Long-term Health Outcomes Among Survivors Exposed to Sulfur Mustard in Iran.

Importance: The prevalence and severity of long-term health complications after exposure to sulfur mustard are unknown. Objective: To investigate the long-term health outcomes among survivors exposed to sulfur mustard during the Iran-Iraq War. Design, Setting, and Participants: In this retrospective cohort study, late-onset health complications of 64 190 Iranian survivors exposed to sulfur mustard during the Iran-Iraq War from 1980 to 1988 were investigated using descriptive statistics. Data involving affected organs and symptom severity were extracted from the Veterans and Martyr Affair Foundation (VMAF) database from 1980 to 2019. Assessments were conducted across 3 groups depending on whether survivors were (1) evacuated and admitted (EA) to a hospital; (2) not evacuated or admitted (NEA) to a hospital; or (3) evacuation or admission status was not documented. Exposures: Analysis of chronic symptom severity following exposure to sulfur mustard. Main Outcomes and Measures: Mild, moderate, or severe rankings of symptoms in lungs, eyes, and skin of survivors exposed to sulfur mustard using data from the VMAF database. Results: Of 64 190 chemical survivors registered in the VMAF database, 60 861 met the inclusion criteria. Of the included survivors, 98.0% were male, and the mean (SD) age was 23.5 (7.7) years. Most survivors (53 675 [88.2%]) had no symptoms or mild lesions, and 7186 survivors (11.8%) had moderate or severe complications. Moderate to severe lung (6540 [10.7%]), eye (335 [0.6%]), or skin (725 [1.2%]) injuries were documented in the exposed population. The proportion of moderate plus severe late complications in eyes was 3 times as high in male survivors compared with female survivors (0.6% [95% CI, 0.53%-0.65%] vs 0.2% [95% CI, 0.09%-0.73%]; P < .001), whereas dermal complications were significantly more common in female survivors (3.9% [95% CI, 2.92%-5.11%] vs 1.14% [95% CI, 1.06%-1.23%]; P < .001). Mild lung lesions were more prevalent in the NEA group than in the EA group (73.9% [95% CI, 73.4%-74.4%] vs 11.0% [95% CI, 10.6%-11.3%]; P < .001). In the NEA group, 83.2% (n = 23 866) developed lung injuries that were mostly mild or moderate, whereas 77% (n = 24 766) of the EA group did not develop lung injuries (P < .001). Conclusions and Relevance: The present study found sex differences in the frequencies of eye and skin complications following sulfur mustard exposure, and lung complications were more prevalent years after sulfur mustard exposure than soon after exposure. Mild lung lesions were observed more frequently among sulfur mustard-exposed survivors who had not been evacuated or hospitalized than among those who had been evacuated or hospitalized. These differences may be due to physiological response or dose of exposure. Close monitoring over an extended period may be required for detection of late pulmonary complications in individuals exposed to sulfur mustard.

Tear and serum interleukin-8 and serum CX3CL1, CCL2 and CCL5 in sulfur mustard eye-exposed patients.

BACKGROUND: The serum and tear levels of four inflammatory chemokines were evaluated in sulfur mustard (SM)-exposed with serious ocular problems. MATERIALS AND METHODS: In this study, 128 SM-exposed patients and 31 healthy control participants participated. Tear and serum levels of chemokines were assessed by ELISA method. RESULTS: There was no significant difference in the serum level of IL-8/CXCL8, CX3CL1/fractalkine, CCL2/MCP-1, and CCL5/RANTES between all SM-exposed subjects and control groups. The tear level of IL-8 in the SM-exposed group was lower than the control group, but the difference was not significant. In the SM-exposed group with the abnormalities in tear breakup time (TBUT) test, fundus and pannus formation were significantly higher than SM-exposed patients without these problems. CX3CL1 levels have significantly increased in SM-exposed group with blepharitis, pterygium, and conjunctival pigmentation as compared with the control group. Besides, significantly higher levels of CX3CL1 were observed in SM-exposed group with or without bulbar conjunctival hyperemia and abnormal vessels a well as with fundus abnormality compared to the control group. Only, SM-exposed group with subconjunctival fibrosis had significantly lower levels of CCL5 than SM-exposed group without this problem. CONCLUSION: The higher level of CX3CL1 and consistent levels of IL-8/CXCL8, MCP-1/CCL2, and RANTES/CCL5 in SM-exposed individuals may indicate an anti-inflammatory response against the destructive effects of SM gas. High tear level of IL-8/CXCL8 reflects the severity of ocular surface abnormalities, yet significantly low tear level found in mild SM-exposed subgroup compared with the control group. The lower levels of CX3CL1 and RANTES/CCL5 may represent the different pathophysiology which requires further studies.

