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1.
Cell Mol Life Sci ; 81(1): 125, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38467757

RESUMO

Adipose triglyceride lipase (ATGL) is involved in lipolysis and displays a detrimental pathophysiological role in cardio-metabolic diseases. However, the organo-protective effects of ATGL-induced lipolysis were also suggested. The aim of this work was to characterize the function of lipid droplets (LDs) and ATGL-induced lipolysis in the regulation of endothelial function. ATGL-dependent LDs hydrolysis and cytosolic phospholipase A2 (cPLA2)-derived eicosanoids production were studied in the aorta, endothelial and smooth muscle cells exposed to exogenous oleic acid (OA) or arachidonic acid (AA). Functional effects of ATGL-dependent lipolysis and subsequent activation of cPLA2/PGI2 pathway were also studied in vivo in relation to postprandial endothelial dysfunction.The formation of LDs was invariably associated with elevated production of endogenous AA-derived prostacyclin (PGI2). In the presence of the inhibitor of ATGL or the inhibitor of cytosolic phospholipase A2, the production of eicosanoids was reduced, with a concomitant increase in the number of LDs. OA administration impaired endothelial barrier integrity in vitro that was further impaired if OA was given together with ATGL inhibitor. Importantly, in vivo, olive oil induced postprandial endothelial dysfunction that was significantly deteriorated by ATGL inhibition, cPLA2 inhibition or by prostacyclin (IP) receptor blockade.In summary, vascular LDs formation induced by exogenous AA or OA was associated with ATGL- and cPLA2-dependent PGI2 production from endogenous AA. The inhibition of ATGL resulted in an impairment of endothelial barrier function in vitro. The inhibition of ATGL-cPLA2-PGI2 dependent pathway resulted in the deterioration of endothelial function upon exposure to olive oil in vivo. In conclusion, vascular ATGL-cPLA2-PGI2 dependent pathway activated by lipid overload and linked to LDs formation in endothelium and smooth muscle cells has a vasoprotective role by counterbalancing detrimental effects of lipid overload on endothelial function.


Assuntos
Eicosanoides , Lipólise , Lipólise/fisiologia , Azeite de Oliva , Ácido Araquidônico/metabolismo , Eicosanoides/metabolismo , Prostaglandinas I/metabolismo , Fosfolipases/metabolismo
2.
Ann Noninvasive Electrocardiol ; 27(4): e12968, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35580147

RESUMO

BACKGROUND: Exercise electrocardiography is a widely used diagnostic modality for diagnosing coronary artery disease. This method has been used for both sexes; however, its diagnostic accuracy in women is limited. METHODS: The study analyzed 332 women participating in the Finnish Cardiovascular Study. Among 332 women, 125 with angiographically proven coronary artery disease (mean age 62.1 ± 9.5 years), 91 with a low likelihood of coronary artery disease (mean age 47.3 ± 13.5 years), and 116 without angiographically proven coronary artery disease (mean age 56.3 ± 9.9 years) were analyzed. The Q, R, S, and ST-segment changes and QRS score were determined by subtracting the Q, R, S, and ST-segment amplitudes immediately after the maximal exercise changes from their rest values (Δ). Receiver operating characteristic curve analysis was performed to evaluate the overall diagnostic performance of the parameters for predicting coronary artery disease. RESULTS: The areas under the receiver operating characteristic curve between coronary artery disease and low likelihood of coronary artery disease groups for the QRS score and ΔSTV5, ΔQaVF, and ΔRaVF were 0.75, 0.73, 0.71, and 0.71, respectively. These areas were lower (0.62, 0.57, 0.60, and 0.60, respectively) between the groups with and without angiographically proven coronary artery disease. QRS score demonstrated the highest sensitivity at 80% specificity (61.5%) and the highest specificity at 80% sensitivity (57.6%). CONCLUSIONS: This study suggests that the QRS and ST-segment depression have a moderate diagnostic ability to predict coronary artery disease in women. Q and R waves in lead aVF showed good diagnostic ability.


