Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice.

BACKGROUND: CCL2/C-C chemokine receptor 2 (CCR2) signalling is suggested to play a significant role in various kidney diseases including diabetic nephropathy. We investigated the renoprotective effect of a CCR2 antagonist, RS102895, on the development of diabetic nephropathy in a type 2 diabetic mouse model. METHODS: Six-week-old diabetic db/db and non-diabetic db/m mice were fed either normal chow or chow mixed with 2 mg/kg/day of RS102895 for 9 weeks. We investigated the effects of CCR2 antagonism on blood glucose, blood pressure, albuminuria and the structure and ultrastructure of the kidney. RESULTS: Diabetes-induced albuminuria was significantly improved after CCR2 antagonist treatment, and glucose intolerance was improved in the RS102895-treated diabetic mice. RS102895 did not affect blood pressure, body weight or kidney weight. Mesangial expansion, glomerular basement membrane thickening and increased desmin staining in the diabetic kidney were significantly improved after RS102895 treatment. The up-regulation of vascular endothelial growth factor mRNA expression and the down-regulation of nephrin mRNA expression were markedly improved in the kidneys of RS102895-treated diabetic mice. Increased renal CD68 and arginase II and urinary malondialdehyde in diabetes were effectively attenuated by RS102895 treatment. CONCLUSION: Blockade of CCL2/CCR2 signalling by RS102895 ameliorates diabetic nephropathy not only by improving blood glucose levels but also by preventing CCL2/CCR2 signalling from altering renal nephrin and VEGF expressions through blocking macrophage infiltration, inflammation and oxidative stress in type 2 diabetic mice.

In vitro cytotoxic effect of glyphosate mixture containing surfactants.

We investigated whether glyphosate influences the cellular toxicity of the surfactants TN-20 and LN-10 on the mouse fibroblast-like cells, alveolar epithelial cells, and a heart cell line. The cytotoxicity of TN-20 and LN-10 (0.4-100 µM), in the presence or absence of glyphosate was determined by assessing membrane integrity. TN-20 toxicity was significantly lower in the presence of 50 µM glyphosate for the fibroblast-like cell (6.25 µM; 3.9% ± 3.4% vs -4.8% ± 0.7%), for the alveolar cells (0.78 µM; 5.7% ± 0.9% vs 0.1% ± 0.6%), and for the heart cell line (25.0 µM; 7.9% ± 3.0% vs 19.4% ± 0.7%) compared to that of TN-20 alone. The cellular toxicity of LN-10 towards the fibroblast-like cells was found to be increased in the presence of 50 µM glyphosate when LN-10 concentrations of 50 µM (31.3% ± 3.9% vs 19.2% ± 0.9%) and 100 µM (62.1% ± 3.4% vs 39.0% ± 0.7%) were compared to that of LN-10 alone. These results suggest that the mixture toxicity may be a factor in glyphosate-surfactant toxicity in patients with acute glyphosate herbicide intoxication.

Cellular toxicity of surfactants used as herbicide additives.

The cellular toxicities of surfactants, a solvent, and an antifreeze that are included in herbicide formulations were assessed by measuring their effects on membrane integrity, metabolic activity, mitochondrial activity, and total protein synthesis rate in a cell culture. Polyethylene glycol, propylene glycol, and monoethylene glycol exhibited no cellular toxicity even at a high concentration of 100 mM. Sodium lauryl ether sulfate and polyoxyethylene lauryl ether significantly damaged the membrane, disturbed cellular metabolic activity, and decreased mitochondrial activity and the protein synthesis rate; however, their toxicity was far below those of the severely toxic chemicals at comparable concentrations. The severely toxic category included polyoxypropylene glycol block copolymer, polyoxyethylene tallow amine, and polyoxyethylene lauryl amine ether. These surfactants were cytotoxic between 3.125 µM and 100 µM in a dose-dependent manner. However, the toxicity graph of concentration vs toxicity had a point of inflection at 25 µM. The slope of the toxicity graph was gentle when the concentration was below 25 µM and steep when the concentration was greater than 25 µM. In conclusion, our results suggest that the toxicity of surfactants be taken care of pertinent treatment of acute herbicide intoxication.

Acute oral poisoning due to chloracetanilide herbicides.

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.

Tissue plasminogen activator and plasminogen activator inhibitor-1 levels in patients with acute paraquat intoxication.

To investigate the effects of reactive oxygen species (ROS) on tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) plasma levels, and their possible implications on clinical outcome, we measured tPA and PAI-1 levels in 101 patients with acute paraquat (PQ) intoxication. The control group consisted of patients who ingested non-PQ pesticides during the same period. tPA and PAI-1 levels were higher in the PQ group than in the controls. PQ levels were significantly correlated with ingested amount, timelag to hospital, tPA level, and hospitalization duration. tPA levels were correlated with PAI-1, fibrin degradation product (FDP), and D-dimer. D-dimer levels were lower in the PQ group than in the controls. Univariate analysis indicated the following significant determinants of death: age, ingested amount, PQ level, timelag to hospital, serum creatinine, lipase, pH, pCO(2), HCO(3) (-), WBC, FDP, PAI-1, and tPA. However, multivariate analysis indicated that only PQ level was significant independent factor predicting death. In conclusion, tPA and PAI-1 levels were higher, while D-dimer levels were lower in the PQ group than in the controls, implying that ROS stimulate tPA and PAI-1, but PAI-1 activity overrides tPA activity in this setting. Decreased fibrinolytic activity appears to be one of the clinical characteristics of acute PQ intoxication.

