Houshang Rafatpanah

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)

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.

High prevalence of HTLV-I infection in Mashhad, Northeast Iran: A population-based seroepidemiology survey

BACKGROUND Mashhad, in the northeast of Iran has been suggested as an endemic area for human T cell lymphotropic virus type I (HTLV-I) infection since 1996. OBJECTIVES We performed a community-based seroepidemiology study to examine the prevalence and risk factors for HTLV-I infection in the city of Mashhad. STUDY DESIGN Between May and September 2009, overall 1678 subjects from all the 12 geographical area of Mashhad were selected randomly by multistage cluster sampling for HTLV antibody. The study population included 763 males and 915 females, with the mean age of 29.1 ± 18.5 years. 1654 serum samples were assessed for HTLV antibody using ELISA and reactive samples were confirmed by Western blot and PCR. RESULTS The overall prevalence of HTLV-I infection in whole population was 2.12% (95% CI, 1.48-2.93) with no significant difference between males and females (p = 0.093) and the prevalence of HTLV-II seropositivity was 0.12% (95% CI, 0.02-0.44). The HTLV-I Infection was associated with age (p<0.001), marital status (p<0.001), education (p = 0.047), and history of blood transfusion (p = 0.009), surgery (p<0.001), traditional cupping (p = 0.002), and hospitalization (p = 0.004). In logistic regression analysis, age was the only variable that had a significant relation with the infection (p = 0.006, OR = 4.33). CONCLUSIONS Our results demonstrated that Mashhad still remains an endemic area for HTLV-I infection despite routine blood screening. Thus, further strategies are needed for prevention of the virus transmission in whole population.

Maternal exposure to titanium dioxide nanoparticles during pregnancy; impaired memory and decreased hippocampal cell proliferation in rat offspring.

Titanium dioxide nanoparticles (TiO2-NPs) are massively produced in the environment, and because of their wide usage, they are a potential risk of damage to human health. TiO2-NPs are often used as additives for paints, papers, and foods. The central nervous system (CNS), including hippocampal regions, is potentially susceptible targets for TiO2-NPs. This study aimed to determine the effects of exposure to TiO2-NPs during pregnancy on hippocampal cell proliferation and the learning and memory of offspring. Pregnant Wistar rats received intragastric TiO2-NPs (100 mg/kg body weight) daily from gestational day (GD) 2 to (GD) 21. Animals in the control group received the same volume of distilled water via gavage. After delivery, the one-day-old neonates were deeply anesthetized and weighed. They were then killed and the brains of each group were collected. Sections of the brains from the rat offspring were stained using Ki-67 immunolabeling and the immunohistochemistry technique. Some of the male offspring (n=12 for each group) were weaned at postnatal day (PND21), and housed until adulthood (PND60). Then the learning and memory in animals of each group were evaluated using passive avoidance and Morris water maze tests. The immunolabeling of Ki-67 protein as a proliferating cell marker showed that TiO2-NPs significantly reduced cell proliferation in the hippocampus of the offspring (P<0.05). Moreover, both the Morris water maze test and the passive avoidance test showed that exposure to TiO2-NPs significantly impaired learning and memory in offspring (P<0.05). These results may provide basic experimental evidence for a better understanding of the neurotoxic effects of TiO2-NPs on neonatal and adult brains.

Alloimmunization among transfusion-dependent thalassemia patients

Background: Thalassemia is a common hemoglobin disorder in Iran and one of the major public health problems. Although blood transfusions are lifesavers for thalassemia patients, they may be associated with some complications especially erythrocyte alloimmunization. The purpose of this study was to investigate the prevalence of red blood cell alloantibodies and to determine types of these antibodies among multiple-transfused thalassemic patients. Materials and Methods: A total of 313 thalassemia patients in the northeast of Iran, who received regular blood transfusion, were included in this study. Screening of antibodies was performed on fresh serum of all patients and then antibodies were identified in patients’ serum that had positive antibody screening test using a panel of recognized blood group antigens. Results: We identified 12 alloantibodies in 9 patients (2.87%) that all were against Rhesus (Rh) blood group antigens (D, C, E). Three patients developed 2 antibodies, and others had one antibody. The most common alloantibodies were Anti-D (88.88%) and followed by Anti-C and Anti-E. Higher frequency of alloimmunization was observed in female, Rh negative and splenectomized patients. Conclusion: This study showed that evaluation of the packed cells for Rh (C, E) from the start of transfusion can be helpful in decreasing the rate of alloantibody synthesis.