Assuntos
Doença da Artéria Coronariana , Adulto , Idoso , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Eletrocardiografia/métodos , Teste de Esforço/métodos , Feminino , Finlândia , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade
3.
Phys Rev Lett ; 127(27): 273603, 2021 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-35061429

RESUMO

Singularities which symbolize abrupt changes and exhibit extraordinary behavior are of a broad interest. We experimentally study optomechanically induced singularities in a compound system consisting of a three-dimensional aluminum superconducting cavity and a metalized high-coherence silicon nitride membrane resonator. Mechanically induced coherent perfect absorption and anti-lasing occur simultaneously under a critical optomechanical coupling strength. Meanwhile, the phase around the cavity resonance undergoes an abrupt π-phase transition, which further flips the phase slope in the frequency dependence. The observed infinite discontinuity in the phase slope defines a singularity, at which the group velocity is dramatically changed. Around the singularity, an abrupt transition from an infinite group advance to delay is demonstrated by measuring a Gaussian-shaped waveform propagating. Our experiment may broaden the scope of realizing extremely long group delays by taking advantage of singularities.

4.
Trop Med Int Health ; 26(1): 89-101, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33012038

RESUMO

OBJECTIVES: Accurate serological assays are urgently needed to support public health responses to Zika virus (ZIKV) infection with its potential to cause foetal damage during pregnancy. Current flavivirus serology for ZIKV infections lacks specificity due to cross-reacting antibodies from closely related other flaviviruses. In this study, we evaluated novel serological tests for accurate ZIKV IgG detection. METHODS: Our ELISAs are based on immune complex binding. The high specificity is achieved by the simultaneous incubation of labelled ZIKV antigen and unlabelled flavivirus homolog protein competitors. Two assays were validated with a panel of 406 human samples from PCR-confirmed ZIKV patients collected in Brazil (n = 154), healthy blood donors and other infections from Brazil, Europe, Canada and Colombia (n = 252). RESULTS: The highest specificity (100% [252/252, 95% confidence interval (CI) 98.5-100.0]) was shown by the ZIKV ED3 ICB ELISA using the ED3 antigen of the ZIKV envelope. A similar test using the NS1 antigen (ZIKV NS1 ICB ELISA) was slightly less specific (92.1% [232/252, 95% CI 88.0-95.1]). The commercial Euroimmun ZIKV ELISA had a specificity of only 82.1% (207/252, 95% CI 76.8-86.7). Sensitivity was high (93-100%) from day 12 after onset of symptoms in all three tests. Seroprevalence of ZIKV IgG was analysed in 87 samples from Laos (Asia) confirming that the ED3 ELISA showed specific reactions in other populations. CONCLUSIONS: The novel ED3 ICB ELISA will be useful for ZIKV-specific IgG detection for seroepidemiological studies and serological diagnosis for case management in travellers and in countries where other flavivirus infections are co-circulating.


Assuntos
Complexo Antígeno-Anticorpo/sangue , Imunoglobulina G/sangue , Infecção por Zika virus/sangue , Infecção por Zika virus/diagnóstico , Zika virus/isolamento & purificação , Adolescente , Adulto , Idoso , Complexo Antígeno-Anticorpo/imunologia , Brasil , Criança , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Imunoglobulina G/imunologia , Laos , Masculino , Pessoa de Meia-Idade , Gravidez , Sensibilidade e Especificidade , Estudos Soroepidemiológicos , Testes Sorológicos , Adulto Jovem , Zika virus/imunologia , Infecção por Zika virus/imunologia
5.
BMC Cardiovasc Disord ; 21(1): 257, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34039285

RESUMO

BACKGROUND: Elevated level of plasma uric acid (PUA) has been associated with cardiovascular disease, but whether uric acid is an independent risk factor or merely a marker remains controversial. METHODS: We investigated in a cross-sectional setting the association of PUA with hemodynamics in 606 normotensive and never-medicated hypertensive subjects (295 men, 311 women, age range 19-73 years) without cardiovascular disease or gout. In all except 15 individuals, PUA was within the normal range. Supine hemodynamics were recorded using whole-body impedance cardiography and radial tonometric pulse wave analysis. RESULTS: The mean concentrations of PUA in age, sex and body mass index adjusted quartiles were 234, 278, 314, and 373 µmol/l, respectively. The highest PUA quartile presented with higher aortic to popliteal pulse wave velocity (PWV) than the lowest quartile (8.7 vs. 8.2 m/s, p = 0.026) in analyses additionally adjusted for plasma concentrations of C-reactive protein, low density lipoprotein cholesterol, triglycerides, and mean aortic blood pressure. No differences in radial and aortic blood pressure, wave reflections, heart rate, cardiac output, and systemic vascular resistance were observed between the quartiles. In linear regression analysis, PUA was an independent explanatory factor for PWV (ß = 0.168, p < 0.001, R2 of the model 0.591), but not for systolic or diastolic blood pressure. When the regression analysis was performed separately for men and women, PUA was an independent predictor of PWV in both sexes. CONCLUSIONS: PUA concentration was independently and directly associated with large arterial stiffness in individuals without cardiovascular disease and PUA levels predominantly within the normal range. Trial registration ClinicalTrials.gov NCT01742702.


