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Methanol ingestion is neurotoxic in humans due to its metabolites, formaldehyde and formic acid. Here, we compared the cytotoxicity of methanol and its metabolites on different types of cells. While methanol and formic acid did not affect the viability of the cells, formaldehyde (200-800 μg/mL) was strongly cytotoxic in all cell types tested. We investigated the effects of formaldehyde on oxidative stress, mitochondrial respiratory functions, and apoptosis on the sensitive neuronal SK-N-SH cells. Oxidative stress was induced after 2 h of formaldehyde exposure. Formaldehyde at a concentration of 400 μg/mL for 12 h of treatment greatly reduced cellular adenosine triphosphate (ATP) levels. Confocal microscopy indicated that the mitochondrial membrane potential (MMP) was dose-dependently reduced by formaldehyde. A marked and dose-dependent inhibition of mitochondrial respiratory enzymes, viz., NADH dehydrogenase (complex I), cytochrome c oxidase (complex IV), and oxidative stress-sensitive aconitase was also detected following treatment with formaldehyde. Furthermore, formaldehyde caused a concentration-dependent increase in nuclear fragmentation and in the activities of the apoptosis-initiator caspase-9 and apoptosis-effector caspase-3/-7, indicating apoptosis progression. Our data suggests that formaldehyde exerts strong cytotoxicity, at least in part, by inducing oxidative stress, mitochondrial dysfunction, and eventually apoptosis. Changes in mitochondrial respiratory function and oxidative stress by formaldehyde may therefore be critical in methanol-induced toxicity.

Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency, which results in the intracellular accumulation of globotriaosylceramide and leads to severe painful neuropathy with progressive renal, cardiovascular, and cerebrovascular dysfunction and early death. We report 52- and 55-year-old women with proteinuria and hematuria that were proven to be due to Fabry disease. A gene analysis using PCR direct sequencing confirmed a missense mutation of the GLA (α -galactosidase A) gene. Electron microscopy of a kidney biopsy showed lamella inclusion bodies, which are typical findings of Fabry disease. The patients were treated with enzyme replacement therapy as outpatients. They had a reduction in proteinuria and normal renal function. (Korean J Med 2015;89:571-575)

To determine the change in pesticides used during suicide attempts after the 2012 paraquat (PQ) ban, we evaluated the annual number of suicide attempts by pesticide ingestion between 2011 and 2014. We extracted demographic, clinical outcome, and pesticide class data from the medical records of 1,331 patients that attempted suicide by pesticide ingestion. Pesticides were sorted into 5 groups: herbicides, insecticides, fungicides, other pesticides, and combined pesticides. Each group was subdivided into various classes based on publications by the respective Resistance Action Committees. The chi-square test for trends was used to compare the annual incidence of categorical variables. The total number of suicide attempts decreased each year, from 399 in 2011 to 245 in 2014. Simultaneously, PQ ingestion decreased from 253 patients in 2011 to 60 in 2014. The proportion of PQ to pesticides also decreased from 63.4% in 2011 to 24.5% in 2014. Furthermore, the rate of decrease in the proportion of PQ to all herbicide categories increased by calendar year. In conclusion, there is a significant trend in increased annual number of suicides and proportion of suicides using glyphosates and glufosinates versus total herbicides. However, the number of suicide attempts using glyphosate and glufosinate is lower than that using PQ. The ratio of persons completing suicide to those attempting suicide after pesticide ingestion has decreased every year after the PQ ban. Graphical Abstract

A78-year-old man on hemodialysis presented to our hospital with erythrocytosis. He had started hemodialysis 4 years previously, with a hemoglobin level of 9.8 g/dL, and was administered eiythropoiesis stimulating agents and ferrous sulfate. Two years previously, his hemoglobin level increased to 14.5 g/dL and the treatment for anemia was discontinued. He continued hemodialysis thrice weekly; however, the hemoglobin level had increased to 17.0 g/dl at the time of presenting to our hospital. His serum erythropoietin level was 31.4 mlU/mL (range, 3.7-31.5 mlU/mL), carboxyhemoglobin level was 0.6% (range, 0-1.5%), and oxygen saturation in ambient air was 95.4%. The JAK2 V617F mutation was not observed and other bone marrow abnormalities were not identified. The patient was diagnosed with bladder cancer and a transurethral resection was performed. Eight months after the treatment of bladder cancer, his hemoglobin level was 15.1 g/dL, and he was diagnosed with idiopathic erythrocytosis. Copyright (C) 2015. The Korean Society of Nephrology. Published by Elsevier. This is an open access article under the CC BY-NC-ND license.

This study evaluated the relationship between bone scintigraphy finding and clinical factors and assessed the prognostic value of bone scintigraphy finding in patients with rhabdomyolysis.We retrospectively enrolled 143 patients with rhabdomyolysis who had undergone bone scintigraphy. Bone scintigraphy was classified into three groups: no or equivocal soft tissue uptake, a localized uptake, and a diffuse uptake. The relationship of bone scintigraphy findings with clinical factors was evaluated. Multiple logistic regression analysis was performed to identify the risk factors for acute renal failure (ARF) and renal replacement therapy (RRT).Of 143 patients, 52 (36.4%) experienced ARF and 12 (8.4%) required RRT. Among cases caused by exercise, 83.7% showed localized soft tissue uptake. Diffuse soft tissue uptake was only shown among the patients with rhabdomyolysis caused by drug and toxin. Patients with localized or diffuse soft tissue uptake had higher levels of serum creatine kinase, myoglobin, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase compared with patients with no or equivocal uptake (P0.05). Multiple logistic regression analysis showed that age, female sex, and serum phosphate level were associated with a risk for ARF and only serum creatinine level was associated with a risk for RRT (P0.05). Bone scintigraphy findings failed to show significance for predicting ARF and RRT (P0.05).Soft tissue uptake on bone scintigraphy in patients with rhabdomyolysis was related to etiologies and showed limited value for predicting ARF and RRT.

