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1.
Lancet Microbe ; 5(5): e452-e458, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38527471

RESUMO

INTRODUCTION: Continued SARS-CoV-2 infection among immunocompromised individuals is likely to play a role in generating genomic diversity and the emergence of novel variants. Antiviral treatments such as molnupiravir are used to mitigate severe COVID-19 outcomes, but the extended effects of these drugs on viral evolution in patients with chronic infections remain uncertain. This study investigates how molnupiravir affects SARS-CoV-2 evolution in immunocompromised patients with prolonged infections. METHODS: The study included five immunocompromised patients treated with molnupiravir and four patients not treated with molnupiravir (two immunocompromised and two non-immunocompromised). We selected patients who had been infected by similar SARS-CoV-2 variants and with high-quality genomes across timepoints to allow comparison between groups. Throat and nasopharyngeal samples were collected in patients up to 44 days post treatment and were sequenced using tiled amplicon sequencing followed by variant calling. The UShER pipeline and University of California Santa Cruz genome viewer provided insights into the global context of variants. Treated and untreated patients were compared, and mutation profiles were visualised to understand the impact of molnupiravir on viral evolution. FINDINGS: Patients treated with molnupiravir showed a large increase in low-to-mid-frequency variants in as little as 10 days after treatment, whereas no such change was observed in untreated patients. Some of these variants became fixed in the viral population, including non-synonymous mutations in the spike protein. The variants were distributed across the genome and included unique mutations not commonly found in global omicron genomes. Notably, G-to-A and C-to-T mutations dominated the mutational profile of treated patients, persisting up to 44 days post treatment. INTERPRETATION: Molnupiravir treatment in immunocompromised patients led to the accumulation of a distinctive pattern of mutations beyond the recommended 5 days of treatment. Treated patients maintained persistent PCR positivity for the duration of monitoring, indicating clear potential for transmission and subsequent emergence of novel variants. FUNDING: Australian Research Council.


Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Citidina , Hidroxilaminas , Hospedeiro Imunocomprometido , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Estudos Retrospectivos , Antivirais/uso terapêutico , Antivirais/farmacologia , Hidroxilaminas/uso terapêutico , Hidroxilaminas/farmacologia , Masculino , Citidina/análogos & derivados , Citidina/uso terapêutico , Citidina/farmacologia , Feminino , Pessoa de Meia-Idade , Mutação , Idoso , COVID-19/imunologia , COVID-19/virologia , Evolução Molecular , Adulto , Genoma Viral/genética
2.
AJNR Am J Neuroradiol ; 41(6): 1070-1075, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32467187

RESUMO

BACKGROUND AND PURPOSE: The Neck Imaging Reporting and Data System is a standardized reporting system intended to risk stratify patients treated for head and neck squamous cell carcinoma. The purpose of this study is to investigate the positive predictive value of the Neck Imaging Reporting and Data System categories 3 and 4 on posttreatment PET/CT in patients treated definitively for head and neck squamous cell carcinoma. MATERIALS AND METHODS: We retrospectively identified patients treated definitively for head and neck squamous cell carcinoma between 2006 and 2018. Patients whose posttreatment PET/CT scans were interpreted as Neck Imaging Reporting and Data System 3 (suspicious) or 4 (definitive recurrence) at the primary site, regional nodes, or at distant sites were included. The reference standard was histopathology or unequivocal imaging or clinical evidence of treatment failure. The positive predictive values of Neck Imaging Reporting and Data System 3 and 4 posttreatment PET/CT were calculated. RESULTS: Seventy-two of 128 patients with posttreatment PET/CT interpreted as Neck Imaging Reporting and Data System 3 at the primary site, regional nodes, or distant sites were proved to have treatment failure at the suspicious sites, yielding an overall positive predictive value of 56% (95% CI, 48%-65%). The positive predictive values of Neck Imaging Reporting and Data System 3 by subsite were as follows: primary site, 56% (44/79); regional nodes, 65% (34/52); and distant sites, 79% (42/53). All 69 patients with posttreatment PET/CT interpreted as Neck Imaging Reporting and Data System 4 had true treatment failure, yielding a positive predictive value of 100% (95% CI, 96%-100%): primary site, 100% (28/28); regional nodes, 100% (32/32); and distant sites, 100% (29/29). CONCLUSIONS: The positive predictive value of Neck Imaging Reporting and Data System 3 on posttreatment PET/CT is relatively low. Thus, Neck Imaging Reporting and Data System 3 findings should be confirmed with tissue sampling before instituting new salvage treatment regimens to avoid unnecessary overtreatment and its associated toxicities. Neck Imaging Reporting and Data System 4 reliably indicates recurrent disease.