Assuntos
Pressão Sanguínea , Hipertensão/sangue , Hipertensão/fisiopatologia , Ácido Úrico/sangue , Rigidez Vascular , Adulto , Idoso , Biomarcadores/sangue , Cardiografia de Impedância , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Hipertensão/diagnóstico , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Adulto Jovem
6.
Ecotoxicol Environ Saf ; 215: 112093, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33721667

RESUMO

Organic aromatic compounds used for dyeing and coloring in the textile industry are persistent and hazardous pollutants that must be treated before they are discharged into rivers and surface waters. Therefore, we investigated the potential of the white rot fungus Phanerochaete velutina to decolorize commonly used reactive dyes. The fungus decolorized in average 55% of Reactive Orange 16 (RO-16) after 14 days at a maximum rate of 0.09 d-1 and a half-life of 8 days. Furthermore, we determined the inhibitory effects of co-present inorganic contaminants Nickel (Ni) and Cobalt (Co) salts on the decolorization potential and determined IC50 values of 5.55 mg l-1 for Co and a weaker inhibition by Ni starting from a concentration of 20 mg l-1. In the decolorization assay for Remazol Brilliant Blue R (RBBR) we observed the interference of a metabolite of P. velutina, which did not allow us to investigate the kinetics of the reaction. The formation of the metabolite, however, could be used to obtain IC50 values of 3.37 mg l-1 for Co and 7.58 mg l-1 for Ni. Our results show that living white rot fungi, such as P. velutina, can be used for remediation of dye polluted wastewater, alternatively to enzyme mixtures, even in the co-presence of heavy metals.


Assuntos
Biodegradação Ambiental , Corantes/metabolismo , Phanerochaete/metabolismo , Poluentes Químicos da Água/metabolismo , Antraquinonas , Compostos Azo , Cobalto , Metais Pesados , Níquel , Sais , Indústria Têxtil , Têxteis , Águas Residuárias , Poluentes Químicos da Água/análise
7.
Phys Rev Lett ; 125(2): 023603, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32701306

RESUMO

Directional transport is obtained in various multimode systems by driving multiple, nonreciprocally interfering interactions between individual bosonic modes. However, systems sustaining the required number of modes become physically complex. In our microwave-optomechanical experiment, we show how to configure nonreciprocal transport between frequency components of a single superconducting cavity coupled to two drumhead oscillators. The frequency components are promoted to Floquet modes and generate the missing dimension to realize an isolator and a directional amplifier. A second cavity left free by this arrangement is used to cool the mechanical oscillators and bring the transduction noise close to the quantum limit. We furthermore uncover a new type of instability specific to nonreciprocal coupling. Our approach is generic and can greatly simplify quantum signal processing and the design of topological lattices from low-dimensional systems.

8.
Phys Rev Lett ; 123(24): 240401, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31922814

RESUMO

The studies of mechanical resonators in the quantum regime not only provide insight into the fundamental nature of quantum mechanics of massive objects, but also introduce promising platforms for novel hybrid quantum technologies. Here we demonstrate a configurable interaction between a superconducting qubit and many acoustic modes in the quantum regime. Specifically, we show how consecutive Landau-Zener-Stückelberg (LZS) tunneling type of transitions, which take place when a system is tuned through an avoided crossing of the coupled energy levels, interfere in a multimode system. The work progresses experimental LZS interference to cover a new class of systems where the coupled levels are those of a quantum two-level system interacting with a multitude of mechanical oscillators. The work opens up applications in controlling multiple acoustic modes via parametric modulation.

