Publications by authors named "Mohammad Varahram"

34 Publications

COVID-19: Molecular and Cellular Response.

Front Cell Infect Microbiol 2021 11;11:563085. Epub 2021 Feb 11.

National Heart and Lung Institute, Imperial College London and the NIHR Imperial Biomedical Research Centre, London, United Kingdom.

In late December 2019, a vtiral pneumonia with an unknown agent was reported in Wuhan, China. A novel coronavirus was identified as the causative agent. Because of the human-to-human transmission and rapid spread; coronavirus disease 2019 (COVID-19) has rapidly increased to an epidemic scale and poses a severe threat to human health; it has been declared a public health emergency of international concern (PHEIC) by the World Health Organization (WHO). This review aims to summarize the recent research progress of COVID-19 molecular features and immunopathogenesis to provide a reference for further research in prevention and treatment of SARS coronavirus2 (SARS-CoV-2) infection based on the knowledge from researches on SARS-CoV and Middle East respiratory syndrome-related coronavirus (MERS-CoV).
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http://dx.doi.org/10.3389/fcimb.2021.563085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904902PMC
March 2021

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

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

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

COVID-19 in Iran: A model for Crisis Management and Current Experience.

Iran J Pharm Res 2020 ;19(2):1-8

Department of Medical-Surgical Nursing, School of Nursing & Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

In February 2020, the first sample test was confirmed as positive for corona virus in Masih Daneshvari Hospital that is the reference center in Iran for all pulmonary and respiratory diseases. The decisions made in a hospital or organization to manage a crisis is very vital. Success in managing any crisis requires a scientific and scholarly attitude. This paper was distilled from experiences gained in Masih Daneshvari Hospital in Tehran, capital of Iran, in March 2020 at the stubborn time of coping and managing corona virus crisis. This study was conducted using participatory action research, a methodology which identifies problems in practice, and finds methods to solve them. This Action research involves five stages: statement of the problem, planning, data interpretation and analysis, action, and evaluation of the research process during performing the study. The whole hospital was equipped for corona virus patients in 10 phases during one week and 250 active beds were equipped for these patients. Three models, namely, "corona virus crisis management model", "Pharmaceutical care management in coronavirus crisis model" and "nursing in coronavirus crisis model" were planned and implemented. During one month of implementing these three models, the supervision team monitored the accurate implementation of instructions and resolving or revising the possible deficiencies and faults. The Masih Daneshvari crisis management model in coronavirus, can be a useful and applicable model in other corona virus centers.
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http://dx.doi.org/10.22037/ijpr.2020.113365.14255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667532PMC
January 2020

Vascular microthrombosis associated with increased interleukin-6. A severe acute respiratory distress syndrome in COVID-19 patients treated with tocilizumab.

Adv Respir Med 2020 ;88(5):468-469

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

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http://dx.doi.org/10.5603/ARM.a2020.0123DOI Listing
November 2020

The Immune Response and Immunopathology of COVID-19.

Front Immunol 2020 26;11:2037. Epub 2020 Aug 26.

Respiratory Section, Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Coronaviruses were first discovered in the 1960s and are named due to their crown-like shape. Sometimes, but not often, a coronavirus can infect both animals and humans. An acute respiratory disease, caused by a novel coronavirus (severe acute respiratory syndrome coronavirus-2 or SARS-CoV-2 previously known as 2019-nCoV) was identified as the cause of coronavirus disease 2019 (COVID-19) as it spread throughout China and subsequently across the globe. As of 14th July 2020, a total of 13.1 million confirmed cases globally and 572,426 deaths had been reported by the World Health Organization (WHO). SARS-CoV-2 belongs to the β-coronavirus family and shares extensive genomic identity with bat coronavirus suggesting that bats are the natural host. SARS-CoV-2 uses the same receptor, angiotensin-converting enzyme 2 (ACE2), as that for SARS-CoV, the coronavirus associated with the SARS outbreak in 2003. It mainly spreads through the respiratory tract with lymphopenia and cytokine storms occuring in the blood of subjects with severe disease. This suggests the existence of immunological dysregulation as an accompanying event during severe illness caused by this virus. The early recognition of this immunological phenotype could assist prompt recognition of patients who will progress to severe disease. Here we review the data of the immune response during COVID-19 infection. The current review summarizes our understanding of how immune dysregulation and altered cytokine networks contribute to the pathophysiology of COVID-19 patients.
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http://dx.doi.org/10.3389/fimmu.2020.02037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479965PMC
October 2020

Correction to: Water-pipe smoke condensate increases the internalization of Mycobacterium Bovis of type II alveolar epithelial cells (A549).