Chronic musculoskeletal pain, phantom sensation, phantom and stump pain in veterans with unilateral below-knee amputation.

BACKGROUND AND AIMS: Many individuals with lower limb loss report concerns about other musculoskeletal symptoms resulting from amputation. The objective of this study was to assess chronic musculoskeletal pain in Iranian veterans with unilateral below-knee amputation. METHODS: The participants agreed to take part in a health needs assessment and were interviewed face-to-face by trained interviewers. The assessment consisted of demographic information, wearing a prosthesis, pain locations in extremities, stump complications, severity of pains related to amputation and low back pain. RESULTS: Of 247 unilateral below knee amputees, 97.9% wore a prosthetic limb and times walking or standing with the prosthesis were 12.47 ± 3.84 and 4.22 ± 3.53 h a day, respectively. Low soft tissue coverage of the stump (15.4%) and symptomatic osteoarthritis in the contralateral lower extremity (40.1%) were the most common complications. The prevalence of stump pain, phantom sensations, phantom pain, low back pain, and knee pain was 84.2%, 77.3%, 73.7%, 78.1%, and 54.7% respectively. The odds ratio of stump pain in amputees with phantom pain was 2.22 times higher than those who did not experience phantom pain [OR = 2.22 (CI: 1.19-4.17); p = 0.012] and the odds ratio of low back pain was higher in amputees with stump pain [OR = 3.06 (CI: 1.50-6.21); p = 0.002]. CONCLUSIONS: This research enhances our understanding of comorbid musculoskeletal problems in below-knee amputees which can help health providers to identify rehabilitation needs and emphasizes the importance of regular assessments. IMPLICATIONS: These findings underline the importance of paying closer attention to different dimensions and aspects of musculoskeletal complications in veterans with unilateral below-knee amputation.

Assessment of orthotic needs in Iranian veterans with ankle and foot disorders.

BACKGROUND: War-related traumas can lead to orthopedic and neurological disorders in victims. However, the scope of such disorders may expand months or even years after the trauma. Orthotic treatment as a rehabilitation process aims to enable people with disabilities to reach and maintain their optimal physical, sensory, intellectual, psychological, and social functional levels. This study aimed to investigate the rate of using orthoses among Iranian veterans with neuromuscular and skeletal disorders of the ankle and foot. Furthermore, the priorities of orthotic treatment in those veterans were explored. METHODS: This qualitative study was a national health needs assessment conducted in 11 provinces of Iran during 2011-2016. A stakeholder research group was established to survey the veterans in respect to their demographic variables, activities of daily living, current health conditions, and rate of using orthoses. RESULTS: Overall, 907 of the 1124 veteran participants completed the survey (response rate: 80.7%). Most of the veterans were men (97.7%), and their age and disability rate were 52.07 ± 8.13 years and 31.92% ± 14.93%, respectively. Nearly 42% of the veterans had experience in using orthoses on a daily and weekly basis. As physical ambulation was the main problematic activity in veterans, most of them were using medical shoes and foot orthoses. Nearly 37% of veterans were in need of some type of lower limb orthoses on the contralateral side to compensate for their hip inequality. In sequential order, the most in need orthoses for veterans were foot orthoses (n = 538), medical shoes (n = 447), lower limb orthoses on the contralateral side (n = 320), spinal orthoses (n = 273), and upper limb orthoses (n = 86). CONCLUSIONS: In spite of the high demands for orthoses among Iranian veterans with ankle and foot disorders, the use of orthoses is insufficient. Hence, there is a discrepancy between the current rate of orthoses use and its ideal situation, and more resources should be provided for service providers to be able to serve veterans. Moreover, veterans should be educated regarding orthoses, their use, and their impacts on the user's health status. The findings of a needs assessment of orthoses can be used in strategic planning and decision making to improve health care services for Iranian veterans.

