Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26
Filtrar
1.
Nature ; 600(7889): 456-461, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34912090

RESUMO

Commercial chemicals are used extensively across urban centres worldwide1, posing a potential exposure risk to 4.2 billion people2. Harmful chemicals are often assessed on the basis of their environmental persistence, accumulation in biological organisms and toxic properties, under international and national initiatives such as the Stockholm Convention3. However, existing regulatory frameworks rely largely upon knowledge of the properties of the parent chemicals, with minimal consideration given to the products of their transformation in the atmosphere. This is mainly due to a dearth of experimental data, as identifying transformation products in complex mixtures of airborne chemicals is an immense analytical challenge4. Here we develop a new framework-combining laboratory and field experiments, advanced techniques for screening suspect chemicals, and in silico modelling-to assess the risks of airborne chemicals, while accounting for atmospheric chemical reactions. By applying this framework to organophosphate flame retardants, as representative chemicals of emerging concern5, we find that their transformation products are globally distributed across 18 megacities, representing a previously unrecognized exposure risk for the world's urban populations. More importantly, individual transformation products can be more toxic and up to an order-of-magnitude more persistent than the parent chemicals, such that the overall risks associated with the mixture of transformation products are also higher than those of the parent flame retardants. Together our results highlight the need to consider atmospheric transformations when assessing the risks of commercial chemicals.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Atmosfera/química , Monitoramento Ambiental , Retardadores de Chama/efeitos adversos , Substâncias Perigosas/análise , Internacionalidade , Organofosfatos/efeitos adversos , Ar/análise , Poluentes Atmosféricos/química , Poluentes Atmosféricos/envenenamento , Animais , Bioacumulação , Cidades/estatística & dados numéricos , Simulação por Computador , Ecossistema , Retardadores de Chama/análise , Retardadores de Chama/envenenamento , Substâncias Perigosas/efeitos adversos , Substâncias Perigosas/química , Substâncias Perigosas/envenenamento , Humanos , Intoxicação por Organofosfatos , Organofosfatos/análise , Organofosfatos/química , Medição de Risco
2.
Toxics ; 9(12)2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34941758

RESUMO

Assessing complex environmental mixtures and their effects is challenging. In this study, we evaluate the utility of an avian in vitro screening approach to determine the effects of passive air sampler extracts collected from different global megacities on cytotoxicity and gene expression. Concentrations of a suite of organic flame retardants (OFRs) were quantified in extracts from a total of 19 megacities/major cities in an earlier study, and levels were highly variable across sites. Chicken embryonic hepatocytes were exposed to serial dilutions of extracts from the 19 cities for 24 h. Cell viability results indicate a high level of variability in cytotoxicity, with extracts from Toronto, Canada, having the lowest LC50 value. Partial least squares (PLS) regression analysis was used to estimate LC50 values from OFR concentrations. PLS modeling of OFRs was moderately predictive of LC50 (p-value = 0.0003, r2 = 0.66, slope = 0.76, when comparing predicted LC50 to actual values), although only after one outlier city was removed from the analysis. A chicken ToxChip PCR array, comprising 43 target genes, was used to determine effects on gene expression, and similar to results for cell viability, gene expression profiles were highly variable among the megacities. PLS modeling was used to determine if gene expression was related to the OFR profiles of the extracts. Weak relationships to the ToxChip expression profiles could be detected for only three of the 35 OFRs (indicated by regression slopes between 0.6 and 0.5 when comparing predicted to actual OFR concentrations). While this in vitro approach shows promise in terms of evaluating effects of complex mixtures, we also identified several limitations that, if addressed in future studies, might improve its performance.

3.
Environ Sci Technol ; 55(20): 13932-13941, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34590828

RESUMO

Trophic magnification of cyclic volatile methyl siloxanes (cVMS) in a terrestrial food web was investigated by measuring concentrations of octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclohexasiloxane (D6) and two reference chemicals within air and biota samples from an avian food web located in a mixed urban-agricultural landscape. Terrestrial trophic magnification factors derived from lipid normalized concentrations (TMFLs) for D5 and D6 were 0.94 (0.17 SE) and 1.1 (0.23 SE) and not statistically different from 1 (p > 0.05); however, the TMFL of D4 was 0.62 (0.11 SE) and statistically less than 1 (p < 0.001). TMFLs of PCB-153 and p,p'-DDE were 5.6 (2.2 SE) and 6.1 (2.8 SE) and statistically greater than 1 (p < 0.001). TMFLs of cVMS in this terrestrial system were similar to those reported in aquatic systems. However, trophic magnification factors derived on a fugacity basis (TMFFs), which recognize differences in body temperature and lipid composition between organisms, were greater than corresponding TMFLs primarily because a temperature-induced thermodynamic biomagnification of hydrophobic chemicals occurs when endothermic organisms consume poikilothermic organisms. Therefore, we recommend that biomagnification studies of food webs including endothermic and poikilothermic organisms incorporate differences in body temperature and tissue composition to accurately characterize the biomagnification potential of chemicals.


