Publications by authors named "Majid Marjani"

98 Publications

Effect of bromhexine in hospitalized patients with COVID-19.

J Investig Med 2021 Mar 15. Epub 2021 Mar 15.

Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Background: Bromhexine is a potent inhibitor of transmembrane serine protease 2 and appears to have an antiviral effect in controlling influenza and parainfluenza infection; however, its efficacy in COVID-19 is controversial.

Methods: A group of hospitalized patients with confirmed COVID-19 pneumonia were randomized using 1:1 allocation to either standard treatment lopinavir/ritonavir and interferon beta-1a or bromhexine 8 mg four times a day in addition to standard therapy. The primary outcome was clinical improvement within 28 days, and the secondary outcome measures were time to hospital discharge, all-cause mortality, duration of mechanical ventilation, the temporal trend in 2019-nCoV reverse transcription-polymerase chain reaction positivity and the frequency of adverse drug events within 28 days from the start of medication.

Results: A total of 111 patients were enrolled in this randomized clinical trial and data from 100 patients (48 patients in the treatment arm and 52 patients in the control arm) were analyzed. There was no significant difference in the primary outcome of this study, which was clinical improvement. There was no significant difference in the average time to hospital discharge between the two arms. There were also no differences observed in the mean intensive care unit stay, frequency of intermittent mandatory ventilation, duration of supplemental oxygenation or risk of death by day 28 noted between the two arms.

Conclusion: Bromhexine is not an effective treatment for hospitalized patients with COVID-19. The potential prevention benefits of bromhexine in asymptomatic postexposure or with mild infection managed in the community remain to be determined.
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http://dx.doi.org/10.1136/jim-2020-001747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970656PMC
March 2021

Comparative evaluation of SARS-CoV-2 IgG assays against nucleocapsid and spike antigens.

Hum Antibodies 2021 Feb 26. Epub 2021 Feb 26.

Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: There are few studies to compare antibody response against anti-spike (S) and anti- nucleoprotein (N) SARS-CoV-2.

Objective: The aim of this study was to evaluate the IgG antibody production against S and N antigens of the virus and their correlation with the time and severity of the disease.

Methods: The IgG antibodies against S and N antigens of SARS-CoV-2 in serum specimens 72 symptomatic patients who tested real-time reverse transcription polymerase chain reaction positive for SARS-CoV-2 were detected using the ELISA technique. Different antibody response was compared and the correlation with the time from disease onset and the severity was evaluated.

Results: Forty-eight of 72 (67%) patients tested positive for anti-SARS-CoV-2 antibodies, while 24 (33%) did not have detectable antibodies. Comparison of antibody levels for N and S antibodies showed that they correlate with each other well (r= 0.81; P< 0.001). However, sensitivity of anti-S SARS-CoV-2 IgG and anti-N SARS-CoV-2 IgG was 30% and 60%, during the first 7 days after symptom onset (r= 0.53; P= 0.111), but increased to 73% and 68% at more than 1-week post symptom onset (r= 0.89, P= 0.111), respectively. Cases with positive IgG response showed a decreased CD8 cell percentage compared to the negative IgG groups (26 ± 14 vs. 58 ± 32, p= 0.066 in anti-N IgG group and 28 ± 15 vs. 60 ± 45, p= 0.004 in anti-S IgG group, respectively).

Conclusion: Nearly one-third of the confirmed COVID-19 patients had negative serology results. Lower percent positivity at early time points after symptom onset (less than 1 week) was seen using anti-S SARS-COV-2 IgG kit compare to the anti-N SARS-CoV-2 IgG; therefore, clinicians should interpret negative serology results of especially anti-S SARS-CoV-2 IgG with caution.
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http://dx.doi.org/10.3233/HAB-210440DOI Listing
February 2021

Evaluation of treatment response in active tuberculosis using QuantiFERON-TB Gold Plus.

Eur Cytokine Netw 2020 Dec;31(4):129-133

Pediatric Infectious Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Tuberculosis (TB) is one of the leading infectious causes of death worldwide and despite the progress recently made in TB control at a global level, the decline in its incidence is still slow. It is therefore crucial to evaluate the performance of new tools for monitoring of TB treatment. The aim of this study was to evaluate the response to tuberculosis treatment using the QuantiFERON-TB Gold Plus (QFT-Plus) kit. Blood samples of 100 patients with active TB were taken before treatment and after three months, if treatment was successful and sputum culture was negative. Whole blood was incubated in the presence or absence of the TB antigens, TB1 and TB2-specific antigens, and the production of IFN-γ was determined using the QuantiFERON-TB Gold Plus (QFT-Plus) test. The data were analyzed using SPSS 16 software and statistical significance was assessed at a two-tailed P value of 0.05. The median values of IFN-γ released following stimulation with TB1 peptides decreased slightly after treatment (2.5 IU/mL (IQR: 0.9-5.3), compared to the baseline (3.4 IU/mL (IQR: 0.5-6.6)). Also, with respect to the TB1 antigen, 38 out of 45 patients were positive for the QFT test before treatment (84.4%) and 37 cases after treatment (82.2%). On the other hand, the median values of IFN-γ determined with the TB2 test declined marginally after treatment (2.7 IU/mL; IQR: 0.95-5.8), as compared to pretreatment (3.0 IU/mL; IQR: 0.7-8.9). Thirty-nine out of 45 patients (86.7%) before initiation of treatment and 37 cases following a 3-month treatment (82.2%) were had positive values. Moreover, the median values of IFN-γ of TB2 minus TB1 before and after treatment were 0.17 (IQR: 0-1.0) and 0.03 (IQR: 0.0.48), respectively; however, these differences were not significant (p value=0.29). Conclusion: The results of this study show no significant differences between the IFN-γ release in TB patients prior to and after treatment. However, more extensive studies are needed in different populations with higher sample sizes to validate these results.
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http://dx.doi.org/10.1684/ecn.2020.0457DOI Listing
December 2020

Serum cytokine levels of COVID-19 patients after 7 days of treatment with Favipiravir or Kaletra.

