Publications by authors named "Abbas Shirdel"

27 Publications

  • Page 1 of 1

Interaction of perforin and granzyme B and HTLV-1 viral factors is associated with Adult T cell Leukemia development.

Iran J Basic Med Sci 2020 Aug;23(8):1007-1011

Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran.

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

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

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

Conclusion: Low expression of perforin and granzyme in ATL patients seems to influence the efficiency of CTL function and destruction of HTLV-1-infected cells, which might contribute to the disease pathogenesis.
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http://dx.doi.org/10.22038/ijbms.2020.38454.9602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478263PMC
August 2020

Evaluating mRNA expression of tax, B chain of PDGF and PDGF-β receptors as well as HTLV-I proviral load in ATL patients and healthy carriers.

J Med Virol 2021 06 14;93(6):3865-3870. Epub 2020 Oct 14.

Immunology Research Centre, Division of Inflammation and Inflammatory Diseases, Mashhad University of Medical Sciences, Mashhad, Iran.

Adult T-cell leukemia (ATL) is a life-threatening malignant neoplasm of CD4 T cells resulted from human T-cell leukemia virus type I (HTLV-I). Tax1 protein of HTLV-I can induce malignant proliferation of T-cells by modulating the expression of growth factors such as platelet-derived growth factor (PDGF). Here, we aimed to investigate the proviral load (PVL) of HTLV-I in ATL and also to evaluate the mRNA expression of B chain of PDGF and PDGF-β receptors in ATL patients and HTLV-I-infected healthy carriers. To this end, peripheral blood mononuclear cells (PBMCs) were isolated by using Ficoll-Histophaque density centrifugation. The mean of HTLV-I PVL in ATL patients (42,759 ± 15,737 copies/10 cells [95% CI, 9557-75962]) was significantly (p = .01) higher than that in healthy carriers (650 ± 107 copies/10 cells [95% CI, 422-879], respectively. The HTLV-I PVL in ATL patients exhibited a significant correlation with PBMC count (R = .495, p = .001). The mRNA expression of Tax, B chain of PDGF, and PDGF-β receptor genes was significantly higher in healthy carriers than in patients with ATL. In conclusion, the expression of the canonical PDGFβ and its receptor, and their correlation with Tax expression cannot be a suitable indicator and/or prognostic factor for progression of ATL in HTLV-I carriers.
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http://dx.doi.org/10.1002/jmv.26510DOI Listing
June 2021

Complete sequence of human T cell leukemia virus type 1 in ATLL patients from Northeast Iran, Mashhad revealed a prematurely terminated protease and an elongated pX open reading frame III.

Infect Genet Evol 2019 09 16;73:460-469. Epub 2019 May 16.

Immunology Research Center, Division of Inflammation and Inflammatory Diseases, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

To gain insight into the origin, evolution, dissemination and viral factors affecting HTLV-1-associated diseases, knowing the complete viral genome sequences is important. So far, no full-length HTLV-1 genome sequence has been reported from Iran. Here we report the complete nucleotide sequence of HTLV-1 viruses isolated from adult T cell leukemia/lymphoma (ATLL) patients from this region. The genome size of HTLV-1-MhD (Mashhad) was found to be 9036 bp and sequence analysis of the LTR region showed that it belongs to cosmopolitan subtype A. Comparing the sequences with isolates from another endemic area (HTLV-1ATK) revealed variations in the U3 region (~3.4%), while there was 99.1% and 97.0% similarity in R and U5 regions, respectively. The nucleotide sequences of HTLV-1 gag, pro and pol genes had a difference of 1.1% compared with HTLV-1 ATK with 16 nucleotides replaced in the gag and 27 in the pol regions. There was no variability in the amino acid sequences in the p24, however three residues were different in the p19 and one in the p15. The nucleotide sequence of env showed a divergence of 1.5% compared to ATK with 22-nucleotide variation. The HTLV-1-MhD Tax, p13, p30, and p12 had 99.1, 100, 98.8, and 98%, respectively similarity with the prototype strain. Four amino acid changes were detected in ORF1 and ORF2 products p12 and p30, respectively, while the p13 region showed 100% conservation. The nucleotide identity between the isolates of Mashhad and those isolated from France, Germany, China, Canada and Brazil was 99.1%, 99.2%, 97.9%, 99% and 99.3%, respectively. Four amino acid changes compared with HTLV-1ATK from Japan were detected in ORF1 and ORF2 products p12 and p30, respectively, while the p13 region showed 100% conservation. This data could provide information regarding the evolutionary history, phylogeny, origin of the virus and vaccine design.
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http://dx.doi.org/10.1016/j.meegid.2019.05.012DOI Listing
September 2019

HTLV-1-host interactions on the development of adult T cell leukemia/lymphoma: virus and host gene expressions.

BMC Cancer 2018 Dec 22;18(1):1287. Epub 2018 Dec 22.

Immunology Research center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Azadi-Square, Medical Campus, Mashhad, Zip code: 9177948564, Iran.

Background: Adult T-cell leukemia/lymphoma (ATLL) is a lymphoproliferative disorder of HTLV-1-host interactions in infected TCD4+ cells. In this study, the HTLV-1 proviral load (PVL) and HBZ as viral elements and AKT1, BAD, FOXP3, RORγt and IFNλ3 as the host factors were investigated.

Methods: The study was conducted in ATLLs, HTLV-1-associated myelopathy/tropical spastic paraparesis patients (HAM/TSPs) and HTLV-1-asympthomatic carriers (ACs). The DNA and mRNA from peripheral blood mononuclear cells were extracted for gene expression assessments via qRT-PCR, TaqMan assay, and then confirmed by western blotting.