The incidence and clinical aspects of seizures remain to be elucidated in patients with acute pesticide intoxication. The present study included subjects who ingested pesticide with the intention of committing suicide and were treated at Soonchunhyang University Hospital (Cheonan, Korea) between January 2011 and December 2014. We analyzed the incidence and characterized the type and frequency of seizure, from the medical records of 464 patients with acute pesticide intoxication, according to the pesticide class. The effect of seizure on the clinical outcome was assessed. The incidence of seizure was 31.5% in patients who ingested glufosinate ammonium {2-amino-4-[hydroxyl (methyl) phosphinoyl] butyrate; ammonium DL-homoalanin-4-yl (methyl) phosphinate}, followed by those who ingested pyrethroid (5.9%) or glycine derivatives (5.4%). All of the seizures developed between 12 and 24 h of pesticide ingestion and had ceased by 72 h after seizure initiation, following treatment with antiseizure medication. Generalized tonic-clonic seizures were the most commonly observed (85.7% of the cases). Multivariable logistic regression analysis showed that the effect of seizure on mortality was not statistically significant. In conclusion, glufosinate ammonium herbicide is the most common seizurogenic pesticide class. Seizure itself was not a risk factor for mortality in patients with acute glufosinate ammonium intoxication.

Central nervous system (CNS) complications such as seizures and reduced consciousness are important in glufosinate and may occur in severe glyphosate poisoning. The aim of this study was to assess the possible role of serum S100B protein as a biochemical marker of CNS complications associated with glyphosate or glufosinate poisoning.The study enrolled 40 patients (23 glyphosate poisoning and 17 glufosinate poisoning). Altered consciousness and seizure were observed during hospitalization. S100B level was measured with fully automated modular analytic E170 system using electrochemoluminometric immunoassay.Among 40 patients, neurologic features were observed in 12 patients with a median time to onset of 21.5 (IQR 8.25-24.75) h. Serum S100B concentrations measured on admission were higher in the group with neurologic features than in the group without neurologic features [0.148 μg/L (IQR 0.128-0.248) vs. 0.072 μg/L (IQR 0.047-0.084), p .001]. Univariate analysis of measured patient raw parameters using a ROC curve showed that S100B was a significant predictor of neurologic features in glyphosate and glufosinate poisoning. The area under the ROC curve was 0.894 (95% confidential interval 0.791-0.998). When S100B was set at 0.0965, its sensitivity and specificity for predicting neurologic features in glyphosate and glufosinate poisoning were 92% and 82%, respectively.In our pilot study, S100B was a significant predictor of neurologic complications in patients with glyphosate and glufosinate poisoning. Large prospective cohorts are needed to confirm this finding.

Although glyphosate intoxication has been considered minimally toxic in animals, severe toxicity has been observed in humans due to surfactant. We aimed to examine the potential therapeutic effects of intravenous lipid emulsion (ILE) on the patients with acute glyphosate intoxication.This study enrolled 64 glyphosate-intoxicated patients with allocation to two groups: those treated with ILE (ILE group, n = 22), and control patients treated with only supportive (conservative) care. Control patients were selected by matching for the amount ingested and time since ingestion. Twenty-two control patients were separately selected from the 42 patients receiving supportive care only. In ILE group, 20% lipid emulsion product was injected intravenously at the rate of 20 mL/h for the patients who ingested less than 100 ml of glyphosate. In the patients who ingested more than 100 ml of glyphosate, the loading dose was 500 ml for 2-3 h according to the status of the patients, followed by a maintenance dose of 1000 ml for the next 24 h.Thirteen patients received high dose of ILE because the ingestion amount was more than 100 ml. None of the ILE group suffered from the complication of hypotension, while approximately 41% of the control group developed the complication. Additionally, arrhythmia was not observed in the ILE group. The incidence of mental change, respiratory failure, and acute kidney injury was similar between the two groups.ILE administration was associated with lower incidence of hypotension and arrhythmia in patients with acute glyphosate intoxication. ILE administration seems to be an effective treatment modality in patients who ingested sufficient amount of glyphosate herbicide that is expected to bring about significant toxicity.

Background/Aims: Cyclophosphamide (CP) is a promising treatment for severe cases of paraquat (PQ) poisoning. We investigated the effective dose of CP for mitigating PQ-induced lung injury. Methods: Adult male Sprague-Dawley rats were allocated into five groups: control, PQ (35 mg/kg, intraperitoneal injection), and PQ + CP (1.5, 15, or 30 mg/kg). The dimensions of lung lesions were determined using X-ray microtomography (micro-CT), and histological changes and cytokine levels were recorded. Results: The micro-CT results showed that 15 mg/kg CP was more effective than 1.5 mg/kg CP for treating PQ-induced lung injury. At a dose of 1.5 mg/kg, CP alleviated the histological evidence of inflammation and altered superoxide dismutase activity. Using 15 mg/kg CP reduced the elevated catalase activity and serum transforming growth factor (TGF)-β1 level. Conclusions: A CP dose of > 15 mg/kg is effective for reducing the severity of PQ-induced lung injury as determined by histological and micro-CT tissue examination, possibly by modulating antioxidant enzyme and TGF-β1 levels.

Background To determine whether initial reactive oxygen species (ROS)-induced endothelial cell injury is involved in early death after paraquat intoxication and concentrations of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and von Willebrand factor (VWF) reflecting endothelial cell injury, we investigated the initial endothelial cell injury marker involved in the pathogenesis of death within 5 days after paraquat ingestion. Material/Methods Sixty patients with paraquat poisoning were prospectively enrolled. Plasma samples were collected at admission. Plasma concentrations of Ang-1, Ang-2, and VWF were measured by enzyme-linked immunosorbent assay. The patients were classified into 3 categories: survivors, early death (died within 5 days after ingestion), and late death (died more than 5 days after ingestion). Results The baseline concentration of Ang-2 and the Ang-2: Ang-1 ratio were significantly higher in patients who died (Ang-2 [pg/mL], 1012.75±468.02 vs. 1986.07±1675.37 [p=0.002]; Ang-2: Ang-1, 0.90±0.49 vs. 2.16±2.28 [p=0.002]). The Ang-2: Ang-1 ratio was significantly higher in the early death group (2.41±2.54) than in the survivors (0.90±0.49) and the late death group (1.33±0.64). The Ang-2: Ang-1 ratio was significantly associated with early death (OR, 2.602; 95% CI, 1.106–6.117; p=0.028) after adjusting for plasma levels of paraquat, age, PCO2, and creatinine. VWF did not predict mortality. Conclusions Endothelial cell damage could be involved in the pathogenesis of early death following paraquat ingestion.