Int Immunopharmacol 2021 Apr 22;93:107407. Epub 2021 Jan 22.

National Heart and Lung Institute, Imperial College London and the NIHR Imperial Biomedical Research Centre, London, UK; Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected 86,4 M patients and resulted in 1,86 M deaths worldwide. Severe COVID-19 patients have elevated blood levels of interleukin-6 (IL-6), IL-1β, tumor necrosis factor (TNF)α, IL-8 and interferon (IFN)γ.

Objective: To investigate the effect of antiviral treatment serum cytokines in severe COVID-19 patients.

Methods: Blood was obtained from 29 patients (aged 32-79 yr) with laboratory-confirmed COVID-19 upon admission and 7 days after antiviral (Favipiravir or Lopinavir/Ritonavir) treatment. Patients also received standard supportive treatment in this retrospective observational study. Chest computed tomography (CT) scans were evaluated to investigate lung manifestations of COVID-19. Serum was also obtained and cytokines levels were evaluated. 19 age- and gender-matched healthy controls were studied.

Results: Anti-viral therapy significantly reduced CT scan scores and the elevated serum levels of C-reactive protein (CRP) and lactate dehydrogenase (LDH). In contrast, serum levels of IL-6, IL-8 and IFNγ were elevated at baseline in COVID-19 subjects compared to healthy subjects with IL-6 (p = 0.006) and IL-8 (p = 0.011) levels being further elevated after antiviral therapy. IL-1β (p = 0.01) and TNFα (p = 0.069) levels were also enhanced after treatment but baseline levels were similar to those of healthy controls. These changes occurred irrespective of whether patients were admitted to the intensive care unit.

Conclusion: Antiviral treatments did not suppress the inflammatory phase of COVID-19 after 7 days treatment although CT, CRP and LDH suggest a decline in lung inflammation. There was limited evidence for a viral-mediated cytokine storm in these COVID-19 subjects.
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http://dx.doi.org/10.1016/j.intimp.2021.107407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826095PMC
April 2021

No clinical benefit of high dose corticosteroid administration in patients with COVID-19: A preliminary report of a randomized clinical trial.

Eur J Pharmacol 2021 Apr 16;897:173947. Epub 2021 Feb 16.

Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

The aim of this study was to evaluate the clinical effects of dexamethasone administration in patients with mild to moderate acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). The study included 50 patients who were randomly assigned to the dexamethasone group or control group. Dexamethasone was administered at a dose of 20 mg/day from day 1-5 and then at 10 mg/day from day 6-10. The need for invasive mechanical ventilation, death rate, duration of clinical improvement, length of hospital stay, and radiological changes in the computed tomography scan were assessed. The results revealed that 92% and 96% of patients in the dexamethasone and control groups, respectively, required noninvasive ventilation (P = 0.500). Among them, 52% and 44% of patients in the dexamethasone and control groups, respectively, required invasive mechanical ventilation (P = 0.389). At the end of the study, 64% of patients in the dexamethasone group and 60% of patients in the control group died (P = 0.500); the remaining patients were discharged from the hospital during the 28-day follow-up period. The median length of hospital stay was 11 days in the dexamethasone group and 6 days in the control group (P = 0.036) and the median length of hospital stay was 7 days in the dexamethasone group and 3 days in the control group (P < 0.001). No significant differences were observed in the other outcomes. This study showed that corticosteroid administration had no clinical benefit in patients with COVID-19-induced mild to moderate ARDS.
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http://dx.doi.org/10.1016/j.ejphar.2021.173947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885705PMC
April 2021

Dynamic Changes of Lymphocyte Subsets in the Course of COVID-19.

Int Arch Allergy Immunol 2021 26;182(3):254-262. Epub 2021 Jan 26.

Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Although the pathophysiology of coronavirus disease 2019 (COVID-19) is not clearly defined, among the proposed mechanisms, immune system dysfunction is more likely than others. The aim of this study was to clarify the characteristics and clinical significance of dynamic changes of lymphocyte subsets in the course of COVID-19.

Methods: In this prospective study, the levels of peripheral lymphocyte subsets including CD4+, CD8+, CD4+CD25+FOXP3+, CD38+, CD3+HLA-DR+, CD19+, CD20+, and CD16+CD56+ cells were measured by flow cytometry in 52 confirmed hospitalized patients with COVID-19 at the day of admission and after 7 days of care. Clinical response was defined as improvement in symptoms (fever, dyspnea, and cough as well as blood oxygen saturation), and patients who met these criteria after 1 week of admission were classified as early responders; others who survived and finally discharged from the hospital were classified as late responders and patients who died were categorized as nonresponders. Immunophenotyping of studied cell changes on the first day of admission and 7 days after treatment were compared. Besides, the correlation between cellular subset variation and clinical response and outcome were analyzed.

Results: Total counts of white blood cell, T cells, CD4+ T cells, CD8+ T cells, CD38+ lymphocytes, and CD3+HLA-DR+ lymphocytes were significantly increased in both early and late responders. No statistically significant difference was observed in CD4+/CD8+ ratio, B cells, FOXP3+Treg lymphocytes, and FOXP3 median fluorescence intensity among studied groups. According to the multivariate analysis, an increase in CD4+ T cells (p = 0.019), CD8+ T cells (p = 0.001), and administration of interferon (p < 0.001) were independent predictors of clinical response.

Conclusion: We found an increasing trend in total T cells, T helpers, cytotoxic T cells, activated lymphocytes, and natural killer cells among responders. This trend was not statistically significant among nonresponders. The findings of this study may enhance our knowledge about the pathogenesis of COVID-19.
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http://dx.doi.org/10.1159/000514202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900469PMC
March 2021

Potential diagnostic value of pleural fluid cytokines levels for tuberculous pleural effusion.

Sci Rep 2021 Jan 12;11(1):660. Epub 2021 Jan 12.