Assuntos
Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Falha de Tratamento
3.
Rev Med Liege ; 73(5-6): 333-337, 2018 May.
Artigo em Francês | MEDLINE | ID: mdl-29926575

RESUMO

Stroke management dramatically changed during the last decades. Evidence shows that an early admission in a stroke unit offers the best chance of recovery to the stroke patient. The most spectacular aspect of the stroke unit activity consists of the hyperacute diagnostic and therapeutic stroke procedures, including prompt neuroimaging, intravenous thrombolysis and mechanical thrombectomy.


La prise en charge de l'accident vasculaire cérébral s'est considérablement modifiée durant la dernière décennie et continue d'évoluer, au bénéfice direct des patients victimes de cette urgence très fréquente. L'accent est mis sur la prise en charge la plus précoce possible par un centre hospitalier équipé d'une unité neurovasculaire. Celle-ci rassemble une équipe multidisciplinaire de professionnels habitués à prendre en charge cette pathologie : neurologues, neuroradiologues, neurochirurgiens, neuropsychologues, logopèdes, médecins physiques, infirmières. La manifestation la plus visible de cette unité consiste en la prise en charge diagnostique et thérapeutique à l'admission du patient. Celle-ci permet de distinguer rapidement les accidents ischémiques des hémorragies ou des thrombophlébites intracrâniennes puis, dans le cas ischémique, de procéder à la désocclusion de l'artère coupable, soit par thrombolyse intraveineuse, soit par thrombectomie mécanique, ou les deux.


Assuntos
Serviços Médicos de Emergência , Acidente Vascular Cerebral/terapia , Serviços Médicos de Emergência/métodos , Humanos , Padrões de Prática Médica , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia
4.
Colorectal Dis ; 19(10): 934-941, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28436214

RESUMO

AIM: Perineal wound complications following abdominoperineal resection continue to be a major challenge. The aim of this study was to compare the clinical outcomes and cost of primary closure (PC) and rectus abdominis myocutaneous (RAM) flap reconstruction. METHOD: This was a retrospective case review of consecutive patients by one surgeon over 11 years. Patient demographics, risk factors, operative details and complications were identified. Inpatient and outpatient costs were calculated. RESULTS: A total of 31 patients underwent a RAM reconstruction and 37 a PC. There were no significant differences in the incidence of wound complications or in the overall costs for either method of perineal closure. When there were no complications the mean costs were significantly higher in the RAM group ($20 948 vs $17 189, P = 0.005), mainly because of the longer operating time. However, the costs of perineal wound complications were greater in the PC group (8394 vs 25 911, P = 0.012). These wounds took longer to heal (median 2 months vs 5.5 months, P = 0.005) and more often required a further reconstructive surgical procedure (RAM 0 vs PC 8, P = 0.006). CONCLUSION: This is the first study reporting on the cost implications of PC and RAM flap reconstruction. The overall costs were similar. This implies appropriate clinical selection when choosing between procedures. While the RAM flap is more expensive to perform, the finding that it decreases the clinical severity and cost of perineal wound complications supports its use when there is a high risk of perineal wound complications.