9.
Mol Cell Biochem ; 447(1-2): 217-224, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29396722

RESUMO

Bladder cancer is a common disease and a significant cause of death worldwide. There is thus great interest in identifying a diagnostic and prognostic biomarker, as well as gaining an understanding of the molecular basis of bladder cancer. Stearoyl-CoA desaturase 1 gene (SCD1) is highly overexpressed in many human cancers. However, the expression of SCD1 has not yet been investigated in patients with bladder cancer. Here, we document that (a) the SCD1 is highly overexpressed in human bladder cancer; (b) high expression of SCD1 is more frequently observed in the late stage of disease and patients with lymph node metastasis; (c) bladder cancer patients with a higher SCD1 mRNA level have a poorer survival rate than those with normal SCD1 expression. Overall, this is the first report to indicate an association between SCD1 mRNA level and clinical indicators of human bladder cancer. Our study has provided evidence supporting the potential role of SCD1 as a biomarker for human bladder cancer prognosis.


Assuntos
Biomarcadores Tumorais/biossíntese , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Estearoil-CoA Dessaturase/biossíntese , Neoplasias da Bexiga Urinária/enzimologia , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/patologia
10.
Proc Natl Acad Sci U S A ; 112(15): 4594-9, 2015 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-25831506

RESUMO

Significant climate risks are associated with a positive carbon-temperature feedback in northern latitude carbon-rich ecosystems, making an accurate analysis of human impacts on the net greenhouse gas balance of wetlands a priority. Here, we provide a coherent assessment of the climate footprint of a network of wetland sites based on simultaneous and quasi-continuous ecosystem observations of CO2 and CH4 fluxes. Experimental areas are located both in natural and in managed wetlands and cover a wide range of climatic regions, ecosystem types, and management practices. Based on direct observations we predict that sustained CH4 emissions in natural ecosystems are in the long term (i.e., several centuries) typically offset by CO2 uptake, although with large spatiotemporal variability. Using a space-for-time analogy across ecological and climatic gradients, we represent the chronosequence from natural to managed conditions to quantify the "cost" of CH4 emissions for the benefit of net carbon sequestration. With a sustained pulse-response radiative forcing model, we found a significant increase in atmospheric forcing due to land management, in particular for wetland converted to cropland. Our results quantify the role of human activities on the climate footprint of northern wetlands and call for development of active mitigation strategies for managed wetlands and new guidelines of the Intergovernmental Panel on Climate Change (IPCC) accounting for both sustained CH4 emissions and cumulative CO2 exchange.


Assuntos
Mudança Climática , Clima , Ecossistema , Áreas Alagadas , Dióxido de Carbono/metabolismo , Ecologia/métodos , Geografia , Atividades Humanas , Humanos , Metano/metabolismo , Modelos Teóricos , Óxido Nitroso/metabolismo , Plantas/classificação , Plantas/metabolismo , Temperatura , Incerteza
11.
Eur J Paediatr Dent ; 19(4): 265-270, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30567441

RESUMO

AIM: The aim of this study was to determine the age at and the reasons for the child's first dental visit, and to assess the oral health status and treatment needs in the analysed group of paediatric patients. MATERIALS AND METHODS: The study involved 320 children (154 girls and 166 boys) aged between 0.7 months and 13.5 years, visiting the dentist for the first time. All parents/legal guardians of the study participants gave written informed consent for participation in the study. Data on the child's age and reason for the dental visit were collected from interviews with parents. The state of oral health and dental treatment needs were assessed based on clinical examination, according to recommendations of the World Health Organization. STATISTICAL ANALYSIS: collected data were entered into an Excel spreadsheet and analysed using IBM SPSS software (version 24). Research hypotheses were verified using the Chi-square independence test at the level of statistical significance p<0.05. RESULTS: The mean age of children at their first dental visit was 3.79 years (+/- 1.82 years). The most common reasons (60%) for the first dental visit were pain followed by dental caries (33.1%) and the presence of decayed teeth (26.9%). The frequency of caries in the population was 75.9%, which means that only one out of four examined children was free from dental caries. Only 23.1% of patients did not require dental treatment and as many as 76.9% of the studied population needed dental treatment. CONCLUSION: Polish children make their first dental visit too late (usually at the age of 4 years) in relation to medical recommendations (between 6 and 12 months of life). The predominant reason for the child's first dental visit is caries and its complications. The results of this study indicate the bad oral health of Polish children making their first dental visit and low health awareness of parents and guardians.