Paraquat is a fatal herbicide following acute exposure. Previous studies have suggested that multidrug resistance protein 1 (MDR1) might help remove paraquat from the lungs and the kidney. MDR1 single-nucleotide polymorphisms (SNPs) are involved in the pharmacokinetics of many drugs. The purpose of this study was to determine whether MDR1 SNPs were associated with the mortality in paraquat intoxicated patients. We recruited 109 patients admitted with acute paraquat poisoning. They were genotyped for C1236T, G2677T/A, and C3435T single-nucleotide polymorphisms (SNPs) of MDR1 gene. Their effects on mortality of paraquat intoxicated patients were evaluated. Overall mortality rate was 66.1%. Regarding the C1236T of the MDR1 gene polymorphism, 21 (19.3%) had the wild type MDR1 while 88 (80.7%) had homozygous mutation. Regarding the C3435T MDR1 gene polymorphism, 37(33.9%) patients had the wild type, 23 (21.1%) had heterozygous mutation, and 49 (45.0%) had homozygous mutation. Regarding the G2677T/A MDR1 gene polymorphism, 38 (34.9%) patients had the wild type, 57 (52.3%) had heterozygous mutation, and 14 (12.8%) had homozygous mutation. None of the individual mutations or combination of mutations (two or three) of MDR1 SNP genotypes altered the morality rate. The mortality rate was not significantly different among SNP groups of patients with

Background: Water soluble and insoluble chemicals in the pesticide formulation may be eliminated more effectively in time if hemodialysis (HD) and hemoperfusion (HP) are performed concurrently. Aim: This study is aimed at evaluating the efficacy of concurrent HP and HD in patients with acute pesticide intoxication. Methods: Between January 2011 and December 2012, we used HP and HD consecutively (HP-HD group, 347 cases), and then during the next 2 years (January 2013 to December 2014), we used concurrent HP and HD (HPD group, 383 cases). We compared the clinical outcomes between the 2 groups. Results: The mortality was higher in the HP-HD group than in the HPD group: (48.1 vs. 20.9%) for the overall mortality and (81.8 vs. 57.9%) for the paraquat (bipyridylium) mortality (p < 0.001). In multiple logistic analyses, age (p = 0.013), ingested volume (p < 0.001), and HP-HD (p = 0.014) were significant risk factors for mortality in the paraquat ingested group. Conclusion: Concurrent HP and HD would be an effective and safe treatment for patients with acute pesticide intoxication, in particular, paraquat intoxication.

When clinicians treat patients with pesticide poisoning, they often pay attention only to the chief toxic agent and ignore the toxicity of the pesticide’s additives or solvents. Occasionally, however, a solvent (e.g. methanol) may itself be the cause of poisoning. We report a case of acute methanol intoxication that occurred after ingestion of a methomyl pesticide that contained methanol as an additive. A 49-year-old man was brought to the emergency department in an unconscious state after ingestion of 20 ml of a carbamate pesticide (chief ingredient: methomyl; active ingredient: methanol). Upon arrival, he was semicomatose and did not breathe spontaneously; however, his cholinesterase level was within normal limits and cholinergic symptoms were not observed. High anion gap metabolic acidosis was present. His blood ethanol level was 74.8 mg/dL. The urine methanol level was 55.60 mg/dL, and urine ethanol level was 22.0 mg/dL. He was treated with hemodialysis; subsequently, his metabolic acidosis resolved and he returned to normal mental status. We guessed that methanol, as the solvent of the methomyl, had produced the symptoms. When treating pesticide-poisoned patients, clinicians should identify the solvent used in the pesticide, because solvents such as methanol may exacerbate the symptoms of poisoned patients.

Oxidative injury can occur in the lung through the generation of reactive oxygen species (ROS) via redox cycling owing to intentional or accidental ingestion of paraquat (PQ), a common herbicide. A wide array of phytochemicals has been shown to reduce cellular oxidative damage by modulating cytoprotective genes. Quercetin, a well-known flavonoid, has been reported to display cytoprotective effects by up-regulating certain cytoprotective genes. In this context, we investigated the effect of quercetin on PQ-induced cytotoxicity in alveolar A549 cells, modulation of antioxidant genes, activation of transcription factor-Nrf2 and its target HO-1 expression. Quercetin reduced PQ-induced cytotoxicity in A549 cells that was evaluated by both 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) and lactate dehydro- genase (LDH) assays. Modulation of antioxidant genes was compared when cells were treated with PQ, quercetin and both using qRT-PCR. Activation of transcription factor-Nrf2 and induction of its target gene, HO-1 was demonstrated by western blot analysis. A remarkable reduction in the ROS level as well as an increase in the total cellular glutathione (GSH) level occurred when PQ-exposed cells were treated with quercetin. Our findings suggest that quercetin may be used to mitigate or minimize oxidative stress via reducing the generation of ROS. Copyright © 2012 John Wiley & Sons, Ltd.

Paraquat (PQ) is the third most extensively used herbicide in the world, causing thousands of deaths due to accidental or intentional self-poisoning in developing countries. Although many therapeutic treatments for PQ-induced poisonings have been proposed and developed, the efficacy of these treatments is still poor and requires further investigation. Methylprednisolone (trade name Solumedrol, hereinafter MP) is a widely used steroid for the treatment of various diseases but the function of MP has not yet been studied in the context of PQ-induced intoxication. The aim of this study was to determine if MP can ameliorate PQ-induced toxicity in an alveolar A549 cell line by inducing ATP-dependent transporter P-glycoprotein (P-gp) expression. P-gp expression and activity in the PQ-treated A549 cell line were enhanced by MP treatment and cytotoxicity by PQ was dramatically decreased. We also found that MP per se or together with PQ induced P-gp expression by both Western blot and qRT-PCR analyses. In addition, induced P-gp transporter was shown to improve the efflux effect on PQ-treated A549 cell lines as was demonstrated using the Calcein-AM fluorescence accumulation assay. In summary, MP induces the transmembrane ATP-dependent transporter P-gp expression, which greatly improves PQ-treated A549 cell viability, reduces accumulation of intracellular PQ and prevents PQ induced cytotoxicity but it should be further evaluated in in vivo studies.