Assuntos
Abdome/cirurgia , Técnicas de Fechamento de Ferimentos Abdominais/economia , Retalho Miocutâneo/economia , Períneo/cirurgia , Complicações Pós-Operatórias/economia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Complicações Pós-Operatórias/etiologia , Reto do Abdome/transplante , Estudos Retrospectivos , Fatores de Tempo , Cicatrização
5.
Int J Stroke ; 10(4): 565-70, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24612428

RESUMO

BACKGROUND AND PURPOSE: In acute ischemic stroke perfusion/diffusion-weighted image, mismatch using magnetic resonance imaging approximates the ischemic penumbra. For early time windows, mismatch salvage improves clinical outcomes, but uncertainty exists at later time epochs. We hypothesized that (a) mismatch may exist up to 48 h; (b) the proportion of mismatch salvage is time independent; and (c) when salvaged, it improves clinical outcomes. METHODS: Magnetic resonance imaging was performed within 48 h of ischemic stroke. Perfusion-weighted image was defined by relative Tmax two-second delay. Perfusion/diffusion-weighted image mismatch was the perfusion-weighted image not overlapped by the diffusion-weighted image when coregistered. Infarct volume and disability (modified Rankin Score) were assessed at three-months. Mismatch salvage was the region not overlapped by final infarction. Favorable outcome was defined as modified Rankin Score 0-1. RESULTS: Sixty-six patients were studied [mean age 69.9 years (standard deviation 13.1), initial median National Institute of Health Stroke Scale 9.0 (interquartile range 6.0, 18.3)]. There was no relationship between time of stroke onset and the proportion of mismatch salvaged (P = 0.73). Age (adjusted odds ratio = 0.92, 95% confidence interval 0.86-0.98, P = 0.01), initial National Institute of Health Stroke Scale (adjusted odds ratio = 0.80, 95% confidence interval 0.70-0.92, P < 0.01), mismatch volume (adjusted odds ratio = 0.98, 95% confidence interval 0.968-0.1, P = 0.05), and percentage of mismatch salvage (adjusted odds ratio = 1.04, 95% confidence interval 0.99-1.07, P = 0.05) were independently associated with favorable outcome. CONCLUSION: Using coregistered perfusion/diffusion-weighted image criteria, mismatch persists up to 48 h post stroke. For the whole group, the proportion of mismatch salvage remains independent of time and, although the effect is small, its salvage is independently associated with improved clinical outcomes at three-months. Larger sample sizes are needed to determine the time limit for mismatch salvage.


Assuntos
Isquemia Encefálica/patologia , Isquemia Encefálica/terapia , Imagem de Difusão por Ressonância Magnética/métodos , Angiografia por Ressonância Magnética/métodos , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/terapia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
6.
Rev Med Liege ; 69(5-6): 315-7, 2014.
Artigo em Francês | MEDLINE | ID: mdl-25065238

RESUMO

Stroke risk increases with aging and one third of ischemic strokes occurs in very elderly (> or = 80 years). These are responsible of two thirds of the overall stroke-related morbi-mortality. Stroke in very elderly differs from younger individuals by sex ratio (more women), risk factors (more atrial fibrillation and hypertension) and usually a worse functional outcome. Very elderly are likely to benefit from stroke unit care and early revascularisation treatments although they have historically been excluded from this urgent management. These issues are likely to worsen in the future with the increasing impact of stroke on our aging societies.


Assuntos
Envelhecimento , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Fatores de Risco , Razão de Masculinidade , Ativador de Plasminogênio Tecidual/uso terapêutico
7.
Clin Radiol ; 69(9): 980-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24969470

RESUMO

Axial T2-weighted fat-saturated imaging provides information not readily available from routine lumbar spine magnetic resonance imaging (MRI) protocols and routine inclusion of this sequence in place of axial T1-weighted imaging provides additional diagnostic information that can be obtained without increasing examination time or cost. The purpose of this review is to highlight the value of axial T2-weighted fat-saturated imaging as part of a routine lumbar spine MRI protocol.


