Introduction: Sulfur mustard (SM) is a potent toxic agent that cause local and systemic changes in the human body such as dysregulation of the immunological system. This gas affects different organs such as lungs, skin, eyes and the gastrointestinal tract. Methods: 128 veterans with SM-induced eye injuries were examined and compared to 31 gender- and age-matched healthy controls. Serum levels of IgM, IgE, IgA, IgG, and IgG subclasses were measured using ELISA method. Results: There was no significant difference in IgM level between two groups with abnormal and normal ocular conditions except for those having bulbar conjunctiva-limbal ischemia and bulbar conjunctiva-hyperemia abnormalities. There were not significant difference in IgA, IgE, and IgG levels between two groups with and without ocular problem also between study groups. IgG1 level in some ocular abnormalities were significantly lower than the healthy control-groups. IgG2 level in SM-exposed participants with stromal abnormality was higher in the SM-exposed groups without this problem. IgG2 levels in the exposed group with some ocular problems were significantly increased compared with control. IgG3 level in all patients did not reveal any significant changes compared with the controls except the fundus abnormality. IgG4 level was not significantly different between two groups with normal and abnormal ocular conditions. Nonetheless, IgG4 level in the exposed participants with some ocular abnormalities significantly increased compared with the controls. Conclusion: The results showed SM exposure could alter immunoglobulins level compared with healthy controls and the changes of IgG2 and IgG1 levels were associated with some ocular problems.

Background: Despite several reports on the clinical manifestations of sulfur mustard (SM) intoxication, there is no study on serum concentrations of thyroid hormones long-term after SM exposure. In this study, the changes in thyroid functioning parameters 20 yr after SM exposure were evaluated. Methods: This study is a part of a larger historical cohort study conducted in 2007 following 20 years of the exposure to SM, called Sardasht–Iran cohort study (SICS). We (SICS) comprised an SM–exposed group from Sardasht City, West Azerbaijan Province, Iran (n=169 as hospitalized group and n=203 as non-hospitalized exposed group); and control participants were selected from Rabat, a town near Sardasht (n=126). Peripheral blood samples were taken in fasting state and then the sera were separated. T4, T3, TSH, antithyroglobulin (anti–Tg), and antithyroid peroxidase (anti–TPO) concentrations in the sera were measured by the ELISA method. Results: The mean of T3 concentration was significantly higher in the exposed than control group (0.88 ± 0.26 nmol/L vs 0.8 ± 0.25 nmol/L, P<0.001). The levels of TSH, T4, and T3up were not significantly different between the exposed and control groups. Thyroglobulin level was significantly higher in the exposed non-hospitalized group (56.07 ± 140.22 µg/L vs 17.66 ± 41.49 µg/L, P=0.004), but the level of anti–Tg and anti–TPO showed no significant differences between the two groups. Conclusion: More studies are needed on the alterations in thyroid hormones, their gene expressions, and mechanisms involved in SM exposure to clarify the causes of these alterations.

Background and objective Aside from direct toxic effects, Sulfur Mustard (SM) induced serum hormone abnormalities may aggravate ocular complaints, including Ocular Surface Discomfort (OSD) (burning, itching, and redness), dry eye sensation, photophobia, blurred vision, foreign body sensation, and pain. The aim of the current study was to investigate the possible association of ocular complaints with serum hormone concentrations in chronic phase of Sulfur Mustard (SM) exposure. Methods:As a part of Sardasht Iran Cohort Study (SICS), 372 SM-exposed patients and 128 non-exposed participants were enrolled. Ocular complaints and ocular surface biomicroscopic conditions and serum hormones were compared. Results:The exposed with tearing group had significantly higher mean serum levels of testosterone and prolactin (ng/mL) than controls (5.75 vs. 4.75, P=0.031; 11.71 vs. 8.42, P=0.009). The exposed with OSD group had significantly higher mean serum levels of prolactin than controls (12.48 vs. 6.90, P=0.002). The exposed with photophobia group had significantly higher mean serum levels of testosterone than the matched exposed (6.25 vs. 5.65, P=0.013). The exposed with blurred vision group had significantly higher mean serum levels of Thyroglobulin (Tg) (ng/mL) than the matched exposed (65.73 vs. 32.6, P=0.003). Conclusion: Higher mean serum levels of testosterone (in exposed with tearing and photophobia) and prolactin (in exposed with tearing and OSD) may play protective roles against SM effects. Higher mean serum levels of Tg may deteriorate the tear film integrity and optical surface, which causes blurred vision. In the chronic phase of SM toxicity, some ocular surface problems are associated with alterations in the serum concentrations of testosterone, prolactin, and Tg.