Chloracetanilide herbicides (alachlor, butachlor, metachlor) are used widely. Although there are much data about chronic low dose exposure to chloracetanilide in humans and animals, there are few data about acute chloracetanilide poisoning in humans. This study investigated the clinical feature of patients following acute oral exposure to chloracetanilide. We retrospectively reviewed the data on the patients who were admitted to two university hospitals from January 2006 to December 2010. Thirty-five patients were enrolled. Among them, 28, 5, and 2 cases of acute alachlor, metachlor, butachlor poisoning were included. The mean age was 49.8 ± 15.4 yr. The poison severity score (PSS) was 17 (48.6%), 10 (28.6%), 5 (14.3%), 2 (5.7%), and 1 (2.9%) patients with a PSS of 0, 1, 2, 3, and 4, respectively. The age was higher for the symptomatic patients (1-4 PSS) than that for the asymptomatic patients (0 PSS) (43.6 ± 15.2 vs 55.7 ± 13.5). The arterial blood HCO3 ¯ was lower in the symptomatic patients (1-4 PSS) than that in the asymptomatic patients (0 PSS). Three patients were a comatous. One patient died 24 hr after the exposure. In conclusion, although chloracetanilide poisoning is usually of low toxicity, elder patients with central nervous system symptoms should be closely monitored and cared after oral exposure.

The human toxicity of synthetic auxin analogue herbicides has not been extensively studied.Clinical outcome was assessed from medical records of 17 patients who had intentionally ingested auxin pesticides with active ingredients like dicamba, triclopyr, MCPA or mecoprop. The patients were interviewed after discharge to follow outcome (interval 2 to 56 months).One patient who had ingested 500 mL of a mecoprop product died of hypotension and respiratory failure 36 hours after hospital admission. The other 16 patients recovered and were discharged by hospital day 28. After discharge, four patients died from causes not related to herbicide intoxication. In the 12 surviving patients, no long-term effects were reported.Human toxicity of synthetic auxins appears relatively benign with conservative treatment. However, when the amount ingested is above several hundred milliliters of commercial product, especially in combination of mecoprop with other intoxicants (e.g. alcohol), shock with respiratory failure may develop and lead to death.

Background/Aims Many patients with acute paraquat (PQ) intoxication die even at low PQ concentrations, whereas others with similar concentrations recover. Therefore, it is possible that individual differences in antioxidant capacity are responsible for the variable clinical outcome in patients with acute PQ intoxication. Methods We investigated whether there was a relationship between the genetic polymorphisms of SOD (V16A), catalase (C262T), and GPX1 (C593T) in 62 patients with acute PQ intoxication and the clinical outcomes of these patients. Results The frequency of the Mn-SOD V/V, V/A, and A/A genotypes were 56.3, 43.5, and 0% in survivors and 86.9, 13.1, and 0% in non-survivors (p > 0.05). The GPX1 C/C, C/T, and T/T genotypes were present in 100, 0, and 0% of all subjects. The catalase C/C, C/T, and T/T genotypes were present in 100, 0, and 0% of survivors, and in 82.6, 17.4, and 0% of non-survivors. Neither erythrocyte SOD activity nor catalase activity were significantly different between survivors and non-survivors. Conclusions No association was found between clinical outcome of acute PQ intoxication and the genetic polymorphism of GPX1 (C593T) or the genetic polymorphisms or enzyme activity of superoxide dismutase (V16A) or catalase (C262T).

Background: We hypothesized that the asymmetric dimethylarginine (ADMA) metabolism in end-stage renal disease may be linked to the rate of protein turnover and to the vast pool of amino acids. In order to determine a correlation between the plasma levels of ADMA and the protein catabolic rate, we measured the ADMA levels as well as nutritional markers such as the normalized protein catabolic rate (nPCR) in patients with newly initiated continuous ambulatory peritoneal dialysis (CAPD). Methods: Twenty-four patients were recruited for this study. All patients were on the standard CAPD protocol, and followed for at least 1 year. Blood samples were collected at baseline before the initiation of peritoneal dialysis, and every 6 months for 1 year. The blood parameters studied included the serum albumin, total cholesterol, glucose, urea nitrogen, creatinine and ADMA. Peritoneal equilibrium test and measurements of weekly Kt/Vurea and nPCR were performed within 4 weeks of the blood sampling. Results: The change of ADMA levels over 1 year was positively correlated with that of haemoglobin (r = 0.592, P = 0.002) and nPCR during the same period (r = 0.508, P = 0.026). Conclusion: The findings of our study suggest that nPCR might influence the change of ADMA levels after initiation of CAPD.

Background/Aims: Maintenance dialysis is made decreased the death rate of patients with end-stage renal disease; however, mortality is still high. The aim of this study was to identify the association between clinical parameters at the start of hemodialysis with survival and compare these findings with data from patients who underwent hemodialysis about 15 years ago at the same dialysis center. Methods: We reviewed 117 patients who started hemodialysis between 2000 and 2004. We analyzed medical histories, laboratory findings, and clinical outcomes, and compared them with patients who started hemodialysis 15 years ago at the same center. Results: The proportion of elderly patients and those with diabetes increased from 17% and 18% in the previous study to 33% and 49% in this study, respectively. Elderly and patients with diabetes had much higher mortalities than their counterparts. Nevertheless, the overall survival rate (66% vs. 71% at 5 years) and survival of patients with diabetes improved (55% vs. 75% at 1.5 years). Common causes of death were infection and cardiovascular disease in the present study; however, inadequate dialysis accounted for 25% of deaths in the previous study. Conclusions: The overall survival rate of patients undergoing hemodialysis has improved over the 15-year interval, even with an increased proportion of elderly patients and patients with diabetes. Adequate dialysis and further medical improvements could ameliorate mortality in patients undergoing dialysis. (Korean J Intern Med 2010;25:188-194)