Assuntos
Edema/patologia , Inflamação/patologia , Vértebras Lombares/patologia , Imageamento por Ressonância Magnética , Doenças da Coluna Vertebral/patologia , Articulação Zigapofisária/patologia , Feminino , Humanos , Aumento da Imagem , Masculino , Variações Dependentes do Observador , Sensibilidade e Especificidade , Síndrome
8.
J Control Release ; 168(3): 251-61, 2013 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-23567045

RESUMO

Lactosylated gramicidin-containing lipid nanoparticles (Lac-GLN) were developed for delivery of anti-microRNA-155 (anti-miR-155) to hepatocellular carcinoma (HCC) cells. MiR-155 is an oncomiR frequently elevated in HCC. The Lac-GLN formulation contained N-lactobionyl-dioleoyl phosphatidylethanolamine (Lac-DOPE), a ligand for the asialoglycoprotein receptor (ASGR), and an antibiotic peptide gramicidin A. The nanoparticles exhibited a mean particle diameter of 73 nm, zeta potential of +3.5mV, anti-miR encapsulation efficiency of 88%, and excellent colloidal stability at 4°C. Lac-GLN effectively delivered anti-miR-155 to HCC cells with a 16.1- and 4.1-fold up-regulation of miR-155 targets C/EBPß and FOXP3 genes, respectively, and exhibited significant greater efficiency over Lipofectamine 2000. In mice, intravenous injection of Lac-GLN containing Cy3-anti-miR-155 led to preferential accumulation of the anti-miR-155 in hepatocytes. Intravenous administration of 1.5 mg/kg anti-miR-155 loaded Lac-GLN resulted in up-regulation of C/EBPß and FOXP3 by 6.9- and 2.2-fold, respectively. These results suggest potential application of Lac-GLN as a liver-specific delivery vehicle for anti-miR therapy.


Assuntos
Antibacterianos/administração & dosagem , Anticorpos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Gramicidina/administração & dosagem , MicroRNAs/imunologia , Nanopartículas/administração & dosagem , Animais , Antibacterianos/química , Anticorpos/química , Proteínas Estimuladoras de Ligação a CCAAT/genética , Carbocianinas/administração & dosagem , Carbocianinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/química , Fatores de Transcrição Forkhead/genética , Gramicidina/química , Células Hep G2 , Humanos , Lactose/química , Lipídeos/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Distribuição Tecidual
9.
Biomaterials ; 33(25): 5924-34, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22652024

RESUMO

Clinical application of small interfering RNA (siRNA) requires safe and efficient delivery in vivo. Here, we report the design and synthesis of lipid nanoparticles (LNPs) for siRNA delivery based on cationic lipids with multiple tertiary amines and hydrophobic linoleyl chains. LNPs incorporating the lipid containing tris(2-aminoethyl)amine (TREN) and 3 linoleyl chains, termed TRENL3, were found to have exceptionally high siRNA transfection efficacy that was markedly superior to lipofectamine, a commercial transfection agent. In addition, inclusion of polyunsaturated fatty acids, such as linoleic acid and linolenic acid in the formulation further enhanced the siRNA delivery efficiency. TRENL3 LNPs were further shown to transport siRNA into the cytosol primarily via macropinocytosis rather than clathrin-mediated endocytosis. The new LNPs have demonstrated preferential uptake by the liver and hepatocellular carcinoma in mice, thereby leading to high siRNA gene-silencing activity. These data suggest potential therapeutic applications of TRENL3 mediated delivery of siRNA for liver diseases.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Lipídeos/química , Fígado/metabolismo , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Animais , Linhagem Celular , Coloides , Regulação para Baixo , Etilenodiaminas/química , Ácidos Graxos Insaturados/química , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Nanopartículas/ultraestrutura , Estabilidade de RNA , RNA Interferente Pequeno/metabolismo , Distribuição Tecidual
10.
Radiol Res Pract ; 2012: 475497, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22550584

RESUMO

Differentiating hemorrhagic infarct from parenchymal intracerebral hemorrhage can be difficult. The immediate and long-term management of the two conditions are different and hence the importance of accurate diagnosis. Using a series of intracerebral hemorrhage cases presented to our stroke unit, we aim to highlight the clues that may be helpful in distinguishing the two entities. The main clue to the presence of hemorrhagic infarct on computed tomography scan is the topographic distribution of the stroke. Additional imaging modalities such as computed tomography angiogram, perfusion, and magnetic resonance imaging may provide additional information in differentiating hemorrhagic infarct from primary hemorrhages.