Assistive technologies for pain management in people with amputation: a literature review.

The prevalence of limb amputation is increasing globally as a devastating experience that can physically and psychologically affect the lifestyle of a person. The residual limb pain and phantom limb pain are common disabling sequelae after amputation surgery. Assistive devices/technologies can be used to relieve pain in people with amputation. The existing assistive devices/technologies for pain management in people with amputation include electrical nerve block devices/technologies, TENS units, elastomeric pumps and catheters, residual limb covers, laser systems, myoelectric prostheses and virtual reality systems, etc. There is a great potential to design, fabricate, and manufacture some portable, wireless, smart, and thin devices/technologies to stimulate the spinal cord or peripheral nerves by electrical, thermal, mechanical, and pharmaceutical stimulus. Although some preliminary efforts have been done, more attention must be paid by researchers, clinicians, designers, engineers, and manufacturers to the post amputation pain and its treatment methods.

MicroRNA expression in serum samples of sulfur mustard veterans as a diagnostic gateway to improve care.

Sulfur mustard is a vesicant chemical warfare agent, which has been used during Iraq-Iran-war. Many veterans and civilians still suffer from long-term complications of sulfur mustard exposure, especially in their lung. Although the lung lesions of these patients are similar to Chronic Obstructive Pulmonary Disease (COPD), there are some differences due to different etiology and clinical care. Less is known on the molecular mechanism of sulfur mustard patients and specific treatment options. microRNAs are master regulators of many biological pathways and proofed to be stable surrogate markers in body fluids. Based on that microRNA expression for serum samples of sulfur mustard patients were examined, to establish specific microRNA patterns as a basis for diagnostic use and insight into affected molecular pathways. Patients were categorized based on their long-term complications into three groups and microRNA serum levels were measured. The differentially regulated microRNAs and their corresponding gene targets were identified. Cell cycle arrest, ageing and TGF-beta signaling pathways showed up to be the most deregulated pathways. The candidate microRNA miR-143-3p could be validated on all individual patients. In a ROC analysis miR-143-3p turned out to be a suitable diagnostic biomarker in the mild and severe categories of patients. Further microRNAs which might own a link to the biology of the sulfur mustard patients are miR-365a-3p, miR-200a-3p, miR-663a. miR-148a-3p, which showed up only in a validation study, might be linked to the airway complications of the sulfur mustard patients. All the other candidate microRNAs do not directly link to COPD phenotype or lung complications. In summary the microRNA screening study characterizes several molecular differences in-between the clinical categories of the sulfur mustard exposure groups and established some useful microRNA biomarkers. qPCR raw data is available via the Gene Expression Omnibus https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE110797.

DNA damage and repair proteins in cellular response to sulfur mustard in Iranian veterans more than two decades after exposure.

Delayed effects of sulfur mustard (SM) exposure on the levels of five important damage/repair proteins were investigated in 40 SM-exposed veterans of Iran-Iraq war and 35 unexposed controls. A major DNA damage biomarker protein - phosphorylated H2AX - along with four DNA repair proteins in cell response to the genome damage MRE11, NBS1, RAD51, and XPA were evaluated in blood lymphocytes from the veterans and controls using western blotting. Mean levels of XPA, MRE11, RAD51 and NBS1 were lower in SM-exposed patients and the decrease in NBS1 was significant. Even though the raised level of phosphor-H2AX in SM-poisoned group compared to the controls was not significant it was consistent with DNA damage findings confirming the severity of damage to the DNA after exposure to SM. There were correlations between the values of RAD51 and NBS1 proteins as well as XPA and MRE11 proteins. More than two decades after exposure to SM, there is still evidences of DNA damage as well as impaired repair mechanisms in cells of exposed individuals. Such disorders in cellular level may contribute to long term health problems of the SM veterans.