In order to evaluate the efficiency and renal protective effects of glutathione during Ca++-EDTA chelation therapy for chronic cadmium intoxication, we measured the renal excretion of cadmium, β2-microglobulin, proteinuria, and hematuria during intravenous administration of glutathione with Ca++-EDTA in a 54-year-old patient with chronic cadmium intoxication. We administered 500 mg of Ca++-EDTA and 50 mg/kg of glutathione alone or in 1 L of normal saline over the next 24 hours and repeated this over 12 consecutive days. During the first 3 days, the basal levels (only saline administration) were determined; during the second 3 days, Ca++-EDTA only was administered, for the third sequence of 3 days, Ca++-EDTA with glutathione was provided, and for the last 3 days, glutathione alone was given. One month later, the same protocol was repeated. There were six blood and urine samples to analyze in each group. The blood cadmium level was higher when the EDTA was infused together with glutathione (7.44 ± 0.73 µg/L, p < 0.01) compared to the basal level of 4.6 ± 0.44 µg/L. Also, the renal cadmium excretion was significantly higher in the EDTA with glutathione group than in the basal group (23.4 ± 15.81 µg/g creatinine vs 89.23 ± 58.52 µg/g creatinine, p < 0.01). There was no difference in the protein/creatinine and β2-microglobulin/creatinine ratio in the urine (p > 0.05) among the groups. Furthermore, microhematuria and proteinuria did not develop over the observation period of 6 months. These results suggest that glutathione administration with EDTA might be an effective treatment modality for patients with cadmium intoxication.

Worldwide expansion of mobile phones and electromagnetic field (EMF) exposure has raised question of their possible biological effects on the brain and nervous system. Radiofrequency (RF) radiation might alter intracellular signaling pathways through changes in calcium (Ca(2+)) permeability across cell membranes. Changes in the expression of calcium binding proteins (CaBP) like calbindin D28-k (CB) and calretinin (CR) could indicate impaired Ca(2+)homeostasis due to EMF exposure. CB and CR expression were measured with immunohistochemistry in the hippocampus of mice after EMF exposure at 835 MHz for different exposure times and absorption rates, 1 h/day for 5 days at a specific absorption rate (SAR)=1.6 W/kg, 1 h/day for 5 days at SAR=4.0 W/kg, 5 h/day for 1 day at SAR=1.6 W/kg, 5 h/day for 1 day at SAR=4.0 W/kg, daily exposure for 1 month at SAR=1.6 W/kg. Body weights did not change significantly. CB immunoreactivity (IR) displayed moderate staining of cells in the cornu ammonis (CA) areas and prominently stained granule cells. CR IR revealed prominently stained pyramidal cells with dendrites running perpendicularly in the CA area. Exposure for 1 month produced almost complete loss of pyramidal cells in the CA1 area. CaBP differences could cause changes in cellular Ca(2+)levels, which could have deleterious effect on normal hippocampal functions concerned with neuronal connectivity and integration.

BACKGROUND, MATERIAL, AND METHODS: To assess plasma malondialdehyde (MDA) level as a clinical marker in acute paraquat (PQ) intoxication, we sequentially investigated 74 patients (40 males and 34 females, aged 49.9 +/- 16.2 years), all of whom ingested PQ as a means of suicide from July to December 2008.The baseline level of MDA (10.8 +/- 3.5 microM) had no correlation with plasma PQ levels of 22.1 +/- 48.7 microg/mL (median: 1.9, range0.01-228.5) or with volume of PQ ingested. However, the following parameters were significantly different between survivors and nonsurvivors: the amount of PQ ingestion, plasma PQ levels, basal MDA levels, WBC, hemoglobin, hematocrit, platelet counts, albumin, BUN, creatinine, potassium, amylase, and arterial blood gas analysis (pH, pCO(2), HCO(-)(3)).The nonsurvivors' baseline MDA (11.4 +/- 3.8 vs. 9.8 +/- 2.8, p = 0.040) was higher than the survivors. However, the baseline level was not a predictor of mortality in the univariate and the multivariate binary logistic analyses. Among the patients whose MDA levels were measured sequentially, 58.3% of the patients (35 out of 60) showed fluctuating MDA levels, 25% (n = 15) showed steady decreases, with only 16.6% (n = 10) showing steady increases in MDA levels during the observation period. These findings imply the presence of active MDA metabolism and/or that the half-life of MDA is very short in the human body.Both cross-sectional and sequential measurements of plasma MDA do not provide reliable information on outcome in patients with acute PQ intoxication.

Extracorporeal removal techniques are effective methods for toxin removal from the body. To define the safety and clinical outcomes of hemoperfusion, we evaluated retrospectively clinical outcomes of hemoperfusion over a 3-year period in our clinical center. From January 2006 to December 2008, we analyzed 803 patients. Mortality, catheter-related bleeding, systemic bleeding, hypocalcemia, and thrombocytopenia were investigated. Medical drugs (n = 54) and pesticide toxins (n = 749) were represented. Pesticides included herbicides (n = 598), insecticides (n = 130), mixed herbicides and insecticides (n = 4), and unknown pesticides (n = 17). Among those with herbicide poisoning, 493 cases were caused by paraquat, and among those affected by insecticides, 67 cases were caused by organophosphate insecticides. After hemoperfusion, systemic bleeding complications were observed in 26 cases (3.0%). Systemic bleeding was a greater mortality risk factor than nonsystemic bleeding (OR 2.779, 95% CI 1.07–7.23). Hypocalcemia was observed in 69.1% and thrombocytopenia in 31.1%. Excess mortality was 44.4%. In hemoperfusion cases, systemic bleeding is a major factor to predict adverse outcome.