11.
Br J Surg ; 99(5): 613-20, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22367850

RESUMO

BACKGROUND: Skin incisions have traditionally been made using a scalpel. Cutting diathermy, a more recent alternative, is thought to increase the risk of infection, impair healing and decrease cosmesis. Recent studies suggest otherwise, claiming that diathermy may offer potential advantages with respect to blood loss, incision time and postoperative pain. The aim of this meta-analysis was to compare skin incisions made by either scalpel or cutting diathermy. METHODS: A systematic literature search and review was performed for studies published from January 1980 until June 2011. Randomized clinical trials comparing scalpel and cutting diathermy for skin incisions of any operation were included. Primary outcomes included wound complication rate, blood loss, incision times and pain scores. RESULTS: Fourteen randomized trials met the criteria for inclusion in the meta-analysis, providing outcome data for a total of 2541 patients (1267 undergoing skin incision by cutting diathermy and 1274 by scalpel). The median length of follow-up across all studies was 6 weeks (range 4 days to 19 months). Compared with a scalpel incision, cutting diathermy resulted in significantly less blood loss (mean difference 0.72 ml/cm(2); P < 0.001) and shorter incision times (mean difference 36 s; P < 0.001), with no differences in the wound complication rate (odds ratio 0.87; P = 0.29) or pain score at 24 h (mean difference 0.89; P = 0.05). CONCLUSION: Skin incisions made by cutting diathermy are quicker and associated with less blood loss than those made by scalpel, and there are no differences in the rate of wound complications or postoperative pain.


Assuntos
Procedimentos Cirúrgicos Dermatológicos , Diatermia/métodos , Complicações Pós-Operatórias/etiologia , Instrumentos Cirúrgicos , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Diatermia/efeitos adversos , Hematoma/etiologia , Humanos , Tempo de Internação , Medição da Dor , Dor Pós-Operatória/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Seroma/etiologia , Deiscência da Ferida Operatória/etiologia , Infecção da Ferida Cirúrgica/etiologia
12.
Br J Pharmacol ; 165(8): 2771-86, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22029876

RESUMO

BACKGROUND AND PURPOSE: Drug candidates must be thoroughly investigated for their potential cardiac side effects. During the course of routine toxicological assessment, the compound RO5657, a CCR5 antagonist, was discovered to have the rare liability of inducing torsades de pointes (polymorphic ventricular arrhythmia) in normal, healthy animals. Studies were conducted to determine the molecular mechanism of this arrhythmia. EXPERIMENTAL APPROACH: Toxicological effects of repeat dosing were assessed in naïve monkeys. Cardiovascular effects were determined in conscious telemetry-implanted monkeys (repeat dosing) and anaesthetized instrumented dogs (single doses). Mechanistic studies were performed in guinea-pig isolated hearts and in cells recombinantly expressing human cardiac channels. KEY RESULTS: In cynomolgus monkeys, RO5657 caused a low incidence of myocardial degeneration and a greater incidence of ECG abnormalities including prolonged QT/QTc intervals, QRS complex widening and supraventricular tachycardia. In telemetry-implanted monkeys, RO5657 induced arrhythmias, including torsades de pointes and in one instance, degeneration to fatal ventricular fibrillation. RO5657 also depressed both heart rate (HR) and blood pressure (BP), with no histological evidence of myocardial degeneration. In the anaesthetized dog and guinea-pig isolated heart studies, RO5657 induced similar cardiovascular effects. RO5657 also inhibited Kv11.1 and sodium channel currents. CONCLUSIONS AND IMPLICATIONS: The molecular mechanism of RO5657 is hypothesized to be due to inhibition of cardiac sodium and Kv11.1 potassium channels. These results indicate that RO5657 is arrhythymogenic due to decreased haemodynamic function (HR/BP), decreased conduction and inhibition of multiple cardiac channels, which precede and are probably the causative factors in the observed myocardial degeneration.


