Assessment of mustard vesicant lung injury and anti-TNF-α efficacy in rodents using live-animal imaging.

Nitrogen mustard (NM) causes acute lung injury, which progresses to fibrosis. This is associated with a macrophage-dominant inflammatory response and the production of proinflammatory/profibrotic mediators, including tumor necrosis factor alpha (TNF-α). Herein, we refined magnetic resonance imaging (MRI) and computed tomography (CT) imaging methodologies to track the progression of NM-induced lung injury in rodents and assess the efficacy of anti-TNF-α antibody in mitigating toxicity. Anti-TNF-α antibody was administered to rats (15 mg/kg, every 8 days, intravenously) beginning 30 min after treatment with phosphate-buffered saline control or NM (0.125 mg/kg, intratracheally). Animals were imaged by MRI and CT prior to exposure and 1-28 days postexposure. Using MRI, we characterized acute lung injury and fibrosis by quantifying high-signal lung volume, which represents edema, inflammation, and tissue consolidation; these pathologies were found to persist for 28 days following NM exposure. CT scans were used to assess structural components of the lung and to register changes in tissue radiodensities. CT scans showed that in control animals, total lung volume increased with time. Treatment of rats with NM caused loss of lung volume; anti-TNF-α antibody mitigated this decrease. These studies demonstrate that MRI and CT can be used to monitor lung disease and the impact of therapeutic intervention.

Nutraceuticals as potential therapeutics for vesicant-induced pulmonary fibrosis.

Exposure to vesicants, including sulfur mustard and nitrogen mustard, causes damage to the epithelia of the respiratory tract and the lung. With time, this progresses to chronic disease, most notably, pulmonary fibrosis. The pathogenic process involves persistent inflammation and the release of cytotoxic oxidants, cytokines, chemokines, and profibrotic growth factors, which leads to the collapse of lung architecture, with fibrotic involution of the lung parenchyma. At present, there are no effective treatments available to combat this pathological process. Recently, much interest has focused on nutraceuticals, substances derived from plants, herbs, and fruits, that exert pleiotropic effects on inflammatory cells and parenchymal cells that may be useful in reducing fibrogenesis. Some promising results have been obtained with nutraceuticals in experimental animal models of inflammation-driven fibrosis. This review summarizes the current knowledge on the putative preventive/therapeutic efficacy of nutraceuticals in progressive pulmonary fibrosis, with a focus on their activity against inflammatory reactions and profibrotic cell differentiation.

[A Potentially Fatal Aphrodisiac: Cantharidin Poisoning]. / Um Afrodisíaco Potencialmente Fatal: Intoxicação por Cantaridina.

Cantharidin is a toxin extracted from coleoptera beetles, commonly known as 'Spanish fly'. Traditionally it was used as an aphrodisiac, a vesicant or as an abortifacient. Intoxication by this substance has been widely reported, generally associated with gastrointestinal complications, such as digestive hemorrhage, and genitourinary disorders, such as hematuria and acute kidney injury. The authors describe the case of a 51-year old male patient who developed severe cantharidin poisoning after ingesting a preparation ('tea formulation') containing the substance. The patient reported a burning sensation in his oral cavity, diarrhea and hematuria, having sustained acute kidney injury and atypical neurological symptoms. Due to the lack of an antidote, the available treatment options are reduced to supportive measures. This case strengthens the need for a thorough medical history to ascertain the use of 'natural' products and medicinal herbs (i.e. of unregulated origin), and the importance of educating the community to their potential toxicity.