Results: As it was expected, the HTLV-1-PVL were higher in ATLLs than ACs (P = 0.002) and HAM/TSP (P = 0.041). The HBZ expression in ATLL (101.76 ± 61.3) was radically higher than in ACs (0.12 ± 0.05) and HAM/TSP (0.01 ± 0.1) (P = 0.001). Furthermore, the AKT1 expression in ATLLs (13.52 ± 4.78) was higher than ACs (1.17 ± 0.27) (P = 0.05) and HAM/TSPs (0.72 ± 0.49) (P = 0.008). However, BAD expression in ATLL was slightly higher than ACs and HAM/TSPs and not significant. The FOXP3 in ATLLs (41.02 ± 24.2) was more than ACs (1.44 ± 1) (P = 0.007) and HAM/TSP (0.45 ± 0.15) (P = 0.01). However, RORγt in ATLLs (27.43 ± 14.8) was higher than ACs (1.05 ± 0.32) (P = 0.02) but not HAM/TSPs. Finally, the IFNλ3 expression between ATLLs (31.92 ± 26.02) and ACs (1.46 ± 0.63) (P = 0.01) and ACs and HAM/TSPs (680.62 ± 674.6) (P = 0.02) were statistically different, but not between ATLLs and HAM/TSPs.

Conclusions: The present and our previous study demonstrated that HTLV-1-PVL and HBZ and host AKT1 and Rad 51 are novel candidates for molecular targeting therapy of ATLL. However, high level of RORγt may inhibit Th1 response and complicated in ATLL progressions.
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http://dx.doi.org/10.1186/s12885-018-5209-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303995PMC
December 2018

BCR-ABL fusion genes and laboratory findings in patients with chronic myeloid leukemia in northeast Iran.

Caspian J Intern Med 2018 ;9(1):65-70

Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: A specific chromosomal abnormality, the Philadelphia chromosome (BCR-ABL fusion), is present in all patients with chronic myeloid leukemia (CML). The b2a2 and b3a2 fusion mRNAs encode p210 fusion protein p210 and e1a2 encode p190. The aim of this study was to evaluate the frequency of BCR-ABL fusion transcript variants in Northeast of Iranian CML patients and to compare the laboratory results of our patients.

Methods: This study was conducted in 85 peripheral blood and bone marrow samples of CML patients. Ribonucleic acid (RNA) was extracted by a commercial kit, RT- PCR for identifying BCR-ABL fusions was carried out by using designed primers and the PCR products were electrophoresed in agarose gels. Finally, statistical analysis was performed for variant frequency identification and their comparison was performed.

Results: All patients examined were positive for BCR/ABL rearrangement. Fusion of b3a2 was detected in 53 (62.35%) patients, b2a2 in 25 (29.41), e1a2 in 1 (1.17%) and coexpression of b3a2 and e1a2 in 6 (7.05%) patients. There were significant differences between the mean age in patients with b3a2 positive ( 44.07 years) and in b3a2 negative group (50.35 years) however, no significant differences were seen between sex and b2a2 (P=0.61), b3a2 (P=0.79) and e1a2 (P=0.20).

Conclusions: This study showed higher frequency b3a2 than b2a2 and e1a2 transcripts in CML patients in Northeast Iran and there was no association between e1a2 transcripts frequencies and monocytosis in peripheral blood.
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http://dx.doi.org/10.22088/cjim.9.1.65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771363PMC
January 2018

Altered Expression of Cell Cycle Regulators in Adult T-Cell Leukemia/ Lymphoma Patients.

Rep Biochem Mol Biol 2017 Oct;6(1):88-94

Inflammation and Inflammatory Diseases Research Centre, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Adult T-cell leukemia/lymphoma (ATLL) is caused by human T-cell lymphotropic virus type-1 (HTLV-1). HTLV-1 oncogenes can induce malignancy through controlled gene expression of cell cycle checkpoints in the host cell. HTLV-I genes play a pivotal role in overriding cell cycle checkpoints and deregulate cellular division. In this study, we aimed to determine and compare the HTLV-1 proviral load and the gene expression levels of cyclin-dependent kinase-2 (CDK2), CDK4, p53, and retinoblastoma (Rb) in ATLL and carrier groups.

Methods: A total of twenty-five ATLL patients (12 females and 13 males) and 21 asymptomatic carriers (10 females and 11 males) were included in this study. TaqMan real-time polymerase chain reaction assay was used for evaluation of proviral load and gene expression levels of CDK2, CDK4, p53, and Rb. Statistical analysis was used to compare proviral load and gene expression levels between two groups, using SPSS version 18.

Results: The mean scores of the HTLV-1 proviral load in the ATLL patients and healthy carriers were 13067.20±6400.41 and 345.79±78.80 copies/10 cells, respectively (P=0.000). There was a significant correlation between the gene expression levels of CDK2 and CDK4 (P=0.01) in the ATLL group.

Conclusion: Our findings demonstrated a significant difference between the ATLL patients and healthy carriers regarding the rate of proviral load and the gene expression levels of p53 and CDK4; accordingly, proviral load and expression levels of these genes may be useful in the assessment of disease progression and prediction of HTLV-1 infection outcomes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643448PMC
October 2017

Evaluation of the role of , , and HTLV-1 proviral load on the survival of ATLL patients.

Blood Res 2017 Jun 22;52(2):106-111. Epub 2017 Jun 22.

Department of Modern Sciences and Technologies, Molecular Medicine Department, Faculty of Medicine, Mashhad University of Medical sciences, Mashhad, Iran.