Oral administration of the purple passion fruit peel extract reduces wheeze and cough and improves shortness of breath in adults with asthma.

Asthma, affecting as many as 400 million individuals worldwide, is one of the most prevalent chronic health condition in the United States. With an increasing number of patients with asthma and the frequent inability of conventional lifestyle modification and therapy to effectively control the problem, nutritional and dietary therapies are being sought. This study was undertaken to investigate the efficacy of the purple passion fruit peel (PFP) extract, a novel mixture of bioflavonoids, on asthma symptoms. Patients with asthma were studied in a 4-week randomized, placebo-controlled, double-blind trial with oral administration of PFP extract (150 mg/d) or placebo pills. The effects of PFP extract were evaluated by assessing the clinical symptoms of asthma and spirometry tests. Most clinical symptoms of asthma of the PFP extract-treated group were moderated significantly compared to the baseline. The prevalence of wheeze, cough, as well as shortness of breath was reduced significantly in group treated with PFP extract (P < .05), whereas the placebo caused no significant improvement. Purple passion fruit peel extract supplementation resulted in a marked increase in forced vital capacity (P < .05) as placebo showed no effect. However, no significant improvement was observed in the forced expiratory volume at 1 second of those supplemented with PFP extract. No adverse effect was reported by any of study participants. The PFP extract may be safely offered to asthmatic subjects as an alternative treatment option to reduce clinical symptoms.

Is there any correlation between high sensitive CRP and disease activity in systemic lupus erythematosus

The role of C-reactive protein (CRP) in systemic lupus erythematosus (SLE) as an inflammatory marker is still controversial. Recently, more sensitive methods, such as high sensitive CRP (hs-CRP) have been used to detect micro-inflammation. The role of hs-CRP in lupus flare has not been documented well. We conducted this study to examine the correlation between hs-CRP serum concentrations and disease activity in lupus. Ninety-two SLE patients and 49 healthy controls contributed to our study. Most confounding factors influencing the hs-CRP values were excluded. Disease activity was estimated using the SLE Disease Activity Index (SLEDAI-2K). hs-CRP values were determined using an enzyme-linked immunosorbent assay (ELISA) kit. Serum values of hs-CRP were significantly higher (p < 0.001, z = 3.29) in patients compared with healthy controls. The cutoff point for hs-CRP between patients and controls was 0.93 mg/L (Youden’s Index = 0.39). There was no correlation between hs-CRP serum levels and disease activity. Furthermore, hs-CRP values did not correlate with any of the laboratory parameters, except for C3 (p = 0.003, rs = −0.2) and C4 (p = 0.02, rs = −0.1). Although hs-CRP serum levels were significantly higher in lupus patients compared with healthy controls, it seems that this marker is not a good indicator for disease activity.

Nitric oxide contributes to learning and memory deficits observed in hypothyroid rats during neonatal and juvenile growth

INTRODUCTION: Severe cognitive impairment follows thyroid hormone deficiency during the neonatal period. The role of nitric oxide (NO) in learning and memory has been widely investigated. METHODS: This study aimed to investigate the effect of hypothyroidism during neonatal and juvenile periods on NO metabolites in the hippocampi of rats and on learning and memory. Animals were divided into two groups and treated for 60 days from the first day of lactation. The control group received regular water, whereas animals in a separate group were given water supplemented with 0.03% methimazole to induce hypothyroidism. Male offspring were selected and tested in the Morris water maze. Samples of blood were collected to measure the metabolites of NO, NO2, NO3 and thyroxine. The animals were then sacrificed, and their hippocampi were removed to measure the tissue concentrations of NO2 and NO3. DISCUSSION: Compared to the control groups offspring, serum thyroxine levels in the methimazole groups offspring were significantly lower (P<0.01). In addition, the swim distance and time latency were significantly higher in the methimazole group (P<0.001), and the time spent by this group in the target quadrant (Q1) during the probe trial was significantly lower (P<0.001). There was no significant difference in the plasma levels of NO metabolites between the two groups; however, significantly higher NO metabolite levels in the hippocampi of the methimazole group were observed compared to controls (P<0.05). CONCLUSION: These results suggest that the increased NO level in the hippocampus may play a role in the learning and memory deficits observed in childhood hypothyroidism; however, the precise underlying mechanism(s) remains to be elucidated.

