- Fimasartan-induced liver injury in a patient with no adverse reactions on other types of angiotensin II receptor blockers: A case report. [Case Reports]
- MMedicine (Baltimore) 2017; 96(47):e8905
- CONCLUSIONS: We emphasize that liver function should be monitored during fimasartan administration because fimasartan may cause hepatotoxicity in patients who have no side effects with other types of ARBs. And fimasartan-induced liver injury may appear later than other ARBs.
- Dinoflagellate cyst abundance is positively correlated to sediment organic carbon in Sydney Harbour and Botany Bay, NSW, Australia. [Journal Article]
- ESEnviron Sci Pollut Res Int 2017 Dec 12
- There is growing public concern about the global expansion of harmful algal bloom species (HABs), with dinoflagellate microalgae comprising the major portion of the harmful taxa. These motile, unicel...
There is growing public concern about the global expansion of harmful algal bloom species (HABs), with dinoflagellate microalgae comprising the major portion of the harmful taxa. These motile, unicellular organisms have a lifecycle involving sexual reproduction and resting cyst formation whereby cysts can germinate from sediments and 'seed' planktonic populations. Thus, investigation of dinoflagellate cyst (dinocyst) distribution in sediments can provide significant insights into HAB dynamics and contribute to indices of habitat quality. Species composition and abundance of dinocysts in relation to sediment characteristics were studied at 18 stations in two densely populated temperate Australian estuaries, Sydney Harbour (Parramatta River/Port Jackson; PS) and Botany Bay (including Georges River; GB). Eighteen dinocyst taxa were identified, dominated by Protoceratium reticulatum and Gonyaulax sp.1 in the PS estuary, together with Archaeperidinium minutum and Gonyaulax sp.1 in the GB estuary. Cysts of Alexandrium catenella, which is one of the causative species of paralytic shellfish poisoning (PSP), were also detected in both estuaries. Out of the measured sediment characteristics (TOC, Cd, Cr, Cu, Fe, Pb, Mn, Ni, Zn and polycyclic aromatic hydrocarbons), TOC was the parameter explaining most of the variation in dinocyst assemblages and was positively correlated to most of the heavy metals. Given the significant relationship between sediment TOC and dinocyst abundance and heavy metal concentrations, this study suggests that sediment TOC could be broadly used in risk management for potential development of algal blooms and sediment contamination in these estuaries.
- Highly Sensitive and High-Throughput Method for the Analysis of Bisphenol Analogues and Their Halogenated Derivatives in Breast Milk. [Journal Article]
- JAJ Agric Food Chem 2017 Dec 06; 65(48):10452-10463
- The structural analogs of bisphenol A (BPA) and their halogenated derivatives (together termed BPs) have been found in the environment, food, and even the human body. Limited research showed that som...
The structural analogs of bisphenol A (BPA) and their halogenated derivatives (together termed BPs) have been found in the environment, food, and even the human body. Limited research showed that some of them exhibited toxicities that were similar to or even greater than that of BPA. Therefore, adverse health effects for BPs were expected for humans with low-dose exposure in early life. Breast milk is an excellent matrix and could reflect fetuses' and babies' exposure to contaminants. Some of the emerging BPs may present with trace or ultratrace levels in humans. However, existing analytical methods for breast milk cannot quantify these BPs simultaneously with high sensitivity using a small sampling weight, which is important for human biomonitoring studies. In this paper, a method based on Bond Elut Enhanced Matrix Removal-Lipid purification, pyridine-3-sulfonyl chloride derivatization, and liquid chromatography electrospray tandem mass spectrometry was developed. The method requires only a small quantity of sample (200 μL) and allowed for the simultaneous determination of 24 BPs in breast milk with ultrahigh sensitivity. The limits of quantitation of the proposed method were 0.001-0.200 μg L-1, which were 1-6.7 times lower than the only study for the simultaneous analysis of bisphenol analogs in breast milk based on a 3 g sample weight. The mean recoveries ranged from 86.11% to 119.05% with relative standard deviation (RSD) ≤ 19.5% (n = 6). Matrix effects were within 20% with RSD < 10% for six different lots of samples. The proposed method was successfully applied to 20 breast milk samples. BPA, bisphenol F (BPF), bisphenol S (BPS), and bisphenol AF (BPAF) were detected. BPA was still the dominant BP, followed by BPF. This is the first report describing the occurrence of BPF and BPAF in breast milk.