Assuntos
Cadeia Alimentar , Poluentes Químicos da Água , Bioacumulação , Temperatura Corporal , Monitoramento Ambiental , Siloxanas/análise , Temperatura , Poluentes Químicos da Água/análise
4.
Environ Sci Technol ; 55(17): 11693-11702, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34431673

RESUMO

This study provides guidance on using polyurethane foam-based passive air samplers (PUF-PASs) for atmospheric nonane chlorinated paraffins (C9-CPs) and short-chain CPs (SCCPs) and reports SCCP concentrations in air in the Greater Toronto Area (GTA), Canada. We estimated the partition coefficients between PUF and air (KPUF-A) and between octanol and air (KOA) for C9-CP and SCCP congeners using the COSMO-RS method, so that PUF disk uptake profiles for each formula group could be calculated. We then measured SCCP concentrations in PUF disk samples collected from distinct source sectors in urban air across the GTA. Concentrations in samplers were used to calculate C9-CP and SCCP concentrations in air and the PUF disk uptake profiles revealed that time-weighted linear phase sampling was possible for congeners having log KOA values greater than 8.5. The highest SCCP concentrations, with an annual average concentration of 35.3 ng/m3, were measured at the industrial site, whereas lower but comparable SCCP concentrations were found in residential and background sites, with annual averages of 7.73 and 10.5 ng/m3, respectively. No consistent seasonal variation in SCCP concentrations was found in the six distinct source sectors. Direct measurements of KPUF-A and KOA values as a function of temperature could be used to increase accuracy in future studies.


Assuntos
Poluentes Atmosféricos , Hidrocarbonetos Clorados , Poluentes Atmosféricos/análise , Alcanos , China , Monitoramento Ambiental , Hidrocarbonetos Clorados/análise , Parafina/análise , Poliuretanos/análise
5.
Cancer Res ; 81(17): 4417-4430, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34233924

RESUMO

High-risk neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood. Here, we show that elevated expression of dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in patients with neuroblastoma. DLST is an E2 component of the α-ketoglutarate (αKG) dehydrogenase complex, which governs the entry of glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. During this irreversible step, αKG is converted into succinyl-CoA, producing NADH for oxidative phosphorylation (OXPHOS). Utilizing a zebrafish model of MYCN-driven neuroblastoma, we demonstrate that even modest increases in DLST expression promote tumor aggression, while monoallelic dlst loss impedes disease initiation and progression. DLST depletion in human MYCN-amplified neuroblastoma cells minimally affected glutamine anaplerosis and did not alter TCA cycle metabolites other than αKG. However, DLST loss significantly suppressed NADH production and impaired OXPHOS, leading to growth arrest and apoptosis of neuroblastoma cells. In addition, multiple inhibitors targeting the electron transport chain, including the potent IACS-010759 that is currently in clinical testing for other cancers, efficiently reduced neuroblastoma proliferation in vitro. IACS-010759 also suppressed tumor growth in zebrafish and mouse xenograft models of high-risk neuroblastoma. Together, these results demonstrate that DLST promotes neuroblastoma aggression and unveils OXPHOS as an essential contributor to high-risk neuroblastoma. SIGNIFICANCE: These findings demonstrate a novel role for DLST in neuroblastoma aggression and identify the OXPHOS inhibitor IACS-010759 as a potential therapeutic strategy for this deadly disease.


Assuntos
Aciltransferases/metabolismo , Neoplasias Encefálicas/metabolismo , Neuroblastoma/metabolismo , Fosforilação Oxidativa , Animais , Apoptose , Linhagem Celular Tumoral , Colágeno/química , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Concentração Inibidora 50 , Complexo Cetoglutarato Desidrogenase/metabolismo , Laminina/química , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Transplante de Neoplasias , Oxigênio/metabolismo , Proteoglicanas/química , Interferência de RNA , Risco , Smegmamorpha , Resultado do Tratamento , Ácidos Tricarboxílicos/metabolismo , Peixe-Zebra
6.
J Pharm Sci ; 110(9): 3176-3182, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34004217