The impact of Zataria multiflora Boiss extract on in vitro and in vivo Th1/Th2 cytokine (IFN-γ/IL4) balance

ETHNOPHARMACOLOGICAL RELEVANCE Anti-inflammatory, anti-oxidant and effect of Zataria multiflora on Th1/Th2 balance were previously described. Different therapeutic effects of this plant have been described in Iranian traditional medicine. To evaluate the immune modulatory effects of Zataria multiflora on Th1/Th2 balance, which may be implicated in inflammatory disorders, in vitro and in vivo studies were carried out. MATERIALS AND METHODS The effects of three concentrations of the extract, dexamethasone, and saline on interleukin 4 (IL-4) and interferon γ (IFN-γ) gene expression were evaluated in phytohemagglutinin (PHA) stimulated and non-stimulated human peripheral blood mononuclear cells (hPBMCs). RNA was extracted from the hPBMCs to make cDNA for real time PCR relative quantification. Furthermore, the effect of the extract on serum level of IL-4 and IFN-γ was assessed in ovalbumin (OA) sensitized guinea pigs (n=6 for each group). RESULTS Dexamethasone showed significant inhibitory effect on both IFN-γ and IL-4 gene expression and serum level of the cytokines and significantly enhanced IFN-γ/IL-4 ratio (p<0.05-p<0.001). The extract inhibited IL-4 and enhance IFN-γ gene expression and IFN-γ/IL-4 ratio too (p<0.05-p<0.001). In sensitized animals also serum level of IL-4 were significantly decreased after treatment with both dexamethasone and extract, but serum level of IFN-γ and IFN-γ/IL-4 ratio were significantly increased due to extract treatment (p<0.01 for medium and p<0.001 for high concentration). CONCLUSIONS These results indicated consistent in vitro and in vivo data for selective immune modulatory effect of the extract of Zataria multiflora which increased IFN-γ, decreased IL-4, and enhanced the ratio of IFN-γ to IL-4 (Th1/Th2 balance). Therefore, the extract of Zataria multiflora may have therapeutic value in inflammatory responses such as allergy, autoimmunity and infectious diseases associated with Th1/Th2 imbalance.

Zidovudine and interferon-α 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

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-α. 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.

The impact of interferon-alpha treatment on clinical and immunovirological aspects of HTLV-1-associated myelopathy in northeast of Iran

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory myelopathy. The pathophysiology of HAM/TSP is not yet fully understood; therefore, effective therapy remains a challenging issue. This study was designed to evaluate the efficacy of interferon-alpha (IFN-α) in HAM/TSP patients in the Northeast of Iran. Forty-nine patients with a definite diagnosis of HAM/TSP were enrolled in this clinical trial. For six months, the patients received three million international units of subcutaneous IFN-α-2b per each injection. The dose regimen was daily injection for the first month, three times administration per week for the months 2 and 3, twice weekly injection for the months 4 and 5 and weekly injection for the sixth month. The clinical and laboratory responses were evaluated based on neurologic examinations and immunovirological markers. IFN-α had significant but temporary effect on the motor and urinary functions of the patients. Comparing to the baseline values, proviral load was significantly decreased one month after treatment in responders (495.20±306.87 to 262.69±219.24 p=0.02) and non-responders (624.86±261.90 to 428.28±259.88 p=0.03). Anti-HTLV-1 antibody titers were significantly decreased among responders (1152.1±200.5 to 511.6±98.2 p=0.009) and non-responders (1280.1±368.1 to 537.6±187 p=0.007). Flow cytometry showed no significant changes in CD4, CD8, CD4CD25 and CD16CD56 counts with IFN-α. The positive impact of IFN-α was observed during the treatment period with significant effects on some clinical aspects of HAM/TSP.