Altered levels of GST activity, Vit C, TPX and Cu in individuals with long-term sulfur mustard-induced lung complications.

CONTEXT: Sulfur mustard (SM) as a cytotoxic and blistering agent can alkylate a variety of cellular components, causing the incidence of ongoing oxidative stress. OBJECTIVE: The present study was conducted to assess oxidative stress index (OSI) in SM-exposed veterans with long-term pulmonary complications. METHODS: Participants consisted of 289 SM-exposed individuals with pulmonary complications (classified into three groups: mild, moderate and severe) and 66 healthy individuals as the control group. Enzymatic and non-enzymatic antioxidant and also trace elements were measured in the study groups. Moreover, some of oxidative stress indicators consist of malondialdehyde (MDA), protein carbonyl (CO), total antioxidant (TA) and total peroxide (TPX) were measured and then OSI was calculated. RESULTS: Glutathione-S-transferase (GST) activity and vitamin C (Vit C) were significantly decreased in SM-exposed patients as compared with controls. Besides, Cu level and Cu/Zn ratio in SM-exposed veterans showed a significant correlation with the severity of the diseases. Serum TPX was significantly increased in SM-exposed individuals, as a result of which the OSI was slightly higher in them than controls. This can be considered as an indicative for oxidative stress in SM-exposed patients. CONCLUSION: This study suggests a particular role for TPX, Cu, Vit C and GST in SM-induced pulmonary complications. Therefore, a special attention should be paid to these factors in designing therapeutic protocols, which can reduce the progression risk of the disease.

Prevalence of metabolic syndrome and health-related quality of life in war-related bilateral lower limb amputees.

BACKGROUND: Lower limb amputation is correlated with considerable impairments in health-related quality of life (HRQOL) in veterans. The aim of this study is to determine the prevalence of metabolic syndrome (MetS) in veterans with bilateral lower limb amputation and to identify its association with HRQOL. METHODS: This cross-sectional study was conducted on 235 Iranian male veterans with bilateral lower limb amputation. Demographics, anthropometrics, and biochemical measurements were assessed and MetS was defined by National Cholesterol Education Program Adult Treatment Panel III definition. HRQOL was assessed using the 36-item Short Form Health Survey (SF-36) questionnaire which measures eight health-related domains. The scores were compared between two groups of bilateral lower limb Amputees who have diagnosed with and without MetS. RESULTS: The response rate was 40.7% and the mean age of the amputees was 52.05 years. 62.1% of participants were suffering from MetS (95% CI: 55.9%-68.4%). Patients with MetS were observed to have higher weight, waist and hip circumferences, FBS, TG, LDL and liver enzymes concentrations (P < 0.05). Although scores on all 8 subscales of SF-36 were low, no significant difference was observed in HRQOL scores between amputees with and without MetS. Moreover, the risk of MetS was not significantly different across subjects in the highest compared to the lowest quartile category of HRQOL scores. CONCLUSIONS: Prevalence of MetS in veterans with bilateral lower limb amputation was higher and their HRQOL was lower compared to general population. Some strategies are needed to reduce the risk of cardiovascular diseases among this susceptible population.

Association between Acne and Serum Pro-inflammatory Cytokines (IL-1α, IL-1ß, IL-1Ra, IL-6, IL-8, IL-12 and RANTES) in Mustard Gas-Exposed Patients: Sardasht-Iran Cohort Study.