A cantaridina é uma toxina extraída de coleópteros, comummente conhecidos como 'Spanish fly'. Historicamente utilizada como afrodisíaco, vesicante e abortivo. A intoxicação por este agente encontra-se amplamente descrita, tipicamente com envolvimento das mucosas gastrointestinal, com hemorragia digestiva, e genitourinária, com hematúria e lesão renal aguda. Os autores apresentam o caso de um doente do sexo masculino, com 51 anos que desenvolveu um quadro de intoxicação aguda por cantaridina, após ingestão de uma preparação ('chá') desta substância, com ardor na cavidade oral, diarreia, disúria, hematúria, lesão renal aguda e com um quadro neurológico atípico. A toxicidade pela cantaridina é sistémica, contudo, o envolvimento neurológico é raro. Dada ausência de um antídoto, preconiza-se a terapêutica de suporte. Este caso reforça a importância de uma anamnese detalhada, incluindo a utilização de produtos 'naturais' ou de ervanária (i.e. de origem não controlada), e da necessidade de alertar os doentes para a sua potencial toxicidade.

Validation of a novel irritant gas syndrome triage algorithm.

OBJECTIVE: Our objective was to validate a novel irritant gas syndrome agent (IGSA) triage algorithm for use in an emergency department (ED). We assessed efficiency, accuracy, and precision of our IGSA triage algorithm based on signs/symptoms of actual patients. DESIGN: After characterizing the signs/symptoms of an actual IGSA exposure event, we developed and validated the IGSA triage algorithm using a simulated computer exercise to compare the IGSA triage algorithm to the preferred hospital triage algorithm, the Emergency Severity Index (ESI). SETTING: This study was a simulated computer exercise using surveys developed in Research Electronic Data Capture software. Nurse volunteers simulated triaging 298 patients. PARTICIPANTS: Patient data included 146 patients treated during the disaster as well as 152 unexposed patients. Twenty-six nurse volunteers were assigned to triage the patients using one of the algorithms in the simulated computer exercise. MAIN OUTCOME MEASURE(S): The precision of the IGSA triage algorithm was 0.82 (confidence interval [CI] 0.78-0.85) and ESI 0.73 (CI 0.69-0.77). Weighted κ for ESI and IGSA accuracy for exposed patients was 0.32 (95% CI 0.26-0.37) and 0.81 (95% CI 0.77-0.85), respectively. RESULTS: The IGSA triage algorithm was more accurate and precise than the ESI algorithm for triaging patients exposed to an irritant gas. CONCLUSIONS: This study validates the IGSA triage algorithm as the basis for the development of a prototype software application to quickly identify victims of a chemical disaster and triage patients efficiently and accurately with the potential to dramatically improve the processing of patients in EDs.

Civilian exposure to chlorine gas: A systematic review.

INTRODUCTION: Halogen pulmonary irritants (HPIs) are volatile liquids that directly damage the respiratory mucosa. Chlorine is readily available in large volumes as an industrial chemical and has a significant potential for accidental or deliberate release. We conducted a systematic review to determine the clinical features; treatment and long-term sequelae of civilian chlorine gas exposure. METHODS: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. Medline; Ovid and Google Scholar databases were searched from 1966 to January 2017. A database of relevant papers was compiled and descriptive statistics used to summarise the data. RESULTS: Thirty-six papers describing 37 incidents involving 1566 individual acute exposers to chlorine gas were identified. The most common reported features were cough (29%), dyspnoea (22%), sore throat (16%), eye features (12%) and excessive sputum or haemoptysis (7%). Acute management included high-flow oxygen (32.8%); steroids (28.4%); bronchodilators (28.2%) and ventilation (2.3%). Nine deaths (0.6%) were reported. Follow-up data available in 60% of cases; full recovery was reported in 90% of cases where data was available. DISCUSSION: Acute chlorine gas exposure in civilian incidents presented with acute respiratory features and irritation of the eyes and throat. The development of pulmonary oedema or ARDS was relatively rare when compared to military experience in the First World War.

Medical documentation, bioanalytical evidence of an accidental human exposure to sulfur mustard and general therapy recommendations.

