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2.
N Engl J Med ; 382(8): 697-705, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31860793

RESUMO

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.).


Assuntos
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
3.
MMWR Morb Mortal Wkly Rep ; 68(45): 1040-1041, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31725707

RESUMO

CDC, the Food and Drug Administration (FDA), state and local health departments, and multiple public health and clinical partners are investigating a national outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI). Based on data collected as of October 15, 2019, 86% of 867 EVALI patients reported using tetrahydrocannabinol (THC)-containing products in the 3 months preceding symptom onset (1). Analyses of THC-containing product samples by FDA and state public health laboratories have identified potentially harmful constituents in these products, such as vitamin E acetate, medium chain triglyceride oil (MCT oil), and other lipids (2,3) (personal communication, D.T. Heitkemper, FDA Forensic Chemistry Center, November 2019). Vitamin E acetate, in particular, might be used as an additive in the production of e-cigarette, or vaping, products; it also can be used as a thickening agent in THC products (4). Inhalation of vitamin E acetate might impair lung function (5-7).


Assuntos
Líquido da Lavagem Broncoalveolar/química , Surtos de Doenças , Lesão Pulmonar/epidemiologia , Vaping/efeitos adversos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Adulto Jovem
4.
Enzyme Microb Technol ; 53(6-7): 373-7, 2013 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-24315639

RESUMO

Hydrogen peroxide (H2O2), produced in living cells by oxidases and by other biochemical reactions, plays an important role in cellular processes such as signaling and cell cycle progression. Nevertheless, H2O2 and other reactive oxygen species are capable of inducing damage to DNA and other cellular components, and oxidative stress caused by overproduction of cellular oxidants has been linked to pathologies such as inflammatory diseases and cancer. Therefore, new approaches for reducing the accumulation of cellular oxidants are of considerable interest from both a biotechnological and a therapeutic perspective. Recognizing that selenium is an essential component of the active sites of several antioxidant enzymes, we have developed a family of novel phenylaminoethyl selenide compounds that are readily taken up into cells and have low toxicity in vivo. We now report chemiluminescent imaging of hydrogen peroxide consumption by phenylaminoethyl selenides, via the use of peroxalate nanoparticle methodology. Further, we demonstrate the ability of phenylaminoethyl selenides to decrease lipopolysaccharide-induced oxidative stress in human embryonic kidney cells. We also report the successful encapsulation of a phenylaminoethyl selenide within poly(lactide-co-glycolide) nanoparticles, and we show that these selenide-loaded nanoparticles exhibit antioxidant activity in cells. Taken together, these results significantly enhance the attractiveness of phenylaminoethyl selenides as potential agents for supplementing cellular defenses against reactive oxygen species.


Assuntos
Antioxidantes/farmacologia , Compostos Organosselênicos/farmacologia , Antioxidantes/metabolismo , Biotecnologia , Etilaminas/farmacologia , Células HEK293 , Humanos , Peróxido de Hidrogênio/metabolismo , Lipopolissacarídeos/farmacologia , Luminescência , Nanopartículas/química , Nanotecnologia , Oxalatos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
5.
J Anal Toxicol ; 37(4): 195-202, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23508653

RESUMO

A sensitive and selective method was developed and validated to detect six volatile nitrosamines (N-nitrosodimethylamine, N-nitrosomethylethylamine, N-nitrosodiethylamine, N-nitrosopiperidine, N-nitrosopyrrolidine and N-nitrosomorpholine) in human urine. This method uses a liquid-liquid extraction cartridge followed by analysis with gas chromatography-tandem mass spectrometry (GC-MS-MS) and quantification based on isotopic dilution. This is the first GC-MS-MS method reported for measuring volatile nitrosamines in human urine. This method reduces the sample volume required in other methods from 5-25 to 2 mL. The limits of detection (2.62, 1.99, 2.73, 0.65, 0.25, 3.66 pg/mL, respectively) were better than existing methods, largely because of improved positive chemical ionization achieved by using ammonia gas and reducing background noise. Using nitrogen as the collision gas allowed the confirmation transition in the low mass region to be monitored. The analysis of human urine using this validated method is accurate (relative bias of 0-19%) and precise (relative standard deviation of 0.2-18% over two months of analyses). The validated method was applied to 100 urine samples and the levels of all six volatile nitrosamines were reported for the first time in urine specimens collected from smokers and nonsmokers, with smoking status determined by urinary cotinine measurement. Among 100 smokers and nonsmokers, the levels of three analytes (N-nitrosodimethylamine, N-nitrosomethylethylamine and N-nitrosopiperidine) were significantly higher in smokers than nonsmokers (p < 0.05).


