Samel Park

The effects of nonyl phenoxypolyethoxyl ethanol on cell damage pathway gene expression in SK-NSH cells

Background/Aims: Most pesticide formulations contain both chief and additive ingredients. But, the additives may not have been tested as thoroughly as the chief ingredients. The surfactant, nonyl phenoxypolyethoxylethanol (NP40), is an additive frequently present in pesticide formulations. We investigated the effects of NP40 and other constituents of a validamycin pesticide formulation on cell viability and on the expression of genes involved in cell damage pathways. Methods: The effects of validamycin pesticide ingredients on cell viability and of NP40 on the mRNA expression of 80 genes involved in nine key cellular pathways were examined in the human neuroblastoma SK-N-SH cell line. Results: The chemicals present in the validamycin pesticide formulation were cytotoxic to SK-N-SH cells and NP40 showed the greatest cytotoxicity. A range of gene expression changes were identified, with both up- and down-regulation of genes within the same pathway. However, all genes tested in the necrosis signaling pathway were down-regulated and all genes tested in the cell cycle checkpoint/arrest pathway were up-regulated. The median fold-change in gene expression was significantly higher in the cell cycle checkpoint/arrest pathway than in the hypoxia pathway category (p = 0.0064). The 70 kDa heat shock protein 4 gene, within the heat shock protein/unfolded protein response category, showed the highest individual increase in expression (26.1-fold). Conclusions: NP40 appeared to be particularly harmful, inducing gene expression changes that indicated genotoxicity, activation of the cell death (necrosis signaling) pathway, and induction of the 70 kDa heat shock protein 4 gene.

The Anion Gap is a Predictive Clinical Marker for Death in Patients with Acute Pesticide Intoxication

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.

Concurrent Hemoperfusion and Hemodialysis in Patients with Acute Pesticide Intoxication

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.

Association of proton pump inhibitor use with renal outcomes in patients with coronary artery disease

Background Several studies have suggested that proton pump inhibitor (PPI) use is associated with adverse renal outcomes, but obvious evidence for this association is lacking. We investigated the association between PPI use and adverse renal outcomes in patients who had undergone percutaneous coronary intervention. Methods Of the 1,284 patients hospitalized for percutaneous coronary intervention between January 2007 and May 2012, 934 patients with baseline estimated glomerular filtration rate greater than 60 mL/min/1.73 m2 were enrolled. Multivariable Cox models were used to examine whether PPI use was associated with acute and chronic adverse renal outcomes. Results In adjusted time-dependent Cox models, PPI use was associated with acute kidney injury (hazard ratio [HR], 1.46; 95% confidence interval [95% CI], 1.05–2.02), especially in patients aged 65 years or younger (HR, 2.08; 95% CI, 1.09 3.96) or in patients with diabetes (HR, 2.00; 95% CI, 1.23–3.25). In multivariable Cox models, the association between duration of PPI use and chronic kidney disease development was not statistically significant (HR of heavy users, 1.50; 95% CI, 0.61–3.67), but a longer duration of PPI use was associated with mild renal progression in patients younger than 65 years (HR of heavy users, 2.24; 95% CI, 1.09–4.60). Conclusion Our results suggest that PPI use increases the risk of AKI development, and that PPI use is more significantly associated with acute and chronic renal injuries in younger patients.

Adefovir-induced Fanconi syndrome associated with osteomalacia

Fanconi syndrome is a dysfunction of the proximal renal tubules that results in impaired reabsorption and increased urinary loss of phosphate and other solutes. The pathophysiology of drug-induced Fanconi syndrome is unclear. Here we report the case of a 36-year-old woman who presented with pain in multiple bones and proteinuria. She had a 7-year history of taking adefovir at 10 mg/day for chronic hepatitis B. Three years previously she had received surgery for a nontraumatic right femur neck fracture, after which she continued to complain of pain in multiple bones, and proteinuria, glycosuria, and phosphaturia were noted. The findings of a light-microscope examination of a renal biopsy sample were normal, but mitochondrial damage of the proximal tubules was evident in electron microscopy. Western blot analysis revealed that the level of serum fibroblast growth factor 23 (FGF23) was lower than in normal controls. After 2 months of treatment, hypophosphatemia and proximal tubular dysfunction were reversed, and serum FGF23 had normalized. This case suggests that direct mitochondrial damage in proximal tubules can cause drug-induced Fanconi syndrome associated with osteomalacia.