Background: Preeclampsia is one of the most common complications of pregnancy that occurs after the 20th weeks of pregnancy. The pathophysiology of this disease is not exactly known. Transforming Growth Factor-Beta (TGF-β) and Nitric Oxide (NO) are the key regulatory factors secreted by Mesenchymal Stem Cells (MSCs). The aim of the present study was to evaluate the TGF-β and NO secretion by adipose-derived MSCs in normal and preeclamptic pregnant women.Materials and Methods: The adipose tissues were collected from 10 preeclamptic patients and 10 age-matched normotensive controls at the time of cesarean section delivery. After isolation and expansion of MSCs, their capability of differentiation and immunophenotyping characteristics were assessed. Next, the release of TGF-ß was evaluated making use of ELISA sandwich method and Griess method was used to measure the level of NO.Results: Adipose derived MSCs in both groups were differentiated into osteocytes and adipocytes. The expression of CD90, CD73, CD44, and CD105 markers and lack of expression of CD-14, CD34, CD45, and HLA-DR markers in cells isolated from adipose in both groups was observed using flow cytometric analysis. The levels of TGF-ß secretion in preeclamptic women were significantly higher than those in control group, but the mean level of NO secreted by adipose derived MSCs did not significantly change in the two groups.Conclusion: It can be concluded that significant increase in the secretion of TGF-β owing to MSCs in preeclamptic participants shows the importance of these cells in controlling immunological balance in these patients. Therefore, MSCs-based therapy seems to regulate TH1/Th2 balance in preeclampsia.

BACKGROUND & OBJECTIVE:Many biochemical features of sulfur mustard (SM) intoxication have remained unknown. So far, the direct association between biochemical parameter changes and ocular problems in patients exposed to SM is not evaluated. The current study aimed at evaluating the associations between the ocular findings in patients with SM intoxication and the changes of serum and blood biochemical parameters.METHODS:In the current study, 372 patients exposed to SM and 128 matched controls were compared concerning the association between their ocular problems and biochemical parameters. Ocular problems include photophobia, ocular surface discomfort (OSD), etc. Biochemical parameters include uric acid, creatinine (Cr), hematocrit (HCT), total, direct and indirect bilirubin, high-density lipoproteins (HDL), alanine aminotransferase (ALT), calcium (Ca), fasting blood sugar (FBS), mean corpuscular hemoglobin concentration (MCHC), etc.RESULTS:The SM-exposed group with photophobia, OSD, tearing, blurred vision, abnormal tear status, and slit-lamp findings had significantly higher mean serum and blood levels of uric acid, Cr, HCT, and total and indirect bilirubin than the controls. The SM-exposed group with photophobia, tearing, ocular pain, blurred vision, bulbar conjunctival and limbal abnormalities had significantly higher mean serum and blood levels of HDL, ALT, Ca, FBS, MCHC, and HDL, indirect and total bilirubin, compared to the control group.CONCLUSION:The association of photophobia with uric acid, OSD and tearing with Cr, photophobia with HDL, ocular pain with Ca, and blurred vision with FBS may be explained for their known ocular effects in the SM-exposed subjects. SM-induced biochemical changes may intensify the ocular problems induced by the direct effects of SM.