- Identification and Characterization of Fenofibrate-Induced Liver Injury. [Multicenter Study]
- DDDig Dis Sci 2017; 62(12):3596-3604
- CONCLUSIONS: Liver injury after fenofibrate exposure occurs with variable latency, enzyme elevation, and histology. Although most cases are self-limited, severe injury and mortality can occur, particularly if drug withdrawal is delayed. Jaundice or abnormal laboratory tests during fenofibrate therapy should trigger prompt discontinuation.
- Deaths Involving Fentanyl, Fentanyl Analogs, and U-47700 - 10 States, July-December 2016. [Journal Article]
- MMMMWR Morb Mortal Wkly Rep 2017 Nov 03; 66(43):1197-1202
- Preliminary estimates of U.S. drug overdose deaths exceeded 60,000 in 2016 and were partially driven by a fivefold increase in overdose deaths involving synthetic opioids (excluding methadone), from ...
Preliminary estimates of U.S. drug overdose deaths exceeded 60,000 in 2016 and were partially driven by a fivefold increase in overdose deaths involving synthetic opioids (excluding methadone), from 3,105 in 2013 to approximately 20,000 in 2016 (1,2). Illicitly manufactured fentanyl, a synthetic opioid 50-100 times more potent than morphine, is primarily responsible for this rapid increase (3,4). In addition, fentanyl analogs such as acetylfentanyl, furanylfentanyl, and carfentanil are being detected increasingly in overdose deaths (5,6) and the illicit opioid drug supply (7). Carfentanil is estimated to be 10,000 times more potent than morphine (8). Estimates of the potency of acetylfentanyl and furanylfentanyl vary but suggest that they are less potent than fentanyl (9). Estimates of relative potency have some uncertainty because illicit fentanyl analog potency has not been evaluated in humans. This report describes opioid overdose deaths during July-December 2016 that tested positive for fentanyl, fentanyl analogs, or U-47700, an illicit synthetic opioid, in 10 states participating in CDC's Enhanced State Opioid Overdose Surveillance (ESOOS) program.* Fentanyl analogs are similar in chemical structure to fentanyl but not routinely detected because specialized toxicology testing is required. Fentanyl was detected in at least half of opioid overdose deaths in seven of 10 states, and 57% of fentanyl-involved deaths also tested positive for other illicit drugs, such as heroin. Fentanyl analogs were present in >10% of opioid overdose deaths in four states, with carfentanil, furanylfentanyl, and acetylfentanyl identified most frequently. Expanded surveillance for opioid overdoses, including testing for fentanyl and fentanyl analogs, assists in tracking the rapidly changing illicit opioid market and informing innovative interventions designed to reduce opioid overdose deaths.
- Role of histone acetylation in activation of nuclear factor erythroid 2-related factor 2/heme oxygenase 1 pathway by manganese chloride. [Journal Article]
- TAToxicol Appl Pharmacol 2017 Dec 01; 336:94-100
- Manganese neurotoxicity is characterized by Parkinson-like symptoms with degeneration of dopaminergic neurons in the basal ganglia as the principal pathological feature. Manganese neurotoxicity studi...