BMC Pulm Med 2020 Sep 22;20(1):250. Epub 2020 Sep 22.

Cell and Molecular Biology Group, Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, UK.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12890-020-01244-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507606PMC
September 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

Stress and burnout in health care workers during COVID-19 pandemic: validation of a questionnaire.

Z Gesundh Wiss 2020 Jun 6:1-6. Epub 2020 Jun 6.

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

Aim: To validate a questionnaire to assess stress and burnout in healthcare workers during COVID-19 pandemic.

Subjects And Methods: In this study, content validity, Cronbach's alpha, and test-retest reliability method were utilized among 60 HCWs to evaluate the validity, internal consistency, and reliability of the questionnaire respectively. The final questionnaire was composed of four parts asking for the background information, questions about the stress caused by the COVID-19, the Depression, Anxiety and Stress Scale - 21 (DASS-21), and six questions from the Copenhagen Burnout Inventory (CBI).

Results: The CVR of 46 questions was equal to 1, making them acceptably valid (CVR > 0.78), so that the items could be arranged into a final questionnaire. Moreover, all items could successfully attain CVI values above 0.79, confirming the content validity of the questionnaire. The Cronbach's alpha was between 0.80-0.95 for different sections of questionaire, confirming the stable reliability and high repeatability of the questionnaire.

Conclusion: The results of this study showed that the DASS-21 offers adequate levels of validity and reliability for assessing the stress, anxiety, and depression among the HCWs engaged with the COVID-19 pandemic. Moreover, the six items adapted from the Copenhagen burnout inventory (CBI) were found to provide a good instrument for investigating the job burnout among the HCWs at Masih Daneshvari Hospital during the outbreak of the COVID-19 epidemic.
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http://dx.doi.org/10.1007/s10389-020-01313-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275852PMC
June 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

Effect of mesenchymal stem cell-derived exosomes on the induction of mouse tolerogenic dendritic cells.

J Cell Physiol 2020 10 11;235(10):7043-7055. Epub 2020 Feb 11.

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

Dendritic cells (DCs) orchestrate innate inflammatory responses and adaptive immunity through T-cell activation via direct cell-cell interactions and/or cytokine production. Tolerogenic DCs (tolDCs) help maintain immunological tolerance through the induction of T-cell unresponsiveness or apoptosis, and generation of regulatory T cells. Mesenchymal stromal cells (MSCs) are adult multipotent cells located within the stroma of bone marrow (BM), but they can be isolated from virtually all organs. Extracellular vesicles and exosomes are released from inflammatory cells and act as messengers enabling communication between cells. To investigate the effects of MSC-derived exosomes on the induction of mouse tolDCs, murine adipose-derived MSCs were isolated from C57BL/6 mice and exosomes isolated by ExoQuick-TC kits. BM-derived DCs (BMDCs) were prepared and cocultured with MSCs-derived exosomes (100 μg/ml) for 72 hr. Mature BMDCs were derived by adding lipopolysaccharide (LPS; 0.1μg/ml) at Day 8 for 24 hr. The study groups were divided into (a) immature DC (iDC, Ctrl), (b) iDC + exosome (Exo), (c) iDC + LPS (LPS), and (d) iDC + exosome + LPS (EXO + LPS). Expression of CD11c, CD83, CD86, CD40, and MHCII on DCs was analyzed at Day 9. DC proliferation was assessed by coculture with carboxyfluorescein succinimidyl ester-labeled BALB/C-derived splenocytes p. Interleukin-6 (IL-6), IL-10, and transforming growth factor-β (TGF-β) release were measured by enzyme-linked immunosorbent assay. MSC-derived exosomes decrease DC surface marker expression in cells treated with LPS, compared with control cells ( ≤ .05). MSC-derived exosomes decrease IL-6 release but augment IL-10 and TGF-β release (p ≤ .05). Lymphocyte proliferation was decreased (p ≤ .05) in the presence of DCs treated with MSC-derived exosomes. CMSC-derived exosomes suppress the maturation of BMDCs, suggesting that they may be important modulators of DC-induced immune responses.
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http://dx.doi.org/10.1002/jcp.29601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496360PMC
October 2020

Mortality and Body Mass Index in Burn Patients: Experience from a Tertiary Referral Burn Center in Southern Iran.