Context: Sulfur mustard (SM), with an old manufacturing history still remains as potential threat due to easy production and extensive effects.Objectives: Increasing studies on SM indicates the interest of researchers to this subject. Almost all human body organs are at risk for complications of SM. This study offers organ-by-organ information on the effects of SM in animals and humans.Methods: The data sources were literature reviews since 1919 as well as our studies during the Iraq-Iran war. The search items were SM and its all other nomenclatures in relation to, in vivo, in vitro, humans, animals, eye, ocular, ophthalmic, lungs, pulmonary, skin, cutaneous, organs and systemic. Amongst more than 1890 SM-related articles, 257 more relevant clinicopathologic papers were selected for this review.Results: SM induces a vast range of damages in nearly all organs. Acute SM intoxication warrants immediate approach. Among chronic lesions, delayed keratitis and blindness, bronchiolitis obliterans and respiratory distress, skin pruritus, dryness and cancers are the most commonly observed clinical sequelae.Conclusion: Ocular involvements in a number of patients progress toward a severe, rapid onset form of keratitis. Progressive deterioration of respiratory tract leads to "mustard lung''. Skin problems continue as chronic frustrating pruritus on old scars with susceptibility to skin cancers. Due to the multiple acute and chronic morbidities created by SM exposure, uses of multiple drugs by several routes of administrations are warranted.

Chemokines play an important role in acute and chronic pulmonary diseases. The aim of this study was to evaluate the levels of chemokines, MMP-9, and PMN elastase in spontaneous sputum and serum of patients 20 years after SM exposure. In context of Sardasht-Iran Cohort Study (SICS) 40 male volunteers with a history of SM exposure in June 1987 and complain of excessive sputum were recruited. The volunteers were clinically examined and their history was collected by internists. Sputum and serum levels of IL-8, fractalkine, MCP-1, RANTES, MMP-9, and PMN elastase were measured using ELISA kits (R&D System). Spirometries were performed on all the participants. Sputum level of fractalkine was significantly lower in the hospitalized group (N=16, Median=1.05; IQR=0.41-2.62) than non-hospitalized group (N=18, 4.031; IQR=0.947-8.203) (p=0.042). However, serum levels of fractalkine were higher in the hospitalized group (Mean±SD=2.08±5.09) than in the non-hospitalized (Mean±SD=0.53±0.87) group (T-test, p=0.03). Serum levels of PMN-elastase were also higher in the hospitalized group (Mean±SD; 64,794.43±26,820.08) than in the non-hospitalized group (Mean±SD=44,049.33±17,675.85) (p=0.017). There was no relationship between the cytokines and the studied factors in sputum and the GOLD classification, but the serum levels of fractalkine and MMP-9 were significantly higher in the more severe (grades 3-4) group. There was no significant correlation between sputum and serum levels of measured inflammatory mediators and pulmonary complications in the patients who were exposed to SM 20 years earlier. Pathophysiologic process involved in SM induced pulmonary problems might be different from those in other chronic pulmonary diseases such as COPD and asthma.

The most important long-term morbidity problem of sulfur mustard (SM) toxicity is pulmonary complications but the pathogenesis of these complications is not clearly understood. This study evaluates the peripheral blood mononuclear sub-sets and their correlation with pulmonary function in SM exposed civilian cases 20 years post-exposure as gathered in the context of the Sardasht-Iran Cohort Study (SICS). Samples were randomly selected from two groups, SM-exposed (n=372) and control (n=128), with the same ethnicity, culture, and demography. Three color flow cytometry was applied for peripheral blood mononuclear sub-population determination. Results indicated a significant decrease in CD45+/CD3+, CD45+/CD3+/CD4+, and an increase in CD3+/CD16+56+ percentages. It was also found that absolute count of NK cells was highly increased in peripheral blood of exposed cases. There was a significant increase in NK cell count of SM exposed group with pulmonary problems as compared to the same group without pulmonary problems (p-value<0.04) based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The findings showed a significant negative correlation between absolute numbers of T lymphocyte and FVC % and positive correlation with FEV1/FVC%. The results also demonstrated that absolute numbers of monocytes had a negative correlation with FVC %. We propose that NK and T cells are probably involved in the pathogenesis or immune reactions to the delayed pulmonary complications induced by SM. This hypothesis should be tested in a more severe pulmonary complicated group.