Assuntos
Assistência Odontológica para Crianças/estatística & dados numéricos , Adolescente , Fatores Etários , Criança , Pré-Escolar , Necessidades e Demandas de Serviços de Saúde , Humanos , Lactente , Entrevistas como Assunto , Saúde Bucal , Polônia , Fatores de Tempo
12.
N Engl J Med ; 371(20): 1867-76, 2014 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-25265494

RESUMO

BACKGROUND: The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS: We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS: The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS: The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azetidinas/administração & dosagem , Indóis/administração & dosagem , MAP Quinase Quinase 1/antagonistas & inibidores , Melanoma/tratamento farmacológico , Piperidinas/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azetidinas/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Indóis/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Melanoma/genética , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Mutação , Piperidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Taxa de Sobrevida , Vemurafenib
13.
Lancet Oncol ; 17(11): 1579-1589, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27617661

RESUMO

BACKGROUND: In patients with platinum-sensitive recurrent serous ovarian cancer, maintenance monotherapy with the PARP inhibitor olaparib significantly improves progression-free survival versus placebo. We assessed the effect of maintenance olaparib on overall survival in patients with platinum-sensitive recurrent serous ovarian cancer, including those with BRCA1 and BRCA2 mutations (BRCAm). METHODS: In this randomised, placebo-controlled, double-blind, phase 2 trial involving 82 sites across 16 countries, patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more courses of platinum-based chemotherapy and had responded to their latest regimen were randomly assigned (1:1) using a computer-generated sequence to receive oral maintenance olaparib (as capsules; 400 mg twice a day) or a matching placebo by an interactive voice response system. Patients were stratified by ancestry, time to progression on penultimate platinum, and response to most recent platinum. Patients and investigators were masked to treatment assignment by the use of unique identifiers generated during randomisation. The primary endpoint of the trial was progression-free survival. In this updated analysis, we present data for overall survival, a secondary endpoint, from the third data analysis after more than 5 years' follow-up (intention-to-treat population). We did the updated overall survival analysis, described in this Article at 77% data maturity, using a two-sided α of 0·95%. As the study was not powered to assess overall survival, this analysis should be regarded as descriptive and the p values are nominal. We analysed randomly assigned patients for overall survival and all patients who received at least one dose of treatment for safety. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT00753545. FINDINGS: Between Aug 28, 2008, and Feb 9, 2010, 265 patients were randomly assigned to olaparib (n=136) or placebo (n=129). 136 patients had deleterious BRCAm. The data cutoff for this analysis was Sept 30, 2015. An overall survival advantage was seen with maintenance olaparib versus placebo in all patients (hazard ratio [HR] 0·73 [95% CI 0·55-0·96]; nominal p=0·025, which did not meet the required threshold for statistical significance [p<0·0095]; median overall survival was 29·8 months [95% CI 26·9-35·7] for those treated with olaparib vs 27·8 months [24·9-33·7] for those treated with placebo), and in patients with BRCAm (HR 0·62 [95% CI 0·41-0·94] nominal p=0·025; 34·9 months [95% CI 29·2-54·6] vs 30·2 months [23·1-40·7]). The overall survival data in patients with BRCA wild-type were HR 0·83 (95% CI 0·55-1·24, nominal p=0·37; 24·5 months [19·8-35·0] for those treated with olaparib vs 26·6 months [23·1-32·5] for those treated with placebo). 11 (15%) of 74 patients with BRCAm received maintenance olaparib for 5 years or more. Overall, common grade 3 or worse adverse events in the olaparib and placebo groups were fatigue (11 [8%] of 136 patients vs four [3%] of 128) and anaemia (eight [6%] vs one [1%]). 30 (22%) of 136 patients in the olaparib group and 11 (9%) of 128 patients in the placebo group reported serious adverse events. In patients treated for 2 years or more, adverse events in the olaparib and placebo groups included low-grade nausea (24 [75%] of 32 patients vs two [40%] of five), fatigue (18 [56%] of 32 vs two [40%] of five), vomiting (12 [38%] of 32 vs zero), and anaemia (eight [25%] of 32 vs one [20%] of five); generally, events were initially reported during the first 2 years of treatment. INTERPRETATION: Despite not reaching statistical significance, patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy after platinum-based chemotherapy appeared to have longer overall survival, supporting the reported progression-free survival benefit. Clinically useful long-term exposure to olaparib was seen with no new safety signals. Taken together, these data support both the long-term clinical benefit and tolerability of maintenance olaparib in patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer. FUNDING: AstraZeneca.