BACKGROUND: Acne vulgaris is a very common chronic inflammatory disorder, yet its pathogenesis is not clearly understood. As part of the SICS, this study was conducted to evaluate the association between the incidence of acne vulgaris in SM-exposed subjects (20 years after the exposure) and serum levels of proinflammatory cytokines (IL-1α, IL-1ß, IL-1Ra, IL-6, IL-8, IL-12 and RANTES) in an attempt to better understand the pathogenesis of long-term skin disorders of these individuals. METHODS: Serum concentrations of cytokines (IL-1α, IL-1ß, IL-1Ra, IL-6, IL-8, IL-12 and RANTES) were measured using sandwich ELISA technique. RESULTS: The median of serum levels of IL-1ß, IL-8 and RANTES were significantly higher in the exposed patients with acne than those without acne (P = 0.05, 0.03 and 0.001 respectively). There was no significant difference in serum levels of IL-1α, IL-1Ra and IL-6 between the exposed subgroups. CONCLUSION: We found a positive association between serum levels of pro-inflammatory cytokines (IL-1ß, IL-8, IL-12 and RANTES) and acne among SM-exposed population.

Down-regulation of TGF-b1, TGF-b receptor 2, and TGF-b-associated microRNAs, miR-20a and miR-21, in skin lesions of sulfur mustard-exposed Iranian war veterans.

Sulfur mustard (SM) affects divergent cellular pathways including cell cycle, apoptosis, necrosis, and inflammatory responses. SM-induced lesions in skin include late-onset hyper-pigmentation, xerosis, and atrophy. It seems that TGF-b signaling pathway is a major player for SM pathogenesis. Here, we have employed a real-time polymerase chain reaction (PCR) approach to evaluate the expression alterations of all TGF-b variants and their receptors in skin biopsies obtained from 10 Iran-Iraq war veterans. Using specific LNA primers, the expression alteration of a TGF-bR2 regulator, miR-20a, and TGF-b downstream target, miR-21, was also assessed in the same samples Our real-time PCR data revealed a significant down-regulation of TGF-b1 and TGF-bR2, the major mediators of TGF-b signaling pathway, in skin biopsies of SM-exposed patients (p = 0.0015 and p = 0.0115, respectively). Down-regulation of TGF-b signaling pathway seems to contribute in severe inflammation observed in SM-exposed patients' tissues. MiR-20a and miR-21, as two important TGF-b associated microRNAs (miRNAs), were also down-regulated in SM-exposed skin lesions, compared to those of control group (p = 0.0003). Based on our findings, these miRNAs could be directly or indirectly involve in the pathogenesis of SM. Altogether, our data suggest the suitability of TGF-b1, TGF-bR2, as well as miR-20a and miR-21 as potential biomarkers for diagnosis and treatment of SM-exposed patients.

Identification of Reliable Reference Genes for Quantification of MicroRNAs in Serum Samples of Sulfur Mustard-Exposed Veterans.

OBJECTIVE: In spite of accumulating information about pathological aspects of sulfur mustard (SM), the precise mechanism responsible for its effects is not well understood. Circulating microRNAs (miRNAs) are promising biomarkers for disease diagnosis and prognosis. Accurate normalization using appropriate reference genes, is a critical step in miRNA expression studies. In this study, we aimed to identify appropriate reference gene for microRNA quantification in serum samples of SM victims. MATERIALS AND METHODS: In this case and control experimental study, using quantitative real-time polymerase chain reaction (qRT-PCR), we evaluated the suitability of a panel of small RNAs including SNORD38B, SNORD49A, U6, 5S rRNA, miR-423-3p, miR-191, miR-16 and miR-103 in sera of 28 SM-exposed veterans of Iran-Iraq war (1980-1988) and 15 matched control volunteers. Different statistical algorithms including geNorm, Normfinder, best-keeper and comparative delta-quantification cycle (Cq) method were employed to find the least variable reference gene. RESULTS: miR-423-3p was identified as the most stably expressed reference gene, and miR- 103 and miR-16 ranked after that. CONCLUSION: We demonstrate that non-miRNA reference genes have the least stabil- ity in serum samples and that some house-keeping miRNAs may be used as more reliable reference genes for miRNAs in serum. In addition, using the geometric mean of two reference genes could increase the reliability of the normalizers.

Epidemiological Study of Child Casualties of Landmines and Unexploded Ordnances: A National Study from Iran.