Background/Aims: Paraquat-induced lung injury has been considered a progressive and irreversible disease. The purpose of this study was to report the long-term evolution of lung lesions in eight survivors with significant paraquat-induced lung injuries who could be followed-up for longer than 6 months. Methods: We retrospectively examined high-resolution computed tomography and pulmonary function test of eight survivors with significant paraquat-induced lung injurys. Results: High-resolution computed tomography revealed a predominant pattern of irregularly shaped consolidation with traction bronchiectasis at 1-2 months after paraquat poisoning, a mixed pattern of irregularly shaped consolidation and ground-glass opacity at 3-12 months, and a mixed pattern of consolidation, groundglass opacity, and honeycombing at 1-2 years. At 3-12 months after paraquat ingestion, the areas of consolidation had markedly decreased and the decreased lung volume had returned to normal. At 1-2 years after paraquat poisoning, the cystic changes had disappeared. At 2-3 years after paraquat poisoning, the decrease in forced vital capacity had greatly improved to the normal range. Conclusions: Recovery of nearly normal pulmonary structure and function may occur over several years following paraquat poisoning. Pulmonary function (both forced vital capacity and forced expiratory volume in 1 sec) evolved toward normal in the long-term survivors of paraquat poisoning with initial prominent lung injuries. (Korean J Intern Med 2009;24:95-100)

Acute paraquat poisoning is often fatal. When ingested, paraquat affects multiple organs including the lung, gastrointestinal tract, pancreas, kidney, heart, and central nervous system. Our center previously found that initial pancreatic function was related to the prognosis of patients with acute paraquat poisoning. However, pancreatic injury after paraquat intoxication has been incompletely studied.This study analyzed the clinical outcome and extent of pancreatic injury in 34 survivors of acute paraquat poisoning. Paraquat exposure was assessed based on a quantitative measure of the plasma level of paraquat by high-performance liquid chromatography. The subsequent variations in the level of pancreatic enzymes, clinical symptoms, and abdominal computed tomography were obtained. Outcomes after acute paraquat poisoning were categorized as pancreatic enzyme elevation group (elevation group: amylase160 IU/L and lipase100 IU/L) and nonelevation group.Pancreatic enzyme elevations occurred in seven cases (20.6%), and the level of pancreatic enzymes peaked at day 7. The elevation in pancreatic enzymes after paraquat ingestion was positively correlated with the plasma paraquat level (p0.05 at days 4 and 7). Creatinine was higher in the elevation group. Abdominal computed tomography of the seven cases showed no evidence of pancreatitis, and significant abdominal pain was not observed.Pancreatic enzyme elevation reflects the systemic toxicity and multiorgan involvement following acute paraquat poisoning.Pancreatic injury was subtle and the elevation of pancreatic enzymes in survivors is clinically benign.

We investigated the cases of depression in farmers associated with pesticide exposure. The group of farmers numbered 82, mostly living in the Western region of South Korea (43 male cases, mean age 51.1 ± 9.1 years, 39 female cases, mean age 49.4 ± 9.1 years). We traced the residential effect on two groups living inside of the orchard compared to those outside, the duration of farming, and the yearly frequency of pesticide spraying. The Beck Depression Inventory (BDI) and Minnesota Multiphasic Personality Inventory 2-Depression (MMPI-D) scale were employed as the vehicle in measuring depression. No difference was traced in the residential effect, in terms of the BDI (11.9 ± 8.6 vs. 11.4 ± 7.2, p = 0.38) and the MMPI1-D (52.9 ± 8.9 vs. 53.2 ± 8.1, p = 0.44) scales. The MMPI-D score showed a positive correlation with alcohol drinking (p < 0.05), the years of farming (p < 0.01), history of intoxication (p < 0.01), yearly frequency of pesticide spraying (p < 0.05), and the BDI score (p < 0.05). In conclusion, personal exposure to pesticide spraying was presumed to be associated with the development of depression in farmers.

This study was designed to determine the minimum effective concentration of paraquat that modulated the expression of PKD-related genes in Drosophila . We first studied the viability of Drosophila and then tested the expression of the PKD-related genes— Parkin , UCH , and tau —in various concentrations of paraquat in the water sucked by Drosophila . The lowest effective concentration of paraquat was approximately 20 μM and the gene expression was induced at paraquat doses between 20 mM and 20 μM. Parkin and tau expression was inhibited, while that of UCH was significantly increased. Next, we examined the expression of the Parkin and UCH genes in the neurons of SOD -reduced mutants under oxidative stress conditions and found that Parkin was up regulated, while UCH was down regulated. We also found that the expression of Parkin was regulated by JNK . This study revealed that paraquat affects the expression of PKD-related genes via oxidative stress. In conclusion, our results showed that paraquat in the water sucked by Drosophila altered the gene expression at a minimum concentration of 20 μM, and that it not only promoted but also inhibited PKD-related gene expression via signal transduction mediated by oxidative stress. In order to confirm whether paraquat is a causal factor of PKD, more balanced and in-depth tests seem to be done looking into multiple aspects.

Paraquat poisoning by ingestion is often fatal. Many studies have investigated treatment modalities and predictor parameters, but there is no standard treatment. Plasma paraquat concentration seems a valid predictable parameter of survival. In order to achieve uniform treatment, including extracorporeal elimination and antioxidant therapy, the outcome of paraquat poisoning based on plasma paraquat level needs to be investigated.This study included 375 paraquat poisoning patients who were diagnosed by means of plasma paraquat concentration within 24 hours after ingestion in the Institute of Pesticide Poisoning of Soonchunhyang University Cheonan Hospital, Korea, from January 2005 to December 2006. All patients were treated according to a uniform protocol including extracorporeal elimination and antioxidant therapy. Plasma paraquat concentration was measured by high-performance liquid chromatography.The mean age of the paraquat-intoxicated patients was 48.42 +/- 6.75. One hundred ten patients (29.3%) survived. The upper limit of plasma paraquat concentration in survivors was 2.64 at 3 hour. All patients with plasma paraquat level above 3.44 died. The minimum paraquat level of the deaths was very low (0.12 microg/ml at 5 hours; 0.02 microg/ml at 12 hours; 0.01 microg/ml at 24 hours).Our data showed that plasma paraquat concentration is good predictor of survivors but is not good predictor of non-survivors in the low plasma paraquat level.