RESUMO

Monoclonal antibody (mAb)-based drugs are often prone to unfavorable solution behaviors including high viscosity, opalescence, phase separation, and aggregation at the high concentrations needed to enable patient-centric subcutaneous dosage forms. Given that these can have a detrimental impact on manufacturability, stability, and delivery, approaches to identifying, monitoring, and controlling these behaviors during drug development are critical. Opalescence presents a significant challenge due to its relationship to liquid-liquid phase separation. Quantitative characterization of opalescence via turbidimetry is often restrictive due to large volume requirements (>2 mL) and alternative microscale approaches based on light transmittance (Eckhardt et al., J Pharm Sci Technol. 1994, 48: 64-70) may pose challenging with respect to accuracy. To address the need for accurate and quantitative microscale opalescence measurements, we have evaluated the use of a 'de-tuned' static light scattering detector which requires <10 µL sample per measurement. We show that tuning of the laser power to a range far below that of traditional light scattering measurements results in a stable detector response that can be accurately calibrated to the nephelometric turbidity unit (NTU) scale using appropriate standards. The calibrated detector signal yields NTU values for mAbs and other protein solutions that are comparable to a commercial turbidimeter. We used this microscale approach to characterize the opalescence of 48 commercial mAb drug products and found that the majority have opalescence below 15 NTU. However, in products with mAb concentrations greater than 75 mg/mL, a broad range of opalescence was observed, in a few cases greater than 20 NTU. These measurements as well as nephelometric characterization of several IgG1 and IgG4 mAbs across a broad pH range highlight subclass-specific tendencies toward opalescence in high concentration solutions.


Assuntos
Anticorpos Monoclonais , Iridescência , Nefelometria e Turbidimetria , Anticorpos Monoclonais/análise , Imunoglobulina G , Soluções , Viscosidade
7.
ACS Appl Bio Mater ; 4(9): 7332-7341, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-35006962

RESUMO

Infections caused by fungal species via their existence as biofilms on medical devices can cause organ damage via candidiasis and candidemia. Different Candida species like Candida albicans can pose a serious threat by resisting host's immune system and by developing drug resistance against existing antimycotic agents. Therefore, targeting of fungal membranes can be used as an alternative strategy to combat the fungal infections. Here, we present screening of different amphiphiles based on cholic acid against different Candida strains as these amphiphiles can act as potent membrane-targeting antimycotic agents. Structure-activity correlations, biochemical assays and electron microscopy studies showed that amphiphiles having 4 and 6 carbon chains are most potent, safe and can act on the fungal membranes. Candida albicans did not show emergence of drug resistance on repeated usage of these amphiphiles unlike fluconazole. We show that these amphiphiles can prevent the formation of biofilms and also have the ability to degrade preformed biofilms on different substrates including acrylic teeth. We further demonstrate that amphiphiles 4 and 6 can clear the Candida albicans wound infections and prevent the biofilm formation on indwelling devices in murine models. Therefore, amphiphiles derived from cholic acid and their coatings provide suitable alternatives for inhibiting the fungal infections.


Assuntos
Antifúngicos , Candidíase , Animais , Antifúngicos/farmacologia , Biofilmes , Candida , Candida albicans , Candidíase/tratamento farmacológico , Ácido Cólico/farmacologia , Camundongos
8.
Sci Adv ; 6(32): eabb0372, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32923611

RESUMO

Despite the therapeutic success of monoclonal antibodies (mAbs), early identification of developable mAb drug candidates with optimal manufacturability, stability, and delivery attributes remains elusive. Poor solution behavior, which manifests as high solution viscosity or opalescence, profoundly affects the developability of mAb drugs. Using a diverse dataset of 59 mAbs, including 43 approved products, and an array of molecular descriptors spanning colloidal, conformational, charge-based, hydrodynamic, and hydrophobic properties, we show that poor solution behavior is prevalent (>30%) in mAbs and is singularly predicted (>90%) by the diffusion interaction parameter (k D), a dilute-solution measure of colloidal self-interaction. No other descriptor, individually or in combination, was found to be as effective as k D. We also show that well-behaved mAbs, a substantial subset of which bear high positive charge and pI, present no disadvantages with respect to pharmacokinetics in humans. Here, we provide a systematic framework with quantitative thresholds for selecting well-behaved therapeutic mAbs during drug discovery.