Assuntos
Antineoplásicos/uso terapêutico , Cistadenocarcinoma Seroso/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/genética , Proteína BRCA2/genética , Cistadenocarcinoma Seroso/mortalidade , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/mortalidade , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos
14.
BMC Cardiovasc Disord ; 16: 101, 2016 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-27216309

RESUMO

BACKGROUND: In a cross-sectional study we examined whether the haemodynamic response to upright posture could be divided into different functional phenotypes, and whether the observed phenotypes were associated with known determinants of cardiovascular risk. METHODS: Volunteers (n = 470) without medication with cardiovascular effects were examined using radial pulse wave analysis, whole-body impedance cardiography, and heart rate variability analysis. Based on the passive head-up tilt induced changes in systemic vascular resistance and cardiac output, the principal determinants of blood pressure, a cluster analysis was performed. RESULTS: The haemodynamic response could be clustered into 3 categories: upright increase in vascular resistance and decrease in cardiac output were greatest in the first (+45 % and -27 %, respectively), smallest in the second (+2 % and -2 %, respectively), and intermediate (+22 % and -13 %, respectively) in the third group. These groups were named as 'constrictor' (n = 109), 'sustainer' (n = 222), and 'intermediate' (n = 139) phenotypes, respectively. The sustainers were characterized by male predominance, higher body mass index, blood pressure, and also by higher pulse wave velocity, an index of large arterial stiffness, than the other groups (p < 0.01 for all). Heart rate variability analysis showed higher supine and upright low frequency/high frequency (LF/HF) ratio in the sustainers than constrictors, indicating increased sympathovagal balance. Upright LF/HF ratio was also higher in the sustainer than intermediate group. In multivariate analysis, independent explanatory factors for higher pulse wave velocity were the sustainer (p < 0.022) and intermediate phenotypes (p < 0.046), age (p < 0.001), body mass index (p < 0.001), and hypertension (p < 0.001). CONCLUSIONS: The response to upright posture could be clustered to 3 functional phenotypes. The sustainer phenotype, with smallest upright decrease in cardiac output and highest sympathovagal balance, was independently associated with increased large arterial stiffness. These results indicate an association of the functional haemodynamic phenotype with an acknowledged marker of cardiovascular risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT01742702.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/inervação , Hemodinâmica , Postura , Rigidez Vascular , Adaptação Fisiológica , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Débito Cardíaco , Cardiografia de Impedância , Doenças Cardiovasculares/diagnóstico , Análise por Conglomerados , Estudos Transversais , Feminino , Frequência Cardíaca , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Pletismografia Total , Valor Preditivo dos Testes , Análise de Onda de Pulso , Teste da Mesa Inclinada , Resistência Vascular , Adulto Jovem
15.
Phys Chem Chem Phys ; 17(36): 23438-47, 2015 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-26291423

RESUMO

A miniaturised electrochemical cell design for Electron Paramagnetic Resonance (EPR) studies is reported. The cell incorporates a Loop Gap Resonator (LGR) for EPR investigation of electrochemically generated radicals in aqueous (and other large dielectric loss) samples and achieves accurate potential control for electrochemistry by using micro-wires as working electrodes. The electrochemical behaviour of the cell is analysed with COMSOL finite element models and the EPR sensitivity compared to a commercial TE011 cavity resonator using 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL) as a reference. The electrochemical EPR performance is demonstrated using the reduction of methyl viologen as a redox probe in both water and acetonitrile. The data reported herein suggest that sub-micromolar concentrations of radical species can be detected in aqueous samples with accurate potential control, and that subtle solution processes coupled to electron transfer, such as comproportionation reactions, can be studied quantitatively using EPR.