Background: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with very poor prognosis and short survival, caused by the human T-lymphotropic virus type-1 (HTLV-1). The HTLV-1 biomarkers trans-activator x (TAX) and HTLV-1 basic leucine zipper factor (HBZ) are main oncogenes and life-threatening elements. This study aimed to assess the role of the and genes and HTLV-1 proviral load (PVL) in the survival of patients with ATLL.

Methods: Forty-three HTLV-1-infected individuals, including 18 asymptomatic carriers (AC) and 25 ATLL patients (ATLL), were evaluated between 2011 and 2015. The mRNA expression of and and the HTLV-1 PVL were measured by quantitative PCR.

Results: Significant differences in the mean expression levels of and were observed between the two study groups (ATLL and AC, =0.014 and =0.000, respectively). In addition, the ATLL group showed a significantly higher PVL than AC (=0.000). There was a significant negative relationship between PVL and survival among all study groups (=0.047).

Conclusion: The HTLV-1 PVL and expression of and were higher in the ATLL group than in the AC group. Moreover, a higher PVL was associated with shorter survival time among all ATLL subjects. Therefore, measurement of PVL, , and may be beneficial for monitoring and predicting HTLV-1-infection outcomes, and PVL may be useful for prognosis assessment of ATLL patients. This research demonstrates the possible correlation between these virological markers and survival in ATLL patients.
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http://dx.doi.org/10.5045/br.2017.52.2.106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503887PMC
June 2017

Assessment of HTLV-1 proviral load, LAT, BIM, c-FOS and RAD51 gene expression in adult T cell leukemia/lymphoma.

Med Microbiol Immunol 2017 Aug 2;206(4):327-335. Epub 2017 May 2.

Immunology Research Center, Inflammation and Inflammatory Diseases Division, Medical School, Mashhad University of Medical Sciences, Azadi-Square, Medical Campus, 9177948564, Mashhad, Iran.

Adult T cell leukemia/lymphoma (ATLL) is a life-threatening malignancy of HTLV-1 infected Th lymphocytes. In the present study host-virus interactions were investigated by assessment of HTLV-1 proviral load (PVL) and host gene expression. A cross-sectional study was carried out on 18 ATLL, 10 HAM/TSP patients and 18 HTLV-1 asymptomatic carriers (ACs). DNA and mRNA of the peripheral blood mononuclear cells were extracted for PVL and LAT, BIM, c-FOS and RAD51 gene expression measurement using qRT-PCR. The mean PVL in ATLL patients was 11,430 ± 3770 copies/10 which was statistically higher than ACs, 530 ± 119 copies/10, (p < 0.001). The expression of BIM, and c-FOS in ATLL patients were higher than HTLV-1 ACs; however, there were no statistically significant differences. The expression of RAD51 as an essential player on DNA repair showed around 160 times increase in ATLL group (166 ± 95) compared to ACs (1.04 ± 0.34) which is statistically significant (p < 0.001). Interestingly, there was a positive correlation between RAD51 expression and HTLV-PVL. The expression of LAT as a central adaptor in TCR signaling interestingly was around 36 times higher in ATLL group than ACs (ATLL; 41.33 ± 19.91 vs. ACs; 1.15 ± 0.22, p < 0.001). This finding showed that TCR signaling pathway mainly provides the growth factors for transformed cells. Furthermore, the overexpression of RAD51 which has been induced in HTLV-1 infected cells as a consequence of virus replication is not able to overcome the DNA damage toward cell transformation.
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http://dx.doi.org/10.1007/s00430-017-0506-1DOI Listing
August 2017

JAK2 V617F Mutation in Adult T Cell Leukemia-Lymphoma.

Indian J Hematol Blood Transfus 2016 Dec 17;32(4):437-441. Epub 2015 Dec 17.

Cancer Molecular Pathology Research Center, Department of Hematology and Blood Bank, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Adult T cell Leukemia/lymphoma (ATL) is a mature T-cell neoplasm that has strong association with the human T-lymphotropic virus type 1 (HTLV-I) infection. This infection is endemic in our region (north eastern Iran). It has been highlighted that Janus Kinase family proteins and specially JAK2 mutations have a pivotal role in the development of many types of hematological malignancies and in particular myeloproliferative neoplasms. So far, the underlying molecular mechanisms leading to the ATL are not well understood. Therefore, in this study it was hypothesized that JAK2 (V617F) mutation may be present in samples from patients with ATL. This case control study was performed in north-eastern Iran. Using polymerase chain reaction, JAK2 (V617F) mutation was performed in 20 DNA samples from ATL patients and 20 HTLV-1 asymptomatic carriers (control group). The results of ATL subjects and the control group were compared by using SPSS software. In the case group 13 (65 %) and 7 patients (35 %) were male and female respectively, with the age range between 40 and 80 years. Only one patients has JAK2 mutation and this mutation was absent in 95 % of ATL patients as well as the HTLV-1 asymptomatic carriers. The results of our study demonstrated that JAK2 V617F mutation is not a common phenomenon in ATL. However, further studies are required to investigate the possible dysregulation of JAK signaling in ATL.
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http://dx.doi.org/10.1007/s12288-015-0620-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074958PMC
December 2016

Association Between HTLV-I Infection with Chronic Lupoid Leishmaniasis.

Iran J Basic Med Sci 2013 Mar;16(3):281-3

Research Centre for Skin Diseases and Cutaneous Leishmaniasis, Department of Dermatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Objective(s): One of the different types of skin leishmaniasis is the Chronic Lupoid Leishmaniasis (CLL), which is caused by abnormal immune response. On the other hand, HTLV-I has been known to exist in some infectious diseases. Human T cell lymphotropic virus type1 (HTLV-I) and cutanous leishmaniasis exists endemically in Mashhad. The objective of this study was to evaluate the prevalence of HTLV-I in CLL patients.