The formulation of most pesticides is proprietary and individual components are therefore not generally known. In a preliminary study, we identified six compounds that are often present in pesticides, of which 4-nonylphenyl-polyethylene glycol (NP-40) was found to be the most toxic. In this study, we investigated the toxicity of NP-40 and underlying mechanism in neuronal SK-N-SH cells. Exposure to NP 40 at concentrations higher than 60μmol/L for 24hr decreased cell viability. The cytotoxicity of NP-40 was time- and concentration-dependent. Nuclear fragmentation and chromatin condensation were apparent starting at 50μmol/L NP-40, and increased at higher concentrations. The expression of apoptotic factors including p53 and B-cell lymphoma (Bcl)-2-associated X protein was upregulated, while that of the anti-apoptotic marker Bcl-2 was downregulated at 80 μmol/L NP-40. Cytochrome c release was observed from 80 to 100μmol/L by confocal microscopy. Caspase-9 and -3/7 activities increased according to concentration, and fluorescence-activated cell sorting analysis showed that apoptosis was induced at 50μmol/L and was increased at 80μmol/L. Our findings indicate that NP-40 stimulates the mitochondrial-mediated apoptosis pathway and reactive oxygen species production in a concentration-dependent manner, and suggest that antioxidant administration may be an effective treatment for patients with acute NP-40 poisoning.

Objective: This study aimed to determine the dialyzability of common pesticide surfactants. Methods: Hemodialysis and hemoperfusion were performed for three surfactants-sodium dodecylbenzenesulfonate, lignosulfonic acid sodium, and naphthalenesulfonic acid polymer with formaldehyde-with buffer solutions (2 L) containing 0.2% surfactant with or without bovine serum albumin (3.0 g/dL). Results: The dialyzability of sodium dodecylbenzenesulfonate during hemodialysis was high and increased with ultrafiltration. The final reduction rates of naphthalene sulfonic acid polymer with formaldehyde and sodium dodecylbenzenesulfonate in bovine serum albumin were higher for hemoperfusion (25.8% and 26.8%, respectively) than for hemodialysis (8.2% and 0%, respectively). In contrast, the final reduction rate of lignosulfonic acid sodium in bovine serum albumin was higher for hemodialysis (37.5%) than for hemoperfusion (13.2%). Conclusion: Our results suggest that extracorporeal elimination may be an effective treatment modality in patients who ingested surfactant mixed pesticides. However, the dialysis method looks likely to be tailored to each surfactant, based on its dialyzability.

Background : Pulmonary damage resulting from lipid peroxidation is a principal effect of paraquat intoxication. The host-defense functions of surfactant are known to be mediated by the surfactant proteins A and D (SP-A and SP-D, respectively). The primary objective of this study was to evaluate the variations over time in levels of surfactant protein and lipid peroxidation (LPO) in lung tissue following free-radical-induced injury. Methods : 42 adult, male, Sprague-Dawley rats were administered intraperitoneal injections of paraquat (35 mg/kg body weight). SP-A and SP-D levels were determined via Western blot. LPO in the left lung homogenate was measured via analyses of the levels of thiobarbituric acid-reactive substances. Results : LPO levels peaked at 6 hours, with no associated histological changes. SP-D levels increased until hour 12 and declined until hour 48; SP-D levels subsequently began to increase again, peaking at hour 72. SP-A levels peaked at hour 6, declining thereafter. Conclusions : We suggest that in the early phase of paraquat injury, SP-D levels reflect alveolar damage and that de novo synthesis of SP-D takes 72 hours. Levels of SP-A, on the other hand, reflect abnormalities in the surfactant system in the late stage of paraquat intoxication. Surfactant proteins may play a role in protecting the lungs from reactive oxygen injury. A time-dependent variation has been observed in the levels of surfactant proteins A and D following paraquat injury, and it has been suggested that these proteins play a role in the protection of lung tissue against ROS-induced injuries.

This study was designed to study patients with intolerance to pesticide smells. Ten subjects chosen were complaining of vague symptoms such as headache, dizziness, fatigue, nausea, vomiting, abdominal pain, myalgia, flu-like symptoms, etc., whenever exposed to the pesticide smells even at low intensity. To determine whether the etiology of this kind of pesticide hypersensitivity was of organic or psychiatric nature, all the subjects underwent tests as follows: complete blood cell count, urinalysis, and blood chemistry as routine tests; esophogastroduodenoscopy and abdomen ultrasonography for the gastrointestinal symptoms; chest x-ray, pulmonary function tests, and electrocardiography for the respiratory and/or cardiac symptoms; nerve conduction velocity and brain magnetic resonance imaging (MRI) for peripheral and central nerve system symptoms; and K-WAIS, Rey-Kim memory test, Rorschach, Mini Mental State Examination (MMSE), and Minnesota Multiphasic Personality Inventory (MMPI) for psychoanalysis. Of the 10 cases in which the chief complaint was headache, symptoms of two cases were caused by maxillary sinusitis. Another two showed typical multiple chemical sensitivity (MCS) or idiopathic environmental intolerance (IEI). Six out of the 10 cases, whose symptoms closely resembled the others, did not conclusively meet the criteria of classic MCS or IEI. The subjects of this case shared vague fears, both fear of pesticides and hypochondriasis. Some subjects faced financial insecurity and social uncertainty; others felt uneasy about the future of their farming life. Thus, to help verify the causes of MCS or IEI, which is strongly suggestive of pesticide smells, diagnosis needs a dual approach: on the anima and soma. Psychoanalysis can delve into the mental status of the patients to see whether the patients are aware of their symptoms. Clinical tests can see through the physical structure and functions of the organs on which patients' complaints are centered.

Free radical-induced lung injury is a major problem that occurs because of paraquat intoxication. Serum surfactant protein D (SP-D) reflects the severity of various lung diseases. The purpose of this study is to investigate the changes in plasma SP-D concentrations and to correlate disease severity with SP-D concentrations in patients with acute paraqaut intoxication. Twelve paraquat-intoxicated patients participated in this study. Their paraquat exposure was assessed by their plasma's paraquat level. Serial plasma SP-Ds were measured by ELISA. SP-D was decreased two and three days after the initial measurement within 2 to 72 hours of ingestion. There was no difference in initial SP-D levels between survivors and non-survivors. The SP-D test revealed a significant positive correlation between the SP-D level and PaO(2) (r = 0.384, p = 0.003, N = 57). SP-D did not predict the likelihood of survival, but it was positively correlated with PaO(2). This finding suggests that low concentrations of plasma SP-D could reflect hypoxia due to free radical-induced injury.