BACKGROUND: Despite landmine-risk education programs and extensive demining activities on the Western border of Iran, landmines and unexploded ordnance (UXOs) still cause civilian and child casualties three decades after the Iraq-Iran war (1980-1988). The objective of this study was to understand the epidemiological patterns and risk factors of injury in child casualties of landmines and UXOs in Western and Southwestern Iran. METHODS: Children who were 18 years old or younger at the time of study and who sustained injuries from landmines and UXOs were identified through a search at the Iranian National Veterans Registry. These children participated in a 5-day gathering. The information on socioeconomic status, health-related issues, quality of life, health care utilization, and clinical profiles concerning the landmine and UXO injuries were collected. The method of data collection consisted of three component surveys: health interview, social survey, and medical examinations. Social surveys and health interviews were conducted in a face-to-face method by utilizing a questionnaire consisting of 39 questions addressing household and individual components, including information on time and type of injuries, physical activity, mental health, and quality of life. A comprehensive team of physicians in different subspecialties evaluated and examined children to assess the current medical and psychiatric conditions and physical activity, and recommended and arranged further medical, rehabilitation, or surgical planning. RESULTS: Seventy-eight child casualties were identified and participated in the study. The mean age of the participants at the time of study was 16.11 years old (SD=2 years). The mean age of victims at the time of injury was 8.2 years (SD=3.12 years; ranged from 2 to 15 years old). Sixty-seven (85.9%) of the children were male. Provinces of Kurdistan and Kermanshah had the highest number of casualties, with a total number of 54 children (68.3%). Eighty percent of the injuries were caused by landmines, and UXO explosions were reported in 20% of the cases. Overall, 24 children (30%) had received some landmine-risk education before or after the events. Sixty percent of the explosions had happened in the morning between 9:00 am and 12:00 pm. Playing and grazing livestock were the most prevalent activities/reasons at the time of injury, which were reported in 77% of the subjects. Sixty-three percent of incidents had multiple casualties and in only 13 explosions were the children the only victims of the explosion. The most prevalent injuries were amputations in 41 subjects (52.56%), followed by hearing loss in 23 subjects (29.5%). Amputations were more common in upper extremities (62%) than in lower extremities (38%). CONCLUSION: Landmines and UXOs comprise a significant safety hazard to the children living in the Western border of Iran decades after the Iraq-Iran War. The large number of injuries and lack of risk training among victims suggest that landmine cleanings and landmine-risk education should be age-specifically targeted and expanded substantially.

Transplanting p75-suppressed bone marrow stromal cells promotes functional behavior in a rat model of spinal cord injury.

BACKGROUND: Bone marrow stromal cells (BMSC) have been successfully employed for movement deficit recovery in spinal cord injury (SCI) rat models. One of the unsettled problems in cell transplantation is the relative high proportion of cell death, specifically after neural differentiation. According to our previous studies, p75 receptor, known as the death receptor, is only expressed in BMSC in a time window of 6-12 hours following neural induction. Moreover, we have recently reported a decreased level of apoptosis in p75-suppressed BMSC in vitro. Therefore, our objective in this research was to explore the functional effects of transplanting p75:siRNA expressing BMSC in SCI rats. METHODS: Laminectomy was performed at L1 vertebra level to expose spinal cord for contusion using weight-drop method. PBS-treated SCI rats (group one) were used as negative controls, in which cavitations were observed 10 weeks after SCI. pRNA-U6.1/Hygro- (group two, as a mock) and pRNA-U6.1/Hygro-p75 shRNA- (group three) transfected BMSC were labeled with a fluorescent dye, CM-DiI, and grafted into the lesion site 7 days after surgery. The Basso-Beattie-Bresnehan locomotor rating scale was performed weekly for 10 weeks. RESULTS: There was a significant difference (P≤0.05) between all groups of treated rats regarding functional recovery. Specifically, the discrepancy among p75 siRNA and mock-transfected BMSC was statistically significant. P75 siRNA BMSC also revealed a higher level of in vivo survival compared to the mock BMSC. CONCLUSION: Our data suggest that genetically modified BMSC that express p75:siRNA could be a more suitable source of cells for treatment of SCI.