Materials And Methods: This cross sectional study involved 51 CLL patients admitted to cutaneous leishmaniasis clinics of Ghaem and Imam Reza hospitals in Mashhad, Iran. The blood samples were examined for serology tests through ELISA method.

Results: The results of the experiments for evaluating the existence of HTLV-I in 51 patients under study in this research were proved to be negative.

Conclusion: According to this pilot study, the distribution of HTLV-I in CLL patients is not higher than normal population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881244PMC
March 2013

Association of IL-10 Gene Polymorphisms and Human T Lymphotropic Virus Type I-Associated Myelopathy/tropical Spastic Paraparesis in North-East of Iran (Mashhad).

Iran J Basic Med Sci 2013 Mar;16(3):258-63

Inflammation and Inflammatory Disease Research Centre, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

The underlying mechanisms leading to the development of human T-cell lymphotropic virus type I (HTLV-I) associated myelopathy/tropical spastic paraparesis (HAM/TSP) in HTLV-I infected individuals are not fully understood. Host genetic factors appear to be involved as risk factors for developing HAM/TSP. We investigated the possible contribution of interleukin-10 (IL-10) as a risk factor to HAM/TSP by comparing frequencies of promoter region single nucleotide polymorphisms in HTLV-I infected Iranian patients who either remained asymptomatic or developed HAM/TSP and asymptomatic HTLV-I carriers. Healthy, uninfected individuals from the same region served as healthy controls. Significant differences were observed in the distribution of IL-10 promoter alleles and genotypes at position -819 and -592 between HAM/TSP patients and healthy controls (P=0.01), and between HTLV-I carriers and healthy controls (P=0.02). The frequency of the low IL-10 producer haplotype (-1082*A, -819*T, -592*A) was significantly associated with HTLV-I carriage or HAM/TSP compared with healthy controls (P=0.02 and 0.01, respectively). Our results suggest that IL-10 -819*T and -592*A alleles are significant risk factors for developing HTLLV-I infection but do not appear to convey additional risk for developing HAM/TSP.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881251PMC
March 2013

Is there any Association Between Human Lymphotropic Virus Type I (HTLV-I) Infection and Systemic Lupus Erythematosus? An Original Research and Literature Review.

Iran J Basic Med Sci 2013 Mar;16(3):252-7

Asthma and Allergy Research Centre, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Objective(s): Systemic lupus erythematosus (SLE) is an autoimmune disease with unknown etiology. Some environmental factors can induce SLE in genetically susceptible individuals; for example, sun exposure and some viral infections may emerge the disease manifestations. Human T lymphotropic virus type 1 (HTLV-I) can dysregulate the human immune system, and the role of this virus in the pathogenesis of autoimmune diseases is under investigation. There are conflicting data about the role of HTLV-I in the pathogenesis of several autoimmune diseases such as SLE. In this study, we have focused on the correlation between HTLV-I infection and SLE in the northeast of Iran, an endemic area for the virus.

Materials And Methods: One hundred and thirty women with SLE and 915 healthy controls were screened for HTLV-I by enzyme linked immunosorbent assay (ELISA). Western blot method was used for confirmation of the positive results done by ELISA in the patients and the control group.

Results: Two (1.5%) of the patients and 23 (2.5%) of the healthy controls were HTLV-I seropositive. There was not a statistical difference between patients and controls in the number of HTLV-I seropositive samples (P=0.49).

Conclusion: This cross-sectional case-control study did not find any association between HTLV-I and SLE. With regard to the previous studies, these controversies may stem from differences in ethnic background. Geographical and environmental factors should also be taken into account.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881250PMC
March 2013

Outcome of Intravenous Immunoglobulin-Transmitted HTLV-I, Hepatitis B, Hepatitis C, and HIV infections.

Iran J Basic Med Sci 2013 Mar;16(3):221-4

Preventive Cardiovascular Care Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran.

Objective(s): Since each unit of Intravenous Immunoglobulin (IVIG) is obtained from different blood donors, blood-borne viral diseases is of high importance. We aimed at investigating the prevalence of various viral infections: Human T-cell Lymphotropic Virus Type 1 (HTLV-I), Hepatitis B (HBV), Hepatitis C (HCV), and Human Immunodeficiency Virus (HIV) among patients referred for IVIG therapy section in Mashhad University of Medical Sciences, Mashhad, Iran.

Materials And Methods: A prospective study was conducted on 130 IVIG recipients admitted to different wards of our Medical Centre: Immunology, Hematology, and Neurology, in 2010. After filling the informed consent form, a 5 cc blood sample was initially taken from each patient. Viral infections including HTLV-I Ab, HIV-Ab, HBsAg, HBc-Ab, and HBV-Ab were assessed using the ELISA technique before and after six three months treatment.

Results: Test results for HTLV-I Ab, HBsAg, HBc Ab, HIV Ab, and HCV Ab were negative in all cases before IVIG therapy. After receiving IVIG, two female cases with CIDP showed positive results for HBV Ab (0.8%) and HBS Ag (0.8%) with ELISA and only one patient confirmed with PCR. There was not any significant relation between HBV Ag (P=0.14) and HBC Ab with type of disorder (P=0.66).

