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N Engl J Med ; 382(8): 697-705, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31860793


BACKGROUND: The causative agents for the current national outbreak of electronic-cigarette, or vaping, product use-associated lung injury (EVALI) have not been established. Detection of toxicants in bronchoalveolar-lavage (BAL) fluid from patients with EVALI can provide direct information on exposure within the lung. METHODS: BAL fluids were collected from 51 patients with EVALI in 16 states and from 99 healthy participants who were part of an ongoing study of smoking involving nonsmokers, exclusive users of e-cigarettes or vaping products, and exclusive cigarette smokers that was initiated in 2015. Using the BAL fluid, we performed isotope dilution mass spectrometry to measure several priority toxicants: vitamin E acetate, plant oils, medium-chain triglyceride oil, coconut oil, petroleum distillates, and diluent terpenes. RESULTS: State and local health departments assigned EVALI case status as confirmed for 25 patients and as probable for 26 patients. Vitamin E acetate was identified in BAL fluid obtained from 48 of 51 case patients (94%) in 16 states but not in such fluid obtained from the healthy comparator group. No other priority toxicants were found in BAL fluid from the case patients or the comparator group, except for coconut oil and limonene, which were found in 1 patient each. Among the case patients for whom laboratory or epidemiologic data were available, 47 of 50 (94%) had detectable tetrahydrocannabinol (THC) or its metabolites in BAL fluid or had reported vaping THC products in the 90 days before the onset of illness. Nicotine or its metabolites were detected in 30 of 47 of the case patients (64%). CONCLUSIONS: Vitamin E acetate was associated with EVALI in a convenience sample of 51 patients in 16 states across the United States. (Funded by the National Cancer Institute and others.).

Lesão Pulmonar Aguda/patologia , Líquido da Lavagem Broncoalveolar/química , Sistemas Eletrônicos de Liberação de Nicotina , Vaping/efeitos adversos , Vitamina E/análise , Lesão Pulmonar Aguda/etiologia , Adolescente , Adulto , Idoso , Fumar Cigarros , Óleo de Coco/análise , Feminino , Humanos , Limoneno/análise , Masculino , Pessoa de Meia-Idade , Estados Unidos , Adulto Jovem
Clin Chim Acta ; 485: 1-6, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29894782


BACKGROUND: Comprehensive information on the effect of time and temperature storage on the measurement of elements in human, whole blood (WB) by inductively coupled plasma-dynamic reaction cell-mass spectrometry (ICP-DRC-MS) is lacking, particularly for Mn and Se. METHODS: Human WB was spiked at 3 concentration levels, dispensed, and then stored at 5 different temperatures: -70 °C, -20 °C, 4 °C, 23 °C, and 37 °C. At 3 and 5 weeks, and at 2, 4, 6, 8, 10, 12, 36 months, samples were analyzed for Pb, Cd, Mn, Se and total Hg, using ICP-DRC-MS. We used a multiple linear regression model including time and temperature as covariates to fit the data with the measurement value as the outcome. We used an equivalence test using ratios to determine if results from the test storage conditions, warmer temperature and longer time, were comparable to the reference storage condition of 3 weeks storage time at -70 °C. RESULTS: Model estimates for all elements in human WB samples stored in polypropylene cryovials at -70 °C were equivalent to estimates from samples stored at 37 °C for up to 2 months, 23 °C up to 10 months, and -20 °C and 4 °C for up to 36 months. Model estimates for samples stored for 3 weeks at -70 °C were equivalent to estimates from samples stored for 2 months at -20 °C, 4 °C, 23 °C and 37 °C; 10 months at -20 °C, 4 °C, and 23 °C; and 36 months at -20 °C and 4 °C. This equivalence was true for all elements and pools except for the low concentration blood pool for Cd. CONCLUSIONS: Storage temperatures of -20 °C and 4 °C are equivalent to -70 °C for stability of Cd, Mn, Pb, Se, and Hg in human whole blood for at least 36 months when blood is stored in sealed polypropylene vials. Increasing the sample storage temperature from -70 °C to -20 °C or 4 °C can lead to large energy savings. The best analytical results are obtained when storage time at higher temperature conditions (e.g. 23 °C and 37 °C) is minimized because recovery of Se and Hg is reduced. Blood samples stored in polypropylene cryovials also lose volume over time and develop clots at higher temperature conditions (e.g., 23 °C and 37 °C), making them unacceptable for elemental testing after 10 months and 2 months, respectively.

Cádmio/sangue , Chumbo/sangue , Magnésio/sangue , Mercúrio/sangue , Selênio/sangue , Temperatura , Humanos , Espectrometria de Massas , Fatores de Tempo
Talanta ; 162: 114-122, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27837806


We improved our inductively coupled plasma mass spectrometry (ICP-MS) whole blood method [1] for determination of lead (Pb), cadmium (Cd), and mercury (Hg) by including manganese (Mn) and selenium (Se), and expanding the calibration range of all analytes. The method is validated on a PerkinElmer (PE) ELAN® DRC II ICP-MS (ICP-DRC-MS) and uses the Dynamic Reaction Cell (DRC) technology to attenuate interfering background ion signals via ion-molecule reactions. Methane gas (CH4) eliminates background signal from 40Ar2+ to permit determination of 80Se+, and oxygen gas (O2) eliminates several polyatomic interferences (e.g. 40Ar15N+, 54Fe1H+) on 55Mn+. Hg sensitivity in DRC mode is a factor of two higher than vented mode when measured under the same DRC conditions as Mn due to collisional focusing of the ion beam. To compensate for the expanded method's longer analysis time (due to DRC mode pause delays), we implemented an SC4-FAST autosampler (ESI Scientific, Omaha, NE), which vacuum loads the sample onto a loop, to keep the sample-to-sample measurement time to less than 5min, allowing for preparation and analysis of 60 samples in an 8-h work shift. The longer analysis time also resulted in faster breakdown of the hydrocarbon oil in the interface roughing pump. The replacement of the standard roughing pump with a pump using a fluorinated lubricant, Fomblin®, extended the time between pump maintenance. We optimized the diluent and rinse solution components to reduce carryover from high concentration samples and prevent the formation of precipitates. We performed a robust calculation to determine the following limits of detection (LOD) in whole blood: 0.07µgdL-1 for Pb, 0.10µgL-1 for Cd, 0.28µgL-1 for Hg, 0.99µgL-1 for Mn, and 24.5µgL-1 for Se.