Long-term effects of sulfur mustard on civilians' mental health 20 years after exposure (The Sardasht-Iran Cohort Study).

BACKGROUND: Sulfur mustard (SM) is an alkylating agent that induces short and long term toxicity on various organs. The aim of this study was to assess the long-term psychological symptoms among samples of exposed to sulfur mustard gas compared with unexposed civilians 20 years after exposure. METHODS: This historical cohort study was conducted on 495 civilians of Sardasht and Rabat in two age matched groups, including 367 sulfur mustard exposed participants from Sardasht and 128 unexposed subjects from Rabat. Psychological symptoms was assessed using the Symptom Check List-90 Revised (SCL-90-R) including measures of somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism providing three global distress indices namely: Global Severity Index (GSI), Positive Symptom Total (PST) and Positive Symptom Distress Index (PSDI). Comparison was made between exposed and unexposed civilians. RESULTS: There were significant differences in somatization (P = 0.002), obsessive-compulsive (P = 0.031), depression (P = 0.007), anxiety (P = 0.042), and hostility (P = 0.002), between the exposed and unexposed groups. In addition there were significant differences between two groups concerning the GSI (P = 0.045) and the PSDI (P < 0.001). The differences between two groups in other subscales were not significant. CONCLUSIONS: The findings from this study showed that civilians who exposed to sulfur mustard gas were suffering from a number of psychological symptoms even 20 years after exposure. Providing mental health services and more resource allocation for this community are highly recommended.

A clinicopathological approach to sulfur mustard-induced organ complications: a major review.

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.

Fibrinogen and inflammatory cytokines in spontaneous sputum of sulfur-mustard-exposed civilians--Sardasht-Iran Cohort Study.

Sulfur mustard (SM) causes late complications in respiratory system of exposed individuals. In this preliminary study, the levels of IL-1α and ß, TNF, IL-1Ra, IL-6 and fibrinogen in the spontaneous sputum of SM-exposed individuals were examined 20 years after exposure and the correlation with pulmonary function was tested. The participants were categorized into two major subgroups (hospitalized and non-hospitalized) based on the severity of the clinical complications immediately after exposure. Every participant was visited by a physician; the respiratory functions were checked using spirometry and were categorized as normal, mild, moderate or severe pulmonary complications. The levels of cytokines in the sputum and serum samples were measured using ELISA method. The mean values of TNF, IL-1α and IL-1ß were 524.15, 115.15, 1951.33 pg/ml respectively, and the mean levels of IL-1Ra and IL-6 were 6410.52 and 124.44 pg/ml respectively; fibrinogen was 71.59 ng/ml and index of IL-Ra/IL-1ß was 7.78. There was more TNF-α and IL-1ß and less IL-1Ra and fibrinogen in the sputum of the hospitalized subgroup. The level of TNF-α and IL-1ß also increased in moderate and severe pulmonary status comparing with the group with mild disorders, while fibrinogen was lower or decreased significantly in problematic patients. IL-1ß and TNF showed positive correlation (r=0.5, and r=0.59, respectively); fibrinogen and IL1Ra/IL-1ß have negative correlation with lung function according to the GOLD classification (r=-0.4, and r=-0.61, respectively). It is concluded that sputum cytokines and fibrinogen, reflect the degree of the severity of airway inflammation and the cytokine levels in the sputum might be completely different from the serum fluctuations.

Salivary levels of secretary IgA, C5a and alpha 1-antitrypsin in sulfur mustard exposed patients 20 years after the exposure, Sardasht-Iran Cohort Study (SICS).