Assuntos
Anticorpos Monoclonais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/uso terapêutico , Difusão , Humanos , Interações Hidrofóbicas e Hidrofílicas , Viscosidade
9.
Environ Pollut ; 267: 115416, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32854027

RESUMO

A pilot study was initiated in 2018 under the Global Atmospheric Passive Sampling (GAPS) Network named GAPS-Megacities. This study included 20 megacities/major cities across the globe with the goal of better understanding and comparing ambient air levels of persistent organic pollutants and other chemicals of emerging concern, to which humans residing in large cities are exposed. The first results from the initial period of sampling are reported for 19 cities for several classes of flame retardants (FRs) including organophosphate esters (OPEs), polybrominated diphenyl ethers (PBDEs), and halogenated flame retardants (HFRs) including new flame retardants (NFRs), tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCDD). The two cities, New York (USA) and London (UK) stood out with ∼3.5 to 30 times higher total FR concentrations as compared to other major cities, with total concentrations of OPEs of 15,100 and 14,100 pg/m3, respectively. Atmospheric concentrations of OPEs significantly dominated the FR profile at all sites, with total concentrations in air that were 2-5 orders of magnitude higher compared to other targeted chemical classes. A moderately strong and significant correlation (r = 0.625, p < 0.001) was observed for Gross Domestic Product index of the cities with total OPEs levels. Although large differences in FR levels were observed between some cities, when averaged across the five United Nations regions, the FR classes were more evenly distributed and varied by less than a factor of five. Results for Toronto, which is a 'reference city' for this study, agreed well with a more in-depth investigation of the level of FRs over different seasons and across eight sites representing different urban source sectors (e.g. traffic, industrial, residential and background). Future sampling periods under this project will investigate trace metals and other contaminant classes, linkages to toxicology, non-targeted analysis, and eventually temporal trends. The study provides a unique urban platform for evaluating global exposome.


Assuntos
Poluentes Atmosféricos , Poluentes Ambientais , Retardadores de Chama , Poluentes Atmosféricos/análise , Cidades , Monitoramento Ambiental , Poluentes Ambientais/análise , Retardadores de Chama/análise , Éteres Difenil Halogenados/análise , Humanos , Londres , New York , Projetos Piloto
10.
Pediatr Crit Care Med ; 21(8): 738-745, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32195905

RESUMO

OBJECTIVES: The aims of this study were to: i) determine the spectrum of brain injury and ii) compare brain volumes between pre- and postoperative brain MRI in the infants receiving extracorporeal membrane oxygenation compared with those who did not require extracorporeal membrane oxygenation. DESIGN: Cohort study of infants with D-transposition of the great arteries or single ventricle physiology. Brain volume (cm) was measured using a segmentation of a volumetric T1-weighted gradient echo sequence. Brain imaging findings (intraventricular hemorrhage, white matter injuries, and stroke) were analyzed with respect to known clinical risk factors for brain injury and adverse neurodevelopmental outcomes. Clinical factors were collected by retrospective chart review. The association between brain volume and extracorporeal membrane oxygenation was evaluated using generalized estimating equations to account for repeated measures. SETTING: Prospective and single-centered study. PATIENTS: One hundred nine infants (median gestational age, 39.1 wk) with D-transposition of the great arteries (n = 77) or single ventricle physiology (n = 32) were studied pre- and postoperatively with MRI as per clinical protocol. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 28 infants (26%) receiving extracorporeal membrane oxygenation, 19 (68%) were supported with extracorporeal membrane oxygenation once, and nine (32%) were supported 2-4 times. On postoperative MRI, new white matter injury was found in only five (17%) of the extracorporeal membrane oxygenation infants versus 40 (49%) in the non-extracorporeal membrane oxygenation group (p = 0.073). The rate of stroke (9% vs 10%), intraventricular hemorrhage (24% vs 29%), and hypoxic ischemia (3% vs 14%) did not differ between the non-extracorporeal membrane oxygenation and extracorporeal membrane oxygenation groups (all p > 0.5). Accounting for D-transposition of the great arteries or single ventricle physiology diagnosis, infants requiring extracorporeal membrane oxygenation had slower brain volume with single (ß = -1.67) or multiple extracorporeal membrane oxygenation runs ([ß = -6.54]; overall interaction p = 0.012). CONCLUSIONS: Patients with d-transposition of the great arteries or single ventricle physiology undergoing extracorporeal membrane oxygenation at our center have a similar incidence of brain injury but more significant impairment of perioperative brain volumes than those not requiring extracorporeal membrane oxygenation.