Serum S100 protein could predict altered consciousness in glyphosate or glufosinate poisoning patients

Abstract Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Clinical characteristics of stress cardiomyopathy in patients with acute poisoning

Patients who attempt intentional suicide suffer from physical or emotional stress. This situation might be an important factor that causes takotsubo cardiomyopathy. We retrospectively investigated the clinical features of Takotsubo cardiomyopathy in patients with acute poisoning. This study included patients who were admitted from January 2010 to December 2015 because of intentional poisoning by ingestion. Among these patients, we selectively collected data of patients who underwent an echocardiogram. We divided the patients into three groups according to the echocardiogram; the non-cardiomyopathy group, the global hypokinesia group, and the takotsubo cardiomyopathy group. One hundred forty-seven patients were analyzed in this study. One hundred thirty-one patients had normal cardiac function without regional wall motion abnormality. Global hypokinesia was observed in five patients. The overall incidence of takotsubo cardiomyopathy was 7.5% (11/147). Levels of cardiac enzymes including CK-MB, Troponin T, a marker of cardiac muscle ischemia, were higher in the global hypokinesia group and the takotsubo cardiomyopathy group compared with the non-cardiomyopathy group. The most commonly consumed poison was organophosphate in the takotsubo cardiomyopathy group. In conclusion, takotsubo cardiomyopathy may be one of the cardiac complications in patients who attempt suicide by consuming a poison.

Soluble klotho as a marker of renal fibrosis and podocyte injuries in human kidneys

Klotho deficiency is relevant to renal fibrosis and podocyte injury in vivo and in vitro. We examined whether histological findings of renal biopsy specimens were associated with the levels of soluble klotho in humans. We investigated renal biopsy specimens of 67 patients and detailed microscopic findings were reviewed. Soluble serum/urinary klotho and urinary angiotensinogen were assessed by enzyme-linked immunosorbent assays, and tissue klotho expression was assessed by immunohistochemical staining. The median age of the study participants was 35.6 years. High serum klotho levels (≥14 pg/mL) were associated with decreased odds ratios (ORs) of interstitial fibrosis (OR = 0.019, P = 0.003) and segmental sclerosis (OR = 0.190, P = 0.022) in multivariable logistic regression analysis. Patients with a lower urinary klotho-to-creatinine ratio (UKCR) were significantly more likely to have diffuse foot process effacement (OR = 0.450, P = 0.010). The area under the receiver-operating characteristic curve (AUC) of serum klotho for predicting interstitial fibrosis was 0.920 (95% CI, 0.844–0.996), and the best cut-off value of serum klotho was 138.1 pg/mL. The AUC of UKCR for predicting diffuse foot process effacement was 0.754 (95% CI, 0.636–0.872), and the best cut-off value of UKCR was 96.7 pg/mgCr. Urinary angiotensinogen-to-creatinine ratio was not associated with serum klotho, UKCR, or any pathological finding. Our data suggested that soluble serum and urinary klotho levels represent a potential biomarker to predict renal fibrosis and podocyte injury in humans.

Human cholestatic hepatitis owing to polyoxyethylene nonylphenol ingestion: A case report

Rationale: The purpose of this study was to identify the chemical responsible for cholestatic hepatitis in a 55-year-old woman who ingested 1,1′-iminodi (octamethylene) diguanidinium triacetate (iminoctadine triacetate), a fungicide. The fungicide formulation was also composed of polyoxyethylene nonylphenol (NP-40) and methanol. Patient concerns: Severe cholestatic hepatitis developed, which led to the patients death on day 88 of hospitalization. Post-mortem necropsy of the liver showed focal hepatocyte necrosis involving mostly the mid-zone, along with intracytoplasmic and intracanalicular cholestasis. Diagnoses: To identify the chemical responsible for hepatic injury, the cellular toxicity of all chemicals in the fungicide formulation was assessed in HepG2 cells using the 3-(4,5-dimethylthiaxol-2yl)-2, 5-diphenyl tetrazolium bromide test. Outcomes: Viability of cells treated with the surfactant NP-40 was significantly lower (P < .001), but that of cells treated with other components of the fungicide, including the active ingredient, iminoctadine triacetate, was unaffected. Fluorescence-activated cell sorting analysis confirmed that necrosis was induced in HepG2 cells treated with 25–80 &mgr;M of NP-40, while significant numbers of apoptotic cells were not detected. Lessons: NP-40 appears to be the chemical responsible for the patients irreversible hepatic injury, accompanied by intracytoplasmic and intracanalicular cholestasis.

Urine Methyl Hippuric Acid Levels in Acute Pesticide Poisoning: Estimation of Ingested Xylene Volume and Association with Clinical Outcome Parameters

To determine the relationship between the oral ingestion volume of xylene and methyl hippuric acid (MHA) in urine, we measured MHA in 11 patients whose ingested xylene volume was identified. The best-fit equation between urine MHA and ingested amount of xylene was as follows: y (ingested amount of xylene, mL/kg) = −0.052x2 + 0.756x (x = MHA in urine in g/g creatinine). From this equation, we estimated the ingested xylene volume in 194 patients who had ingested pesticide of which the formulation was not available. Our results demonstrated that oxadiazole, dinitroaniline, chloroacetamide, organophosphate, and pyrethroid were xylene-containing pesticide classes, while the paraquat, glyphosate, glufosinate, synthetic auxin, fungicide, neonicotinoid, and carbamate classes were xylene-free pesticides. Sub-group univariate analysis showed a significant association between MHA levels in urine and ventilator necessity in the pyrethroid group. However, this association was not observed in the organophosphate group. Our results suggest that MHA in urine is a surrogate marker for xylene ingestion, and high urine MHA levels may be a risk factor for poor clinical outcome with some pesticide poisoning.