Sulfur mustard (SM) is a chemical warfare agent (CWA) that was first used in World War I and in several military conflicts afterwards. The threat by SM is still present even today due to remaining stockpiles, old and abandoned remainders all over the world as well as to its ease of synthesis. CWA are banned by the Chemical Weapons Convention (CWC) interdicting their development, production, transport, stockpiling and use and are subjected to controlled destruction. The present case report describes an accidental exposure of three workers that occurred during the destruction of SM. All exposed workers presented a characteristic SM-related clinical picture that started about 4h after exposure with erythema and feeling of tension of the skin at the upper part of the body. Later on, superficial blister and a burning phenomenon of the affected skin areas developed. Similar symptoms occurred in all three patients differing severity. One patient presented sustained skin affections at the gluteal region while another patient came up with affections of the axilla and genital region. Fortunately, full recovery was observed on day 56 after exposure except some little pigmentation changes that were evident even on day 154 in two of the patients. SM-exposure was verified for all three patients using bioanalytical GC MS and LC MS/MS based methods applied to urine and plasma. Urinary biotransformation products of the ß-lyase pathway were detected until 5 days after poisoning whereas albumin-SM adducts could be found until day 29 underlining the beneficial role of adduct detection for post-exposure verification. In addition, we provide general recommendations for management and therapy in case of SM poisoning.

Web based listing of agents associated with new onset work-related asthma.

BACKGROUND: Work-related asthma is common and yet remains a challenge to diagnose. Access to a listing of agents associated with work-related asthma has been suggested as useful in assisting in the diagnosis. METHODS: The Association of Occupational and Environmental Clinics (AOEC) developed criteria that were used to review the peer-reviewed medical literature published in English. Based on this review, substances were designated either as a sensitizing agent or an irritant. The reviews were conducted by a board certified internist/pulmonologist/occupational medicine specialist from 2002 to 2007 and a board certified internist/occupational medicine physician from 2008- date. All reviews were then reviewed by the nine member AOEC board of directors. RESULTS: The original list of agents associated with new onset work-related asthma was derived from the tables of a text book on work-related asthma. After 13 years of review, there are 327 substances designated as asthma agents on the AOEC list; 173 (52.9%) coded as sensitizers, 35 (10.7%) as generally recognized as an asthma causing agent, four (1.2%) as irritants, two (0.6%) as both a sensitizer and an irritant and 113(34.6%) agents that still need to be reviewed. CONCLUSIONS: The AOEC has developed a readily available web based listing of agents associated with new onset work-related asthma in adults. The listing is based on peer-reviewed criteria. The listing is updated twice a year. Regular review of the peer-reviewed medical literature is conducted to determine whether new substances should be added to the list. Clinicians should find the list useful when considering the diagnosis of work-related asthma.

Irritants and corrosives.

This article reviews toxic chemicals that cause irritation and damage to single and multiple organ systems (corrosion) in an acute fashion. An irritant toxic chemical causes reversible damage to skin or other organ system, whereas a corrosive agent produces irreversible damage, namely, visible necrosis into integumentary layers, following application of a substance for up to 4 hours. Corrosive reactions can cause coagulation or liquefaction necrosis. Damaged areas are typified by ulcers, bleeding, bloody scabs, and eventual discoloration caused by blanching of the skin, complete areas of alopecia, and scars. Histopathology should be considered to evaluate questionable lesions.

Cardiopulmonary exercise capacity and ventilation effectiveness in patients after clinical cure of acute irritant gas poisoning.

The aim of this study is to assess the medium to long-term effect of acute irritant gas poisoning on cardiopulmonary exercise function in patients after clinical cure. Fourteen patients after an average of 18.5 months of clinical cure of acute irritant gas poisoning were recruited, and 14 healthy individuals were selected as control. All subjects were examined by resting pulmonary function testing (RPFT), cardiopulmonary exercise testing (CPET), and arterial blood gas (ABG) analysis. No statistically significant differences were found between poisoning and control groups for baseline parameters (age, height, and weight) or ABG values (pH, PaO2, PaCO2, and SaO2) (P > 0.05). For most RPFT parameters, including FEV1/FVC, FEV1, FEV1%pred, RV/TLC, DLCO%, and FVC%, no statistically significant differences were observed between poisoning and control groups (P > 0.05). However, MVV% was significantly lower in poisoning group compared with healthy individuals (P < 0.05). Statistically significant differences were observed for some CPET parameters, including peak VO2, peak VO2/kg, peak VE, and lowest VE/VCO2 (P < 0.05), and peak load, V D/V T, and peak PETCO2 (P < 0.01) between the two groups. However, there were no statistically significant differences in peak VO2%pred or peak O2 pulse between poisoning and control groups (P > 0.05). Compared with controls, patients with acute irritant gas poisoning had decreased cardiopulmonary exercise capacity and ventilation effectiveness after clinical cure.