World J Plast Surg 2019 Sep;8(3):382-387

Burn and Wound Healing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Background: The role of obesity has been widely studied as a determinant factor of increasing mortality in surgical patients. In this study we aimed to investigate the association of mortality determinants with obesity classification and BMI score in burn patients admitted to a tertiary referral center in Southern Iran.

Methods: In this retrospective cross-sectional study, medical profiles of burn patients admitted from 2016 to 2017 were obtained from Amiralmomenin Burn Hospital, a tertiary referral burn center affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. Demographic, and clinical characteristics as well as patient outcomes were recorded to determine prognostic factors in fatal burns based on anthropometric measurements.

Results: Among 101 patients who were enrolled in this study including 73 males and 28 females, mean age was 34.85±12.04 years, total burn surface area (TBSA) was 37.37 (10.50%), BMI was 25.46±5.33 kg/m and hospital stay was 22.28±13.62 days. Overall mortality rate was 24.7% with 25 expired cases. Logistic regression demonstrated significant association of older age, male gender, and greater TBSA with mortality. However, difference in mortality rate in patients with BMI of 25 kg/m2 (27.4%) in comparison to patients with BMI<25 kg/m2 (18%) did not reach statistical significance.

Conclusion: Although patients with higher BMI had increased mortality rate following burn injury, this finding showed no significant association. Further studies with larger samples may be necessary to conclude a causal association between BMI and mortality in burn patients.
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http://dx.doi.org/10.29252/wjps.8.3.382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790264PMC
September 2019

EPA and DHA have selective toxicity for PBMCs from multiple myeloma patients in a partly caspase-dependent manner.

Clin Nutr 2020 Jul 9;39(7):2137-2143. Epub 2019 Sep 9.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands; Nutricia Research Centre for Specialized Nutrition, Utrecht, Netherlands.

Poly-unsaturated fatty acids (PUFAs) have been shown to have cytotoxic effects in both solid and non-solid tumors. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are among the most studied PUFAs. The aim of the present study was to evaluate the cytotoxic effects of these two fatty acids (FAs) in the peripheral blood mononuclear cells (PBMCs) obtained from untreated patients (new cases) with confirmed symptomatic multiple myeloma (MM). Our results showed that EPA at the concentration of 100 μM and DHA at 50 and 100 μM induce potent apoptotic effects in the PBMCs of MM patients (P < 0.05) as evidenced by Annexin V and propidium iodide (PI) staining, while they have little or no effects on the PBMCs isolated from healthy donors (P > 0.05). The observed effects were concentration- and time-dependent and 72 h treatment with DHA at a concentration of 100 μM had the strongest effect (P < 0.01). CD138 + cells isolated from MM patients showed great sensitivity to EPA/DHA. EPA- and DHA-induced apoptosis was significantly inhibited by the pan-caspase inhibitor (Z-VAD-FMK), indicating that cell death was at least partly dependent on caspase activation. The results of the present study showed that EPA and DHA have selective toxicities for malignant human plasma cells from MM patients, but not for mononuclear cells of healthy donors. These results warrant further studies with larger study populations to investigate the usefulness of PUFAs as a promising adjunctive therapy in the treatment of MM.
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http://dx.doi.org/10.1016/j.clnu.2019.08.031DOI Listing
July 2020

Serum Exosomal miRNAs Are Associated with Active Pulmonary Tuberculosis.

Dis Markers 2019 11;2019:1907426. Epub 2019 Feb 11.

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

Introduction: Tuberculosis (TB) remains a major threat to human health. Due to the limited accuracy of the current TB diagnostic tests, it is critical to determine novel biomarkers for this disease. Circulating exosomes have been used as diagnostic biomarkers in various diseases.

Objective Of The Study: In this pilot study, we examined the expression of miRNAs as biomarker candidates for the diagnosis of TB infection.

Methods: Serum-derived exosomes were isolated from TB patients and matched control subjects. The expression of miR-484, miR-425, and miR-96 was examined by RT-PCR methods.

Results: The expression of miR-484, miR-425, and miR-96 were significantly increased in serum of TB patients which correlated with the TB infection level. A receiver operating characteristic (ROC) curve analysis showed the diagnostic potency of each individual serum exosomal miRNA with an area under the curve (AUC) = 0.72 for miR-484 ( < 0.05), 0.66 for miR-425 ( < 0.05), and 0.62 for miR-96 ( < 0.05).