Department of Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Patients with tuberculous pleural effusion (TPE) or malignant pleural effusions (MPE) frequently have similar pleural fluid profiles. New biomarkers for the differential diagnosis of TPE are required. We determined whether cytokine profiles in the PE of patients could aid the differential diagnosis of TPE. 30 patients with TPE, 30 patients with MPE, 14 patients with empyema (EMP) and 14 patients with parapneumonic effusion (PPE) were enrolled between Dec 2018 and 2019. The levels of interleukin (IL)-6, IL-18, IL-27, CXCL8, CCL-1 and IP-10 were determined in PE by ELISA along with measurements of adenosine deaminase (ADA). The best predictors of TPE were combined ADA.IL-27 [optimal cut-off value = 42.68 (10 U ng/l), sensitivity 100%, specificity 98.28%], ADA [cut off value 27.5 (IU/l), sensitivity 90%, specificity 96.5%] and IL-27 [cut-off value = 2363 (pg/ml), sensitivity 96.7%, specificity 98.3%, p ≤ 0.0001]. A high level of IL-6 [cut-off value = 3260 (pg/ml), sensitivity 100%, specificity 67.2%], CXCL8 [cut-off value = 144.5 (pg/ml), sensitivity 93.3%, specificity 58.6%], CCL1 [cut-off value = 54 (pg/ml), sensitivity 100%, specificity 70.7%] and IP-10 [cut-off value = 891.9 (pg/ml), sensitivity 83.3%, specificity 48.3%] were also predictive of TPE. High ADA.IL-27, ADA and IL-27 levels differentiate between TPE and non-TPE with improved specificity and diagnostic accuracy and may be useful clinically.
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http://dx.doi.org/10.1038/s41598-020-79685-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803752PMC
January 2021

Combination therapy of IFNβ1 with lopinavir-ritonavir, increases oxygenation, survival and discharging of sever COVID-19 infected inpatients.

Int Immunopharmacol 2021 Mar 26;92:107329. Epub 2020 Dec 26.

Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Interferon Beta-1a (IFN-β1-a), an immunomodulatory mediator with antiviral effects, has shown in vivo and in vitro activities especially on coronavirus including SARS-CoV-2. COVID-19 defined as the disease caused by infection with SARS-CoV-2. The virus has been illustrated inhibits the production of IFN-β1-a from inflammatory cells. We conducted a retrospective study of all adult confirmed COVID-19 hospitalized patients who received combination of three doses of 12 million international units of IFN-β1-a and Lopinavir 400 mg and Ritonavir 100 mg every 12 h (case group) for 14 days besides standard care and age- and sex- matched COVID-19 patients with receiving lopinavir/ritonavir (control group) at Masih Daneshvari Hospital as a designated hospital for COVID-19 between Feb 19 and Apr 30, 2020. Multivariate analysis was done to determine the impact of IFN-β1-a on outcome and all-cause mortality. 152 cases in IFN-β1-a group and 304 cases as control group were included. IFN-β1-a group stayed at hospital longer and required noninvasive ventilation more than control group (13 vs. 6 days, p = 0.001) and (34% vs. 24%, p = 0.04), respectively. During treatment, 57 (12.5%) patients died. The death rate in case and control groups was 11% and 13% respectively. In multivariate analysis, not receiving IFN-β1-a (HR 5.12, 95% CI: 2.77-9.45), comorbidity (HR 2.28, 95% CI: 1.13-4.60) and noninvasive ventilation (HR 2.77, 95% CI: 1.56-4.93) remained significantly associated with all-cause mortality. In this study, risk of death decreased by using IFN-β1-a in COVID-19 patients. More clinical study will be necessary to measure efficacy of IFN-β1-a in COVID-19 treatment.
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http://dx.doi.org/10.1016/j.intimp.2020.107329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762801PMC
March 2021

Plasmapheresis reduces cytokine and immune cell levels in COVID-19 patients with acute respiratory distress syndrome (ARDS).

Pulmonology 2020 Dec 4. Epub 2020 Dec 4.

Cell and Molecular Biology Group, Airways Disease Section, Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK; Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.

Background: In December 2019, pneumonia associated with a novel coronavirus (COVID-19) was reported in Wuhan, China. Acute respiratory distress syndrome (ARDS) is the most frequently observed complication in COVID-19 patients with high mortality rates.

Objective Of Study: To observe the clinical effect of plasmapheresis on excessive inflammatory reaction and immune features in patients with severe COVID-19 at risk of ARDS.

Materials And Methods: In this single-center study, we included 15 confirmed cases of COVID-19 at Masih Daneshvari Hospital, in March 2020 in Tehran, Iran. COVID-19 cases were confirmed by RT-PCR and CT imaging according to WHO guidelines. Plasmapheresis was performed to alleviate cytokine-induced ARDS. The improvement in oxygen delivery (PaO/FiO, total number of T cells, liver enzymes, acute reaction proteins, TNF-α and IL-6 levels were evaluated.

Results: Inflammatory cytokine levels (TNF-α, IL-6), and acute phase reaction proteins including ferritin and CRP were high before plasmapheresis. After plasmapheresis, the levels of PaO/FiO, acute phase reactants, inflammatory mediators, liver enzymes and bilirubin were significantly reduced within a week (p < 0.05). In contrast, although the number of T helper cells decreased immediately after plasmapheresis, they rose to above baseline levels after 1 week. Nine out of fifteen patients on non-invasive positive-pressure ventilation (NIPPV) survived whilst the six patients undergoing invasive mechanical ventilation (IMV) died.

Conclusion: Our data suggests that plasmapheresis improves systemic cytokine and immune responses in patients with severe COVID-19 who do not undergo IMV. Further controlled studies are required to explore the efficacy of plasmapheresis treatment in patients with COVID-19.
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http://dx.doi.org/10.1016/j.pulmoe.2020.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834188PMC
December 2020

Differential genes expression analysis of invasive aspergillosis: a bioinformatics study based on mRNA/microRNA.