Assuntos
Oxigenação por Membrana Extracorpórea , Cardiopatias Congênitas , Transposição dos Grandes Vasos , Adulto , Encéfalo/diagnóstico por imagem , Estudos de Coortes , Oxigenação por Membrana Extracorpórea/efeitos adversos , Humanos , Lactente , Estudos Prospectivos , Estudos Retrospectivos
11.
Environ Sci Technol ; 53(24): 14398-14408, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31756294

RESUMO

The environmental risks and health impacts associated with particulate organophosphate flame retardants (OPFRs), which are ubiquitous in the global atmosphere, have not been adequately assessed due to the lack of data on the reaction kinetics, products, and toxicity associated with their atmospheric transformations. Here, the importance of such transformations for OPFRs are explored by investigating the reaction kinetics, degradation chemical mechanisms, and toxicological evolution of two OPFRs (2-ethylhexyl diphenyl phosphate (EHDP) and diphenyl phosphate (DPhP)) coated on (NH4)2SO4 particles upon heterogeneous OH oxidation. The derived reaction rate constants for the heterogeneous loss of EHDP and DPhP are (1.12 ± 0.22) × 10-12 and (2.33 ± 0.14) × 10-12 cm3 molecules-1 s-1, respectively. Using recently developed real-time particle chemical composition measurements, particulate products from heterogeneous photooxidation and the associated degradation mechanisms for particulate OPFRs are reported for the first time. Subsequent cytotoxicity analysis of the unreacted and oxidized OPFR particles indicated that the overall particle cytotoxicity was reduced by up to 94% with heterogeneous photooxidation, likely due to a significantly lower cytotoxicity associated with the oxidized OPFR products relative to the parent OPFRs. The present work not only provides guidance for future field sampling for the detection of transformation products of OPFRs, but also strongly supports the ongoing risk assessment of these emerging chemicals and most critically, their products.


Assuntos
Retardadores de Chama , Poeira , Cinética , Organofosfatos , Oxirredução
12.
Chemosphere ; 234: 925-930, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31519101

RESUMO

Organophosphate esters (OPEs), novel flame retardants (NFRs) and organochlorine pesticides (OCPs) are volatile to semi-volatile chemicals and therefore susceptible to approach equilibrium during typical deployments of polyurethane foam (PUF) disk passive air samplers. A generator column approach was used to measure the PUF-air partitioning coefficient (KPUF-air) for these targeted chemicals. KPUF-air values are required for these chemicals to estimate sampled equivalent air volumes, which vary substantially with temperature. Log KPUF-air measurements were made at temperatures ranging from +6 to +35 °C and resulting values ranged from 5.14 to 7.77. Enthalpies of phase change for PUF to air (ΔHPUF-air, kJ/mol) ranged from 51.3 to 98.9. Two relationships of log KPUF-air versus log Koctanol-air (KOA) were derived, grouping OPEs and NFRs separately. The relationship for NFRs was in fair agreement (within about 0.6 log units) to a long-standing relationship by Shoeib and Harner (since 2002) for polychlorinated biphenyls (PCBs). However, the estimated values using Shoeib-Harner relationship substantially underestimates KPUF-air for the OPEs than directly measured values (by about an order of magnitude). These findings highlight the importance of the direct measurements of KPUF-air for emerging classes of chemicals whose concentrations are at risk of equilibrating in PUF disk samplers.


Assuntos
Poluentes Atmosféricos/análise , Monitoramento Ambiental/métodos , Poliuretanos/química , Retardadores de Chama/análise , Hidrocarbonetos Clorados/análise , Organofosfatos , Praguicidas/análise , Bifenilos Policlorados , Poliuretanos/análise , Temperatura
13.
Artigo em Inglês | MEDLINE | ID: mdl-31427303

RESUMO

Interkingdom polymicrobial biofilms formed by Gram-positive Staphylococcus aureus and Candida albicans pose serious threats of chronic systemic infections due to the absence of any common therapeutic target for their elimination. Herein, we present the structure-activity relationship (SAR) of membrane-targeting cholic acid-peptide conjugates (CAPs) against Gram-positive bacterial and fungal strains. Structure-activity investigations validated by mechanistic studies revealed that valine-glycine dipeptide-derived CAP 3 was the most effective broad-spectrum antimicrobial against S. aureus and C. albicans CAP 3 was able to degrade the preformed single-species and polymicrobial biofilms formed by S. aureus and C. albicans, and CAP 3-coated materials prevented the formation of biofilms. Murine wound and catheter infection models further confirmed the equally potent bactericidal and fungicidal effect of CAP 3 against bacterial, fungal, and polymicrobial infections. Taken together, these results demonstrate that CAPs, as potential broad-spectrum antimicrobials, can effectively clear the frequently encountered polymicrobial infections and can be fine-tuned further for future applications.