Conclusion: This study showed that HTLV-I viral replication and the other investigated viral transmissions do not occur in plasma; therefore, the IVIG products are safe.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881258PMC
March 2013

Comparison of HTLV-I Proviral Load in Adult T Cell Leukemia/Lymphoma (ATL), HTLV-I-Associated Myelopathy (HAM-TSP) and Healthy Carriers.

Iran J Basic Med Sci 2013 Mar;16(3):208-12

Inflammation and inflammatory research centre, Medical School, Mashhad University of Medical Science, Mashhad- Iran ; Internal medicine Dept. Medical School, Mashhad University of Medical Science, Mashhad- Iran.

Objective(s): Human T Lymphocyte Virus Type one (HTLV-I) is a retrovirus that infects about 10-20 million people worldwide. Khorasan province in Iran is an endemic area. The majority of HTLV-I-infected individuals sustain healthy carriers but small proportion of infected population developed two progressive diseases: HAM/TSP and ATL. The proviral load could be a virological marker for disease monitoring, therefore in the present study HTLV-I proviral load has been evaluated in ATL and compared to HAM/TSP and healthy carriers.

Materials And Methods: In this case series study, 47 HTLV-I infected individuals including 13 ATL, 23 HAM/TSP and 11 asymptomatic subjects were studied. Peripheral blood mononuclear cells (PBMCs) were investigated for presence of HTLV-I DNA provirus by PCR using LTR and Tax fragments. Then in infected subjects, HTLV-I proviral load was measured using real time PCR TaqMan method.

Results: The average age of patients in ATL was 52±8, in HAM/TSP 45.52±15.17 and in carrier's 38.65±14.9 years which differences were not statistically significant. The analysis of data showed a significant difference in mean WBC among study groups (ATL vs HAM/TSP and carriers P=0.0001). Moreover, mean HTLV-I proviral load was 11967.2 ± 5078, 409 ± 71.3 and 373.6 ± 143.3 in ATL, HAM/TSP and Healthy Carriers, respectively. The highest HTLV-I proviral load was measured in ATL group that had a significant correlation with WBC count (R=0.495, P=0.001). The proviral load variations between study groups was strongly significant (ATL vs carrier P=0.0001; ATL vs HAM/TSP P= 0.0001 and HAM/TSP vs carriers P< 0.05). Conclusion : The present study demonstrated that HTLV-I proviral load was higher in ATL group in comparison with HAM/TSP and healthy carriers. Therefore, HTLV-I proviral load is a prognostic factor for development of HTLV-I associated diseases and can be used as a monitoring marker for the efficiency of therapeutic regime.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881246PMC
March 2013

Human T Lymphotropic Virus Type I (HTLV-I) Oncogenesis: Molecular Aspects of Virus and Host Interactions in Pathogenesis of Adult T cell Leukemia/Lymphoma (ATL).

Iran J Basic Med Sci 2013 Mar;16(3):179-95

Immunology Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran.

The study of tumor viruses paves the way for understanding the mechanisms of virus pathogenesis, including those involved in establishing infection and dissemination in the host tumor affecting immune-compromised patients. The processes ranging from viral infection to progressing malignancy are slow and usually insufficient for establishment of transformed cells that develop cancer in only a minority of infected subjects. Therefore, viral infection is usually not the only cause of cancer, and further environmental and host factors, may be implicated. HTLV-I, in particular, is considered as an oncovirus cause of lymphoproliferative disease such as adult T cell leukemia/lymphoma (ATL) and disturbs the immune responses which results in HTLV-I associated meylopathy/tropical spastic parapresis (HAM/TSP). HTLV-I infection causes ATL in a small proportion of infected subjects (2-5%) following a prolonged incubation period (15-30 years) despite a strong adaptive immune response against the virus. Overall, these conditions offer a prospect to study the molecular basis of tumorgenicity in mammalian cells. In this review, the oncogencity of HTLV-I is being considered as an oncovirus in context of ATL.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881257PMC
March 2013

Homocysteine, Cobalamin and Folate Status and their Relations to Neurocognitive and Psychological Markers in Elderly in Northeasten of Iran.

Iran J Basic Med Sci 2013 Jun;16(6):772-80

Paramedical School, Mashhad University of Medical Sciences, Mashhad, Iran.

Objective(s): Incidence of neurocognitive and psychological disorders may be related to serum homocystein (Hcy), cobalamin (vitamin B12) and folate levels in old people. The aim of this study was to assess the relation between Hcy, cobalamin, folate and neurocognitive and/or psychological disorders in the elderly.

Materials And Methods: In this cross-sectional study, 280 subjects with ≥ 65 years old ,were evaluated. The subjects were selected from 12 regions of Mashhad, Iran, over March to October 2009. After blood sampling, data were collected by questionnaire, face to face interview and performing neurocognitive and psychological tests. The sera of 250 persons were analyzed for cobalamin and folate by RIA method. Amongst the aforementioned samples, 78 cases with cobalamin <300 pg/ml and folate <6.5 ng/ml were analyzed for Hcy by ELISA method.

Results: Amongst the people, 126 (45%) were male and 154 (55%) were female. The prevalence of hyperhomocysteinemia (HHcy) was 59.5% and 37.1% in male and female respectively (P -value =0.049). Hcy inversely correlated to cobalamin (r=-0.282, P=0.014) and to folate (r=-0.203, P=0.014). Hcy, cobalamin and folate correlations to neurocognitive and psychological impairments were not statically significant.