Pesticide formulation includes solvents (methanol and xylene) and antifreeze (ethylene glycol) whose metabolites are anions such as formic acid, hippuric acid, and oxalate. However, the effect of the anion gap on clinical outcome in acute pesticide intoxication requires clarification. In this prospective study, we compared the anion gap and other parameters between surviving versus deceased patients with acute pesticide intoxication. The following parameters were assessed in 1,058 patients with acute pesticide intoxication: blood chemistry (blood urea nitrogen, creatinine, glucose, lactic acid, liver enzymes, albumin, globulin, and urate), urinalysis (ketone bodies), arterial blood gas analysis, electrolytes (Na+, K+, Cl- HCO3-, Ca++), pesticide field of use, class, and ingestion amount, clinical outcome (death rate, length of hospital stay, length of intensive care unit stay, and seriousness of toxic symptoms), and the calculated anion gap. Among the 481 patients with a high anion gap, 52.2% had a blood pH in the physiologic range, 35.8% had metabolic acidosis, and 12.1% had acidemia. Age, anion gap, pesticide field of use, pesticide class, seriousness of symptoms (all P < 0.001), and time lag after ingestion (P = 0.048) were significant risk factors for death in univariate analyses. Among these, age, anion gap, and pesticide class were significant risk factors for death in a multiple logistic regression analysis (P < 0.001). In conclusions, high anion gap is a significant risk factor for death, regardless of the accompanying acid-base balance status in patients with acute pesticide intoxication., Graphical Abstract

This study was designed to compare organic farmers (comparison group) and pesticide-using farmers (pesticide group) in terms of neurobehavioral performance and sensorimotor function. The subjects were recruited in October 2004 from Chungnam Province and the neighboring Jeolla Province in western South Korea. Psychological assessment was carried out using the Wechsler Adult Intelligence Scale, the Mini-Mental State Examination, and the Bender Gestalt test. Neuroselective sensory nerve conduction threshold was measured at both left and right middle fingers by using an electrodiagnostic device to determine current perception thresholds (CPTs). Three independent CPT measurements were obtained from each test site by using sinusoidal stimuli at three frequencies. CPT testing showed no difference between the two groups. No significant differences were found in the large myelinated (2000 Hz stimulation; cutaneous touch, pressure), small myelinated (250 Hz stimulation; mechanoreceptive, pressure, temperature, fast...

Study objectives Pulmonary fibrosis due to lipid peroxidation is a major symptom of paraquat intoxication. Ethane in the expired breath (exEth) reflects lipid peroxidation and may be a measure of the damage effected by oxygen radicals in acute lung injury. The purpose of this study was to evaluate the clinical efficacy of exEth as a measure of exposure to paraquat and as an indicator of lung damage. Design Exposure levels were evaluated by the amount ingested, semiquantitative measurement of urine paraquat levels, and plasma paraquat concentration. End-tidal breath was collected for measurement of ethane 24 h after paraquat ingestion. Renal function and blood gas analyses were conducted on the same day as the breath collection, and the final clinical outcome was defined as either recovery or death. Associations between exEth and paraquat exposure profiles and clinical outcomes were assessed using linear regression models. Patients Twenty-one patients poisoned by paraquat were selected for the study during 2001 and 2002. Results exEth could not be used as a predictor of laboratory parameters such as Pao2, Paco2, serum creatinine, and lung injury (as graded by high-resolution CT). A logistical analysis revealed that only the amount of paraquat ingested was a significant predictor of fatality (p = 0.021). The strength of the association between exEth and fatality was unaffected by the addition of potential confounders such as age, sex, and time interval and paraquat concentration. Conclusion exEth cannot be used as either an independent predictor of survival or a specific marker of lung injury in patients with acute paraquat poisoning.

BACKGROUND There has been a lack of study on the structural changes of serum albumin in patients with minimal change disease (MCD). To determine whether glycation and/or conformational transitions of albumin are involved in the pathogenesis of albuminuria, nine patients with MCD were enrolled in a prospective follow-up study for comparison of these parameters in serum albumin during the remission and relapse of nephrotic syndrome. METHODS Circular dichroism measurements were made with purified albumin. Ellipticities at each wavelength were transformed to mean residue ellipticity. Monosaccharide composition was analyzed by high-pH anion-exchange chromatography with pulsed amperometric detection. RESULTS There was no difference in the proportions of alpha-helix, beta-conformation, and beta-turn of albumin between the sera of control patients and those with nephrotic syndrome. However, the proportion of the random configuration was slightly higher in the plasma albumin of patients in relapse than in those in remission. The proportion of the random configuration was lower in the albumin of the serum than in the urine of patients with nephrotic syndrome, but there was no difference in the proportions of alpha-helix, beta-conformation, and beta-tum of albumin between their plasma and urine. CONCLUSION Our results suggest that conformational changes in albumin are involved in albuminuria in patients with MCD.

Acute paraquat poisoning is often fatal. Many studies have investigated successful treatment modalities, but no standard treatment yet exists. The purpose of this study was to determine the predictors of survival after acute paraquat poisoning in 602 patients. The paraquat exposure was assessed based on the amount of ingested paraquat and a semiquantitative measure of the urine level of paraquat. Initial clinical parameters including vital signs, hemoglobin, white-blood-cell count, pH, PaCO2, PaO2, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, total bilirubin, amylase, and glucose were obtained at the time of arrival at the emergency room. Outcomes after acute paraquat poisoning were categorized as survivors and nonsurvivors. Multiple logistic regression analysis was applied to assess the predictors of survival after acute paraquat poisoning. Some patients (55.5%) survived after oral ingestion of paraquat, whereas all those exposed to paraquat percutaneous or inhalational route survived. The amount of paraquat (24.5% concentrate of 1,1′-dimethyl-4,4′-bipyridium dichloride) ingested was 45.69 / 74.1 mL (mean9 / SD). In addition to degree of paraquat exposure, survival after acute paraquat poisoning was associated with age, respiratory rate, pH, PaCO2, hemoglobin, white-blood-cell count, blood urea nitrogen, amylase, and the number of failed organs in multiple logistic regression analysis. In conclusion, young age, percutaneous or inhalational route, exposure to less paraquat, and lesser degrees of leukocytosis, acidosis, and renal, hepatic, and pancreatic failures on admission are good prognostic factors of survival after acute paraquat poisoning.