Assuntos
Dietilnitrosamina/urina , Dimetilnitrosamina/urina , N-Nitrosopirrolidina/análise , Nitrosaminas/urina , Fumar/urina , Cotinina/urina , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Extração Líquido-Líquido , Reprodutibilidade dos Testes , Tabaco , Compostos Orgânicos Voláteis/urina
6.
Arch Biochem Biophys ; 515(1-2): 112-9, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21906582

RESUMO

Anthracyclines are potent anticancer agents, but cardiotoxicity mediated by free radical generation limits their clinical use. This study evaluated the anticancer activity of phenyl-2-aminoethyl selenide (PAESe) and its potential to reduce doxorubicin (DOX)-induced cardiotoxicity. Growth inhibitory effects of PAESe with DOX, and vincristine, clinically used anticancer agents, and tert-butylhydroperoxide (TBHP), a known oxidant, on the growth of human prostate carcinoma (PC-3) cells was determined. PAESe (≤1µm) did not alter the growth of PC-3 cells, however, concomitant use of PAESe decreased the oxidative-mediated cytotoxicity of TBHP, but had limited effect on vincristine or DOX activity. Further, PAESe decreased the formation of intracellular reactive oxygen species from TBHP and DOX. The effect of PAESe on the activity of DOX was determined using a tumor (PC-3) xenograft model in mice. PAESe did not alter DOX antitumor activity and showed evidence of direct antitumor activity relative to controls. DOX treatment decreased mice body weight significantly, whereas concomitant administration of PAESe and DOX was similar to controls. Most importantly, PAESe decreased DOX-mediated infiltration of neutrophil and macrophages into the myocardium. These data suggest PAESe had in vivo antitumor activity and in combination with DOX decreased early signs of cardiotoxicity while preserving its antitumor activity.


Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Coração/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular , Feminino , Humanos , Masculino , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Arch Biochem Biophys ; 506(2): 201-7, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21081105

RESUMO

Selenium has a long history of association with human health and disease, and a low concentration of selenium in plasma has been identified in epidemiological studies as a risk factor for several disorders associated with oxidative stress. This association suggests that organoselenium compounds capable of propagating a selenium redox cycle might supplement natural cellular defenses against oxidants, such as peroxynitrite and hydrogen peroxide. While several such organoselenium compounds are under active investigation as potential therapeutic agents, chemical characterization of reaction intermediates involved in their redox cycling has been problematical. We now report evidence that the reaction between phenylaminoalkyl selenoxides and glutathione (GSH) proceeds through the intermediacy of a thioselenurane species. The results of stopped-flow kinetic experiments were consistent with a rapid and stoichiometric initial reaction of GSH with selenoxide to generate a kinetically-detectable intermediate, followed by a slower reaction of this intermediate with a second molecule of GSH to produce the final selenide and GSSG products. Flow injection ESI-MS and ESI-MS/MS experiments confirmed that the reaction intermediate is indeed a thioselenurane. Final structural characterization of the thioselenurane intermediate was obtained from analysis of the daughter ions produced in flow injection ESI-MS/MS experiments. These results help to elucidate the chemical nature of the redox cycling of phenylaminoalkyl selenides, and represent, to our knowledge, the first evidence for the intermediacy of a thioselenurane species in the reaction of thiols with selenoxides.


Assuntos
Glutationa/metabolismo , Compostos Organosselênicos/metabolismo , Análise de Injeção de Fluxo , Dissulfeto de Glutationa/metabolismo , Humanos , Técnicas In Vitro , Cinética , Modelos Biológicos , Ressonância Magnética Nuclear Biomolecular , Compostos Organosselênicos/química , Oxirredução , Estresse Oxidativo , Selênio/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Compostos de Sulfidrila/metabolismo
8.
Anim Cogn ; 12(5): 671-8, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19462189

RESUMO

There has been considerable research into the ability of nonhuman primates to process sequential information, a topic that is of interest in part because of the extensive involvement of sequence processing in human language use. Surprisingly, no previous study has unambiguously tested the ability of nonhuman primates to encode and immediately reproduce a novel temporal sequence of perceptual events, the ability tapped in the immediate serial recall (ISR) task extensively studied in humans. We report here the performance of a rhesus macaque on a spatial ISR task, closely resembling tasks widely used in human memory research. Detailed analysis of the monkey's recall performance indicates a number of important parallels with human ISR, consistent with the idea that a single mechanism for short-term serial order memory may be shared across species.


Assuntos
Macaca/psicologia , Rememoração Mental , Percepção do Tempo , Animais , Masculino , Percepção Espacial
9.
Integr Physiol Behav Sci ; 39(4): 334-40, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-16295775

RESUMO

Research on consolidation of long-term memory suggests that acute immune system activation induced by endotoxin lipopolysaccharide (LPS) may disrupt consolidation of newly acquired learning. Adult male Sprague-Dawley rats were trained to perform a simple Y-maze task and were immediately afterwards administered LPS (15 microg/kg) or saline. After a seven-day interval, subjects were returned to the Y-maze and were retrained to criterion. It was found that subjects treated with saline required significantly fewer trials to relearn the task relative to the LPS group and a no-partial-learning control group, which themselves did not differ. These results are most readily explained in terms of a disruptive effect of acute immune system activation on consolidation of newly induced acquired memories.


Assuntos
Lipopolissacarídeos/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Animais , Alimentos , Masculino , Ratos , Ratos Sprague-Dawley
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