Conclusion: Hyper Hcy or low cobalamin and folate in the elderly, are prevalent but their relationships with neurocognitive and psychological impairments is controversial. If these relationships had been confirmed, performing a single serum Hcy or cobalamin test would have been enough enough to diagnose and prevent neurocognitive impairments and inversely, neurocognitive-psychological sign and symptoms could have meant probable tissue vitamin deficiencies. However methods of assessing neurocognitive and psychological markers with validity and reliability of clinical and laboratory tests for finding aforementioned relationships should be revised.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3758032PMC
June 2013

The combination of arsenic, interferon-alpha, and zidovudine restores an "immunocompetent-like" cytokine expression profile in patients with adult T-cell leukemia lymphoma.

Retrovirology 2013 Aug 20;10:91. Epub 2013 Aug 20.

Department of Biology, Faculty of Sciences, Lebanese University, Hadath, Lebanon.

Background: HTLV-I associated adult T-cell leukemia/lymphoma (ATL) carries a dismal prognosis due to chemo-resistance and immuno-compromised micro-environment. The combination of zidovudine and interferon-alpha (IFN) significantly improved survival in ATL. Promising results were reported by adding arsenic trioxide to zidovudine and IFN.

Results: Here we assessed Th1/Th2/T(reg) cytokine gene expression profiles in 16 ATL patients before and 30 days after treatment with arsenic/IFN/zidovudine, in comparison with HTLV-I healthy carriers and sero-negative blood donors. ATL patients at diagnosis displayed a T(reg)/Th2 cytokine profile with significantly elevated transcript levels of Foxp3, interleukin-10 (IL-10), and IL-4 and had a reduced Th1 profile evidenced by decreased transcript levels of interferon-γ (IFN-γ) and IL-2. Most patients (15/16) responded, with CD4⁺CD25⁺ cells significantly decreasing after therapy, paralleled by decreases in Foxp3 transcript. Importantly, arsenic/IFN/zidovudine therapy sharply diminished IL-10 transcript and serum levels concomittant with decrease in IL-4 and increases in IFN-γ and IL-2 mRNA, whether or not values were adjusted to the percentage of CD4⁺CD25⁺ cells. Finally, IL-10 transcript level negatively correlated with clinical response at Day 30.

Conclusions: The observed shift from a T(reg)/Th2 phenotype before treatment toward a Th1 phenotype after treatment with arsenic/IFN/zidovudine may play an important role in restoring an immuno-competent micro-environment, which enhances the eradication of ATL cells and the prevention of opportunistic infections.
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http://dx.doi.org/10.1186/1742-4690-10-91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751834PMC
August 2013

An investigation of the spectrum of common and rare inherited coagulation disorders in north-eastern Iran.

Blood Transfus 2013 Apr 10;11(2):233-40. Epub 2012 Oct 10.

Allergy Research Centre, Ghaem Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Health care officials and legislators need accurate data on prevalence and numbers of individuals with bleeding disorders in order to plan and allot their budgets; the manufacturers of coagulation factors also need these data to estimate the amount of factors required to prevent scarcity of these products.

Materials And Methods: We surveyed the prevalence of haemophilia A, haemophilia B, von Willebrand's disease and rare bleeding disorders in North-Eastern Iran. The survey was done in the period from September 2009 to March 2011. Information was collected from the medical records in three major hospitals and a haemophilia centre; the patients' updated data were obtained by telephone.

Results: Overall in the current survey 552 patients with inherited coagulation disorders were identified and their medical records obtained. Of these, 429 (77.5%) had common bleeding disorders (haemophilia A, haemophilia B, von Willebrand's disease), 85 (15.6%) had rare bleeding disorders (deficiency of coagulation factors V, VII, X, XIII, I, XI, combined factor V and VIII deficiency) and 38 (6.9%) had platelet disorders.The commonest bleeding disorders were haemophilia A (n=287, 51.9%), haemophilia B (n=92, 16.6%), von Willebrand's disease (n=50, 9%), factor V deficiency (n=21, 3.8%), factor VII deficiency (n=19, 3.4%), factor X deficiency (n=2, 0.36%), combined factor V and VIII deficiency (n=28, 5.8%), factor XIII deficiency (n=11, 1.99%), factor XI deficiency (n=2, 0.4%), afibrinogenaemia (n=2, 0.36%) and platelet disorders (n=38, 6.9%).

Discussion: There is notable population of individuals with bleeding disorders in North-Eastern Iran.
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http://dx.doi.org/10.2450/2012.0023-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3626474PMC
April 2013

Association between HLA-DQB1 gene and patients with acute lymphoblastic leukemia (ALL).

Int J Hematol 2012 May 21;95(5):551-5. Epub 2012 Mar 21.

Department of Immunogenetics, BuAli Research Institute, Mashhad University of Medical Sciences (MUMS), BuAli Square, Mashhad, Iran.

Acute lymphoblastic leukemia (ALL) affects both children and adults. Survival in ALL has improved in recent decades due to recognition of its biological heterogeneity. Although children have higher remission and cure rates than adults, both populations have benefited from these improvements. Our aim in this study is to determine the association between HLA-DQB1 genes with childhood and adult ALL patients. To define this association, we compared HLA-DQB1 allele frequencies and allele carrier frequencies in a cohort of 135 adults and children with ALL with 150 controls, using polymerase chain reaction with sequence-specific primers. Allele carrier frequencies in childhood ALL show a deficiency in DQ2 (*0201) (P 0.049 and RR 0.75), but an increase in DQ5 (*0501-*0504) and DQ7 (*0301, *0304) compared to the control group (P 0.001 RR 1.89, P 0.003 RR 1.48, respectively). Allele carrier frequencies in adult ALL indicated an increase in DQ5 (*0501-*0504) (P0.045 RR 2.28). Allelic frequencies in childhood ALL revealed the same increase in DQ5 and DQ7, and a decrease in DQ2. In adult ALL it shows a decrease in DQ7. Therefore, our results in adult ALL were similar to childhood ALL addressing DQ5 allele carriers, which showed an increase in both age groups. We suggest that DQ5 could be more strongly considered as an ALL susceptibility allele, and that this allele may underlie a pathogenic phenotype with a major role in the immunologic process involved in both adults and children with ALL.
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http://dx.doi.org/10.1007/s12185-012-1051-8DOI Listing
May 2012

Acquired haemophilia A in a woman with autoimmune hepatitis and systemic lupus erythematosus; review of literature.