The aim of this study was to evaluate possible association between ophthalmic complications in sulfur mustard (SM) exposed patients with mild ocular injuries and serum soluble adhesion molecules. Serum levels of sICAM-1, sL-selectin, sP-selectin and sE-selectin in 367 SM-exposed individuals with or without eye injuries were checked and compared with 128 unexposed controls. All participants underwent ocular examinations. Serum sICAM-1 level in SM exposed with blurred vision, was significantly (p=0.021) higher than in SM exposed with no blurred vision. Serum sL-selectin level was significantly (p=0.024) higher in SM exposed with photophobia than SM exposed with no photophobia. Serum P-selectin level in exposed without any slit lamp findings was significantly (p=0.003) lower than the matched control groups. Similar finding was seen in exposed group without ocular problem compared with the control groups. Serum sE-selectin level in exposed with normal ocular condition except for photophobia and blurred vision was significantly (p<0.05) higher than the matched controls. Serum E-selectin level in exposed with photophobia condition was significantly (p=0.047) higher than the control group with photophobia. In conclusion it seems that the changes in the E- and P-selectins is a regulatory mechanism for inhibition of SM induced ocular problems, although the local levels are more important and further investigations required in more severe ocular problems in SM exposed patients.

Exposure to SM leads to short and long term adverse effects on various organs including the skin. Cherry angioma is one of the late skin disorders in SM exposed individuals. The pathogenesis of abnormal angiogenesis in cherry angioma is not well known but the role of inflammatory mediators and certain hormones, including prolactin, in the regulation of angiogenesis in other diseases has been reported. Alterations in serum levels of prolactin and chemokines in SM-exposed victims and the impact on angiogenesis are indications of the role in SM-induced cherry angioma. As part of the SICS, this study seeks to evaluate the possible association of prolactin and chemokines in the emergence of SM-induced cherry angioma. The serum concentrations of prolactin, IL-8/CXCL8, RANTES/CCL5, MCP-1/CCL2, and fractalkine/CX3CL1 were titrated using sandwich ELISA technique. There was a significant difference in the level of prolactin between the exposed subgroups (with cherry angioma n = 72; mean: 10.13) and without cherry angioma (n = 268; mean: 13.13, p < 0.0096). Median of the serum levels of CCL2 in the exposed patients with cherry angioma was significantly higher than exposed patients without cherry angioma (median = 203.5 pg/ml and median = 187.10 pg/ml respectively, p = 0.035). There was no significant difference in the serum levels of IL-8, RANTES and CX3L1 between the exposed subgroups with cherry angioma and without cherry angioma. This finding serves as a basis for further research on the molecular mechanisms and pathways involved in the pathogenesis of cherry angioma and other related disorders.

Respiratory complications are the foremost long term debilitating effects after sulfur mustard toxicity. The underlying immunological mechanisms of sulfur mustard induced lung damage are still poorly understood. The question of the involvement of immunoglobulin classes and subclasses in delayed pulmonary complications induced by SM was addressed in this study as a part of Sardasht-Iran Cohort Study (SICS).In SICS, 372 male participants who were exposed to SM 20years earlier were compared with 128 unexposed age-matched controls. At the time of study (2007), the clinical evaluations and spirometry was performed for all subjects according to the American Thoracic Society Criteria, and at the same time, the sera were isolated, labeled and aliquots were kept frozen in −80°C. Serum immunoglobulin (Ig) levels including IgM, IgA, IgE, IgG, and IgG subclasses (IgG1, IgG2, IgG3 and IgG4) were measured using quantitative Elisa method. It was found that among immunoglobulin classes and IgG subclasses only IgM and IgG4 were significantly decreased in the peripheral blood of exposed cases. IgM level also positively correlated with FEV1 only in the SM exposed group. These results indicated a weak but significant role for IgA in control of the delayed pulmonary complications. There were no strong correlations between other immunoglobulin classes or IgG subclasses with pulmonary disease severity in sulfur mustard intoxicated subjects. The authors proposed that systemic levels of immunoglobulins do not exert essential roles in severity of delayed pulmonary complications following SM toxicity. However, more studies on local and systemic levels of immunoglobulins in more severe groups are suggested.