Conclusion: These results demonstrate that exosomal miRNAs have diagnostic potential in active tuberculosis. The diagnostic power may be improved when combined with conventional diagnostic markers.
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http://dx.doi.org/10.1155/2019/1907426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388314PMC
July 2019

miR-1224 Expression Is Increased in Human Macrophages after Infection with Bacillus Calmette-Guérin (BCG).

Iran J Allergy Asthma Immunol 2018 Jun;17(3):250-257

Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK AND Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, New South Wales, Australia.

Tuberculosis (TB) remains a major threat to human health. Understanding the strategies mycobacteria take to overcome immune defense is important in order to control the infection. Micro (mi)RNAs are master regulators of most pathways in the human body.  Infection with mycobacterium impacts upon the host metabolic pathways as they are subverted to obtain the nutrition for intracellular TB survival. In this study, we aimed to investigate the effect of Bacillus Calmette-Guérin (BCG) infection on the expression of three miRNAs (miR-1224, -484 and -425), which are important in infection and in the regulation of metabolic pathways. Peripheral blood monocyte-derived macrophage (MDM) cultures were prepared and infected with BCG at a multiplicity of infection (MOI)=10 or left uninfected as a control. 72h post-infection, RNA was extracted from the cultured cells and cDNA synthesis and real-time PCR performed. Expression levels miRNAs were normalized to the levels of U6 snRNA (Rnu6) using the 2-ΔΔCt method. Infection with BCG resulted in a highly significant increase in miR-1224 expression (24.4±3.8-fold induction) in human MDMs. The induction of miR-484 (1.8±0.3-fold increase) and of miR-425 (1.2±0.2-fold increase) was less increased compared to miR-1224. Mycobacterium tolerates a hostile microenvironment by escaping from lysosomal degradation and providing a lipid-rich niche by trigger with and re-pattering host metabolism. This study highlighted the potential roles of miRNAs in host responses upon mycobacterium infection.
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June 2018

Exosomes in Severe Asthma: Update in Their Roles and Potential in Therapy.

Biomed Res Int 2018 8;2018:2862187. Epub 2018 May 8.

Cell and Molecular Biology Group, Airways Disease Section, Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK.

Exosomes are nanosized vesicles and have recently been recognized as important players in cell-to-cell communication. Exosomes contain different mediators such as proteins, nucleic acids (DNA, mRNA, miRNAs, and other ncRNAs), and lipid mediators and can shuttle their exosomal content to both neighboring and distal cells. Exosomes are very effective in orchestrating immune responses in the airways and all cell types can contribute to the systemic exosome pool. Intracellular communication between the broad range of cell types within the lung is crucial in disease emphasizing the importance of exosomes. In asthma, exosomes affect the inflammatory microenvironment which ultimately determines the development or alleviation of the pathological symptoms. Recent studies in this area have provided insight into the underlying mechanisms of disease and led to interest in using exosomes as potential novel therapeutic agents.
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http://dx.doi.org/10.1155/2018/2862187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964496PMC
October 2018

What Immunological Defects Predispose to Non-tuberculosis Mycobacterial Infections?

Iran J Allergy Asthma Immunol 2018 Apr;17(2):100-109

Cell and Molecular Biology Group, Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.

Nontuberculous mycobacteria (NTM) are categorized as one of the large and diverse groups of environmental organisms which are abundant in water and soil.  NTM cause a variety of diseases in humans that mainly affect the lung. A predisposition to pulmonary NTM is evident in patients with parenchymal structural diseases including bronchiectasis, emphysema, tuberculosis (TB), cystic fibrosis (CF), rheumatologic lung diseases and other chronic diseases with pulmonary manifestations. Lung infections are not the only consequences of being infected by NTM as they can also infect skin and soft tissue and may also cause lymphadenitis (predominantly in young children) and disseminated disease in human immunodeficiency virus (HIV)-infected patients or those with severely compromised immune system. NTM are also found in many subjects without any known risk factors.  Although the recent advances in imaging and microbiologic techniques including gene sequencing have provided a better view of the problems caused by NTM and has enhanced our understanding of the disease, many uncertainties regarding the immunologic response to NTM still exist. There is also limited data on the immunogenetics of NTM infection. Here, the authors reviewed the main immunogenetic defects as well as other immunological conditions which are associated with an increased the risk of NTM infections.
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April 2018

The Potential Biomarkers and Immunological Effects of Tumor-Derived Exosomes in Lung Cancer.

Front Immunol 2018 18;9:819. Epub 2018 Apr 18.

