Brodifacoum induces early hemoglobinuria and late hematuria in rats: novel rapid biomarkers of poisoning.

INTRODUCTION: Brodifacoum (BDF) is a superwarfarin that is used primarily as a rodenticide. There have been increasing numbers of reports of human cases of accidental or intentional BDF ingestion with high mortality rate. Its broad availability and high lethality suggest that BDF should be considered a potential chemical threat. Currently, there is no biomarker for early detection of BDF ingestion in humans; patients typically present with severe coagulopathy. Since we demonstrated earlier that warfarin can induce acute kidney injury with hematuria, we tested whether BDF would also lead to change in urinary biomarkers. MATERIAL AND METHODS: BDF was administered to Sprague Dawley rats via oral gavage. N-acetylcysteine (NAC) was given per os in drinking water 24 h prior to BDF. Urinalysis was performed at different times after BDF administration. Anticoagulation and serum creatinine levels were analyzed in the blood. RESULTS: We observed that within a few hours the animals developed BDF-dose-dependent transient hemoglobinuria, which ceased within 24 h. This was accompanied by a transient decrease in hematocrit, gross hemolysis and an increase in free hemoglobin in the serum. At later times, animals developed true hematuria with red blood cells in the urine, which was associated with BDF anticoagulation. NAC prevented early hemoglobinuria, but not late hematuria associated with BDF. CONCLUSIONS: We propose that transient early hemoglobinuria (associated with oxidative stress) with consecutive late hematuria (associated with anticoagulation) are novel biomarkers of BDF poisoning, and they can be used in clinical setting or in mass casualty with BDF to identify poisoned patients.

An obesity paradox: an inverse correlation between body mass index and atherosclerosis of the aorta.

BACKGROUND AND AIMS: Morbid obesity generally has been associated with higher morbidity and mortality for a variety of diseases. However, a number of exceptions to this have been reported and referred to as the "obesity paradox." The purpose of the present study was to obtain objective data on aortic atherosclerosis and its relationship to body mass index (BMI, kg/m2), based on autopsy findings in a large cohort of overweight and obese decedents. METHODS: Decedents were ≥18 years who had autopsies between 2003 and 2014, a subset of whom were morbidly obese (BMI≥40). Autopsy findings were reviewed and compared to a control group (BMI<40) who had consecutive autopsies performed between January 2013 and June 2014. Atherosclerosis was assessed by gross pathologic examination using a semiquantitative grading scale (from 0 to 3), and for statistical analysis, the scores were stratified into two groups: nonsevere (<2) or severe (≥2). RESULTS: There were 304 decedents in the study: 66 were morbidly obese (BMI≥40), 94 were either Class I or II obese (BMI 30-40), 127 were either overweight (BMI 25.0-29.9) or normal weight (BMI 20-24.9), and 17 were underweight (BMI<20). Decedents with mild atherosclerosis were significantly younger than those with severe disease (55.2 vs. 67.3, P<.0001). Decedents were further stratified by age and BMI. Univariate analysis revealed that decedents >60 years were more likely to have severe atherosclerosis than those ≤60 years (61% vs. 30%, P<.0001). There was a highly significant (P=.008) inverse relationship between severe aortic atherosclerosis and BMI. Twenty of 66 decedents (30%) with a BMI≥40 had severe atherosclerosis vs. 122 of 238 decedents (51%) with BMIs<40 (P=.001). As BMI increased, the probability of developing severe disease decreased. Hypertension increased the probability of having severe atherosclerosis (54% vs. 33%, P=.007). After adjusting for other covariates, multivariable analysis revealed that age and hypertension were still positively correlated with the severity of atherosclerosis (P=.014 and 0.028, respectively), and the inverse relationship between BMI and atherosclerosis remained (adjusted relative risk of BMI≥40 vs. <40=0.64, 95% confidence interval: 0.4-1; P=.03). CONCLUSIONS: Our data extend the previously described obesity paradox to another disease entity, atherosclerosis of the aorta. Morbid obesity appeared to have a protective effect for developing severe aortic atherosclerosis, for the reasons for which are yet to be determined. However, the mean age at death of decedents with BMIs≥40 was younger than those with BMIs in the 20-30 range (55.9 vs. 63.2 years, P=.001), confirming that morbid obesity was not associated with increased longevity.

Morphometric data on severely and morbidly obese deceased, established on forensic and non-forensic autopsies.

With the widespread increase in the incidence of obesity, autopsies on severely and morbidly obese deceased have become common in the USA. Standard reference tables for organ weights provide little or no information on individuals with a body mass index greater than 35 kg/m(2). Although several recent reports have provided organ weights for small numbers of morbidly obese persons who died naturally from a variety of causes, these data may have been affected by comorbidities. Furthermore, they did not provide information relative to differences in organ weight based on gender, age, and race. The aim of the present study was to fill this void by developing reference tables for organ weights of severely and morbidly obese individuals. Our study was based on data from 802 forensic and medical autopsies, including 435 cases of death of natural and 367 of non-natural causes. Organ weights were compared between these groups, and reference ranges were generated. Significant variability was found in organ weights especially among deceased older than 40 years who died naturally, suggesting that comorbidities affect organ weight. Reference tables were compiled for organ weights and morphometric data based on gender, age, and race. Since obesity is a pathological condition affecting organ weight, these reference tables do not reflect normal organ weights but only weight as seen in severely and morbidly obese individuals. They should be useful to pathologists who perform forensic and non-forensic autopsies.

Oral warfarin and the thrombin inhibitor dabigatran increase blood pressure in rats: hidden danger of anticoagulants?

BACKGROUND: Hypertension is a common comorbidity in patients with chronic kidney disease (CKD). We reported earlier that oral anticoagulants, including warfarin and dabigatran, may induce acute kidney injury. No effects of oral anticoagulants on blood pressure (BP) have been previously reported. The aim of this study was to examine in detail the relationship of anticoagulant therapy and BP in rats. METHODS: Sham-operated and 5/6 nephrectomy rats were treated with different doses of oral anticoagulants (warfarin and dabigatran), superoxide scavenger N-acetylcysteine (NAC), vitamin K, and protease activated receptor 1 (PAR-1) inhibitor SCH79797. BP was measured by a tail cuff daily. RESULTS: Warfarin and dabigatran both increased systolic BP in sham-operated and 5/6 nephrectomy rats in a dose-dependent manner. SCH79797 also increased systolic BP in a dose-dependent manner. Vitamin K prevented warfarin-induced increase in BP but did not affect BP when administered alone. NAC delayed the warfarin-associated increase in BP. Warfarin effects on BP were similar in 5/6 nephrectomy rats with different CKD stages. CONCLUSIONS: Both warfarin and dabigatran increase systolic BP in rats. The mechanism of this effect is not clear, but our data suggest that it is related to decreased thrombin activity associated with anticoagulant treatment. The superoxide scavenger NAC delayed, but did not prevent, warfarin-induced hypertension.