Chronic health effects of sulphur mustard exposure with special reference to Iranian veterans

The widespread use of sulphur mustard (SM) as an incapacitating chemical warfare agent in the past century has proved its long-lasting toxic effects. It may also be used as a chemical terrorist agent. Therefore, all health professionals should have sufficient knowledge and be prepared for any such chemical attack. SM exerts direct toxic effects on the eyes, skin, and respiratory tissue, with subsequent systemic action on the nervous, immunological, haematological, digestive, and reproductive systems. SM is an alkylating agent that affects DNA synthesis, and, thus, delayed complications have been seen since the First World War. Cases of malignancies in the target organs, particularly in haematopoietic, respiratory, and digestive systems, have been reported. Important delayed respiratory complications include chronic bronchitis, bronchiectasis, frequent bronchopneumonia, and pulmonary fibrosis, all of which tend to deteriorate with time. Severe dry skin, delayed keratitis, and reduction of natural killer cells with subsequent increased risk of infections and malignancies are also among the most distressing long-term consequences of SM intoxication. However, despite a lot of research over the past decades on Iranian veterans, there are still major gaps in the SM literature. Immunological and neurological dysfunction, as well as the relationship between SM exposure and mutagenicity, carcinogenicity, and teratogenicity are important fields that require further studies, particularly on Iranian veterans with chronic health effects of SM poisoning. There is also a paucity of information on the medical management of acute and delayed toxic effects of SM poisoning—a subject that greatly challenges health care specialists

Computational and experimental studies of bilayer peptide interactions

This thesis describes the combination of experimental (neutron diffraction) and computational techniques (molecular dynamics simulations) to investigate membrane peptide interactions.The first part deals with a comparison of human and rat form of the amyloid inducing peptide islet amyloid polypeptide (IAPP). Lamellar neutron diffraction was performed and a structural comparison on the differing modes of actions of the rat and human forms of IAPP are reported.A computational model for a di-oleoyl phosphatidylcholine (DOPC) bilayer was then constructed. Once this bilayer had been verified with experimental data (namely area per headgroup, volume per lipid, order parameter of the oleoyl chains and electron density profile) a mixed bilayer of DOPC and di-oleoyl phopshatidylglycerol (DOPG) was then constructed. The mixed bilayer was verified in the same mannerA peptide (adenosine diphosphate ribosylation factor-1 (pARF-1)) was then inserted into the pre-equilibrated mixed bilayer. The orientation of this peptide with respect to the membrane was based on previous neutron diffraction studies, carried out by other group members. Four possible orientations had resulted from analysis of the neutron data. The four orientations of pARF-1 were then subjected to molecular dynamics simulations. The time course of these simulations was 4 ns. The simulation's trajectories were analysed for each of the four models. Particular emphasis was placed upon the positional changes of the phenylalanine label positions that were derived from the neutron data. It was concluded that model A was the most likely orientation of pARF-1 in relation to the bilayer.Having established the technique, and confirmed that the most likely orientation of the peptide was what was originally proposed, another peptide, the fusion peptide of simian immunodeficiency virus (SIV) was placed into a previously equilibrated DOPC bilayer. In this case, only the proposed orientation of the SIV fusion peptide in relation to the bilayer was studied utilizing molecular dynamics simulations. The results are interpreted in relation to the actions of SIV fusion peptide upon the membrane, with particular emphasis on the disruption of oleoyl chain order parameters and secondary structure of the membrane bound fusion peptide

Deoxyribonucleic acid damage in Iranian veterans 25 years after wartime exposure to sulfur mustard

• Background: More than 100,000 Iranian veterans and civilians still suffer from various long-term complications due to their exposure to sulfur mustard (SM) during the Iran–Iraq war in 1983–88. The aim of the study was to investigate DNA damage of SM in veterans who were exposed to SM, 23–27 years prior to this study. • Materials and Methods: Blood samples were obtained from the veterans and healthy volunteers as negative controls. Lymphocytes were isolated from blood samples and DNA breaks were measured using single-cell microgel electrophoresis technique under alkaline conditions (comet assay). Single cells were analyzed with “Tri Tek Comet Score version 1.5” software and DNA break was measured based on the percentage of tail DNA alone, or in the presence of H2O2 (25 μM) as a positive control. • Results: A total of 25 SM exposed male veterans and 25 male healthy volunteers with similar ages (44.66 ± 6.2 and 42.12 ± 5.75 years, respectively) were studied. Percentage of the lymphocyte DNA damage was significantly (p < 0.01) higher in the SM-exposed individuals than in the controls (6.47 ± 0.52 and 1.31 ± 0.35, respectively). Percentages of DNA damage in the different age groups of 35–39, 40–44, 45–49, and 50–54 years in SM-exposed veterans (5.48 ± 0.17, 6.7 3 ± 1.58, 6.42 ± 0.22, and 7.27 ± 0.38, respectively) were all significantly (p < 0.05) higher than the controls (1.18 ± 0.25, 1.53 ± 0.22, 1.27 ± 0.20, and 1.42 ± 0.10, respectively). The lymphocytes incubated with H2O2 had much higher DNA damage as expected. The average of tail DNA is 42.12 ± 2.75% for control cells + H2O2 and 18.48 ± 2.14% for patients cells + H2O2; P < 0.001. • Conclusion: SM exposure of the veterans revealed DNA damage as judged by the comet assay

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

Changes of QT Dispersion in Patients Suffering from Aluminium Phosphide Poisoning (Rice Pill)