Airways Disease Section, Imperial College London, National Heart & Lung Institute, London, United Kingdom.

Lung cancer remains the leading cause of cancer-related deaths worldwide. Despite considerable achievements in lung cancer diagnosis and treatment, the global control of the disease remains problematic. In this respect, greater understanding of the disease pathology is crucially needed for earlier diagnosis and more successful treatment to be achieved. Exosomes are nano-sized particles secreted from most cells, which allow cross talk between cells and their surrounding environment transferring their cargo. Tumor cells, just like normal cells, also secrete exosomes that are termed Tumor-Derived Exosome or tumor-derived exosome (TEX). TEXs have gained attention for their immuno-modulatory activities, which strongly affect the tumor microenvironment and antitumor immune responses. The immunological activity of TEX influences both the innate and adaptive immune systems including natural killer cell activity and regulatory T-cell maturation as well as numerous anti-inflammatory responses. In the context of lung cancer, TEXs have been studied in order to better understand the mechanisms underlying tumor metastasis and progression. As such, TEX has the potential to act both as a biomarker for lung cancer diagnosis as well as the response to therapy.
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http://dx.doi.org/10.3389/fimmu.2018.00819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915468PMC
June 2019

Zymosan attenuates melanoma growth progression, increases splenocyte proliferation and induces TLR-2/4 and TNF-α expression in mice.

J Inflamm (Lond) 2018 22;15. Epub 2018 Mar 22.

7Airways Disease Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK.

Background: Melanoma is one of the most common types of skin malignancies. Since current therapies are suboptimal, considerable interest has focused on novel natural-based treatments. Toll-like receptors (TLRs) play an important role in evoking innate immunity against cancer cells. Zymosan, a known TLR-2 agonist, is a glucan derived from yeast cell walls with promising immunomodulatory effects. The aim of this study was to evaluate whether -derived zymosan-modulated skin melanoma progression by regulation of TLR-2 and TLR-4 expression in peritoneal macrophages and serum TNF-α level.

Methods: Male C57BL/6 mice were divided into four groups: i) zymosan-treated (Z), ii) Melanoma-bearing mice (M), iii) Melanoma-bearing mice treated with zymosan (ZM) and iv) a healthy control group (negative control). 15 days after melanoma induction, mice were injected i.p. with zymosan (10 μg) daily for 4 consecutive days. Mice were CO-euthanized and serum TNF-α level, TLR-2 and TLR-4 expression in peritoneal macrophages and tumor growth measured. Splenocytes were treated ex-vivo with zymosan to determine viability and proliferation.

Results: Tumor weight significantly decreased following therapeutic dosing with zymosan ( < 0.05). This was associated with zymosan-induced upregulation of TLR-2, TLR-4 and TNF-α mRNA in peritoneal macrophages and enhanced serum TNF-α levels ( < 0.05). Splenocyte number and viability were increased in a concentration-dependent manner by zymosan.

Conclusions: Our study suggests that zymosan-induced upregulation of TLR-2, TLR-4 and TNF-α gene expression and of TNF-α release; together with increased level of lymphocyte proliferation may play a role in the inhibition of melanoma progression.
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http://dx.doi.org/10.1186/s12950-018-0182-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863857PMC
March 2018

Susceptibility to mycobacterial disease due to mutations in IL-12Rβ1 in three Iranian patients.

Immunogenetics 2018 06 18;70(6):373-379. Epub 2017 Dec 18.

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

In the last decade, autosomal recessive interleukin-12 receptor β1 (IL-12Rβ1) deficiency, the most common cause of Mendelian susceptibility to mycobacterial disease (MSMD), has been diagnosed in a few children and adults with severe tuberculosis in Iran. Here, we report three cases referred to the Immunology, Asthma and Allergy ward at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD) at Masih Daneshvari Hospital from 2012 to 2017 with Mycobacterium tuberculosis and non-tuberculous mycobacteria infections due to defects in IL-12Rβ1 but with different clinical manifestations. All three were homozygous for either an IL-12Rβ1 missense or nonsense mutation that caused the IL-12Rβ1 protein not to be expressed on the cell membrane and completely abolished the cellular response to recombinant IL-12. Our findings suggest that the presence of IL-12Rβ1 deficiency should be determined in children with mycobacterial infections at least in countries with a high prevalence of parental consanguinity and in areas endemic for TB like Iran.
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http://dx.doi.org/10.1007/s00251-017-1041-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943370PMC
June 2018

A new ataxia-telangiectasia mutation in an 11-year-old female.