Pepper spray injury severity: ten-year case experience of a poison control system.

BACKGROUND: Pepper spray is a common lacrimator used by law enforcement and the public to subdue individuals and for self-defense. The risk factors for severe injury due to pepper spray exposure are not well documented and there is a lack of guidelines to identify patients that require transport and medical evaluation in an emergency department. OBJECTIVE: The aim of this study was to determine the prevalence of and circumstances associated with symptoms suggestive of tissue injury beyond transient irritation in persons exposed to pepper spray. METHODS: We reviewed all human exposures to pepper spray reported to a poison control system between 2002 and 2011. Cases were differentiated into 2 outcome groups: minor or self-limiting symptoms versus those with more severe symptoms suggestive of tissue injury that warranted a medical evaluation. A comparison of the variables between the outcome groups was performed using odds ratios (ORs), 95% confidence intervals (CIs), and associated P values. RESULTS: A total of 4,544 cases were identified and 3,671 met the inclusion criteria. Of these, 249 cases (6.8%) were found to have more severe symptoms that warranted a medical evaluation. There were no reported deaths. The cases with more severe symptoms most commonly involved the ocular (53.8%), respiratory (31.7%), and dermal (17.7%) organ systems. Factors with largest independent associations with more severe outcomes were use for law enforcement training (OR, 7.39; 95% CI, 2.98-18.28), direct intentional exposure for purposeful use to incapacitate (OR, 3.02; 95% CI, 1.80-5.06), and for law enforcement on individual target suspects or crowd control (OR, 2.45; 95% CI, 1.42-4.23). CONCLUSIONS: There was a low 1 in 15 potential risk for more severe adverse health effects in persons exposed to pepper spray that warranted a medical evaluation. The risk was highest when used for training of law enforcement personnel and involved severe ocular symptoms. This suggests that routine use of pepper spray for training of law enforcement or military personnel be reconsidered. Protective goggles may be an option when direct spraying into the face of trainees. Transport for medical evaluation should be considered for exposed persons that manifest persistent ocular or respiratory symptoms.

[Irritant-induced asthma]. / Ärsytyksen aiheuttama astma.

Irritant-induced asthma is a rare disease, usually being caused by an accidental or other exceptionally strong exposure to substances irritating the respiratory passages. High-dose inhaled corticosteroid medication is immediately started at the emergency call service. If severe exposure is suspected, it is important to monitor the patient at least for a couple of days in hospital. Immediately after the acute stage diagnostic investigations are carried out, including a metacholine or histamine challenge test, since demonstration of airway hyperreactivity is of diagnostic and prognostic significance. The asthma may remain permanent.

Antidotes and treatments for chemical warfare/terrorism agents: an evidence-based review.

This article reviews the evidence supporting the efficacy of antidotes used or recommended for the potential chemical warfare agents of most concern. Chemical warfare agents considered include cyanide, vesicants, pulmonary irritants such as chlorine and phosgene, and nerve agents. The strength of evidence for most antidotes is weak, highlighting the need for additional research in this area.

[Cutaneous and systemic toxicology of vesicants used in warfare]. / Toxicología cutánea y sistémica de los agentes vesicantes de guerra.

Vesicants are a group of chemicals used in warfare. The most representative agent is yperite, also known as mustard gas. The blisters that appeared on those exposed to yperite during combat in the First World War are responsible for the current name--vesicants--for this group of chemicals. Their affects are produced mainly through localized action of liquid or vapor forms on the skin, eyes, and respiratory tract. However, the high absorption of the liquid form through the skin or the vapor form on inhalation may cause substantial systemic effects. Here we analyze these effects, treatment of intoxication, and long-term sequelae, drawing on our experience and a review of the literature.

