatpanah

Asthma is a common and major allergic disease in the world. We aimed to investigate the impact of supplements with vitamin D, folic acid, selenium, zinc, and copper in patients with moderate to severe asthma.

In this clinical trial study 70 patients above six years old with moderate to severe asthma, were divided into two groups, randomly; one group received daily Asmavit syrup, 10 ml (Asmavit, Vitabiotics Ltd, London, UK), and the other group received daily 1000 IU vitamin D3 drops (Asmavit, Vitabiotics Ltd, London, UK) for two months along with ordinary treatment for asthma. Clinical and physical examinations, immunological and biochemical tests were carried out for each patient before and after the treatment.

The mean age of patients was 39.9± 14.7 years old, and the mean disease duration was 8.8 ± 9.8 years. A significant increase in lung function, asthma control, and quality of life score tests was observed in both groups after the treatment (P< 0.05). There was no significant difference in cytokines expression levels before and after the treatment with vitamin D3 or Asmavit (P> 0.05). Serum levels of selenium and folic acid before treatment were correlated with disease severity, while post-treatment vitamin D levels significantly increased FEV1 (P> 0.05). Oxidative stress levels reduced in both groups, with greater reduction in the vitamin D group (P< 0.05).

Supplements, particularly vitamin D, when combined with standard asthma treatment, may effectively improve clinical symptoms and enhance the quality of life for asthmatic patients.

Acute-phase inflammatory and oxidative response following major gastrointestinal surgeries may lead to critical conditions in pediatric patients. Selenium plays a key role in the antioxidant defense system and anti-inflammatory pathways, which are important in the clinical outcomes of patients admitted to the pediatric intensive care unit (PICU). The present study aimed to assess the possible correlations between serum selenium levels and clinical outcomes in PICU patients undergoing major gastrointestinal surgeries.

This cross-sectional study was conducted on 66 critically ill pediatric patients who were in the postoperative stage of major gastrointestinal surgeries. Serum selenium concentration was assessed using the atomic absorption method, and the clinical outcomes were collected prospectively.

Serum selenium concentration upon PICU admission was 38.9±9.8 ng/ml, and no significant correlation was observed between the serum selenium level and the nutritional status of the patients. Furthermore, no significant associations were denoted between the serum selenium concentration and some clinical outcomes, such as the duration of ventilator dependency, PICU length of stay, and PICU/28-day mortality. However, the statistical analysis of the obtained data showed negative, significant associations between the serum selenium concentration, infection rate, and length of hospital stay (P= 0.01 and P=0.04, respectively).

According to the results, serum selenium concentration decreased in the post-gastrointestinal-surgery patients admitted to the PICU upon PICU admission, and the reduction was associated with prolonged hospitalization and a higher infection rate.

The immunoregulatory properties of mesenchymal stromal/stem cells (MSCs) bring a promise for the treatment of inflammatory diseases. However, their ability to suppress the immune system is unstable. To enhance their effectiveness against immune responses, it may be necessary to manipulate MSCs. Although some dsRNA transcripts come from invading viruses, the majority of dsRNA has an endogenous origin and is known as endo-siRNA. DICER1 is a ribonuclease protein that can generate small RNAs to modulate gene expression at the post-transcriptional level. We aimed to evaluate the expression of several immune-related genes at mRNA and protein levels in MSCs overexpressing DICER1 exogenously.

In this comparative transcriptomic experimental study, the adipose-derived MSCs (Ad-MSCs) were transfected using the pCAGGS-Flag-hsDicer vector for the DICER1 overexpression. Following the RNA extraction, mRNA expression level of DICER1 and several inflammatory cytokines were examined. We performed a relative real-time polymerase chain reaction (PCR) assay and transcriptome analysis between two groups including DICER1- transfected MSCs and control MSCs. Moreover, media from the transfected MSCs were evaluated for various interferon response factors by ELISA.

The overexpression of DICER1 is associated with a significant increase in the mRNA expression level of COX-2, DDX-58, IFIH1, MYD88, RNase L, TLR3/4, and TDO2 genes and a downregulation of the TSG-6 gene in MSCs. Moreover, the expression levels of IL-1, 6, 8, 17, 18, CCL2, INF-γ, TGF-β, and TNF-α were higher in the DICER1-transfected MSCs group.

It seems that the ectopic expression of DICER1 in Ad-MSCs is linked to alterations in the expression level of immune-related genes. It is suggested that the manipulation of immune-related pathways in MSCs via the Dicer1 overexpression could facilitate the development of MSCs with distinct immunoregulatory phenotypes.