Blood Coagul Fibrinolysis 2012 Jan;23(1):71-4

Rheumatic Disease Research Center, Ghaem Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Acquired haemophilia A, secondary to systemic lupus erythematosus (SLE) is a rare bleeding diathesis. Here we report a 37-year-old woman with autoimmune hepatitis who developed SLE and acquired haemophilia caused by factor VIII inhibitors. She presented with spontaneous ecchymosis and haematuria. There were a prolongation of the activated partial thromboplastin time, reduced factor VIII activity and a high titer of FVIII inhibitors. Therapeutic regimen was started with intravenous methylprednisolone pulse, continued with prednisolone, intravenous pulse cyclophosphamide and fresh frozen plasma. After 8 weeks, factor VIII inhibitor assay was negative.
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http://dx.doi.org/10.1097/MBC.0b013e32834c6cceDOI Listing
January 2012

Acquired haemophilia A in a woman with autoimmune hepatitis and systemic lupus erythematosus: review of literature.

Blood Coagul Fibrinolysis 2011 Dec;22(8):738-41

Rheumatic Disease Research Center, Ghaem Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Acquired haemophilia A, secondary to systemic lupus erythematosus (SLE), is a rare bleeding diathesis. Here we report a 37-year-old woman with autoimmune hepatitis who developed SLE and acquired haemophilia caused by factor VIII (fVIII) inhibitors. She presented with spontaneous ecchymosis and haematuria. There were a prolongation of the activated partial thromboplastin time, reduced fVIII activity and a high titre of fVIII inhibitors. Therapeutic regimen was started with intravenous methylprednisolone pulse, continued with prednisolone, intravenous pulse cyclophosphamide and fresh frozen plasma. After 8 weeks, fVIII inhibitor assay was negative.
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http://dx.doi.org/10.1097/MBC.0b013e32834a5c8eDOI Listing
December 2011

Phase 2 study of the efficacy and safety of the combination of arsenic trioxide, interferon alpha, and zidovudine in newly diagnosed chronic adult T-cell leukemia/lymphoma (ATL).

Blood 2009 Jun 1;113(26):6528-32. Epub 2009 May 1.

Immunology Research Centre, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Adult T-cell leukemia/lymphoma (ATL) is resistant to chemotherapy and carries a dismal prognosis particularly for the acute and lymphoma subtypes. Promising results were obtained with the combination of zidovudine and interferon-alpha. Chronic ATL has a relatively better outcome, but poor long-term survival is noted when patients are managed with a watchful-waiting policy or with chemotherapy. In ATL cell lines, arsenic trioxide shuts off constitutive NF-kappaB activation and potentiates interferon-alpha apoptotic effects through proteasomal degradation of Tax. Clinically, arsenic/interferon therapy exhibits some efficacy in refractory aggressive ATL patients. These results prompted us to investigate the efficacy and safety of the combination of arsenic, interferon-alpha, and zidovudine in 10 newly diagnosed chronic ATL patients. An impressive 100% response rate was observed including 7 complete remissions, 2 complete remissions but with more than 5% circulating atypical lymphocytes, and 1 partial response. Responses were rapid and no relapse was noted. Side effects were moderate and mostly hematologic. In conclusion, treatment of chronic ATL with arsenic, interferon-alpha, and zidovudine is feasible and exhibits an impressive response rate with moderate toxicity. Long-term follow up will clarify whether this will translate to disease cure. Overall, these clinical results strengthen the concept of oncogene-targeted cancer therapy.
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http://dx.doi.org/10.1182/blood-2009-03-211821DOI Listing
June 2009

Tranexamic acid reduces blood loss in off-pump coronary artery bypass surgery.

J Cardiothorac Vasc Anesth 2009 Jun 21;23(3):312-5. Epub 2008 Dec 21.

Department of Anesthesiology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashad, Iran.

Objective: This study was designed to evaluate the hemostatic effect of tranexamic acid in off-pump coronary artery bypass surgery.

Design: A prospective, randomized, double-blind, placebo-controlled study.

Setting: The Department of Anesthesiology and Cardiac Surgery, Medical Sciences University.

Participants: One hundred eight patients undergoing off-pump coronary artery bypass surgery were enrolled into the study. Eight patients were withdrawn, and 100 patients were divided into 2 groups.

Interventions: Fifty patients received tranexamic acid (bolus 1 g before skin incision and followed by maintenance dose of 400 mg/h during surgery), and 50 patients received saline.

Measurement And Main Results: Hematologic parameters, volume of blood loss, blood transfusion, and other clinical data were recorded throughout the perioperative period. Twenty-four-hour postoperative blood loss was significantly less in the tranexamic acid group compared with the control group (471 +/- 182 v 844 +/- 303). Patients in the tranexamic acid group received significantly less allogeneic blood (8 v 31 units).