Assuntos
Antagonistas dos Receptores CCR5 , Coração/efeitos dos fármacos , Compostos Orgânicos/farmacologia , Torsades de Pointes/induzido quimicamente , Animais , Pressão Sanguínea/efeitos dos fármacos , Carbamatos , Cães , Drogas em Investigação/efeitos adversos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/fisiologia , Feminino , Cobaias , Coração/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Técnicas In Vitro , Macaca fascicularis , Masculino , Piperidinas , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Sódio/efeitos adversos , Canais de Sódio/fisiologia , Torsades de Pointes/fisiopatologia
13.
Neurosci Lett ; 503(1): 10-4, 2011 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-21843597

RESUMO

Spinal cord injury (SCI) produces a significant loss of oligodendrocytes (OL) and demyelination. The oligodendrocyte precursor cells (OPCs) response includes a group of cellular changes in OPCs that are directed to replenish OL loss from the injury. However, this adaptive response is hampered and OPCs eventually die or fail to differentiate to mature and functional OL. In this study, we wanted to evaluate if overexpression of human superoxide dismutase 1 (hSOD1) in OPCs from the SOD1 transgenic rat could improve some of the features of the OPC response in vitro. We found that hSOD1 overexpression increases the proliferation of OPCs and accelerates their differentiation to mature OL in vitro. Furthermore, hSOD1 overexpression reduces oxidative stress-mediated death in OPCs. These results suggest hSOD1 as a therapeutic target to increase OPC response success and potentially, OL replacement and remyelination after SCI.


Assuntos
Proliferação de Células , Oligodendroglia/fisiologia , Células-Tronco/fisiologia , Superóxido Dismutase/metabolismo , Análise de Variância , Animais , Bromodesoxiuridina/metabolismo , Antígeno CD11b/metabolismo , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Relação Dose-Resposta a Droga , Gangliosídeos/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Proteína Básica da Mielina/metabolismo , Oligodendroglia/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Células-Tronco/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxido Dismutase-1 , Fatores de Tempo , terc-Butil Hidroperóxido/farmacologia
14.
J Colloid Interface Sci ; 347(1): 120-6, 2010 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-20394940

RESUMO

Sorption of inorganic elements onto carbonate minerals has been intensively described in the literature by two reaction steps: (1) a first one rapid and completed within a few hours and (2) a second one slower, eventually irreversible, and occurring at a constant rate. The first step is often attributed to an ion-exchange process, but its reversibility is rarely investigated. Consequently, discrimination of the global sorption phenomenon into two different mechanisms is not always justified. In this study, we investigated, by batch experiments, both sorption and desorption of Ca(II), HCO(3)(-), and Zn(II), radiolabeled with isotopes (45)Ca(II), H(14)CO(3)(-), and (65)Zn(II), respectively, onto synthetic pure calcite. Solutions were preequilibrated with atmospheric p(CO2) and saturated with respect to calcite. Therefore, our purpose was to: (1) obtain experimental distribution coefficients of major elements (Ca(II) and HCO(3)(-)) and a trace element (Zn(II)) onto calcite from sorption and desorption experiments, (2) test the validity of a first-occurring ion-exchange process generally noted in the literature, by calculating distribution coefficients for the "sole" exchange process, and (3) quantify the amounts of Ca(II), HCO(3)(-), and Zn(II) sorbed on the calcite surface by the sole "exchange process" and compare them with surface crystallochemical data. Ca(II) or HCO(3)(-) sorption experimental data suggest that a significant fraction of these two elements was sorbed irreversibly onto or in the calcite. By using a method based on isotopic ratios, the Ca(II) or HCO(3)(-) concentrations, which are reversibly adsorbed on the calcite, have been quantified. These concentrations are respectively estimated at 4.0+/-2.0 x 10(-4) and 7.0+/-1.5 x 10(-4) mol/kg. The obtained Ca(II) surface concentration value is one order of magnitude lower than the one obtained from isotopic measurement by former authors [Geochim. Cosmochim. Acta 55 (1991) 1549; Geochim. Cosmochim. Acta 51 (1987) 1477; Geochim. Cosmochim. Acta 52 (1988) 2281] at the same pH. On the other hand, the kinetics of Zn(II) sorption onto calcite was followed over more than 1000 h. Sorption/desorption experimental results suggest that the sorption is totally reversible at least when total aqueous Zn concentration is less than 10(-6) mol/L and when experiments are performed in equilibrium with both calcite and p(CO2)=10(-3.5) atm. Under these conditions and at pH 8.3, the occupancy rate of Zn(II) onto the calcite surface is estimated to represent approximately 1% of the total surface-site density.