Glucocorticoid receptor α (GRα) gene is a transcription factor with clinically significant immune-modulating properties in various autoimmune diseases. However, the expression pattern of the GRα gene and associations with clinical features in patients with systemic lupus erythematosus (SLE) is controversial. This study aimed to assess the correlation between the GRα expression and different clinical and laboratory-related parameters in SLE patients.

A total of 45 women with newly diagnosed SLE and 31 gender and age-matched healthy controls were enrolled in this cross-sectional study. The real-time quantitative PCR (qRT-PCT) method evaluated the differences in GRα expression in peripheral blood mononuclear cells from cases and controls. The correlation between the GRα gene expression levels, clinicolaboratory features, and potential prognostic application was also analyzed.

Compared to the healthy individuals, the GRα gene expression in newly diagnosed SLE patients who did not receive any treatment was numerically reduced, but this reduction did not achieve statistical significance P=0.87. No significant correlation was also found with the activity and severity of SLE according to SLEDAI2K (P=0.41). The GRα gene expression showed a negative correlation with CRP (P=0.034) and a positive correlation with lupus anticoagulant (P=0.039) levels in SLE. The receiver operating characteristic (ROC) curve analysis indicated that the GRα expression level might be a predictor biomarker for low CRP and positive lupus anticoagulant in SLE, respectively.

This study proposed that expression of the GRα in newly diagnosed lupus patients has no statistically significant difference with healthy age and sex-matched controls. Besides, its expression does not correlate with lupus disease activity according to SLEDAI2k. However, further studies in this area are required.

Increased vascular permeability is one of the main mechanisms in the production of pleural effusion (PE) and vascular endothelial growth factor (VEGF) has a significant role in its pathogenesis. This study aimed to compare pleural levels of VEGF in transudative and exudative PEs besides the other pleural markers.
In this prospective cross-sectional study, 80 patients with PE were divided into 4 groups as transudative (N=15), parapneumonic (N=15), tuberculosis (N=25), and malignant (N=25) PE. Biochemical tests measured the pleural protein, LDH, cholesterol, glucose, polymorphonuclear cell (PMN), and lymphocyte. ELISA measured the pleural VEGF level.
Out of 80 patients, 51 were male, and the total mean age was 55.34±18.53. There were significant differences in pleural VEGF between exudative and transudative effusion (P<0.001) and between malignant and benign effusion (P=0.014). The highest mean difference in pleural VEGF levels was seen in the comparison of transudative and malignant groups (Mean difference=-136.56; P<0.002). The VEGF level in 3 groups was not significantly different; transudative vs tuberculous, parapneumonic vs tuberculous, and parapneumonic vs malignant. Furthermore, VEGF higher than 73.09 pg/ml had a 64% sensitivity and 82% specificity for the diagnosis of malignancy. Among pleural markers (VEGF, protein, LDH, and glucose), VEGF had the highest area under curve (AUC=0.734). Moreover, pleural protein, LDH, and glucose levels significantly correlated with pleural VEGF; however, pleural cholesterol, PMN, and lymphocyte were not correlated.
VEGF is assumed as an important factor in the pathogenesis of exudative PE, especially malignant effusion. It can distinguish between lymphocytic exudative PEs.

The B18R protein encoded by the Vaccinia virus decoys Type 1 interferons and inhibits the activity of several type I IFN members. In vitro transcription protocols benefit from this molecule’s involvement in enhancing cell viability by inhibiting interferon signal transduction. As a result of their immunomodulatory properties and potential to regenerate, mesenchymal stromal cells (MSCs) are increasingly considered an alternative treatment for a wide range of immune disorders. In this study, we investigated the modification of expression of several genes involved in immune-related pathways after preconditioning MSCs with two immune stimuli, including poly(I:C) and LPS. 

ASCs were isolated and primed with B18R, and after exposure to poly(I:C) and LPS, the expression of the same sets of genes as in the previous experiment was evaluated. Following total RNA isolation from primed cells and cDNA preparation, real-time quantitative PCR was performed for several immunomodulatory and immune-related genes, including IDO1, TDO2, COX-2, TGF-β1, TNF-α, IL-1β, IL-6, TLR3, TLR4, and MCP-1. 

Pretreatment of MSCs with poly(I:C) and LPS significantly increased the expression of all mentioned genes, while upon the B18R challenge followed by poly(I:C) and LPS treatment, they were down-regulated. Finally, it was observed that the relative expression level of IFN-β has significantly decreased in MSCs+B18R+poly(I:C) and LPS in comparison with these groups without B18R.