Immunogenetics 2017 07 9;69(7):415-419. Epub 2017 May 9.

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

Ataxia-telangiectasia (A-T), a rare inherited disorder, usually affects the nervous and immune systems, and occasionally other organs. A-T is associated mainly with mutations in the ataxia telangiectasia mutated (ATM) gene, which encodes a protein kinase that has a major role in the cellular response to DNA damage. We report here a novel ATM mutation (c.3244_3245insG; p.His1082fs) in an 11-year old female. This subject presented with typical features, with the addition of chest manifestations including mediastinal lymphadenopathy and diffuse bilateral micronodular infiltration of the lungs, along with a high EBV titer. The subject died as a result of rapid B-cell lymphoma progression before chemotherapy could be initiated. This case highlights the need for the rapid diagnosis of A-T mutations and the detection of associated life-threatening outcomes such as cancers.
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http://dx.doi.org/10.1007/s00251-017-0983-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486830PMC
July 2017

Water-pipe smoke condensate increases the internalization of Mycobacterium Bovis of type II alveolar epithelial cells (A549).

BMC Pulm Med 2017 04 21;17(1):68. Epub 2017 Apr 21.

Cell and Molecular Biology Group, Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, UK.

Background: Tuberculosis (TB) is a major global health problem, and there is an association between tobacco smoke and TB. Water pipe smoking has become an increasing problem not only in Middle Eastern countries but also globally because users consider it as safer than cigarettes. The presence of high levels of toxic substances in water-pipe smoke may be a predisposing factor that enhances the incidence of pulmonary disorders. For example, uncontrolled macropinocytosis in alveolar epithelial cells following exposure to water-pipe smoke may predispose subjects to pulmonary infection. Here, we studied the effects of water-pipe condense (WPC) on the internalization of Mycobacterium Bovis BCG by macropinocytosis in the alveolar epithelial cell line A549.

Methods: A549 cells were exposed to WPC (4 mg/ml) for 24, 48, 72 and 96 h. Cell viability was studied using the methyl thiazolyldipenyl-tetrazolium bromide (MTT) reduction assay and proliferation by bromodeoxyUridine (BrdU) incorporation. Cells were exposed to FITC-Dextran (1 mg/ml) (as a control) and FITC-BCG (MOI = 10) for 20 min at 37 °C before cells were collected and the uptake of BCG-FITC determined by flow cytometry. Similar experiments were performed at 4 °C as a control. The Rho-associated protein kinase (ROCK) inhibitor Y-27632 (1 μM) was used to assess the mechanism by which WPC enhanced BCG uptake.

Results: WPC (4 mg/ml) increased the uptake of BCG-FITC after 72 (1.3 ± 0.1 fold, p < 0.05) and 96 (1.4 ± 0.05 fold, p < 0.05) hours. No effect on BCG-FITC uptake was observed at 24 or 48 h. WPC also significantly increased the uptake of FITC-Dextran (2.9 ± 0.3 fold, p < 0.05) after 24 h. WPC significantly decreased cell viability after 24 (84 ± 2%, p < 0.05), 48 (78±, 3%, p < 0.05), 72 (64 ± 2%, p < 0.05) and 96 h (45 ± 2%, p < 0.05). Y-27632 completely attenuated the increased uptake of BCG by WPC. Cell proliferation showed a decreasing trend in a time-dependent manner with WPC exposure.

Conclusion: WPC exposure increased epithelial cell endocytosis activity and death as well as enhancing their capacity for macropinocytosis. Our in vitro data indicates possible harmful effects of WPC on the ability of lung epithelial cells to phagocytose mycobacterium.
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http://dx.doi.org/10.1186/s12890-017-0413-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5401461PMC
April 2017

Identification of different subtypes of rapid growing Atypical Mycobacterium from water and soil sources: Using PCR-RFLP using hsp65 and rRNA 16s-23s genes.

Int J Mycobacteriol 2016 Dec 14;5 Suppl 1:S212-S213. Epub 2016 Nov 14.

Mycobacteriology Research Centre (MRC), National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Objective/background: Nontuberculosis mycobacteria (NTM) are a diverse group of microorganisms that cause a variety of diseases in humans including skin, respiratory, and gastrointestinal tract infection. Generally, NTM are classified into two categories: rapid (<7days) and slow growing (>7days). In this study, we aimed to investigate NTM frequency and prevalence in environmental samples. Additionally, we tried to identify various subtypes of isolated rapid growing mycobacteria (RGM).