Mol Biol Res Commun 2020 Dec;9(4):173-180

Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Invasive is a severe opportunistic infection with high mortality in immunocompromised patients. Recently, the roles of microRNAs have been taken into consideration in the immune system and inflammatory responses. Using bioinformatics approaches, we aimed to study the microRNAs related to invasive to understand the molecular pathways involved in the disease pathogenesis. Data were extracted from the gene expression omnibus (GEO) database. We proposed 3 differentially expressed genes; S100B, and related to pathogenesis of invasive . Using miRWalk 2.0 predictive tool, microRNAs that targeted the selected genes were identified. The roles of microRNAs were investigated by microRNA target prediction and molecular pathways analysis. The significance of combined expression changes in selected genes was analyzed by ROC curves study. Thirty-three microRNAs were identified as the common regulator of , and genes. Several of them were previously reported in the pathogenesis of fungal infections including miR-132. Predicted microRNAs were involved in innate immune response as well as toll-like receptor signaling. Most of the microRNAs were also linked to platelet activation. The ROC chart in the combination mode of , showed the sensitivity of 95.65 percent and the specificity of 69.23 percent. New approaches are needed for rapid and accurate detection of invasive . Given the pivotal signaling pathways involved, predicted microRNAs can be considered as the potential candidates of the disease diagnosis. Further investigation of the microRNAs expression changes and related pathways would lead to identifying the effective biomarkers for IA detection.
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http://dx.doi.org/10.22099/mbrc.2020.37432.1509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731968PMC
December 2020

Clinical Manifestations of Patients with Coronavirus Disease 2019 (COVID-19) in a Referral Center in Iran.

Tanaffos 2020 Nov;19(2):122-128

Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Following the recent epidemic of coronavirus disease 2019 (COVID-19) in Wuhan, China, a novel betacoronavirus was isolated from two patients in Iran on February 19, 2020. In this study, we aimed to determine the clinical manifestations and outcomes of the first confirmed cases of COVID-19 infection (n=127).

Materials And Methods: This prospective study was conducted on all COVID-19-suspected cases, admitted to Masih Daneshvari Hospital (a designated hospital for COVID-19), Tehran, Iran, since February 19, 2020. All patients were tested for COVID-19, using reverse transcription-polymerase chain reaction (RT-PCR) assay. Data of confirmed cases, including demographic characteristics, clinical features, and outcomes, were collected and compared between three groups of patients, requiring different types of admission (requiring ICU admission, admission to the general ward, and transfer to ICU).

Results: Of 412 suspected cases, with the mean age of 54.1 years (SD=13.4), 127 (31%) were positive for COVID-19. Following the patients' first visit to the clinic, 115 cases were admitted to the general ward, while ten patients required ICU admission. Due to clinical deterioration in the condition of 25 patients (out of 115 patients), ICU admission was essential. Based on the results, the baseline characteristics of the groups were similar. Patients requiring ICU admission were more likely to have multiorgan involvement (liver involvement, P<0.001; renal involvement, P<0.001; and cardiac involvement, P=0.02), low O saturation (P<0.001), and lymphopenia (P=0.05). During hospital admission, 21 (16.5%) patients died, while the rest (83.5%) were discharged and followed-up until March 26, 2020. Also, the survival rate of patients, who received immunoglobulin, was higher than other patients (60.87% vs. 39.13%).

Conclusion: The mortality rate of COVID-19 patients was considerable in our study. Based on the present results, this infection can cause multiorgan damage. Therefore, intensive monitoring of these patients needs to be considered.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680520PMC
November 2020

A Novel Coronavirus Disease (COVID-19): a Review of Host Cell Signaling Pathways.

Tanaffos 2020 Nov;19(2):108-111

Clinical Tuberculosis and Epidemiology Research Center, NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Coronaviruses (CoVs) are the largest group of positive-sense RNA viruses. By increasing our understanding of the interactions between CoVs and the host innate immune system, we can evaluate the development and persistence of inflammation in the lungs and reduce the risk of CoV-induced lung inflammation with a new group of genetic variants. Here, we aim to discuss some recent changes in host cell factors that may be used by CoV to promote the proliferation cycle. We also discuss different host cell signaling pathways that can be considered in the host-pathogen interactions at the molecular level. The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created new challenges for the cultural, economic, and health infrastructures. Therefore, it is important that healthcare systems and physicians recognize a global integrated framework for monitoring the progression of COVID-19 to develop targeted therapies that can potentially save human lives.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680516PMC
November 2020

Bruton's Tyrosine Kinase: A Promising Target for the Treatment of COVID-19.

Tanaffos 2020 Nov;19(2):85-88

Clinical Tuberculosis and Epidemiology Research Center, NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680521PMC
November 2020

Evaluating the effects of Intravenous Immunoglobulin (IVIg) on the management of severe COVID-19 cases: A randomized controlled trial.

Int Immunopharmacol 2021 Jan 13;90:107205. Epub 2020 Nov 13.

Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Background: The newly discovered coronavirus has turned into coronavirus disease 2019 (COVID-19) pandemic and it rages at an unprecedented rate. Considering the findings of previous studies on the use of Intravenous Immunoglobulin (IVIg) for treating severe HN infection and the satisfying results for reducing viral load and mortality, this study aimed to investigate the potential usefulness of IVIg for the management of severe cases.

Methods: In this randomized controlled trial, 84 patients were included: 52 in the IVIg group and 32 in the control group. The intervention group received IVIg at a dose of 400 mg/kg, IV, daily for three days. Both groups received hydroxychloroquine, lopinavir/ritonavir and supportive care. The demographic data, mortality rate, the need for mechanical ventilation, length of stay in hospital and in Intensive Care Unit (ICU), and imaging findings were recorded and compared in terms of the mentioned factors.

Results: The mean time from admission to IVIg initiation was 3.84 ± 3.35 days. There was no significant difference between the two groups in terms of mortality rate (P-value = 0.8) and the need for mechanical ventilation (P-value = 0.39). The length of hospital stay was significantly lower for the control group than that of the intervention group (P-value = 0.003). There was a significant positive relationship between the time from hospital admission to IVIg initiation and the length of stay in the hospital and ICU among the survivors (P-value < 0.001 and =0.01, respectively).