The data indicated that the presence of B18R prevents the overexpression of several immune-related genes, which are overexpressed in the in vitro inflammatory environment.

Human T leukemia virus type one (HTLV-1) causes two life-threatening diseases in around five percent of infected subjects, a T cell malignancy and a neurodegenerative disease. TAX and HBZ are the main virulence agents implicated in the manifestation of HTLV-1–associated diseases. Therefore, this study aims to produce these HTLV-1 factors as recombinant Fc fusion proteins to study the structures, their immunogenic properties as vaccines, and their capability to produce specific neutralization antibodies.

TAX and HBZ sequences were chosen from the NCBI-nucleotide database, then designed as human Fc chimers and cloned into Pichia pastoris. Produced proteins were purified by HiTrap affinity chromatography and subcutaneously injected into rabbits. Rabbit Abs were purified by batch chromatography, and their neutralization activities for the HTLV-1-infected MT-2 cell line were assessed. Furthermore, the protective abilities of recombinant proteins were evaluated in Tax or HBZ immunized rabbits by MT-2 cell line inoculation and measurement of HTLV-1-proviral load.

Specific Abs against Tax and HBZ can eliminate 2 million MT-2 cells in 1/1000 dilution in vitro. In challenging assays, the immunization of the animals using Tax or HBZ had no protective activity as HTLV-1 PVL was still positive.

The result suggests that recombinant TAX and HBZ: hFcγ1 proteins can produce a proper humoral immune response. Therefore, they could be considered a passive immunotherapy source for HTLV-1-associated diseases, while total TAX and HBZ proteins are unsuitable as HTLV-1 vaccine candidates.

Despite advances in the treatment of adult T-cell leukemia/lymphoma (ATLL), the survival rate of this malignancy remains significantly low. Auraptene (AUR) is a natural coumarin with broad-spectrum anticancer activities. To introduce a more effective therapeutic strategy for ATLL, we investigated the combinatorial effects of AUR and arsenic trioxide (ATO) on MT-2 cells. The cells were treated with different concentrations of AUR for 24, 48, and 72 hr, and viability was measured by alamarBlue assay. Then, the combination of AUR (20 μg/ml) and ATO (3 μg/ml) was administrated and the cell cycle was analyzed by PI staining followed by flow cytometry analysis. In addition, the expression of NF-κB (REL-A), CD44, c-MYC, and BMI-1 was evaluated via qPCR. Assessment of cell viability revealed increased toxicity of AUR and ATO when used in combination. Our findings were confirmed by accumulation of cells in the sub G1 phase of the cell cycle and significant down-regulation of NF-κB (REL-A), CD44, c-MYC, and BMI-1. Obtained findings suggest that combinatorial use of AUR and ATO could be considered for designing novel chemotherapy regimens for ATLL.

Recently, several infectious agents including Epstein-Barr virus and Escherichia coli have been suggested as possible contributing factors to the pathogenesis of rheumatoid arthritis (RA). This study was designed to compare serum and synovial fluid markers of herpes simplex virus (HSV) and Helicobacter pylori of RA and osteoarthritis (OA) patients.This comparative study was conducted on two hundred OA and RA patients who referred to the Rheumatic Diseases Research Center (RDRC) affiliated with Mashhad University of Medical Sciences, Mashhad, Iran, from March 2015 to 2016. Synovial fluid was obtained from all individuals. Two years later, participants attended a follow-up session to collect blood samples for serum markers of these two infectious agents.Twenty-five patients (96.15%) in the RA group and 23 individuals (92%) in the OA group had positive serum IgG antibodies for HSV. As for Helicobacter pylori, 13 individuals (50%) in RA and 12 individuals (48%) had positive serum IgG antibodies (p value = 0.66). In addition, 9 (34.6%) and 8 (30.8%) in the RA group and 10 (40%) and 3 (12%) in the OA group had positive serum IgA and IgM antibodies for Helicobacter pylori, respectively (p value = 0.89 and p value = 0.13, respectively). Collected fluid samples were negative for both Helicobacter pylori and HSV1 and 2 DNA particles in all individuals.Based on the results of the current study, there is no difference between RA and OA patients in terms of Herpes simplex virus and Helicobacter pylori infection.

HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory disorder associated with HTLV-1. Cytokines and inflammatory mediators have a major role in forming inflammation in HAM/TSP patients. This study aimed to measure the levels of IL-32, a proinflammatory cytokine associated with autoinflammatory disorders, and also cyclooxygenase -2 (COX-2) as a key mediator of inflammatory pathways in HAM/TSP patients and HTLV-1 asymptomatic carriers (ACs). Peripheral blood monocyte cells (PBMCs) were isolated from HAM/TSP patients, ACs, and healthy controls (HCs), and DNA and RNA were extracted to evaluate HTLV-1 proviral load (PVL) and expression of IL-32 and COX-2, using real-time PCR. Serum levels of IL-32 were determined by using an ELISA assay. The expression level of IL-32 was significantly higher in ACs compared with HAM/TSP patients and HCs (p 0.05, respectively). There were no statistically significant differences in the expression levels of Cox-2 and protein levels of IL-32 between the study groups.  HTLV-1 PVL was higher in HAM/TSP patients compared with ACs.  Results showed increased mRNA levels of IL-32 in ACs. Since HTLV-1 PVL in ACs is lower than in HAM/TSP patients, it could be concluded that IL-32 might be an HTLV-1 inhibitor that seems to control virus replication. Despite the difference in IL-32 mRNA levels between study groups, no statistically significant differences were observed in IL-32 serum levels. Also, there were no significant differences in COX-2 expression.

Several studies have reported that two promoter variants (c.-3279T>G and c.-3156G>A) in UDP-glucuronosyltransferase (UGT1A1) gene may contribute to neonatal hyperbilirubinemia. However, these variants have not been investigated in Iranian neonates. This cross-sectional study aimed to determine if the UGT1A1 promoter variants are significant risk factors associated with neonatal hyperbilirubinemia.

A total of 178 unrelated neonates, including newborns with neonatal jaundice (n=95) and healthy controls (n=83), were included in this study. Each individual was genotyped by the PCR-RFLP and COP-PCR at nucleotides -3279 and -3156, respectively, using fresh blood DNA. Logistic regression analyses were performed to assess the association of UGT1A1 promoter variants with the presence of significant hyperbilirubinemia. Anthropometric indices and clinical variables were also compared between the different genotype groups.

Allele and genotype analysis of the c.-3279T>G and c.-3156G>A variants showed no significant association with the risk of neonatal hyperbilirubinemia neither in the crude nor after adjustment for gestational age, gender, and birth weight in different genetic models (P>0.05). However, in haplotype-association analysis, only one haplotype (A-T) was found to be associated with the risk of neonatal hyperbilirubinemia (OR=0.19, 95% CI; [0.18–0.20], P=0.001).

This study failed to demonstrate that c.-3279T>G and c.-3156G>A variants alone might contribute to the risk of neonatal hyperbilirubinemia in Iranian neonates. However, the A-T haplotype may play a significant role in increasing the risk of hyperbilirubinemia.

Rheumatoid arthritis (RA) is described as a systemic and chronic autoimmune disease characterized by inflammatory polyarthritis. Lymphocyte-activation gene 3 (LAG3) is a membrane glycoprotein expressed on activated, exhausted, and regulatory T cells. LAG3 plays a major role in the function of Treg cells. LAG3 also has a soluble form (sLAG3) with a controversial role. To evaluate the serum level of sLAG3 in rheumatoid arthritis patients in comparison with healthy subjects and assess its association with the disease activity. This cross-sectional study was performed on 105 patients with RA referred to Ghaem hospital of Mashhad, Iran. We divided the participants into four groups: 1) 35 untreated patients with newly diagnosed RA, 2) 35 active RA patients, 3) 35 patients in the remission phase of the disease, and 4) 35 healthy individuals matched in terms of age and sex. After completing the interview and questionnaire, the sLAG3 was evaluated by commercial ELISA. The serum level of sLAG3 significantly increased in RA patients (76.78 ng/ml) as compared with the healthy participants (51.67, p=0.002). However, there was no significant difference between RA patients in the remission phase of the disease (114.11 ng/ml) and those with moderate to high disease activity (63.06 ng/ml, p=0.076). This study provided insights into the role of sLAG3 in the immunopathogenesis of ‎RA disease, but further investigations are also warranted.

Prevention and treatment of the Human T-cell leukemia virus, type 1 (HTLV-1) which was discovered nearly 40 years ago, still remain challenging. The reported high prevalence of HTLV-1 in some countries around the world triggered an open letter to the World Health Organization (WHO), urging action against HTLV-1 infection in 2018. This highlights the importance of virus elimination strategies to eradicate HTLV-1 infection. In Iran, we have documented our experiences with the virus in order to achieve and promote the possible ways to manage, control, and eliminate HTLV-1. Although there has been considerable progress apropos of HTLV-1, a series of additional challenges need to be tackled to control HTLV-1 infection in Iran.