Doxycycline loaded poly(ethylene glycol) hydrogels for healing vesicant-induced ocular wounds.

Half mustard (CEES) and nitrogen mustard (NM) are commonly used surrogates and vesicant analogs of the chemical warfare agent sulfur mustard. In the current study, in situ forming poly(ethylene glycol) (PEG)-based doxycycline hydrogels are developed and evaluated for their wound healing efficacy in CEES and NM-exposed rabbit corneas in organ culture. The hydrogels, characterized by UV-Vis spectrophotometry, rheometry, and swelling kinetics, showed that the hydrogels are optically transparent, have good mechanical strength and a relatively low degree of swelling (<7%). In vitro doxycycline release from the hydrogel disks (0.25% w/v) was found to be biphasic with release half times of approximately 12 and 72h, respectively, with 80-100% released over a 7-day period. Permeation of doxycycline through vesicant wounded corneas was found to be 2.5 to 3.4 fold higher than non-wounded corneas. Histology and immunofluorescence studies showed a significant reduction of matrix metalloproteinase-9 (MMP-9) and improved healing of vesicant-exposed corneas by doxycycline hydrogels compared to a similar dose of doxycycline delivered in phosphate buffered saline (PBS, pH 7.4). In conclusion, the current studies demonstrate that the doxycycline-PEG hydrogels accelerate corneal wound healing after vesicant injury offering a therapeutic option for ocular mustard injuries.

Long-term outcomes of acute irritant-induced asthma.

RATIONALE: The long-term outcomes of acute irritant-induced asthma (IIA) are mostly unknown. OBJECTIVES: To study the long-term outcomes of IIA. METHODS: We reassessed 35 subjects who experienced IIA at a mean interval of 13.6 +/- 5.2 years. MEASUREMENTS AND MAIN RESULTS: The causal agent was chlorine in 20 cases (57%). At diagnosis, the mean +/- SD FEV(1) was 74.5 +/- 19.5% predicted, and all subjects showed bronchial hyperresponsiveness. At reassessment, all subjects reported respiratory symptoms, and 24 (68%) were on inhaled steroids. There were no significant improvements in FEV(1) and FEV(1)/FVC values. Twenty-three subjects had a methacholine test, and only six subjects had normal levels of responsiveness. Of the remaining 12 subjects, six had improvement in FEV(1) after bronchodilator >or=10%. In samples of induced sputum obtained from 27 subjects, six had eosinophils >or=2%. Levels of inflammatory and remodeling mediators were higher than in control subjects but were no different from subjects with occupational asthma due to sensitization. Quality of life score was 4.4 +/- 1.5 on a 0 (worst) to 7 (best) scale. Twelve subjects had an abnormal depression score. CONCLUSIONS: This study provides the first evidence of significant long-term impact of acute IIA on various outcomes.

[A technique for investigating the component of cantharidin blisters by flow cytometry].

OBJECTIVE: Cantharidimide cause blister. The effect of blister on immunoregulation was investigated. METHODS: Cantharidimide was placed on the skin, 48h later, the blister was analyzed by flow cytometry. RESULTS: The blister contained 1 x 10(6) - 1 x 10(7) cells per ml, most of which were neutrophils, macrophages, dendritic cells (DC), and IL-12 secreted by Thl cells. CONCLUSION: There are high concent of DC in the blister, which is differential and induce the secretion of Th1, the activation of T cell. The blister modulate the biological response of patients and is helpful for treatment with infective disease.

Irritative effects of fumes and aerosols of bitumen on the airways: results of a cross-shift study.