Conclusions: Our findings did not support the use of IVIg in combination with hydroxychloroquine and lopinavir/ritonavir in treatment of severe COVID-19 cases.
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http://dx.doi.org/10.1016/j.intimp.2020.107205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665876PMC
January 2021

Diffuse alveolar damage and thrombotic microangiopathy are the main histopathological findings in lung tissue biopsy samples of COVID-19 patients.

Pathol Res Pract 2020 Oct 19;216(10):153228. Epub 2020 Sep 19.

Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Since the outbreak of the novel coronavirus disease-2019 (COVID-19) in December 2019, limited studies have investigated the histopathologic findings of patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).

Material And Methods: This study was conducted on 31 deceased patients who were hospitalized for COVID-19 in a tertiary hospital in Tehran, Iran. A total of 52 postmortem tissue biopsy samples were obtained from the lungs and liver of decedents. Clinical characteristics, laboratory data, and microscopic features were evaluated. Reverse transcription polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 was performed on specimens obtained from nasopharyngeal swabs and tissue biopsies.

Results: The median age of deceased patients was 66 years (range, 30-87 years) and 25 decedents (81 %) were male. The average interval from symptom onset to death was 13 days (range, 6-34 days). On histopathologic examination of the lung specimens, diffuse alveolar damage and thrombotic microangiopathy were the most common findings (80 % and 60 %, respectively). Liver specimens mainly showed macrovesicular steatosis, portal lymphoplasmacytic inflammation and passive congestion. No definitive viral inclusions were observed in any of the specimens. In addition, 92 % of lung tissue samples tested positive for SARS-CoV-2 by RT-PCR.

Conclusions: Further studies are needed to investigate whether SARS-CoV-2 causes direct cytopathic changes in various organs of the human body.
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http://dx.doi.org/10.1016/j.prp.2020.153228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837112PMC
October 2020

A Fourteen-day Experience with Coronavirus Disease 2019 (COVID-19) Induced Acute Respiratory Distress Syndrome (ARDS): An Iranian Treatment Protocol.

Iran J Pharm Res 2020 ;19(1):31-36

Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

COVID-19 is currently causing concern in the medical community as the virus is spreading around the world. It has a heavy global burden, particularly in low-income countries. The clinical spectrum of COVID-19 pneumonia ranges from mild to critically ill cases and Acute Respiratory Distress Syndrome. An expert panel was held and an internal protocol was developed to manage the COVID-19 induced ARDS according to WHO recommendations and NIH guidelines. Different therapeutic regimens were employed on this protocol based on the ARDS severity and the patients' special characteristics. The mortality rate, the rate of survivors, and non-survivors were reported. Of the 231 suspected cases of COVID-19 admitted to the hospital during two weeks, 72 patients were admitted to ICU with diagnosis confirmed by RT-PCR. In total, mortality in the ICU was 25% (n = 18) among ARDS patients over two weeks. COVID-19 induced ARDS is a major concern. The rapid progression of ARDS needs specific protocol based on patients' characteristics and rapid action.
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http://dx.doi.org/10.22037/ijpr.2020.113337.14239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462513PMC
January 2020

Thalidomide against Coronavirus Disease 2019 (COVID-19): A Medicine with a Thousand Faces.

Iran J Pharm Res 2020 ;19(1):1-2

Student Research Committee, Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

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http://dx.doi.org/10.22037/ijpr.2020.113369.14259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462477PMC
January 2020

Promising effects of tocilizumab in COVID-19: A non-controlled, prospective clinical trial.

Int Immunopharmacol 2020 Nov 4;88:106869. Epub 2020 Aug 4.

Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Background: The clinical presentation of SARS-CoV-2 infection ranges from mild symptoms to severe complications, including acute respiratory distress syndrome. In this syndrome, inflammatory cytokines are released after activation of the inflammatory cascade, with the predominant role of interleukin (IL)-6. The aim of this study was to evaluate the effects of tocilizumab, as an IL-6 antagonist, in patients with severe or critical SARS-CoV-2 infection.

Methods: In this prospective clinical trial, 76 patients with severe or critical SARS-CoV-2 infection were evaluated for eligibility, and ultimately, 42 patients were included. Tocilizumab was administered at a dose of 400 mg as a single dose via intravenous infusion. Primary outcomes included changes in oxygenation support, need for invasive mechanical ventilation, and death. Secondary outcomes included radiological changes in the lungs, IL-6 plasma levels, C-reactive protein levels, and adverse drug reactions. The data were analyzed using SPSS software.

Results: Of the 42 included patients, 20 (48%) patients presented the severe infection stage and 22 (52%) were in the critical stage. The median age of patients was 56 years, and the median IL-6 level was 28.55 pg/mL. After tocilizumab administration, only 6 patients (14%) required invasive ventilation. Additionally, 35 patients (83.33%) showed clinical improvement. By day 28, a total of 7 patients died (6 patients in the critical stage and 1 patient in the severe stage). Neurological adverse effects were observed in 3 patients.

Conclusions: Based on the current results, tocilizumab may be a promising agent for patients with severe or critical SARS-CoV-2 infection, if promptly initiated during the severe stage.
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http://dx.doi.org/10.1016/j.intimp.2020.106869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402206PMC
November 2020

The association between leptin and adiponectin, and metabolic syndrome components and serum levels of lipid peroxidation in bipolar disorder patients treated with lithium and valproic acid.

Heliyon 2020 Jul 27;6(7):e04553. Epub 2020 Jul 27.

Metabolic Disorders Research Center, Department of Biochemistry and Biophysics, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Golestan province, Iran.

Background: The aim of study is to assess a relation between the adiponectin and leptin levels, and metabolic syndrome components and lipid peroxidation treated with Li and VPA in bipolar disorder patients and compared with controls.