 Pediatric observational studies have indicated that most critically ill children have low serum selenium level, which is associated with the increased incidence of multiple organ failure and deteriorated clinical outcomes. Selenium plays a key role in the endogenous antioxidant defense mechanism and inflammatory pathways.

 The present study aimed to assess the effects of high-dose selenium supplementation on the improvement of inflammatory and oxidative stress indices, as well as clinical outcomes, in pediatric patients with severe oxidative stress and inflammation following major gastrointestinal surgeries.

 This prospective, single-blind, randomized, parallel group superiority trial was conducted at the pediatric intensive care unit (PICU) of Akbar Pediatric Hospital in Mashhad, Iran in 2019. Patients were assigned to the supplementation (high-dose selenium: 20 µg/kg/d) and control groups (placebo with the recommended dietary allowance doses of selenium) using stratified blocks. Among 72 eligible critically ill children after gastrointestinal surgery, 66 patients completed the study. Inflammatory markers were measured and compared between the groups, including high-sensitivity C-reactive protein (hsCRP), interleukin 1 beta (IL-1β), prooxidant-antioxidant balance (PAB) assay, and clinical outcomes. Data analysis was performed in SPSS version 20 using the intention-to-treat approach.

 Only 14 patients had optimal serum selenium concentrations before the surgery and PICU admission. At the end of the study, 90.6% of the patients (n = 29) in the intervention group and 100% (n = 34) of those in the placebo group had suboptimal serum selenium levels (< 50 ng/mL). Although supplementation with high-dose selenium decreased the inflammatory markers in the post-surgical critically ill children (-18 mg/mL and -37.5 pg/mL for hsCRP and IL-1β, respectively), the administered dose could not improve the serum glutathione peroxidase (GPx) concentrations as the selenium functional marker, as well as the PAB assay as the single test to assess the balance/imbalance of the oxidants and antioxidants simultaneously. Additionally, clinical outcomes such as infections, length of ICU stay, and 28-day mortality did not improve after the intervention.

 According to the results, high-dose selenium supplementation (20 µg/kg/d) in the post-surgical critically ill children could improve the serum inflammatory markers. However, the changes were suboptimal with no significant effects of the serum GPx concentrations, antioxidant defense system, and clinical outcomes.

Vitamin D insufficiency and deficiency can be associated with adverse effects on fetus and pregnancy outcomes. This study aimed at evaluating the effect of 1,25VitD3 on specific transcription factor and markers of Tregs and Th17 cells in the PBMCs of women with URPL as a case group and the PBMCs of healthy women as a control group.

Samples from 20 non-pregnant patients with a history of URPL were compared to 20 normal non-pregnant women. PBMCs were divided into three wells for each subject in the presence of 1,25VitD3 (50 nM, for 16 hours), PHA (10 µM; positive control) and without any treatment (negative control). By Real-time PCR (Taqman assay), specific transcription factors of Tregs and Th17 cells, FOXP3, ROR-γt, GITR, and CTLA-4 mRNA expressions in two groups were measured.

FOXP3/ROR-γt mRNA expression in PBMCs decreased significantly in women experiencing URPL compared to the control group (p = 0.0001). Although 1,25VitD3 (50 nM) increased FOXP3 gene expression (p = 0.0001), it did not significantly affect ROR-γt gene expression. 1,25VitD3 treatment significantly increased FOXP3/ROR-γt mRNA expression from baseline in the PBMCs of the fetal loss group compared to that of the control group (p = 0.01). The 1,25VitD3 also increased GITR gene expression (p = 0.017) in the PBMCs of URPL women compared to the controls.

Vitamin D deficiency may be a contributor to recurrent pregnancy loss and suggests that the supplementation of women with Vitamin D pre-pregnancy may be protective against URPL via affecting Tregs signature genes, FOXP3 and GITR.

Human T cell leukaemia virus type 1 (HTLV-1) is associated with adult T cell leukaemia (ATL), a malignant lymphoproliferative disease that infects CD4 T cells. It is not clear why the majority of HTLV-1-infected individuals remain asymptomatic carries (ACs) and a minority develop ATL. Cellular immune response has a critical role in ATL and destroys malignant and HTLV-1-infected cells. Perforin and granzyme have important functional roles in apoptosis and destruction of infected cells. In the present study we examined the role of perforin and granzyme in ATL patients and ACs.