Assuntos
Anti-Infecciosos/farmacologia , Biofilmes/efeitos dos fármacos , Ácido Cólico/farmacologia , Peptídeos/farmacologia , Animais , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana/métodos , Viabilidade Microbiana/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos
14.
Circulation ; 139(24): 2728-2738, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31132861

RESUMO

BACKGROUND: Brain injury, impaired brain growth, and long-term neurodevelopmental problems are common in children with transposition of the great arteries. We sought to identify clinical risk factors for brain injury and poor brain growth in infants with transposition of the great arteries undergoing the arterial switch operation, and to examine their relationship with neurodevelopmental outcome. METHODS: The brains of 45 infants with transposition of the great arteries undergoing surgical repair were imaged pre- and postoperatively using magnetic resonance imaging. Brain weight z scores were calculated based on brain volume and autopsy reference data. Brain injury scores were determined as previously described. Neurodevelopment was assessed at 18 months using the Bayley-III scores of infant development. The relationships between clinical variables, brain injury, perioperative brain growth, and 18-month Bayley-III scores were analyzed. RESULTS: On preoperative imaging, moderate or severe white matter injury was present in 10 of 45 patients, whereas stroke was seen in 4 of 45. A similar prevalence of injury was seen on postoperative imaging, and we were unable to identify any clinical risk factors for brain injury. Brain weight z scores decreased perioperatively in 35 of 45 patients. The presence of a ventricular septal defect ( P=0.009) and older age at surgery ( P=0.007) were associated with impaired perioperative brain growth. When patients were divided into those undergoing surgery during the first 2 weeks of life (32/45) versus those being repaired later (13/45), infants repaired later had significantly worse perioperative brain growth (late repair postoperative brain weight z = -1.0±0.90 versus early repair z = -0.33±0.64; P=0.008). Bayley-III testing scores fell within the normal range for all patients, although age at repair ( P=0.03) and days of open chest ( P=0.03) were associated with a lower composite language score, and length of stay was associated with a lower composite cognitive score ( P=0.02). CONCLUSIONS: Surgery beyond 2 weeks of age is associated with impaired brain growth and slower language development in infants with transposition of the great arteries cared for at our center. Although the mechanisms underlying this association are still unclear, extended periods of cyanosis and pulmonary overcirculation may adversely impact brain growth and subsequent neurodevelopment.


Assuntos
Transposição das Grandes Artérias , Encefalopatias/etiologia , Encéfalo/crescimento & desenvolvimento , Desenvolvimento Infantil , Transposição dos Grandes Vasos/cirurgia , Fatores Etários , Autopsia , Encéfalo/diagnóstico por imagem , Encefalopatias/diagnóstico por imagem , Encefalopatias/fisiopatologia , Linguagem Infantil , Imagem de Difusão por Ressonância Magnética , Humanos , Lactente , Comportamento do Lactente , Recém-Nascido , Ontário , Tamanho do Órgão , Estudos Prospectivos , Fatores de Tempo , Transposição dos Grandes Vasos/complicações , Transposição dos Grandes Vasos/diagnóstico por imagem , Resultado do Tratamento
15.
Environ Pollut ; 247: 89-97, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30665191

RESUMO

Based on distinct land-use categories, a sampling campaign was carried out at eight locations across Toronto and the Greater Toronto Area in 2016-2017. Source sectors' dependent patterns of atmospheric concentrations of 9 organophosphate esters (OPEs), 9 polybrominated diphenyl ethers (PBDEs) and 5 novel flame retardants (NFRs) showed dominance of OPEs and PBDEs at highly commercialised urban and traffic sites, while NFRs, were dominant at residential sites. Overall, average concentrations of Σ9OPEs (1790 pg/m3) were two orders of magnitude higher than Σ9PBDEs (9.17 pg/m3) and Σ5NFRs (8.14 pg/m3). The atmospheric concentrations of given chemical classes also showed a general trend of lower levels in winter as compared to summer months. Statistically significant negative correlations between the natural logarithm of concentrations and inverse of temperature for some OPEs and PBDEs highlighted the role of volatilization from local sources at given sites as primarily influencing their atmospheric concentrations. Overall, this study adds to the current knowledge of urban settings as a major emitter of the chemicals of emerging concern and their replacements, as well as the ongoing problem of phased out PBDEs due to their presence in existing inventories of commercial/recycled products. It is recommended that long-term monitoring programs targeting flame retardants (FRs) include urban sites, which provide an early indicator of effectiveness of control measures of targeted FRs, while at the same time providing information on emission sources and trends of replacement FR chemicals.