Materials And Methods: 56 patients and 31 healthy controls were enrolled. The ATP III criteria were used to determine metabolic syndrome components. Leptin, adiponectin, lipid peroxidation and lipid profiles were measured.

Results: Malondialdehyde in Li patients was higher than VPA patients. BMI, waist circumference (WC), triglyceride, malondialdehyde and adiponectin levels were increased, whereas HDL-cholesterol (VPA treated patients) and leptin were decreased in patients compared with controls. Leptin and adiponectin were correlated with WC, triglyceride and malondialdehyde in both groups. Adiponectin was correlated with HDL-cholesterol in VPA patients.

Conclusion: Patients should be checked metabolic syndrome components, serum leptin and adiponectin level occasionally to prevent possible deficiency or pathologic increase of these parameters.
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http://dx.doi.org/10.1016/j.heliyon.2020.e04553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393417PMC
July 2020

Immunologic Features in Coronavirus Disease 2019: Functional Exhaustion of T Cells and Cytokine Storm.

J Clin Immunol 2020 10 10;40(7):974-976. Epub 2020 Jul 10.

Department of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

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http://dx.doi.org/10.1007/s10875-020-00824-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347401PMC
October 2020

The effect of simvastatin on gene expression of low-density lipoprotein receptor, sterol regulatory element-binding proteins, stearoyl-CoA desaturase 1 mRNA in rat hepatic tissues.

Arch Physiol Biochem 2020 Jul 9:1-8. Epub 2020 Jul 9.

Metabolic Disorders Research Center, Department of Biochemistry and Biophysics, Gorgan Faculty of Medicine, Golestan University Medical Sciences, Gorgan, Iran.

The study aimed to assess the effect of simvastatin on gene expression of LDLR, SREBPs, and SCD1 in rat hepatic tissues fed with high-fat diets (HFD) and its association with some biochemical parameters. Thirty-two male Wister albino rats were divided into four equal groups (three test and one control groups). The biochemical parameters were determined by using spectrophotometer techniques and the Elisa method. Low-density lipoprotein receptor, sterol regulatory element-binding proteins, stearoyl-CoA desaturase1, Beta-actin were analysed by real-time quantitative polymerase chain reaction (RT-PCR) method. At the end of study, the livers of the rats were separated and changes of hepatic tissue were determined. LDLR, SREBP2, and SCD1 expression increased significantly when compared G1 versus G4 and G2 versus G4. The expression of LDLR, SREBP2, and SCD1 also increased significantly when compared G2 versus G3, G1versus G3 and G1 versus G3 and G2 versus G3. The serum level of cholesterol, triglyceride, glucose, LDL, and HDL increased significantly when compared G1 versus G3. LDL showed significantly decreased when compared G1 versus G2. Cholesterol, glucose and HDL and triglyceride levels were increased significantly when compared G1 versus G4 and G2. Treatment of rats with HFD and simvastatin 20 mg/kg, triglyceride and LDL were almost the same as a control group and LDLR expression increased 98% in liver tissue. Gene expressions may be up-regulated in liver tissue and they showed different effects on biochemical parameters.
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http://dx.doi.org/10.1080/13813455.2020.1772829DOI Listing
July 2020

Genetic polymorphisms -137 (G > C) (rs187238) and -607 (C > A) (rs1946518) and serum level of interleukin 18 in Fars ethnic groups with metabolic syndrome in Northern Iran.

Arch Physiol Biochem 2020 Jul 7:1-7. Epub 2020 Jul 7.

Metabolic Disorders Research Center, Department of Biochemistry and Biophysics, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.

We aimed to determine the genetic polymorphisms and serum level of interleukin 18 in Fars ethnic groups. 226 Fars ethnic groups were participated. The ATP III criteria were used to assess MS components. The SNPs of the IL-18 gene were determined with ARMS-PCR. The GG, GC, and CC genotypes of -137 were 50%, 40%, and 10%. The CC, CA, and AA genotypes of -607 were 45%, 37%, and 18%. The GG, GC, and CC genotypes of -137 were 44.20%, 43.40%, and 12.40%, and were 55.75%, 36.28%, and 7.97% in subjects with and without MS, respectively. The CC, CA, and AA genotypes of -607 were 48.70%, 37.20%, and 14.20% and were 41.60%, 37.20%, and 21.20% in both groups, respectively. IL-18 gene may different in specific populations, different ethnic groups and geographic regions. The IL-18 polymorphisms might not be used as a marker of metabolic syndrome.
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http://dx.doi.org/10.1080/13813455.2020.1784954DOI Listing
July 2020

Successful Treatment of Covid-19 Associated Cytokine Release Syndrome with Colchicine. A Case Report and Review of Literature.

Immunol Invest 2020 Jul 7:1-7. Epub 2020 Jul 7.

Department of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences , Tehran, Iran.

We describe the case of a 42 year old, healthy patient with Covid-19 who despite improvement in his respiratory symptoms developed a mild to moderate cytokine release syndrome (CRS) and an associated monoarticular gout flare. Since the patient refused admission to the hospital and had stable vital signs, we chose to treat him with a safe anti-inflammatory and non-immunosuppressive therapy. To hit two birds with one stone, we considered colchicine, as it has systemic anti-inflammatory effects and is also effective in gout flare. Unexpectedly, 48 hours after treatment, not only did his ongoing fever and toe pain disappear, he also had significant improvements in his general state of health and all his inflammatory markers including fibrinogen, ferritin, D-dimer, and IL-6 levels normalized. To our knowledge, the use of colchicine in Covid-19 and CRS has not been reported. This observation merits the consideration of colchicine as a safe, inexpensive and oral medication for the treatment of mild to moderate CRS in Covid-19 patients. More importantly, in Covid-19 patients with early lung involvement colchicine may be an appropriate candidate to prevent CRS in adjunction with routine antiviral agents. Indeed, multicenter, randomized controlled studies are required to evaluate the benefits of this therapy.
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http://dx.doi.org/10.1080/08820139.2020.1789655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441796PMC
July 2020

Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical and Genetic Features of 32 Iranian Patients.