Peripheral blood mononuclear cells (PBMCs) were isolated from ATL patients and ACs by using Ficoll-hypaque density centrifugation. RNA was extracted and cDNA was synthesized. A real-time PCR TaqMan method was designed and optimized for evaluation of perforin, granzyme, tax, and HBZ gene expression. HTLV-1 proviral load (PVL) was quantified in patients with ATL and ACs.

The mRNA expression of tax and HBZ was significantly higher in ATL patients than ACs (P=0.011 and P=0.0001,respectively). The HTLV-1 PVL was higher in ATL patients compared to with AC group (P=0.015). There was a significant increase in perforin gene expression in ACs compared with ATL patients (P=0.002).  Furthermore, the expression of granzyme was also higher in ACs compared with ATL patients, and significant differences were observed between the two groups (P=0.036).

Low expression of perforin and granzyme in ATL patients seems to influence the efficiency of CTL function and destruction of HTLV-1-infected cells, which might contribute to the disease pathogenesis.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoid malignancy with low survival rate and distinct geographical distribution. In search for novel chemotherapeutics against ATLL, we investigated the combinatorial effects of parthenolide, a sesquiterpene lactone with valuable pharmaceutical activities, and arsenic trioxide (ATO) in vitro. MT2 cells, an ATLL cell line, were treated with increasing concentrations of parthenolide (1.25, 2.5, and 5 μg/ml) and ATO (2, 4, 8, and 16 µM) to determine their IC50. Then, cells were treated with a combination of sub-IC50 concentrations of parthenolide (1 μg/ml) and ATO (2 µM) for 72 hr. Cell viability and cell cycle changes were assessed by Alamar blue and PI staining, respectively. To understand the mechanisms responsible for observed effects, expression of CD44, NF-κB (REL-A), BMI-1, and C-MYC were investigated by real-time PCR. Assessment of cell viability indicated that parthenolide significantly increased the toxicity of ATO, as confirmed by accumulation of MT2 cells in the sub G1 phase of the cell cycle. Moreover, molecular analysis revealed significant down-regulation of CD44, NF-κB (REL-A), BMI-1, and C-MYC upon combinatorial administration of parthenolide and ATO in comparison with relevant controls. Taken together, present results showed that parthenolide significantly enhanced the toxicity of ATO in MT2 cells. Therefore, the future possible clinical impact of our study could be combinatorial use of parthenolide and ATO as a novel and more effective approach for ATLL.

Coronary artery disease (CAD) is known as a life threatening disease, worldwide. In this study the role of HTLV-1 infection was evaluated on cardiac involvement in an endemic region of northeastern Iran. Serologic and molecular tests for HTLV-1 infection were carried out in subjects who had coronary angiography. A real-time PCR, TaqMan method, to quantify HTLV-1 proviral load (PVL), and routine hematological and biochemical tests were performed for study subjects. Twenty nine patients were HTLV-1+CAD+ and 13 cases were HTLV-1+CAD-. Although, there were no significant differences for risk factors like FBS, HDL, triglyceride, systolic and diastolic blood pressure (Cbp, Dbp), waist circumference (WC), hip circumference (WL), cholesterol  (P=0.003), and LDL (P=0.007) levels, and monocyte count (P=0.05) had meaningful differences. The mean HTLV-1 PVL in HTLV-1+CAD+ subjects was 992.62±120 which was higher compared with HTLV-1+CAD- group (406.54±302 copies/104 PBMCs). Moreover, HTLV-1 PVL in males (833±108) was lower compared with females (1218±141 copies/104 PBMCs) (P=0.05). Patients with HTLV-1-PVL of more than 500 copies/104 had more diffused atherosclerosis plaque than patients with less than 500 (OR=6.87, 95% CI=1.34-35.05; P=0.016). Furthermore, patients with diffused coronary atherosclerosis had significantly higher levels of HTLV-1 PVL than patients with middle, proximal, and normal location of coronary sclerotic lesions (P<0.05). Taken together, in endemic area, HTLV-1 infection, more likely is a facilitating factor for heart complications and the high HTLV-1 PVL might affect CAD manifestations.

From the academic perspective, the differences between the educational curriculum of Medical Doctor (MD) and Doctor of Philosophy (Ph.D.) are quite clear in basic medical sciences. Therefore, it is necessary to establish a more effective relationship between these two programs to provide better clinical services and conduct joint research projects. In this regard, the present study was conducted to review the evidences of the Ph.D. in medical sciences to MD course  in other countries and to make suggestions for set up this course in Iran.