To describe the long-term health status of Sardasht civilians 20 years after sulfur mustard exposure, a historical cohort study was carried out in Sardasht (Iran) that included 372 exposed and 128 unexposed civilians. Their symptoms, diagnoses, drug use, and general health were compared. The most common complaints were about the respiratory system (93.5%), eyes (52%), skin (94.7%), and anxiety and depression (69.2%). Respiratory (42.5%), skin (75.5%), ophthalmic (19.6%), and mental (62.7%) diseases were diagnosed by specialists and they were more common in the exposed group than the control group (P<0.001). Most of the exposed group had used drugs (70.6%), which was more than control group (42.8%). It seems that exposure to sulfur mustard caused a lot of health problems in Sardasht. Identifying the pathophysiology of these problems can help them more, but more investigation is needed.

Sulfur mustard (SM) is a vesicant or blistering chemical agent that possesses mutagenic and carcinogenic properties and alkylates DNA. Little is known about the long-term effects of sulfur mustard on blood cells. The aim of this study is to examine the long-term effects of SM on peripheral blood cells in SM victims of the Iraq-Iran war (1980-1988). This study, which is a part of Sardasht Iran Cohort Study (SICS) was designed in two groups: exposed (372 participants from Sardasht) and control (128 unexposed people from Rabat). The exposed group was divided into hospitalized and not hospitalized subgroups based on the severity of lesions at exposure time. A comparison was made between the study groups' overall blood exams. The hospitalized group had significantly higher numbers of red blood cells (p=0.003) than not hospitalized and the control groups. The exposed group had significantly higher HCT and MCV (P=0.007) than the control group. Exposure group had significantly lower numbers of PLT (P=0.001), WBC (P=0.006) and PMN (P=0.001) than the control group but from clinical viewpoint this difference is not valuable. Further, lymph cells (P=0.001) in the exposed group were significantly higher than in the control group. Our research findings suggested the probability of severe damage to bone marrow and predisposing to infection in other organs (especially lung) due to exposure to SM in the exposed group.

BACKGROUND:Insights into long-term clinical consequences of sulfur mustard have emerged from some investigations but less is known about the basic and molecular mechanisms of these complications. Sardasht-Iran Cohort Study is a comprehensive historical cohort study on Sardasht chemical victims' population which was designed to find out the long-term complications of sulfur mustard exposure and the basic mechanisms underlying clinical manifestations. This paper describes the design and methodology of Sardasht-Iran Cohort Study.METHODS:In Sardasht-Iran Cohort Study, 500 individuals including 372 subjects from Sardasht, as the exposed group, and 128 subjects from Rabat, as the unexposed age-matched control group were evaluated. The exposed group was divided into two groups based on the severity of clinical complications at the time of exposure. Different samples including blood, sputum, saliva, tear, urine, and semen were collected for immunologic, hematologic, biochemical, and other laboratory analysis. Data were gathered from medical records, clinical examinations, laboratory tests, and questionnaires for psychological and lifestyle situations.CONCLUSION:The important distinctions setting this study apart from the previous ones are discussed. The Sardasht-Iran Cohort Study provides important information on various aspects of long-term consequences of sulfur mustard exposure. This database will provide a better position to suggest guidelines for the diagnosis, treatment, and prevention of delayed complications in the patients exposed to sulfur mustard.

Sulfur mustard was employed as a chemical warfare agent by the Iraqi forces in the borderline regions of Iran during the Iraq-Iran war (1980–1988). The short- and long-term biological effects of sulfur mustard agent have been studied in both basic and clinical aspects. One organ that was primarily affected was the respiratory system. Among the adults, regular physical activity positively affects the respiratory system as well as the individual’s ability to perform important daily tasks. We investigated the self reported physical activity in chemical victims 20 years after sulfur mustard exposure, compared the data with those of the matched counterparts, and explored any potential association with BMI. The exposed group was 357 and the control group was 125 individuals. Physical activity was measured using the global physical activity questionnaire (GPAQ) that evaluates work, recreational, transport and sitting activities. A significant difference was found between the control and exposed groups in terms of total physical activity MET (metabolic equivalent), total physical activity min/week and total transport-related physical activity min/week in BMI >30 kg/m2. In addition, total work-related physical activity showed a significant difference between the control and exposed groups with BMI <25 kg/m2. The results show that a significant correlation was present between the increase of body weight and the reduction of total physical activity and MET in exposed group 20 years after sulfur mustard exposure.