Manganese neurotoxicity is characterized by Parkinson-like symptoms with degeneration of dopaminergic neurons in the basal ganglia as the principal pathological feature. Manganese neurotoxicity studies may contribute to a good understanding of the mechanism of Parkinson's disease (PD). In this study, we first confirmed that MnCl2 can promote the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) protein in the nucleus or cytoplasm while increasing the binding activity of Nrf2 and antioxidant response elements, further promoting the expression of downstream target gene heme oxygenase 1 (HO-1) and leading to increase levels of reactive oxygen species (ROS) and reduce the levels of reduced glutathione (GSH). Second, we investigated the role of histone acetylation in the activation of Nrf2/HO-1 pathway by manganese chloride in rat adrenal pheochromocytoma (PC12) cells. Histone acetyltransferase inhibitor (anacardic acid) and histone deacetylase inhibitor (trichostatin A, TSA) were used as pretreatment reagents to adjust the level of histone acetylation. Here, we show that downregulation of histone acetylation can inhibit Mn-induced Nrf2 nuclear translocation and further inhibits the Mn-activated Nrf2/HO-1 pathway. This downregulation also promotes manganese-induced increase of ROS and decrease of GSH in neurons. These results suggest that the downregulation of histone acetylation may play an important role in the neurotoxicity caused by manganese and that TSA may provide new ideas and targets in treating manganese-induced Parkinson's syndrome and PD.
- Dual antioxidant structures with potent anti-inflammatory, hypolipidemic and cytoprotective properties. [Journal Article]
- BMBioorg Med Chem Lett 2017 Nov 01; 27(21):4800-4804
- Novel amide derivatives of trolox, 3,5-di-tert-butyl-4-hydroxybenzoic acid, (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid and cinnamic acid with cysteamine and l-cysteine ethyl ester were syn...
Novel amide derivatives of trolox, 3,5-di-tert-butyl-4-hydroxybenzoic acid, (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid and cinnamic acid with cysteamine and l-cysteine ethyl ester were synthesised. In four cases, the disulfide derivatives were also isolated and tested. All compounds were examined for antioxidant activity, expressed as their ability to inhibit lipid peroxidation and to scavenge free radicals. They were found to demonstrate up to 17-fold better activity than that of the parent antioxidant acids. They could reduce acute inflammation up to 87%. The most active antioxidant compounds were further tested for their in vivo hypolipidemic effect, which ranged from 47% to 73%, and for their ability to protect the liver against oxidative toxicity caused by high paracetamol dose. The disulfide derivatives of 3,5-di-tert-butyl-4-hydroxybenzoic acid and cinnamic acid had no antioxidant activity and presented equal or lower anti-inflammatory effect than their thiol analogues, indicating that their molecular characteristics may not permit biological barrier penetration.
- Determination of Propofol by GC/MS and Fast GC/MS-TOF in Two Cases of Poisoning. [Case Reports]
- JAJ Anal Toxicol 2017 Nov 01; 41(9):771-776
- Two cases of suspected acute and lethal intoxication caused by propofol were delivered by the judicial authority to the Department of Sciences for Health Promotion and Mother-Child Care in Palermo, S...
Two cases of suspected acute and lethal intoxication caused by propofol were delivered by the judicial authority to the Department of Sciences for Health Promotion and Mother-Child Care in Palermo, Sicily. In the first case a female nurse was found in a hotel room, where she lived with her mother; four 10 mg/mL vials and two 20 mg/mL vials of propofol were found near the decedent along with syringes and needles. In the second case a male nurse was found in the operating room of a hospital, along with a used syringe. In both cases a preliminary systematic and toxicological analysis indicated the presence of propofol in the blood and urine. As a result, a method for the quantitative determination of propofol in biological fluids was optimized and validated using a liquid-liquid extraction protocol followed by GC/MS and fast GC/MS-TOF. In the first case, the concentration of propofol in blood was determined to be 8.1 μg/mL while the concentration of propofol in the second case was calculated at 1.2 μg/mL. Additionally, the tissue distribution of propofol was determined for both cases. Brain and liver concentrations of propofol were, respectively, 31.1 and 52.2 μg/g in Case 1 and 4.7 and 49.1 μg/g in Case 2. Data emerging from the autopsy findings, histopathological exams as well as the toxicological results aided in establishing that the deaths were due to poisoning, however, the manner of death in each were different: homicide in Case 1 and suicide in Case 2.