Sulfur mustard (SM) is a strong toxic agent that causes acute and chronic health effects on a myriad of organs following exposure. Although the primary targets of inhaled mustard gas are the epithelia of the upper respiratory tract, the lower respiratory tract is the focus of the current study, and upper tract complications remain obscure. To our knowledge there is no study addressing the secretory IgA (S-IgA), C5a, alpha 1 antitrypsin (A1AT) in the saliva of SM-exposed victims. In this study, as many as 500 volunteers, including 372 SM-exposed cases and 128 control volunteers were recruited. A 3 ml sample of saliva was collected from each volunteer, and the level of secretory IgA, C5a, and alpha 1 antitrypsin in the samples were compared between the two groups. The SM-exposed group showed a significantly higher amount of salivary alpha 1 antitrypsin and secretary IgA compared to the control group (p<.006 and p<.018 respectively). The two groups showed no significant difference (p=0.192) in the level of C5a. The results also showed that the level of salivary A1AT is more than that of IgA in severely injured cases. The findings presented here provide valuable insight for both researchers and practitioners dealing with victims of the chemical warfare agent, sulfur mustard. This research indicates that certain branches of the inflammatory processes mandate serious attention in therapeutic interventions.

Pro-inflammatory cytokines among individuals with skin findings long-term after sulfur mustard exposure: Sardasht-Iran Cohort Study.

Sulfur mustard (SM) is a potent alkylating vesicant warfare chemical agent which causes severe damages to the interface organs, skin, lungs and eyes. The most common chronic skin lesions are mustard scars, xerosis, eczema, seborrheic dermatitis, cherry angioma and hyperpigmentation. This study is part of Sardasht-Iran Cohort Study (SICS) which was performed to compare the serum levels of inflammatory cytokines in SM-exposed individuals (n=372) with long-term relevant skin findings versus unexposed controls (n=128). Serum levels of pro-inflammatory cytokines including IL-1α, IL-1ß, IL-1Ra, IL-6, and TNF (tumor necrosis factor) were titrated using ELISA method, 79.9% (n=290) of the exposed group and 60.5% (n=98) of the control group showed skin findings. In the exposed group, 52.1% (n=189) had only skin findings (OSFE) and in the control group, 32% (n=41) had no problem (NC, normal). Median serum levels of cytokines IL-1α, IL-1ß, IL-1Ra, IL-6 and TNF-α in the OSFE group were: 1.077, 1.745, 25.640, 0.602 and 12.768 pg/ml, respectively. These values in normal controls were 1.889, 1.896, 32.190, 1.022 and 23.786 pg/ml, respectively which are higher than the corresponding values in the OSFE group, the differences were statistically significant only for IL-1α and TNF-α. This may be due to a damage incurred upon precursors of cytokine producing cells or failure of their functions, increase in suppressive mediators or other mechanisms which are not well known. More studies are needed in molecular dimensions of the immune and cytokine responses in the SM-exposed patients.

Association of serum immunoglobulins levels and eye injuries in sulfur mustard exposed: Sardasht-Iran Cohort Study.

In this study the associations between ocular problems and serum levels of immunoglobulins in sulfur mustard (SM) exposed population 20 years after exposure in context of Sardasht-Iran Cohort Study was explored. Serum immunoglobulins (Ig) levels including IgM, IgA, IgE, IgG, and subclasses of IgG (IgG1, IgG2, IgG3 and IgG4) in 372 SM-exposed patients were titrated and compared with 128 unexposed controls considering their ocular problems. In exposed patients with tearing and blurring of vision, serum IgM levels were significantly lower than matched controls (P=0.026 and 0.027, respectively). Serum IgM levels in exposed patients with normal ocular conditions were significantly lower (P<0.050) than that of matched controls. Serum levels of IgA, IgE and IgG and IgG3 levels were not significantly different between the two groups with abnormal and normal ocular conditions. Mean serum IgG1 levels in exposed patients with normal ocular conditions were significantly higher than the matched controls (P<0.05) except for tearing and photophobia. Mean serum IgG2 levels in exposed with blurring of vision and without tearing, ocular pain, photophobia, lids and bulbar conjuctival abnormalities were significantly higher than that of matched controls (P<0.050). Mean serum levels of IgG4 in exposed patients with normal ocular conditions and most of the abnormal ocular conditions were significantly lower than the matched controls (P<0.05). The results of the current study showed that even 20 years after SM exposure serum immunoglobulins are different from matched normal controls and the levels of IgM and IgG4 are associated with some aspects of ocular surface problems.