This study was conducted by reviewing the English articles published from 1960 to 2019 in PubMed, Scopus, Google Scholar, and Web of Science databases using the keywords, such as "Ph.D." AND "MD" OR "Ph.D. to MD course" in combination with the "Curriculum" OR "Program" OR "Course".

The results of the present study showed that the plans of the Ministry of Health in encouraging MD graduates to enter the Ph.D. courses in medical sciences have been effective in promoting clinical services. Therefore, this experience can be used to set up the Ph.D. to the MD course. Moreover, given the existence of the Ph.D. to MD course at some prestigious universities worldwide and considering the medical education program in Iran, this course can be set up at some internally accredited universities.    

It seems that launching the Ph.D. to MD courses in Iran as a 4-year course can provide an effective link between basic and clinical sciences, improve the quality of medical research, and increase the motivation of Ph.D. students and graduates.

Context: Asthma, characterized by airway inflammation, is a common chronic disease of childhood. Cytokines and chemokines could be used in the diagnosis, treatment, and management of asthma severity in children. In this review, we have explained the application of cytokines and chemokines as biomarkers in pediatric asthma. Evidence Acquisition: All related articles were separately searched by two researchers using the following keywords in PubMed, Scopus, and Embase databases: Cytokine biomarkers, chemokines biomarkers, and children asthma. Articles published from 2000 to 2017 were investigated in the research, and 28 articles were included in the final analysis for this review. About cytokines, serum Interleukin 4 (IL-4) level is a marker of the presence of asthma, and IL-13 is a key cytokine involved in the manifestation of asthma symptoms. High IL-13 concentration and number of IL-13+ cells in the bronchial submucosa specimens are characteristic of severe asthma. Serum IL-5 concentration 3.1 times in children with severe asthma. IL-17 is involved in airway obstruction. IFN-γ gene polymorphism (+874A/T) in children elevates susceptibility to asthma. TGFB1 polymorphisms are considered as indicators of asthma severity. IL-26 plays an important role in asthma severity. IP-10 may be a useful inflammatory marker of asthma severity. High periostin level has been identified in pediatric asthma. PDGF level, which is high in asthma patients, plays an important role in bronchial fibrosis. About chemokines, plasma TARC concentration may be a useful biomarker of airway inflammation and asthma severity in children. Studies have supported the association between high serum RANTES levels and severe airway obstruction in children. CXCR4 levels are high in pediatric asthma and are associated with disease severity. A wide range of cytokines and chemokines may play important roles in asthma severity in pediatric patients. Therefore, several studies have recommended the use of multiple molecular biomarkers, such as cytokines, for determining asthma severity in children.

Targeted co-delivery of siRNA and a chemotherapeutic drug is an attractive approach to cancer drug design and treatment. This study was carried out to design an anti-Mucin1 aptamer (Apt)-conjugated chitosan nanoparticle (NP) for targeted co-delivery of insulin-like growth factor receptor 1 (IGF-1R) Silencer siRNA and docetaxel (DTX) to SKBR3 cells. Characterization of nano-drugs, cellular uptake of NPs, cell viability, and gene expression studies were evaluated based on metastatic breast cancer cells. The results of this study showed that NPs had spherical and smooth morphology with 110-118 nm in size and had positive zeta potential (12-14 mV). siRNA and DTX were considerably loaded into NPs. The appropriate conjugation of the Apt to the NPs was affirmed by gel electrophoresis. The Apt-conjugated NPs were observed to enhance the cellular uptake of NPs into the SKBR3 cells. Although the combination treatment significantly decreased the cell viability of SKBR3 cells, the augmentative effect was observed when Apt was conjugated to NPs. Furthermore, Apt-conjugated NPs dramatically reduced the genetic expression of IGF-1R, signal transducers and activators of transcription 3 (STAT3), matrix metalloproteinases (MMP9), and vascular growth factor (VEGF). The targeted NPs may augment the targeting of pathways involved in tumorigenesis and metastasis of breast cancer. Therefore, more animal model experiments are needed to further clarify the efficacy and safety of this functionalized nanodrug.

