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      Skin manifestations in sulfur mustard exposed victims with ophthalmologic complications: Association between early and late phase

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          Abstract

          Context

          Sulfur mustard (SM) was used during the Iraq-Iran war (1980–1988). Exposed veterans continue to suffer from its ocular, skin, and respiratory complications.

          Objective

          We aimed to evaluate associations between early (at the time of acute exposure) and decades later skin manifestations in individuals with severe ophthalmologic complications secondary to sulfur mustard exposure.

          Materials and methods

          One hundred forty-nine veterans with severe ocular injuries were evaluated for acute and chronic skin complications. Logistic regression models were used to examine the associations between early and late skin manifestations.

          Results

          Late skin complaints were observed in nearly all survivors who had early skin lesions (131 out of 137; 95.62%). Seven out of 12 patients (58.33%) who did not have early skin lesions ultimately developed late skin complications. There was a significant relationship between the presence of lesions at the time of exposure and developing late skin complaints (two-sided Fisher's exact test, OR = 15.59, p < 0.001). There was an association between having at least one early skin lesion and occurrence of late skin complications. Survivors with blisters at the time of chemical exposure were more likely to complain of itching (95% CI: 3.63–25.97, p < 0.001), burning (OR = 11.16; 95% CI: 2.97–41.89, p < 0.001), pigmentation changes (OR = 10.17; 95% CI: 2.54–40.75, p = 0.001), dryness (OR = 6.71, 95% CI: 1.22–37.01, p = 0.03) or cherry angioma (OR = 2.59; 95% CI:1.21–5.55, p = 0.01) during the late phase. Using multivariate logistic models, early blisters remained significantly associated with latent skin complaints. Of note, the genitalia and great flexure areas were the most involved anatomical sites for both early and late skin lesions in SM exposed survivors.

          Conclusion

          According to this study, the presence of blisters at the time of exposure to SM is the most important predictor of developing dermatologic complications decades later in patients with severe ophthalmologic complications from sulfur mustard exposure.

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          Most cited references24

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          Comparison of early and late toxic effects of sulfur mustard in Iranian veterans.

          Sulfur mustard is an alkylating agent that reacts with ocular, respiratory, cutaneous, and bone marrow tissues, resulting in early and late toxic effects. We compare these effects based on the experience in Iranian veterans exposed to the agent during the Iran-Iraq conflict (1983-88). The first clinical manifestations of sulfur mustard poisoning occurred in the eyes with a sensation of grittiness, lacrimation, photophobia, blepharospasm, and corneal ulceration. Respiratory effects appeared as rhinorhea, laryngitis, tracheobronchitis, and dyspnoea. Skin lesions varied from erythema to bullous necrotization. Initial leukocytosis and lymphopenia returned to normal within four weeks in recovered patients, but marked cytopenia with bone marrow failure occurred in fatal cases. Late toxic effects of sulfur mustard were most commonly found in lungs, skin and eyes. Main respiratory complications were chronic obstructive pulmonary disease, bronchiectasis, asthma, large airway narrowing, and pulmonary fibrosis. Late skin lesions were hyperpigmentation, dry skin, atrophy, and hypopigmentation. Fifteen of the severely intoxicated patients were diagnosed with delayed keratitis, having corneal vascularization, thinning, and epithelial defect. Respiratory complications exacerbated over time, while cutaneous and ocular lesions decreased or remained constant. Both the severity and frequency of bronchiectatic lesions increased during long-term follow-up. The only deteriorating cutaneous complication was dry skin. The maximum incidence of delayed kaeratitis was observed 15 to 20 years after initial exposure. Being suggested as the main cause ofassociated with malignancies and recurrent infections, natural killer cells were significantly lower 16 to 20 years after intoxication.
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            Incidence of cancer in Iranian sulfur mustard exposed veterans: a long-term follow-up cohort study.

            It is estimated that during the Iraq-Iran war of the 1980s, over 100,000 Iranians (military or civilian) were exposed to sulfur mustard (SM), and a considerable proportion of them are still suffering with long-term consequences of exposure. The aim of the present article is to address carcinogenesis of SM following these acute exposures.
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              Inflammatory biomarkers of sulfur mustard analog 2-chloroethyl ethyl sulfide-induced skin injury in SKH-1 hairless mice.

              Sulfur mustard (HD) is an alkylating and cytotoxic chemical warfare agent, which inflicts severe skin toxicity and an inflammatory response. Effective medical countermeasures against HD-caused skin toxicity are lacking due to limited knowledge of related mechanisms, which is mainly attributed to the requirement of more applicable and efficient animal skin toxicity models. Using a less toxic analog of HD, chloroethyl ethyl sulfide (CEES), we identified quantifiable inflammatory biomarkers of CEES-induced skin injury in dose- (0.05-2 mg) and time- (3-168 h) response experiments, and developed a CEES-induced skin toxicity SKH-1 hairless mouse model. Topical CEES treatment at high doses caused a significant dose-dependent increase in skin bi-fold thickness indicating edema. Histopathological evaluation of CEES-treated skin sections revealed increases in epidermal and dermal thickness, number of pyknotic basal keratinocytes, dermal capillaries, neutrophils, macrophages, mast cells, and desquamation of epidermis. CEES-induced dose-dependent increases in epidermal cell apoptosis and basal cell proliferation were demonstrated by the terminal deoxynucleotidyl transferase (tdt)-mediated dUTP-biotin nick end labeling and proliferative cell nuclear antigen stainings, respectively. Following an increase in the mast cells, myeloperoxidase activity in the inflamed skin peaked at 24 h after CEES exposure coinciding with neutrophil infiltration. F4/80 staining of skin integuments revealed an increase in the number of macrophages after 24 h of CEES exposure. In conclusion, these results establish CEES-induced quantifiable inflammatory biomarkers in a more applicable and efficient SKH-1 hairless mouse model, which could be valuable for agent efficacy studies to develop potential prophylactic and therapeutic interventions for HD-induced skin toxicity.
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                Author and article information

                Contributors
                Journal
                Toxicol Rep
                Toxicol Rep
                Toxicology Reports
                Elsevier
                2214-7500
                01 September 2016
                2016
                01 September 2016
                : 3
                : 679-684
                Affiliations
                [a ]Skin and Stem Cell Research Center, Tehran University of Medical Sciences, No 4, Maryam alley, Pashazohri St, Sadr Blvd, Tehran, Iran
                [b ]Janbazan Medical and Engineering Research Center(JMERC), No.17, Farokh st, Moghadas Ardabili st, Tehran, Iran
                [c ]Moradi Skin Laser Clinic & Chemical Warfare Victims’ Clinic, Eram building, Next to Amin Ali pharmacy, Daneshjoo square, Eram St, Shiraz, Iran
                [d ]Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, No. 415, Taleqani Ave., Tehran, Iran
                [e ]Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Poursina Avenue, Qods Street, Enqelab Square, Tehran, Iran
                Author notes
                [* ]Corresponding author. mousavi.b@ 123456gmail.com
                Article
                S2214-7500(16)30063-4
                10.1016/j.toxrep.2016.08.007
                5616011
                e4c6e38c-f062-48a2-91a2-edbb129ed6e1
                © 2016 Published by Elsevier Ireland Ltd.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 28 May 2016
                : 23 August 2016
                : 23 August 2016
                Categories
                Article

                skin manifestations,ophthalmologic complications,sulfur mustard

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