Exposição Dietética/análise , Monitoramento Ambiental/métodos , Exposição por Inalação/análise , Espectrometria de Massas/métodos , Oligoelementos/sangue , Cádmio/sangue , Calibragem , Monitoramento Ambiental/instrumentação , Humanos , Chumbo/sangue , Manganês/sangue , Mercúrio/sangue , Controle de Qualidade , Padrões de Referência , Reprodutibilidade dos Testes , Selênio/sangue , Oligoelementos/normas
Nucleic Acids Res ; 39(10): 4265-74, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21266485


Heterocyclic diamidines are compounds with antiparasitic properties that target the minor groove of kinetoplast DNA. The mechanism of action of these compounds is unknown, but topological changes to DNA structures are likely to be involved. In this study, we have developed a polyacrylamide gel electrophoresis-based screening method to determine topological effects of heterocyclic diamidines on four minor groove target sequences: AAAAA, TTTAA, AAATT and ATATA. The AAAAA and AAATT sequences have the largest intrinsic bend, whereas the TTTAA and ATATA sequences are relatively straight. The changes caused by binding of the compounds are sequence dependent, but generally the topological effects on AAAAA and AAATT are similar as are the effects on TTTAA and ATATA. A total of 13 compounds with a variety of structural differences were evaluated for topological changes to DNA. All compounds decrease the mobility of the ATATA sequence that is consistent with decreased minor groove width and bending of the relatively straight DNA into the minor groove. Similar, but generally smaller, effects are seen with TTTAA. The intrinsically bent AAAAA and AAATT sequences, which have more narrow minor grooves, have smaller mobility changes on binding that are consistent with increased or decreased bending depending on compound structure.

Amidinas/química , Antiparasitários/química , DNA/química , Sequência de Bases , Eletroforese em Gel de Poliacrilamida , Compostos Heterocíclicos/química , Conformação de Ácido Nucleico , Ressonância de Plasmônio de Superfície
Nucleic Acids Res ; 37(16): 5550-8, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19578063


To determine what topological changes antiparasitic heterocyclic dications can have on kinetoplast DNA, we have constructed ligation ladders, with phased A5 and ATATA sequences in the same flanking sequence context, as models. Bending by the A5 tract is observed, as expected, while the ATATA sequence bends DNA very little. Complexes of these DNAs with three diamidines containing either furan, thiophene or selenophene groups flanked by phenylamidines were investigated along with netropsin. With the bent A5 ladder the compounds caused either a slight increase or decrease in the bending angle. Surprisingly, however, with ATATA all of the compounds caused significant bending, to values close to or even greater than the A5 bend angle. Results with a mixed cis sequence, which has one A5 and one ATATA, show that the compounds bend ATATA in the same direction as a reference A5 tract, that is, into the minor groove. These results are interpreted in terms of a groove structure for A5 which is largely pre-organized for a fit to the heterocyclic amidines. With ATATA the groove is intrinsically wider and must close to bind the compounds tightly. The conformational change at the binding site then leads to significant bending of the alternating DNA sequence.

Amidinas/química , Antiparasitários/química , DNA de Cinetoplasto/química , Amidinas/farmacologia , Antiparasitários/farmacologia , Sequência de Bases , Benzamidinas/química , Benzamidinas/farmacologia , DNA de Cinetoplasto/efeitos dos fármacos , Eletroforese em Gel de Poliacrilamida , Netropsina/química , Netropsina/farmacologia , Conformação de Ácido Nucleico/efeitos dos fármacos , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Tiofenos/química , Tiofenos/farmacologia
Biochimie ; 90(7): 999-1014, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18343228


Designed, synthetic heterocyclic diamidines have excellent activity against eukaryotic parasites that cause diseases such as sleeping sickness and leishmania and adversely affect millions of people each year. The most active compounds bind specifically and strongly in the DNA minor groove at AT sequences. The compounds enter parasite cells rapidly and appear first in the kinetoplast that contains the mitochondrial DNA of the parasite. With time the compounds are also generally seen in the cell nucleus but are not significantly observed in the cytoplasm. The kinetoplast decays over time and disappears from the mitochondria of treated cells. At this point the compounds begin to be observed in other regions of the cell, such as the acidocalcisomes. The cells typically die in 24-48h after treatment. Active compounds appear to selectively target extended AT sequences and induce changes in kinetoplast DNA minicircles that cause a synergistic destruction of the catenated kinetoplast DNA network and cell death.

Antiparasitários/química , DNA de Protozoário/química , Sistemas de Liberação de Medicamentos , Eucariotos/efeitos dos fármacos , Pentamidina/química , Animais , Antiparasitários/farmacologia , DNA de Protozoário/efeitos dos fármacos , Compostos Heterocíclicos/química , Humanos , Modelos Moleculares , Conformação de Ácido Nucleico/efeitos dos fármacos , Pentamidina/análogos & derivados , Pentamidina/farmacologia