Assuntos
Poluentes Atmosféricos/análise , Monitoramento Ambiental , Retardadores de Chama/análise , Éteres Difenil Halogenados/análise , Habitação , Ontário , Organofosfatos/análise , Estações do Ano , Volatilização
16.
J Med Chem ; 61(14): 6261-6276, 2018 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-29860841

RESUMO

Diacylglycerol-lactones have proven to be a powerful template for the design of potent ligands targeting C1 domains, the recognition motif for the cellular second messenger diacylglycerol. A major objective has been to better understand the structure activity relations distinguishing the seven families of signaling proteins that contain such domains, of which the protein kinase C (PKC) and RasGRP families are of particular interest. Here, we synthesize a series of aryl- and alkyl-substituted diacylglycerol-lactones and probe their relative selectivities for RasGRP3 versus PKC. Compound 96 showed 73-fold selectivity relative to PKCα and 45-fold selectivity relative to PKCε for in vitro binding activity. Likewise, in intact cells, compound 96 induced Ras activation, a downstream response to RasGRP stimulation, with 8-29 fold selectivity relative to PKCδ S299 phosphorylation, a measure of PKCδ stimulation.


Assuntos
Diglicerídeos/química , Desenho de Fármacos , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Lactonas/química , Lactonas/metabolismo , Fatores de Troca do Nucleotídeo Guanina/química , Células HEK293 , Humanos , Ligantes , Modelos Moleculares , Domínios Proteicos , Proteína Quinase C-alfa/metabolismo , Proteína Quinase C-épsilon/metabolismo , Especificidade por Substrato , Fatores ras de Troca de Nucleotídeo Guanina
17.
Thyroid ; 28(6): 799-810, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29580170

RESUMO

BACKGROUND: Beta blockers are standard therapy for myocardial infarction (MI). Preclinical studies have shown efficacy and safety of thyroid hormone (TH) treatment of cardiovascular disorders. Since THs interact with the sympathoadrenergic system, this study aimed to compare triiodothyronine (T3) and metoprolol (Met) in the treatment of rats with MI on pathophysiology and TH-adrenergic signaling. METHODS: Female Sprague-Dawley rats aged 12 weeks underwent left anterior descending coronary artery ligation (MI) or sham surgeries. T3 (5 µg/kg/day) or Met (100 mg/kg/day) was given in drinking water immediately after surgery for eight weeks. At the terminal of the experiments, the rats were subjected to morphological, functional, and molecular examination. RESULTS: T3 and Met significantly enhanced left ventricular contractility (left ventricular fractional shortening 21.37 ± 2.58% and 21.14 ± 3.71%, respectively) compared to untreated MI (17.88 ± 1.23%), and decreased the incidence of inducible atrial tachyarrhythmia by 87.5% and 62.5%, respectively. Although both treatments showed efficacy, T3 but not Met showed statistically significant improvements compared to MI in arrhythmia duration, left atrial diameter (T3 vs. MI 4.33 ± 0.63 vs. 5.65 ± 1.32 mm; p < 0.05), fibrosis (6.1 ± 0.6%, 6.6 ± 0.6% vs. 8.2 ± 0.7%, T3, Met vs. MI, respectively), and aortic vasorelaxation responsiveness to acetylcholine (pD2 6.97 ± 0.22, 6.83 ± 0.21 vs. 6.66 ± 0.22, T3, Met vs. MI, respectively). Quantitative polymerase chain reaction showed that T3 and Met attenuated expression of genes associated with inflammation and oxidative stress and restored expression of ion channels and contractile proteins. CONCLUSION: These results support comparable efficacy of T3 and Met treatments, suggesting that T3 may provide a therapeutic alternative to standard ß-receptor blockade, especially for patients intolerant to treatment with ß-blockers after MI.