BACKGROUND: Aluminium phosphide (ALP) or rice pill is a substance used in developing countries due to its low cost as pesticides. The availability of this substance has been lead to an increased rate of the use of this toxic inorganic compound for suicide. Complications are considered to be dose-related toxicity and hospitalisation time, varying from hemodynamic disorder, hypoglycemia, hyperglycemia, shock, cardiotoxicity, pulmonary and renal failures. The consumption of this substance is one of the major causes of mortality due to heart arrhythmia. QT dispersion represents a regional difference in ventricular repolarisation and electrical instability of the heart. AIM: The purpose of this study was to investigate the effect of ALP poisoning on QT dispersion. METHODS: In this study, 70 patients with ALP poisoning were enrolled, and 10 patients were excluded due to the exclusion criteria. QT dispersion rate was calculated in 60 patients using the standard electrocardiography at the time of referral. The above data were compared with the control group, which included 40 subjects with normal coronary angiography, and without cardiovascular risk factors. RESULTS: The findings presented herein indicated a significant correlation between QT dispersion and control group (P &lt; 0.0.5). There was a significant relationship between the severity of acidosis and the patient's tablets –taking a number (P &lt; 0.05). However, there was no relationship between QT dispersion with the severity of acidosis and mortality in patients. CONCLUSION: Because there is no CAD risk factor in the population, it can be concluded that increase in QT dispersion in these individuals can be due to ALP poisoning; nevertheless, this is not considered to be a factor in increasing the morbidity of these patients

Highly sensitive C-reactive protein levels in Iranian patients with pulmonary complication of sulfur mustard poisoning and its correlation with severity of airway diseases

Background: Sulfur mustard (SM) is a chemical warfare agent that can cause serious pulmonary complications. This study was designed to determine serum highly sensitive C-reactive protein (hs-CRP) and evaluate its correlation with lung function parameters in patients with chronic obstructive pulmonary disease (COPD) due to SM poisoning. Methods: Fifty consecutive SM patients with stable COPD and a mean age 46.3 + 9.18 years were enrolled in this cross sectional study. Thirty healthymen were selected as controls. Lung function parameters were evaluated. Serum hs-CRP by immunoturbidometry assay was measured in both the patients and controls. Results: In the case group, the mean forced expiratory volume in one second (FEV1) was 2.14 + 0.76 L (58.98%+17.51% predicted). The mean serum hs-CRP was 9.4+6.78 SD and 3.9+1.92 SDmg/L in the cases and controls, respectively, with significant statistical differences (p < .001). There was negative correlation between the serum hs-CRP and FEV1 levels (p ¼ .01). The serum hs-CRP levels were also correlated with Global Initiative for ChronicObstructive Lung disease (GOLD) stages (r ¼ .45, p < .001). Conclusions:Our findings suggest that the serum hs-CRP level is increased in SM patients with COPD and may have a direct correlation with disease severity. It may then be used as a marker for the severity of COPD in patients with SM poisoning

Neutron diffraction reveals sequence-specific membrane insertion of pre-fibrillar islet amyloid polypeptide and inhibition by rifampicin

AbstractHuman islet amyloid polypeptide (hIAPP) forms amyloid deposits in non-insulin-dependent diabetes mellitus (NIDDM). Pre-fibrillar hIAPP oligomers (in contrast to monomeric IAPP or mature fibrils) increase membrane permeability, suggesting an important role in the disease. In the first structural study of membrane-associated hIAPP, lamellar neutron diffraction shows that oligomeric hIAPP inserts into phospholipid bilayers, and extends across the membrane. Rifampicin, which inhibits hIAPP-induced membrane permeabilisation in functional studies, prevents membrane insertion. In contrast, rat IAPP (84% identical to hIAPP, but non-amyloidogenic) does not insert into bilayers. Our findings are consistent with the hypothesis that membrane-active pre-fibrillar hIAPP oligomers insert into beta cell membranes in NIDDM

Effect of Sulfur Mustard Toxicity on FLT3-ITD Gene Mutation in Sulfur Mustard Veterans

Background: Sulfur mustard (SM) is a chemical blistering warfare that affects different organs especially hematopoietic system. Prevalence of acute myeloblastic and lymphoblastic leukemia is increased by sulfur mustard exposure. FLT3-ITD mutation can be effective on leukemogenesis. Therefore, the aim of this study was to verify the frequency of FLT3-ITD mutation in the patients who exposed to SM. Methods: This study was implemented on 42 people poisoned by SM during Iraq-Iran war about three decades ago and is now resident in Mashhad, Iran. The control group included 30 healthy males that are relatives of the patients with first-degree. After DNA extraction, PCR was performed for FLT3-ITD analysis. Results: By analysis of PCR products, no FLT3-ITD mutation was detected in the patient or control groups. There was no significant difference in hematological factors between the two groups. Conclusion: Other mechanisms can lead to leukemia in SM exposed persons. Elapsed time after exposure to sulfur mustard can be effective on leukemogenesis, then future more study may be beneficial for early diagnosis of leukemia in SM exposed veterans

Investigating Interactions of Biomembranes and Alcohols: A Multiscale Approach

We study the interaction of lipid bilayers with short chain alcohols using molecular dynamics on different length scales. We use detailed atomistic modeling and modeling on the length scale where an alcohol is just an amphiphilic dimer. Our strategy is to calibrate a coarse--grained model against the detailed model at selected state points at low alcohol concentration and then perform a wider range of simulations using the coarse--grained model. We get semiquantitative agreement with experiment for the major observables such as order parameter and area per molecule. We find a linear increase of area per molecule with alcohol concentration. The alcohol molecules in both system descriptions are in close contact with the glycerol backbone. Butanol molecules can enter the bilayer to some extent in contrast to the behavior of shorter alcohols. At very high alcohol concentrations we find clearly increased interdigitation between leaflets.Comment: 14 pages, 6 figure