Juvenile idiopathic arthritis (JIA) is one of the most common chronic rheumatic diseases in children. The complex nature of this immune-mediated disease owes itself to several predisposing genes and environmental factors affecting its pathogenesis. Conducted in Iran, this study was originally intended to investigate every possible association between HLA DRB1 alleles and a susceptibility to JIA.
In this case-control study, 45 patients with a definite diagnosis of JIA based on International League against Rheumatism (ILAR) criteria were compared against 46 healthy controls. DNA samples taken from both groups were analyzed using PCR-sequence specific primers (PCR-SSP) method. Data analysis including parametric and nonparametric test and multivariate analysis was undertaken using the SPSS 11.5 software. A P-value Mean ages in case group and healthy controls were 14.64±6.21 and 13.73±6.39, respectively with no significant difference between the two groups (P=0.515). Sex difference between JIA group and healthy controls was also not significant (P=0.068) .The frequency of HLA-DRB1*01 was found the most frequent HLA-RB1 in our patients (33.3%). No significant statistical correlation between various HLA-DRB1 alleles and clinical subtypes of the disease could be established from the data. HLA-DRB1*11 was shown to raise protection to JIA (P=0.035, OR=2.755, 95% CI=0.963-8.055) in northeastern Iran. In addition, we found that HLA-RB1*09 is nominally associated with an increased risk of JIA (P=0.56, OR=2, 05, 95% CI=0.18-23.63).
HLA-DRB1*11 was shown to raise protection to JIA in northeastern Iran. The disparity of findings in other ethnicities prompts further investigations with larger sample sizes.

The effects of serum vitamin D levels on the evolution or severity of asthma have been widely researched; however, conflicting results have been achieved. This study was designed to evaluate the relationship between serum vitamin D levels and pulmonary function tests in asthmatic and non-asthmatic people with vitamin D deficiency. This was a prospective cross-sectional study on healthy adults and asthmatic patients. Standard spirometry and serum 25-hydroxyvitamin D test were performed for all participants. Forty asthmatic patients and 40 healthy controls were tested. The mean age of participants was 42.86 ± 1.6. High prevalence of vitamin D deficiency was found in both the asthmatic and control groups. No significant correlation was found between serum vitamin D levels and spirometry parameters in either of the groups (P = 0.83).
Serum levels of 25-hydroxyvitamin D were not correlated with the severity of asthma as evaluated by pulmonary function tests in asthmatics.

Adult T-cell leukemia/lymphoma (ATLL) is caused by human T-cell lymphotropic virus type-1 (HTLV-1). HTLV-1 oncogenes can induce malignancy through controlled gene expression of cell cycle checkpoints in the host cell. HTLV-I genes play a pivotal role in overriding cell cycle checkpoints and deregulate cellular division. In this study, we aimed to determine and compare the HTLV-1 proviral load and the gene expression levels of cyclin-dependent kinase-2 (CDK2), CDK4, p53, and retinoblastoma (Rb) in ATLL and carriers groups. A total of twenty-five ATLL patients (12 females and 13 males) and 21 asymptomatic carriers (10 females and 11 males) were included in this study. TaqMan real-time polymerase chain reaction assay was used for evaluation of proviral load and gene expression levels of CDK2, CDK4, p53, and Rb. Statistical analysis was used to compare proviral load and gene expression levels between two groups, using SPSS version 18. The mean scores of the HTLV-1 proviral load in the ATLL patients and healthy carriers were 13067.20±6400.41 and 345.79±78.80 copies/104 cells, respectively (P=0.000). There was a significant correlation between the gene expression levels of CDK2 and CDK4 (P=0.01) in the ATLL group. Our findings demonstrated a significant difference between the ATLL patients and healthy carriers regarding the rate of proviral load and the gene expression levels of p53 and CDK4; accordingly, proviral load and expression levels of these genes may be useful in the assessment of disease progression and prediction of HTLV-1 infection outcomes.

Several biological and medical benefits of Saffron, Crocus sativus (Iridaceae), have been demonstrated. However, mechanisms of actions for purified constituents are greatly unknown.
To examine the effects of Safranal, a main constituent of Saffron stigma, on cell viability and cytokine profile of peripheral blood mononuclear cells (PBMC) were examined.
Effects of Safranal at 0.1, 0.5 and 1 mM concentrations were evaluated on cell viability and production of interleukin 4 (IL-4), IL-10 and interferon-γ (IFN-γ) from non-stimulated and phytohemagglutinin (PHA) stimulated PBMCs, compared to 0.1 mM dexamethasone and saline.
In stimulated cells, different concentrations of Safranal caused significant decrease of lymphocytes viability (p The IFN-γ/IL-4 ratio increases in the presence of Safranal which indicates an effect on Th1/Th2 balance. Therefore, Safranal may have therapeutic effects in inflammatory diseases associated with Th1/Th2 imbalance.