J Clin Immunol 2020 08 30;40(6):872-882. Epub 2020 Jun 30.

Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital condition characterized by a selective predisposition to infections caused by weakly virulent mycobacteria and other types of intra-macrophagic pathogens. The 16 genes associated with MSMD display a considerable level of allelic heterogeneity, accounting for 31 distinct disorders with variable clinical presentations and prognosis. Most of MSMD deficiencies are isolated, referred to as selective susceptibility to mycobacterial diseases. However, other deficiencies are syndromic MSMD, defined by the combination of the mycobacterial infection with another, equally common, infectious, specific phenotypes. Herein, we described a series of 32 Iranian MSMD cases identified with seven distinct types of molecular defects, all of which are involved in the interferon gamma (IFNγ) immunity, including interleukin IL-12 receptor-β1 (IL-12Rβ1) deficiency (fifteen cases), IL-12p40 deficiency (ten cases), and IL-23R deficiency (three cases), as well as IFNγ receptor 1 (IFNγR1) deficiency, IFNγ receptor 2 (IFNγR2) deficiency, interferon-stimulated gene 15 (ISG15) deficiency, and tyrosine kinase 2 (TYK2) deficiency each in one case. Since the first report of two MSMD patients in our center, we identified 30 other affected patients with similar clinical manifestations. As the number of reported Iranian cases with MSMD diagnosis has increased in recent years and according to the national vaccination protocol, all Iranian newborns receive BCG vaccination at birth, early diagnosis, and therapeutic intervention which are required for a better outcome and also prevention of similar birth defects. Therefore, we investigated the clinical and molecular features of these 32 patients. The current report also defined novel classes of pathological mutations, further expanding our knowledge of the MSMD molecular basis and associated clinical manifestations.
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http://dx.doi.org/10.1007/s10875-020-00813-7DOI Listing
August 2020

Subcutaneous administration of interferon beta-1a for COVID-19: A non-controlled prospective trial.

Int Immunopharmacol 2020 Aug 7;85:106688. Epub 2020 Jun 7.

Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Background: Recently, a new coronavirus spreads rapidly throughout the countries and resulted in a worldwide epidemic. Interferons have direct antiviral and immunomodulatory effects. Antiviral effects may include inhibition of viral replication, protein synthesis, virus maturation, or virus release from infected cells. Previous studies have shown that some coronaviruses are susceptible to interferons. The aim of this study was to evaluate the therapeutic effects of IFN-β-1a administration in COVID-19.

Methods: In this prospective non-controlled trial, 20 patients included. They received IFN-β-1a at a dose of 44 µg subcutaneously every other day up to 10 days. All patients received conventional therapy including Hydroxychloroquine, and lopinavir/ritonavir. Demographic data, clinical symptoms, virological clearance, and imaging findings recorded during the study.

Results: The mean age of the patients was 58.55 ± 13.43 years. Fever resolved in all patients during first seven days. Although other symptoms decreased gradually. Virological clearance results showed a significant decrease within 10 days. Imaging studies showed significant recovery after 14-day period in all patients. The mean time of hospitalization was 16.8 ± 3.4 days. There were no deaths or significant adverse drug reactions in the 14-day period.

Conclusions: Our findings support the use of IFN-β-1a in combination with hydroxychloroquine and lopinavir/ritonavir in the management of COVID-19.

Clinical Trial Registration Number: IRCT20151227025726N12.
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http://dx.doi.org/10.1016/j.intimp.2020.106688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275997PMC
August 2020

The evaluation of interleukin-4 and interleukin-13 in the serum of pulmonary sarcoidosis and tuberculosis patients.

J Res Med Sci 2020 18;25:24. Epub 2020 Mar 18.

Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Sarcoidosis and tuberculosis (TB) are two granulomatous inflammatory diseases with several common symptoms. The aim of the present study was to compare the serum levels of biomarkers including interleukin-4 (IL-4) and IL-13, calcium (Ca), hemoglobin, sedimentation rate, and lymphocyte-to-neutrophil ratio between patients with pulmonary TB, patients with sarcoidosis, and control group.

Materials And Methods: This case-control study was performed on patients referred to the Masih Daneshvari Hospital, Tehran, from April 2017 to 2018. In this study, 24 newly diagnosed patients with active pulmonary TB, 34 patients with pulmonary sarcoidosis, and 30 healthy individuals as the control group were enrolled. Demographic data, erythrocyte sedimentation rate (ESR), the ratio of neutrophil-to-lymphocyte (NLR), serum Ca level, hemoglobin (Hb), and IL-4 and IL-13 were compared between the study groups. Receiver operating characteristic (ROC) curve analysis, sensitivity, and specificity were also calculated using SPSS 16.0 software.

Results: The mean age was 47.71 ± 10.88 and 55.25 ± 21.58 years in the sarcoidosis and TB. The mean ESR in sarcoidosis patients was 21.45 ± 13.37 mm/h and 41.4 ± 17 mm/h in the TB group. The percentage of peripheral blood lymphocytes in sarcoidosis and TB patients was 28.02 ± 12.20 and 21.41 ± 12.49, respectively, which was significantly higher among patients with sarcoidosis. NLR was also 2.4 ± 1.6 and 4.4 ± 2.9 in sarcoidosis and TB patients, respectively, which showed a significant difference among the groups. Regarding the evaluation of the level of IL-4 and IL-13 in patients, it is worth noting that IL-4 in patients with sarcoidosis was 90 pg/ml compared to 20 pg/ml for TB patients ( < 0.001). There was no significant difference in the levels of IL-13 in the TB and control groups, which varied between 20 and 80 pg/ml ( = 0.35). However, its value was significantly higher in patients with sarcoidosis ( = 0.01) than in the healthy control group and TB ( = 0.01). The ROC curves showed that the diagnostic cutoff of ESR level, Ca, NLR, and Hb could be valuable due to the area under the curves. The cutpoint of 34 mm/h for ESR had a sensitivity of 86% as well as 80% specificity to distinguish TB from the sarcoidosis.