- Sensory axonal polyneuropathy due to 2,4-dinitrophenol. [Case Reports]
- RSRinsho Shinkeigaku 2017 10 27; 57(10):599-602
- A 24-year-old man developed subacute onset of numbness and pain in the upper and lower limbs. Physical examination demonstrated decreased pinprick sensation, but was otherwise normal. Blood and cereb...
A 24-year-old man developed subacute onset of numbness and pain in the upper and lower limbs. Physical examination demonstrated decreased pinprick sensation, but was otherwise normal. Blood and cerebrospinal fluid parameters were normal except for mild hepatic dysfunction. No data were suggestive of connective tissue disease. Nerve conduction studies demonstrated sensory neuropathy. A detailed medical interview revealed that the patient had been taking self-imported 2,4-dinitrophenol (DNP) for 2 months to decrease body weight. Six months after discontinuing DNP, subjective symptoms and liver dysfunction resolved completely, and the patient was diagnosed with drug-induced peripheral neuropathy and hepatopathy. There are no case reports of health risks posed by DNP in Japan, and even worldwide, cases of peripheral neuropathy due to DNP are rare. Obtaining a detailed drug history is important, as is providing information on the dangers of self-imported medicines.
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- HLA-DR7 and HLA-DQ2: Transgenic mouse strains tested as a model system for ximelagatran hepatotoxicity. [Journal Article]
- PlosPLoS One 2017; 12(9):e0184744
- The oral thrombin inhibitor ximelagatran was withdrawn in the late clinical trial phase because it adversely affected the liver. In approximately 8% of treated patients, drug-induced liver injury (DI...
The oral thrombin inhibitor ximelagatran was withdrawn in the late clinical trial phase because it adversely affected the liver. In approximately 8% of treated patients, drug-induced liver injury (DILI) was expressed as transient alanine transaminase (ALT) elevations. No evidence of DILI had been revealed in the pre-clinical in vivo studies. A whole genome scan study performed on the clinical study material identified a strong genetic association between the major histocompatibility complex alleles for human leucocyte antigens (HLA) (HLA-DR7 and HLA-DQ2) and elevated ALT levels in treated patients. An immune-mediated pathogenesis was suggested. Here, we evaluated whether HLA transgenic mice models could be used to investigate whether the expression of relevant HLA molecules was enough to reproduce the DILI effects in humans. In silico modelling performed in this study revealed association of both ximelagatran (pro-drug) and melagatran (active drug) to the antigen-presenting groove of the homology modelled HLA-DR7 molecule suggesting "altered repertoire" as a key initiating event driving development of DILI in humans. Transgenic mouse strains (tgms) expressing HLA of serotype HLA-DR7 (HLA-DRB1*0701, -DRA*0102), and HLA-DQ2 (HLA-DQB1*0202,-DQA1*0201) were created. These two lines were crossed with a human (h)CD4 transgenic line, generating the two tgms DR7xhCD4 and DQ2xhCD4. To investigate whether the DILI effects observed in humans could be reproduced in tgms, the mice were treated for 28 days with ximelagatran. Results revealed no signs of DILI when biomarkers for liver toxicity were measured and histopathology was evaluated. In the ximelagatran case, presence of relevant HLA-expression in a pre-clinical model did not fulfil the prerequisite for reproducing DILI observed in patients. Nonetheless, for the first time an HLA-transgenic mouse model has been investigated for use in HLA-associated DILI induced by a low molecular weight compound. This study shows that mimicking of genetic susceptibility, expressed as DILI-associated HLA-types in mice, is not sufficient for reproducing the complex pathogenesis leading to DILI in man.