Methods: Through a prospective descriptive cross-sectional study, water and soil samples were gathered from four neighboring towns around Tehran, the capital of Iran, at different geographic directions. Every 100m of the studied areas gave one sample containing 6g of soil in 3-5cm depth deposited in 50mL sterile water as sampling media. After digestion and decontamination, DNA from culture-positive specimens (RGM) were extracted using phenol-chloroform methods. Then the molecular identification of species and subspecies were performed using 16s-23s rRNA and hsp65 gene.

Results: In total, 341 RGM were found, out of which 322 (94.4%) were identified and 20 (5.8%) could not be identified. The most frequent RGM was, Mycobacterium fortuitum (72; 22%), Mycobacterium senegalense (58; 17.7%), Mycobacterium parafortuitum (44; 13.4%) and Mycobacterium conceptionense type 1 (24; 7.2%), and Mycobacterium cheloni type 1 (20; 6.0%). As shown in Table 1, M. fortuitum had more subtypes (8), and the frequency of subtypes 1 (27.7%), 4 (16.6%), and 5 (13.8%) were higher. Among subtypes of M. senegalense, subtype 1 had a higher frequency (70.4%) in comparison to subtype 2 (29.5%). M. cheloni had just one subtype.

Conclusion: Our results showed M. fortuitum as the most prominent strain isolated from environmental samples. The frequency was similar in different places, irrespective of climatic variations. Availability of various subtypes of M. fortuitum might indicate a large circulation of this RGM in soil and water of Iranian territory. This high prevalence of M. fortuitum might raise the risk infection, especially in children, immunocompromised patients, diabetics, and cancer cases.
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http://dx.doi.org/10.1016/j.ijmyco.2016.09.057DOI Listing
December 2016

The roles of miRNAs as potential biomarkers in lung diseases.

Eur J Pharmacol 2016 Nov 12;791:395-404. Epub 2016 Sep 12.

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

MicroRNAs (miRNAs) are small non-coding RNAs which can act as master regulators of gene expression, modulate almost all biological process and are essential for maintaining cellular homeostasis. Dysregulation of miRNA expression has been associated with aberrant gene expression and may lead to pathological conditions. Evidence suggests that miRNA expression profiles are altered between health and disease and as such may be considered as biomarkers of disease. Evidence is increasing that miRNAs are particularly important in lung homeostasis and development and have been demonstrated to be the involved in many pulmonary diseases such as asthma, COPD, sarcoidosis, lung cancer and other smoking related diseases. Better understanding of the function of miRNA and the mechanisms underlying their action in the lung, would help to improve current diagnosis and therapeutics strategies in pulmonary diseases. Recently, some miRNA-based drugs have been introduced as possible therapeutic agents. In this review we aim to summarize the recent findings regarding the role of miRNAs in the airways and lung and emphasise their potential therapeutic roles in pulmonary diseases.
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http://dx.doi.org/10.1016/j.ejphar.2016.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094636PMC
November 2016

Are There Any Epigenetic Similarities Between Treatment Unresponsive Sarcoidosis, COPD and Severe Asthma?

Iran J Allergy Asthma Immunol 2015 Oct;14(5):472-5

Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.

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October 2015

Anti-Inflammatory Effects of Lactobacillus Rahmnosus and Bifidobacterium Breve on Cigarette Smoke Activated Human Macrophages.

PLoS One 2015 28;10(8):e0136455. Epub 2015 Aug 28.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands; Nutricia Research Centre for Specialized Nutrition, Utrecht, The Netherlands.

Background: Chronic obstructive pulmonary disease (COPD) is a major global health problem with cigarette smoke (CS) as the main risk factor for its development. Airway inflammation in COPD involves the increased expression of inflammatory mediators such as CXCL-8 and IL-1β which are important mediators for neutrophil recruitment. Macrophages are an important source of these mediators in COPD. Lactobacillus rhamnosus (L. rhamnosus) and Befidobacterium breve (B. breve) attenuate the development of 'allergic asthma' in animals but their effects in COPD are unknown.

Objective: To determine the anti-inflammatory effects of L. rhamnosus and B. breve on CS and Toll-like receptor (TLR) activation.

Design: We stimulated the human macrophage cell line THP-1 with CS extract in the presence and absence of L. rhamnosus and B. breve and measured the expression and release of inflammatory mediators by RT-qPCR and ELISA respectively. An activity assay and Western blotting were used to examine NF-κB activation.