Conclusion: Serum levels of the biomarkers indicated a stronger immunological background in sarcoidosis using NLR, Ca, ESR, and Hb.
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http://dx.doi.org/10.4103/jrms.JRMS_74_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213005PMC
March 2020

Effect of Leaf Extract on Glucose Metabolism in HepG2, CRI-D2 and C2C12 Cell Lines.

Diabetes Metab Syndr Obes 2020 14;13:1109-1116. Epub 2020 Apr 14.

Metabolic Disorders Research Center, Department of Biochemistry and Biophysics, Gorgan Faculty of Medicine, Golestan University Medical Sciences, Gorgan, Iran.

Introduction: The aim of this study was to assess the effects of on glucose metabolism in HepG2, CRI-D2 and C2C12 cell lines.

Materials and methods: was collected in Golestan province, Iran. Three different cell lines HepG2 (human liver cell), CRI-D2 (mice pancreatic cell) and C2C12 (rat myoblast) were used for cell culture experiments. Cell viability was measured using MTT assay. Cells were treated with various concentrations of the extract (6.25-400 μg/mL) and then the extracellular glucose level and intracellular glycogen content were measured using colorimetric methods. The insulin level of the culture medium was measured using the ELISA method.

Results: Our findings showed that extract enhances glucose uptake and consumption by all three cell lines. The extract exposure also elevated cellular glycogen content in HepG2 and C2C12 cells (for 200 and 100 μg/mL) significantly. We found a significant increase in glucose uptake and consequently higher stimulation of insulin secretion in CRI-D2 cell pancreatic cells treated with extract.

Conclusion: The appears to activate glucose uptake and cellular glycogen synthesis probably by activating the glycogenesis or inhibition of glycogenolysis pathways. The extract enhances insulin secretion in the pancreatic cells by increased glucose uptake.
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http://dx.doi.org/10.2147/DMSO.S244850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166088PMC
April 2020

Differential gene expression of ASUN, NEMF, PTPRC and DHX29: Candidate biomarkers for diagnosis of active and latent tuberculosis.

Infect Disord Drug Targets 2020 Mar 13. Epub 2020 Mar 13.

Pediatric Infectious Diseases Research Center, Infectious Disease Department, Tehran University of Medical Sciences, Tehran, Iran.

Introduction: Tuberculosis (TB) remains as one of the most important infectious causes of death through the world. A wide range of technologies have been used for the diagnosis of TB. However, current diagnostic tests are inadequate. The aim of this study was to evaluate expression of four genes, namely ASUN, NEMF, PTPRC and DHX29 as candidate biomarkers for the discrimination of Latent tuberculosis infection (LTBI) and active TB among individuals with active TB, LTBI, and healthy Bacilli Calmette-Guerin (BCG) vaccinated cases.

Material And Methods: The expression of the mentioned four genes as well as ACTB as a housekeeping gene was evaluated by real-time PCR. Receiver operating characteristic (ROC) curve analysis was conducted to assess the specificity and sensitivity of each validated biomarker.

Results: The results of real-time PCR presented that these four differentially expressed genes could be perceived as potential biomarkers for the detection of active and latent TB infections. ROC analysis showed that the expression level of ASUN, PTPRC and DHX29 may discriminate active TB patients from healthy individuals, whereas ASUN and NEMF could differentiate LTBI from healthy BCG vaccinated cases. In addition, DHX29 and PTPRC could be used to discriminate LTBI from active TB patients.

Conclusion: Expression of these four host genes can accurately differentiate between active TB/LTBI cases and healthy individuals as well as between LTBI and active TB patients. However, our findings deserve further validation in larger studies.
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http://dx.doi.org/10.2174/1871526520666200313144951DOI Listing
March 2020

Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency.

N Engl J Med 2020 01;382(5):437-445

From St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University (S.B.D., D.H., N.H., S.B., F.R., B.B., R.F., E.J., J.B., L.A., S.B.-D., J.-L.C.), the Department of Microbiology and Immunology, Weill Cornell Medicine (R.B., C.N.), and Howard Hughes Medical Institute (J.-L.C.) - all in New York; the Pediatric Respiratory Diseases Research Center (D.M., S.A.M.), the Department of Clinical Immunology and Infectious Diseases (D.M., N. Mansouri), and the Clinical Tuberculosis and Epidemiology Research Center (D.M., M.M.), National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; the Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM Unité 1163 (A.-L.N., L.L.-D., E.J., J.B., L.A., S.B.-D., V.B., J.-L.C.), Paris University, Imagine Institute (A.-L.N., L.L.-D., E.J., J.B., L.A., S.B.-D., V.B., J.-L.C.), and the Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP) (J.B.), and the Pediatric Immunology-Hematology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, and the Department of Pathology, Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt (J.-F.E.) - all in France; the Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany (A.-L.N.); the Research Branch, Sidra Medicine (M.R., T.K., F.A.A., N. Marr), and the College of Health and Life Sciences, Hamad Bin Khalifa University (N. Marr), Doha, Qatar; and the Division of Pulmonary Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (N. Mansouri).

Background: Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitric oxide synthase 2 () are susceptible to the related murine CMV infection.

Methods: We studied a previously healthy 51-year-old man from Iran who after acute CMV infection had an onset of progressive CMV disease that led to his death 29 months later. We hypothesized that the patient may have had a novel type of inborn error of immunity. Thus, we performed whole-exome sequencing and tested candidate mutant alleles experimentally.

Results: We found a homozygous frameshift mutation in encoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, all variants that we found in homozygosity in public databases encoded functional proteins, as did all other variants with an allele frequency greater than 0.001.

Conclusions: These findings suggest that inherited NOS2 deficiency was clinically silent in this patient until lethal infection with CMV. Moreover, NOS2 appeared to be redundant for control of other pathogens in this patient. (Funded by the National Center for Advancing Translational Sciences and others.).
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http://dx.doi.org/10.1056/NEJMoa1910640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063989PMC
January 2020