Assuntos
Metoprolol/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Tri-Iodotironina/uso terapêutico , Animais , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/fisiopatologia , Modelos Animais de Doenças , Ecocardiografia , Eletrofisiologia , Feminino , Fibrose , Átrios do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hemodinâmica , Inflamação , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Hormônios Tireóideos/sangue , Hormônios Tireóideos/metabolismo , Tiroxina/uso terapêutico , Função Ventricular Esquerda
18.
Biochim Biophys Acta Biomembr ; 1860(5): 1046-1056, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29317197

RESUMO

The PKC isozymes represent the most prominent family of signaling proteins mediating response to the ubiquitous second messenger diacylglycerol. Among them, PKCθ is critically involved in T-cell activation. Whereas all the other conventional and novel PKC isoforms have twin C1 domains with potent binding activity for phorbol esters, in PKCθ only the C1b domain possesses potent binding activity, with little or no activity reported for the C1a domain. In order to better understand the structural basis accounting for the very weak ligand binding of the PKCθ C1a domain, we assessed the effect on ligand binding of twelve amino acid residues which differed between the C1a and C1b domains of PKCθ. Mutation of Pro9 of the C1a domain of PKCθ to the corresponding Lys9 found in C1b restored in vitro binding activity for [3H]phorbol 12,13-dibutyrate to 3.6 nM, whereas none of the other residues had substantial effect. Interestingly, the converse mutation in the C1b domain of Lys9 to Pro9 only diminished binding affinity to 11.7 nM, compared to 254 nM in the unmutated C1a. In confocal experiments, deletion of the C1b domain from full length PKCθ diminished, whereas deletion of the C1a domain enhanced 5-fold (at 100 nM PMA) the translocation to the plasma membrane. We conclude that the Pro168 residue in the C1a domain of full length PKCθ plays a critical role in the ligand and membrane binding, while exchanging the residue (Lys240) at the same position in C1b domain of full length PKCθ only modestly reduced the membrane interaction.


Assuntos
Ésteres de Forbol/metabolismo , Domínios e Motivos de Interação entre Proteínas , Proteína Quinase C-theta/química , Proteína Quinase C-theta/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Sítios de Ligação/genética , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Ligação Proteica/genética , Domínios e Motivos de Interação entre Proteínas/genética , Proteína Quinase C-theta/genética , Células Tumorais Cultivadas
19.
Environ Int ; 106: 97-104, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28624751

RESUMO

Concentrations of 13 organophosphate ester flame retardants (OPEs) were measured in air, dust and window wipes from 63 homes in Canada, the Czech Republic and the United States in the spring and summer of 2013 to look for abundances, differences among regions, and partitioning behavior. In general, we observed the highest concentrations for halogenated OPEs, particularly TCEP, TCIPP and TDCIPP, and also non-halogenated TPHP. Differences between regions strongly depended on the matrix. The concentrations of OPEs in dust were significantly higher in the US than in Canada (CAN) and Czech Republic (CZ). CZ had the highest concentrations in window film and CAN in air. ΣOPE concentrations were 2-3 and 1-2 orders of magnitude greater than ΣBFRs in air, and dust and window films, respectively. We found a significant relationship between the concentrations in dust and air, and between the concentrations in window film and air for OPEs with log KOA values <12, suggesting that equilibrium was reached for these compounds but not for those with log KOA>12. This hypothesis was confirmed by a large discrepancy between values predicted using a partitioning model and the measured values for OPEs with log KOA values >12.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , Ésteres/análise , Retardadores de Chama/análise , Organofosfatos/análise , República Tcheca , Poeira/análise , Monitoramento Ambiental , Indiana , Ontário , Estações do Ano
20.
Environ Sci Technol ; 50(17): 9289-97, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27507188

RESUMO

The accumulation of phthalate esters, brominated flame retardants (BFRs) and organophosphate esters (OPEs) by clothing from indoor air and transfer via laundering to outdoors were investigated. Over 30 days cotton and polyester fabrics accumulated 3475 and 1950 ng/dm(2) ∑5phthalates, 65 and 78 ng/dm(2) ∑10BFRs, and 1200 and 310 ng/dm(2) ∑8OPEs, respectively. Planar surface area concentrations of OPEs and low molecular weight phthalates were significantly greater in cotton than polyester and similar for BFRs and high molecular weight phthalates. This difference was significantly and inversely correlated with KOW, suggesting greater sorption of polar compounds to polar cotton. Chemical release from cotton and polyester to laundry water was >80% of aliphatic OPEs (log KOW < 4), < 50% of OPEs with an aromatic structure, 50-100% of low molecular weight phthalates (log KOW 4-6), and < detection-35% of higher molecular weight phthalates (log KOW > 8) and BFRs (log KOW > 6). These results support the hypothesis that clothing acts an efficient conveyer of soluble semivolatile organic compounds (SVOCs) from indoors to outdoors through accumulation from air and then release during laundering. Clothes drying could as well contribute to the release of chemicals emitted by electric dryers. The results also have implications for dermal exposure.


Assuntos
Ésteres , Retardadores de Chama , Vestuário , Organofosfatos , Água
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...