15.
Neurology ; 74(6): 487-93, 2010 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-20142615

RESUMO

BACKGROUND: The in vivo diagnosis of cerebral amyloid angiopathy (CAA) is inferred from clinical and structural imaging features. (11)C-Pittsburgh compound B (PIB) is a PET ligand that binds to beta-amyloid in extracellular plaques and vessel walls. We hypothesized that patients with a clinical diagnosis of CAA-related hemorrhage (CAAH) have increased (11)C-PIB uptake and that the pattern differs from Alzheimer disease (AD). METHODOLOGY: Patients with CAAH based on established clinical criteria were studied using (11)C-PIB PET and were compared with age-matched controls and patients with AD. Distribution volume ratio (DVR) parametric maps were created using the cerebellar cortex as a reference region. RESULTS: Twelve patients with CAAH of mean age 73.9 (range 58-93) years were compared with 22 normal controls and 13 patients with AD of mean age 71.8 (59-83) and 73.8 (56-90) years, respectively. CAAH PIB median DVR binding was higher in cortical regions (1.69, interquartile range 1.44-1.97) compared with controls (1.32, 1.21-1.44, p = 0.002) but lower than AD (2.04, 1.93-2.26, p = 0.004). The occipital-global uptake ratio was lower among patients with AD than among patients with CAAH (p = 0.008), and the frontal-global uptake ratio was higher (p = 0.012). CONCLUSION: (11)C-Pittsburgh compound B (PIB) binding is moderately increased in most patients with probable cerebral amyloid angiopathy (CAA)-related intracerebral hemorrhage. The distribution may differ from that seen in Alzheimer disease. (11)C-PIB PET may assist in the in vivo diagnosis of CAA and serve as a surrogate marker for future therapeutic studies.


Assuntos
Benzotiazóis/metabolismo , Radioisótopos de Carbono/metabolismo , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Hemorragia/complicações , Hemorragia/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Estudos Prospectivos , Estudos Retrospectivos , Inquéritos e Questionários , Tiazóis
16.
Comb Chem High Throughput Screen ; 12(8): 812-23, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19531008

RESUMO

Drug discovery efforts advance in step with advancements in assay technologies, as new technologies provide new lenses through which biology can be viewed. The novel information gathered results in the better understanding of drug-target interactions leading to better decision making during the drug discovery process. One area of rapid development is within label-free technologies. Label-free technologies offer many distinct advantages to the drug discovery workflow. One such novel technology is the CellKey System, an impedance-based label-free live cell assay platform. The system is based on impedance technology and is a universal platform for the functional measurement of all classes of G-protein coupled receptors (GPCRs). Data are generated in a kinetic fashion on both endogenously expressed and transfected receptors in a wide variety of cell types. In the studies detailed here, we used the system to perform an enhanced selectivity screen of a small panel of compounds simultaneously against two unrelated GPCR targets signaling through different pathways. Utilizing both the quantitative measures of cellular activation and the qualitative information inherent in the rich output data, we gained knowledge not only about the relative selectivity of each compound across both targets, but also about the character of the interaction of each with the cellular target. In this manner, we successfully demonstrated proof of principal for using an impedance-based technology to perform selectivity analyses and to triage lead compounds in a simplified format.