Possible health hazards of fumes and aerosols of bitumen are in discussion, and data on their adverse effects on human airways under current exposure conditions are limited. To assess the irritative effects of exposure to fumes and aerosols of bitumen on the airways, a cross-sectional cross-shift study was conducted including external and internal exposure measurements, spirometry and especially non-invasive methods like nasal lavage collection and induction of sputum in order to identify and evaluate more precisely inflammatory process in the upper and lower airways. The cross-shift study comprised 74 mastic asphalt workers who were exposed to fumes and aerosols of bitumen and 49 construction workers without this exposure as reference group. Questionnaire, spirometry, ambient monitoring and urinary analysis were performed. Humoral and cellular parameters were measured in nasal lavage fluid (NALF) and induced sputum. For data analysis, a mixed linear model was performed on the different outcomes with exposure group, time of measurement (pre-, post-shift), current smoking, German nationality and age as fixed factors and subjects as random factor. Based on personal exposure measurements during shift, mastic asphalt workers were classified into a low (< or =10 mg/m(3); n = 46) and a high (>10 mg/m(3); n = 28) exposure group. High exposure was accompanied by significant higher urinary post-shift concentrations of 1-hydroxypyrene and the sum of hydroxyphenanthrenes. Acute respiratory symptoms were reported more frequently in the high exposure group after shift. Significant cross-shift declines in lung function parameters (forced expiratory volume in 1 s [FEV(1) (% predicted)] and forced vital capacity [FVC (% predicted)]) were measured in mastic asphalt workers. Pre-shift FEV(1) (% predicted) and FVC (% predicted) were higher in the low exposure group. In pre- and post-shift NALF samples, interleukin (IL)-1beta-, IL-8- and total protein concentrations were lower in the low exposure group compared to the reference and the high exposure group. Pre- and post-shift neutrophil percentages in both nasal and sputum samples were also lower in the low exposure group. Significantly higher pre- and post-shift sputum concentrations of IL-8, IL-6, nitrogen oxide (NO) derivatives and total protein were detected especially in highly exposed workers. Irritative effects of exposure to fumes and aerosols of bitumen on the upper and lower airways were apparent, especially in mastic asphalt workers with exposure above 10 mg/m(3).

[Characterization of severe acute occupational poisoning accidents related to irritating gases in China between 1989 and 2003].

OBJECTIVE: To analyze severe acute occupational poisoning accidents related to irritating gases reported in China between 1989 and 2003, and to study the characteristics of severe acute occupational poisoning accidents and provide scientific evidences for prevention and control strategies. METHODS: The data from the national occupational poisoning case reporting system were analyzed with descriptive methods. RESULTS: (1) There were 92 severe acute occupational poisoning accidents related to asphyxiating gases during 15 years, which showed that there were 14.5 accidents occurred each year. Forty types of chemicals were reported to cause poisoning accidents directly. On average, there were 14.5 persons poisoned and 0.8 persons died of poisoning in each event. The number of death of poisoning reached 7 in most of the severe accidents. Chlorine was the main irritating gas resulting in poisoning accidents according to the number of accidents, cases and death. CONCLUSION: (1) The severe acute occupational poisoning related to irritating gases are more dangerous than others because of it is involved in more cases in each accident. (2) The accidents have concentricity in the certain types of chemicals, industries and jobs, and should be focused on control. (3) It is important to develop the program about early warning and forecast and the first aid.

Mycotoxins revisited: Part II.

Mushrooms are ubiquitous in nature. They are an important source of nutrition, however, certain varieties contain chemicals that can be highly toxic to humans. Industrially cultivated mushrooms are historically very safe, whereas foraging for mushrooms or accidental ingestion of mushrooms in the environment can result in serious illness and death. The emergency department is the most common site of presentation for patients suffering from acute mushroom poisoning. Although recognition can be facilitated by identification of a characteristic toxidrome, the presenting manifestations can be variable and have considerable overlap with more common and generally benign clinical syndromes. The goal of this two-part article is to review the knowledge base on this subject and provide information that will assist the clinician in the early consideration, diagnosis and treatment of mushroom poisoning. Part I reviewed the epidemiology and demographics of mushroom poisoning, the physical characteristics of the most toxic varieties, the classification of the toxic species, and presented an overview of the cyclopeptide-containing mushroom class. Part II is focused on the presentation of the other classes of toxic mushrooms along with an up-to-date review of the most recently identified poisonous varieties.