[A case of liposarcoma arising in the mesentery].

A liposarcoma is the most common soft tissue sarcoma in adults with an incidence of about 20% of all soft tissue sarcomas. Although incidence differs from a region of origination, a case arisen from mesentery has rarely been reported. We experienced a case of liposarcoma arising from the mesentery of a 51-year-old male patient. He was treated by wide excision. Histologically, the tumor was composed of a mixed well-differentiated liposarcoma with myxoid and spindle cell type.

Clinical outcome of acute intoxication due to ingestion of auxin-like herbicides.

BACKGROUND: The human toxicity of synthetic auxin analogue herbicides has not been extensively studied. METHODS: 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). RESULT: 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. CONCLUSION: 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.

Surfactant volume is an essential element in human toxicity in acute glyphosate herbicide intoxication.

BACKGROUND: Glyphosate, one of the most commonly used herbicides worldwide, has been considered as minimally toxic to humans. However, clinical toxicologists occasionally encounter cases of severe systemic toxicity. The purpose of this study was to determine the effect of glyphosate-surfactants ("glyphosate-surfactant toxicity") in patients with acute glyphosate intoxication. METHODS: In all, 107 patients (69 men and 38 women, aged 52.3 ± 15.5 years) with acute glyphosate intoxication were enrolled in this study. From their medical records, we identified the formulation of ingested glyphosate products and derived clinical parameters, which focused on clinical outcome, admission days, duration in the intensive care unit, development of respiratory failure, cardiovascular deterioration, renal failure, altered mental status, and convulsions. The effect of surfactants on clinical complications was also assessed. RESULTS: For surfactant ingestion volumes of 8 mL, the incidence of clinical complications was (in rank order) as follows: hypotension, 47.1%; mental deterioration, 38.6%; respiratory failure, 30.0%; acute kidney injury, 17.1%; and arrhythmia, 10.0%. These complications were influenced by the volume of surfactant and not the type of surfactant-ingredient in the herbicide product. Two patients died of refractory shock, metabolic acidosis, and respiratory failure. However, the final clinical outcomes of the surviving patients were benign, and cardiovascular, respiratory, kidney, and mental functions were fully restored to normal levels. CONCLUSIONS: Our results indicate that treatment of patients with acute glyphosate herbicide intoxication should take into account the volume and not the type of surfactants in herbicide formulations.

Plasma level of malondialdehyde in the cases of acute paraquat intoxication.

UNLABELLED: 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. RESULTS: 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, range <0.01-228.5) 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. CONCLUSION: Both cross-sectional and sequential measurements of plasma MDA do not provide reliable information on outcome in patients with acute PQ intoxication.

Comparison of patients starting hemodialysis with those underwent hemodialysis 15 years ago at the same dialysis center in Korea.

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.

Association of the superoxide dismutase (V16A) and catalase (C262T) genetic polymorphisms with the clinical outcome of patients with acute paraquat intoxication.

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).

Paraquat intoxication in subjects who attempt suicide: why they chose paraquat.

BACKGROUND/AIMS: Paraquat (PQ) has been used in suicide attempts; an estimated 2,000 toxic ingestions occur annually, with 60-70% mortality. We sought to determine why PQ is such a common agent for suicide attempts in Korea. METHODS: We analyzed 250 cases (143 males, 107 females) of attempted suicide by PQ ingestion from January to December 2007. The procurement of the PQ was divided into two categories: purchased and preexisting. RESULTS: Men were more likely to have purchased PQ than women (66% vs. 22%, p=0.042). Additionally, men were more likely to be unmarried (n=34, 23.9% vs. n=10, 9.3%) or divorced or separated (n=16, 11.3% vs. n=5, 4.6%) than the women (p<0.001). The group who intentionally selected PQ (38.4%) consisted of 96 cases (54 males, 42 females) and the group who did not intentionally select PQ (61.6%) included 154 cases (89 males, 65 females). The incidence of PQ purchase was higher in the intentional selection PQ group (46.9% vs. 18.2%, p<0.01). CONCLUSIONS: Only 38% of patients who attempted suicide with PQ intentionally selected PQ. Thus, greater control of PQ availability is needed, especially in patients at risk.

Factors for determining survival in acute organophosphate poisoning.

BACKGROUND/AIMS: Organophosphate poisoning has a high mortality rate. Recently, differences among organophosphorus insecticides in human self-poisoning were reported. This study investigated the prognostic risk factors and the mortality of different organophosphates following acute organophosphate poisoning. METHODS: This retrospective study included 68 patients with acute organophosphate poisoning. We investigated patient survival according to initial parameters, including the initial Acute Physiology and Chronic Health Evaluation (APACHE) II score, serum cholinesterase level, and hemoperfusion and evaluated the mortality according to organophosphate types. RESULTS: Thirteen of the 68 patients died. The agents responsible for mortality were different. The APACHE II score was a significant predictor of mortality (odds ratio [OR], 1.194; p<0.01; 95% confidence interval [CI], 1.089 to 1.309) and respiratory failure (OR, 1.273; p<0.01; 95% CI, 1.122 to 1.444). The mortality was 0% for dichlorvos, malathion, chlorpyrifos and profenofos. However, other organophosphates showed different mortality (16.7% for O-ethyl-O-4-nitrophenyl phenylphosphonothioate, 25% for phenthoate, 37.5% for phosphamidon, 50% for methidathion). The usefulness of hemoperfusion appears to be limited. CONCLUSIONS: The initial APACHE II score is a useful prognostic indicator, and different organophosphates have different mortality.