Assuntos
Bioensaio/métodos , Receptores Acoplados a Proteínas G/metabolismo , Animais , Bioensaio/instrumentação , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Descoberta de Drogas/instrumentação , Descoberta de Drogas/métodos , Cinética , Ligantes , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Sensibilidade e Especificidade , Coloração e Rotulagem
17.
J Neurol Neurosurg Psychiatry ; 80(9): 991-6, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19357125

RESUMO

BACKGROUND AND AIMS: The mismatch between perfusion weighted images (PWI) and diffusion weighted images (DWI) using MR is increasingly being applied in patient selection for therapeutic trials. Two approaches to the calculation of the mismatch volume exist--the commonly used volumetric and the more precise co-registration method, the latter of which considers lesion topography. That there are differences in the mismatch volume analysed by each method and that these are time dependent was hypothesised. METHODS: Patients within 48 h of ischaemic stroke onset had baseline MR PWI/DWI mismatch and T2 outcome volumes at 3 months. Volumetric mismatch volume was defined as PWI minus DWI lesion. Co-registration mismatch volume was defined as the PWI defect lesion not overlapped by the co-registered DWI lesion. RESULTS: 72 patients of median age 74.0 years were studied. Median baseline MR was at 5.9 h (IQR 3.0, 20.4 h) after stroke onset. Consistent underestimation of the mismatch volume occurred using the volumetric method (volumetric median 9.3 ml, IQR 0, 63 ml; co-registration median 20.1 ml, IQR 3.2, 69.8 ml; p<0.0001). This difference increased with time from stroke onset (p = 0.006). CONCLUSIONS: Volumetric analysis consistently underestimates the PWI/DWI mismatch volume compared with the more precise co-registration method. This effect increases with time.


Assuntos
Imagem de Difusão por Ressonância Magnética , Imageamento por Ressonância Magnética , Acidente Vascular Cerebral/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Estudos de Coortes , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Acidente Vascular Cerebral/diagnóstico , Adulto Jovem
19.
Radiat Prot Dosimetry ; 131(3): 385-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18640998

RESUMO

Radon has been identified as the second leading cause of lung cancer after tobacco smoking. Information on indoor radon concentrations is required to assess the lung cancer burden due to radon exposure. However, radon data in highly populated southern Ontario are very limited. Since radon in soil is believed to be the main source of radon in homes, measurements of soil gas radon concentrations can be used to estimate variations in radon potential of indoor environments. This study reports a transect survey of natural background variation in soil radon levels across southern Ontario. The results indicate that radon risk could be high in some areas of southern Ontario.


Assuntos
Poluentes Radioativos do Ar/análise , Poluição do Ar em Ambientes Fechados/análise , Radônio/análise , Poluentes Radioativos do Solo/análise , Radiação de Fundo , Canadá , Humanos
20.
Indoor Air ; 18(4): 346-8, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18503537

RESUMO

UNLABELLED: With the announcement of the Government of Canada's Radon Guideline and increased public awareness of radon risk, more and more Canadians wish to test their homes for radon. Radon service providers available on the Internet have attracted many homeowners' attention. These services provide an easy and less expensive way for homeowners to test radon levels in their homes. However, a question has frequently been asked, 'How reliable are the radon testing services available on the Internet?' To answer this question, we ordered 36 radon testing kits from 10 service providers on the Internet. The test results showed that online radon testing services could collectively meet the performance requirement. However, the quality of a few service providers needs to be improved. PRACTICAL IMPLICATIONS: Indoor radon tests were performed with detectors ordered from 10 service providers available on the Internet. The results showed that online radon testing services could collectively meet the performance requirement. However, the quality of a few service providers needs to be improved.


Assuntos
Comércio , Monitoramento Ambiental/instrumentação , Internet , Radônio/análise , Canadá , Monitoramento Ambiental/normas , Desenho de Equipamento , Habitação , Controle de Qualidade , Sensibilidade e Especificidade
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