Results: Both L. rhamnosus and B. breve were efficiently phagocytized by human macrophages. L. rhamnosus and B. breve significantly suppressed the ability of CS to induce the expression of IL-1β, IL-6, IL-10, IL-23, TNFα, CXCL-8 and HMGB1 release (all p<0.05) in human THP-1 macrophages. Similar suppression of TLR4- and TLR9-induced CXCL8 expression was also observed (p<0.05). The effect of L. rhamnosus and B. breve on inflammatory mediator release was associated with the suppression of CS-induced NF-κB activation (p<0.05).

Conclusions: This data indicate that these probiotics may be useful anti-inflammatory agents in CS-associated disease such as COPD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136455PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552661PMC
June 2016

Association of Mycobacterium Tuberculosis Lineages with IFN-γ and TNF-α Gene Polymorphisms among Pulmonary Tuberculosis Patient.

Mediterr J Hematol Infect Dis 2014 16;6(1):e2014015. Epub 2014 Feb 16.

Mycobacteriology Research Centre, National Research Institute of Tuberculosis and Lung Disease [NRITLD], Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences.

The six major lineages of Mycobacterium tuberculosis [MTB] are found to be strongly associated with specific geographical outbreaks. But whether these bacterial lineages influence the host genetic polymorphism is uncertain. The present study was designed to evaluate the relevance of strain diversity and host genetic polymorphisms in susceptibility to pulmonary tuberculosis [PTB]. For this reason, single -nucleotide polymorphisms [SNPs] in interferon- γ [IFN-γ] receptor-1[G-611A], IFNG [G+ 2109A] and tumor necrosis factors [TNF-α] genes [at -238, 308,-857position] in patients [n=151] were analyzed and compared with controls [n=83]. The genetic diversity of M. tuberculosis isolates was performed using spacer oligonucleotide typing. Thereafter, the profile of IFN-γ and TNF-α allele frequency were investigated in each subtype of M.tuberculosis. The results showed C allele of TNF 857 and A allele of TNF 238 were more frequent in PTB cases [[TNF 857 C allele OR [CI95%] 0.6[0.4-0.9], p= 0.02] for TNF 238 A allele OR [CI95%] 5.5[3.4-9.0], p= 0.00]]. Similarly, G allele in IFNG+ 2109 A/G polymorphism were significantly more in patients than control subject[OR[CI95%] 0.3; p< 0.05]. The major identified clinical isolates of M. tuberculosis were EAI[42; 27.8% ], Haarlem[ 31; 20.5% ], CAS [ 23;15.2% ], Beijing[14; 9.2%], and T [11; 7.2% ] lineages. No correction was observed between strains diversity and frequency of SNPs in studied PTB cases. In conclusions, we exclude the possibility of genetic mutation in IFN-γ and TNF-α gene by different subtypes of M. tuberculosis. Although, our results supports a positive correlation between host SNPs and susceptibility to PTB.
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http://dx.doi.org/10.4084/MJHID.2014.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965727PMC
March 2014

A retrospective analysis of isoniazid-monoresistant tuberculosis: among Iranian pulmonary tuberculosis patients.

Open Microbiol J 2013 7;8:1-5. Epub 2014 Feb 7.

Mycobacteriology Research Centre, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background And Objectives: Isoniazid (INH) is one of the most potent anti-tuberculosis (TB) drugs. The spread and transmission of INH- resistant bacilli are likely to pose a significant problem for National TB control Program (NTP). In this study, we aimed to determine the trend of INH-monoresistant TB in Iran.

Methods: The susceptibility patterns of Mycobacterium tuberculosis (MTB) strains that were isolated from clinical samples were retrospectively analyzed (January 2003-December 2011). Identification and drug susceptibility testing (DST) were performed using both conventional and molecular methods. The associated risk factors were assessed using the Chi-square test.

Results: Out of 4825 culture-positive isolates, 6.1% were resistant to INH, with an increasing trend over the study period. The INH-monoresistance from 4.4 in 2003 reached to 9.4% in 2011. Among the studied risk factors, age was significantly associated with INH-monoresistance (p < 0.05).

Conclusions: The increased trend in INH-monoresistance underlines the need for greater enforcement of national TB control programs. In this regard, better management of TB cases, establishing advanced diagnostic facilities and use of standard treatment regimens are recommended to avoid further emergence of INH resistant cases.
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http://dx.doi.org/10.2174/1874285801408010001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942868PMC
March 2014