ObjectiveIn large cohort studies comorbidities are usually self-reported by the patients. This way to collect health information only represents conditions known, memorized and openly reported by the patients. Several studies addressed the relationship between self-reported comorbidities and medical records or pharmacy data, but none of them provided a structured, documented method of evaluation. We thus developed a detailed procedure to compare self-reported comorbidities with information on comorbidities derived from medication inspection. This was applied to the data of the German COPD cohort COSYCONET.MethodsApproach I was based solely on ICD10-Codes for the diseases and the indications of medications. To overcome the limitations due to potential non-specificity of medications, Approach II was developed using more detailed information, such as ATC-Codes specific for one disease. The relationship between reported comorbidities and medication was expressed by a four-level concordance score.ResultsApproaches I and II demonstrated that the patterns of concordance scores markedly differed between comorbidities in the COSYCONET data. On average, Approach I resulted in more than 50% concordance of all reported diseases to at least one medication. The more specific Approach II showed larger differences in the matching with medications, due to large differences in the disease-specificity of drugs. The highest concordance was achieved for diabetes and three combined cardiovascular disorders, while it was substantial for dyslipidemia and hyperuricemia, and low for asthma.ConclusionBoth approaches represent feasible strategies to confirm self-reported diagnoses via medication. Approach I covers a broad spectrum of diseases and medications but is limited regarding disease-specificity. Approach II uses the information from medications specific for a single disease and therefore can reach higher concordance scores. The strategies described in a detailed and reproducible manner are generally applicable in large studies and might be useful to extract as much information as possible from the available data.

1 Dimercaprol (BAL), 2,3-dimercaptopropanesulpho nate sodium (DMPS) and meso-2,3-dimercaptosucci nic acid (DMSA) are effective arsenic antidotes, but the question which one is preferable for optimal therapy of arsenic poisoning is still open to discussion. Major drawbacks of BAL include (a) its low therapeutic index, (b) its tendency to redistribute arsenic to brain and testes, for example, (c) the need for (painful) intramuscular injection and (d) its unpleasant odour. 2 The newer antidotes DMPS and DMSA feature low toxicity and high therapeutic index. They can be given orally or intravenously due to their high water solubility. While these advantages make it likely that DMPS and DMSA will replace BAL for the treatment of chronic arsenic poisoning, acute intoxication - espe cially with lipophilic organoarsenicals - may pose a problem for the hydrophilic antidotes, because their ionic nature can adversely affect intracellular avail ability. 3 This article focuses on aspects dealing with the power of BAL, DMPS, and DMSA to mobilize tissue-bound arsenic in various experimental models, such as monolayers of MDCK (=Madin-Darby canine kidney) cells from dog kidney, isolated perfused liver from guinea-pigs, and perfused jejunal segments from rat small intestine. 4 The results show that hydrophilic DMPS and DMSA may fail to rapidly and completely remove arsenic that has escaped from the extracellular space across tight epithelial barriers. However, owing to their low toxicity, which allows larger doses to be applied, and the potential modification of their pharmacokinetics by means of inert oral anion-exchange resins, DMPS and DMSA may advantageously replace BAL when ever intervention time is not critical. With severe intoxication by organic arsenicals, when the point-of- no-return is a limiting factor, BAL may still have a place as an arsenic antidote.

No abstract

The transient receptor potential ankyrin 1 (TRPA1) cation channel is expressed in different tissues including skin, lung and neuronal tissue. Recent reports identified TRPA1 as a sensor for noxious substances, implicating a functional role in the molecular toxicology. TRPA1 is activated by various potentially harmful electrophilic substances. The chemical warfare agent sulfur mustard (SM) is a highly reactive alkylating agent that binds to numerous biological targets. Although SM is known for almost 200 years, detailed knowledge about the pathophysiology resulting from exposure is lacking. A specific therapy is not available. In this study, we investigated whether the alkylating agent 2-chloroethyl-ethylsulfide (CEES, a model substance for SM-promoted effects) and SM are able to activate TRPA1 channels. CEES induced a marked increase in the intracellular calcium concentration ([Ca(2+)]i) in TRPA1-expressing but not in TRPA1-negative cells. The TRP-channel blocker AP18 diminished the CEES-induced calcium influx. HEK293 cells permanently expressing TRPA1 were more sensitive toward cytotoxic effects of CEES compared with wild-type cells. At low CEES concentrations, CEES-induced cytotoxicity was prevented by AP18. Proof-of-concept experiments using SM resulted in a pronounced increase in [Ca(2+)]i in HEK293-A1-E cells. Human A549 lung epithelial cells, which express TRPA1 endogenously, reacted with a transient calcium influx in response to CEES exposure. The CEES-dependent calcium response was diminished by AP18. In summary, our results demonstrate that alkylating agents are able to activate TRPA1. Inhibition of TRPA1 counteracted cellular toxicity and could thus represent a feasible approach to mitigate SM-induced cell damage.

A 44-year-old man ingested 83 mg/kg Thiomersal. He developed gastritis, renal tubular failure, dermatitis, gingivitis, delirium, coma, polyneuropathy and respiratory failure. Treatment was symptomatic plus gastric lavage and the oral chelating agents dimercaptopropane sulfonate and dimercaptosuccinic acid. The patient recovered completely. Maximum mercury concentrations were blood 14 mg/L, serum 1.7 mg/L, urine 10.7 mg/L, and cerebrospinal fluid 0.025 mg/L. Mercury concentration in blood declined with two velocities: first with half-time 2.2 days, then with half-time 40.5 days. The decline of mercury concentration in blood, urinary mercury excretion, and renal mercury clearance were not substantially influenced by chelation therapy.