Conclusion: Bleeding and hemorrhagic complications and the consequent need for allogeneic transfusion are still major problems after off-pump coronary artery bypass surgery. Tranexamic acid appears to be effective in reducing postoperative bleeding and the need for allogeneic blood products.
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http://dx.doi.org/10.1053/j.jvca.2008.09.018DOI Listing
June 2009

Specific cutaneous manifestations in adult T-cell leukemia/lymphoma.

Int J Dermatol 2008 Apr;47(4):359-62

Department of Dermatology, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy which may occur in individuals infected with human T-cell lymphotropic virus type-I (HTLV-I). HTLV-I is endemic in Khorasan, with a frequency of 2.3% in the general population. As specific cutaneous manifestations of lymphoma may occur in a significant number of patients, we studied these manifestations in ATLL patients admitted to the Hematology and Dermatology Departments of Ghaem Hospital, Mashhad, Iran, during 1995-2004.

Methods: In this descriptive study, demographic and clinical information was obtained from 23 patients suffering from ATLL with specific cutaneous lesions (atypical lymphocytes on histopathology of cutaneous lesions), and was analyzed statistically.

Results: Of the 23 patients, 11 were male and 12 were female. The mean age was 48.17 +/- 14.1 years. The birth place in over 85% of cases was the north of Khorasan. The most common type of specific skin lesion was a maculopapular eruption (11 cases; 47.8%); papular lesions were seen in four cases (17.4%). Other lesions included plaques, ichthyosis-like lesions, erythroderma, tumors, papules, and nodular lesions. In most patients (56.5%), the skin lesions were generalized.

Conclusion: The most common type of specific skin lesion in ATLL was maculopapular eruption, especially with a generalized distribution. Other types of specific skin lesion, in order of frequency, were papules, plaques, ichthyosis-like skin lesions, nodules, tumors, and erythroderma.
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http://dx.doi.org/10.1111/j.1365-4632.2008.03526.xDOI Listing
April 2008

Increased microvessel density in involved organs from patients with HTLV-I associated adult T cell leukemia lymphoma.

Leuk Lymphoma 2008 Feb;49(2):265-70

Immunology Research Centre, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Adult T-cell leukemia-lymphoma (ATLL) is a rapidly progressive lymphoproliferative disorder secondary to infection with the human T cell lymphotropic virus type I (HTLV-I). The role of angiogenesis in the development and prognosis of many hematologic malignancies is established. We have previously shown that ATLL derived cells secrete high levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF), induce endothelial tube formation in vitro and establish functional gap junction-mediated communication with endothelial cells. We also demonstrated that plasma from ATLL and tropical spastic paraparesis/HTLV-I associated myelopathy patients exhibit very high levels of VEGF and b-FGF. Recently, we showed that treatment with the combination of zidovudine and interferon alpha reduced both HTLV-I proviral load and importantly VEGF plasma levels suggesting a potential anti-angiogenic effect of this therapy. In this report, we evaluated microvessel density (MVD) in involved organs from 20 patients with ATLL, as compared to normal organs from matched controls. We show evidence of significantly increased MVD in all tested involved organs from ATLL patients, suggesting that angiogenesis plays an important role in the development or organ invasion of ATLL, and could represent a potentially interesting target for anti-angiogenic therapy of ATLL.
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http://dx.doi.org/10.1080/10428190701760060DOI Listing
February 2008

Zidovudine and interferon-alpha treatment induces a high response rate and reduces HTLV-1 proviral load and VEGF plasma levels in patients with adult T-cell leukemia from North East Iran.

Leuk Lymphoma 2007 Feb;48(2):330-6

Immunology Research Centre, Bu-Ali Research institute, Mashhad University of Medical Sciences, Iran.

Human T-cell lymphotropic virus type I (HTLV-I) associated adult T-cell leukemia/lymphoma (ATLL) is endemic in southern Japan, the Caribbean, intertropical Africa, and Brazil. Recently north east Iran, particularly the region of Mashhad, has been recognized as a new endemic region. ATLL is an aggressive T-cell lymphoproliferative disorder. Patients with ATLL have high plasma levels of VEGF that induce angiogenesis. Prognosis of ATLL remains poor because of immunosuppression and intrinsic resistance to chemotherapy. Important advances in the treatment of ATLL were reported with the combination of zidovudine (AZT) and interferon-alpha. We investigated the effect of AZT/IFN treatment on vascular endothelium growth factor (VEGF) plasma levels and HTLV-I proviral load in ATLL patients from the region of Mashhad. We confirmed that AZT/IFN treatment induces a high response rate and prolonged survival with minimal side effects. We also confirmed that VEGF plasma levels and HTLV-I proviral load are higher in ATLL patients than in asymptomatic carriers. We finally showed that AZT/IFN treatment reduced both HTLV-I proviral load and importantly VEGF plasma levels, suggesting a potential antiangiogenic effect of this therapy. These results provide further evidence for the efficacy and the mechanism of action of AZT/IFN therapy for ATLL in a developing country.
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http://dx.doi.org/10.1080/10428190601071717DOI Listing
February 2007

Extramedullary hematopoiesis with spinal cord compression in beta-thalassemia intermedia.

Eur J Intern Med 2005 Dec;16(8):596-7

Department of Rheumatology and Department of Hematology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.

Spinal cord compression due to extramedullary hematopoiesis is a rare manifestation of thalassemia. We present a 28-year-old woman with beta-thalassemia intermedia and progressive paraparesis. She had a thoracic extradural extramedullary mass lesion on MRI. She improved after receiving multiple transfusions. Clinical awareness of this phenomenon with early treatment is essential for a successful outcome.
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http://dx.doi.org/10.1016/j.ejim.2005.04.010DOI Listing
December 2005
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