16.
Nature ; 507(7490): 45, 47, 2014 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-24598635
17.
Adv Neurobiol ; 39: 137-163, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39190074

RESUMO

In the intricate landscape of neurophysiology, astrocytes have been traditionally cast as homeostatic cells; however, their mechanistic involvement in allostasis-particularly how they modulate the adaptive response to stress and its accumulative impact that disrupts cognitive functions and precipitates psychiatric disorders-is now starting to be unraveled. Here, we address the gap by positing astrocytes as crucial allostatic players whose molecular adaptations underlie cognitive flexibility in stress-related neuropsychiatric conditions. We review how astrocytes, responding to stress mediators such as glucocorticoid and epinephrine/norepinephrine, undergo morphological and functional transformations that parallel the maladaptive changes. Our synthesis of recent findings reveals that these glial changes, especially in the metabolically demanding prefrontal cortex, may underlie some of the neuropsychiatric mechanisms characterized by the disruption of energy metabolism and astrocytic networks, compromised glutamate clearance, and diminished synaptic support. We argue that astrocytes extend beyond their homeostatic role, actively participating in the brain's allostatic response, especially by modulating energy substrates critical for cognitive functions.


Assuntos
Alostase , Astrócitos , Cognição , Homeostase , Córtex Pré-Frontal , Estresse Psicológico , Astrócitos/metabolismo , Humanos , Córtex Pré-Frontal/metabolismo , Homeostase/fisiologia , Alostase/fisiologia , Cognição/fisiologia , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Animais , Metabolismo Energético/fisiologia
18.
Nat Commun ; 15(1): 7395, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39191798

RESUMO

Dissipation and the accompanying fluctuations are often seen as detrimental for quantum systems since they are associated with fast relaxation and loss of phase coherence. However, it has been proposed that a pure state can be prepared if external noise induces suitable downwards transitions, while exciting transitions are blocked. We demonstrate such a refrigeration mechanism in a cavity optomechanical system, where we prepare a mechanical oscillator in its ground state by injecting strong electromagnetic noise at frequencies around the red mechanical sideband of the cavity. The optimum cooling is reached with a noise bandwidth smaller than but on the order of the cavity decay rate. At higher bandwidths, cooling is less efficient as suitable transitions are not effectively activated. In the opposite regime where the noise bandwidth becomes comparable to the mechanical damping rate, damping follows the noise amplitude adiabatically, and the cooling is also suppressed.

19.
J Urol ; 189(4): 1377-82, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23103801

RESUMO

PURPOSE: Urinary storage symptoms are the most common and most bothersome urinary symptoms. Many studies on the relation between body weight and urinary symptoms have focused on urinary incontinence in women. We evaluated the association of obesity with urinary storage symptoms in a population based study of men and women age 18 to 79 years old. MATERIALS AND METHODS: Questionnaires were mailed to 6,000 adults randomly identified from the Finnish Population Register. Self-reported height and weight were used to calculate body mass index. Urinary frequency, nocturia, urgency, stress urinary incontinence and urgency urinary incontinence were assessed using validated instruments. Multivariate logistic regression analyses (adjusted for age, comorbidity and medications, and sociodemographic, lifestyle and reproductive factors) were performed to evaluate associations between body mass index and each symptom. RESULTS: Of the 6,000 individuals approached 3,727 participated (62.4% response, 53.7% women). In men and women obesity was associated with nocturia (adjusted OR 2.0, 95% CI 1.2-3.3 for men; OR 2.4, 95% CI 1.5-3.8 for women) but not with urgency (adjusted OR 1.2, 95% CI 0.7-2.3 for men; OR 1.2, 95% CI 0.7-2.1 for women). In men obesity was also associated with urinary frequency (OR 2.0, 95% CI 1.0-3.9), and in women it was associated with stress urinary incontinence (OR 1.9, 95% CI 1.2-3.0) and urgency urinary incontinence (OR 3.0, 95% CI 1.2-7.4). However, the number of men with stress urinary incontinence or urgency urinary incontinence was insufficient for precise analyses. CONCLUSIONS: This study extends previous research by providing symptom specific associations between obesity and urinary storage symptoms in a population based sample of men and women. Obesity impacts individual urinary storage symptoms differently and these associations may be influenced by gender.


Assuntos
Obesidade/complicações , Incontinência Urinária/etiologia , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
J Vasc Surg ; 57(2): 586-592.e2, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23254185

RESUMO

OBJECTIVE: To survey the Society for Vascular Surgery (SVS) membership with regard to practice trends related to work effort, employment status, practice ownership, endovascular cases, and anticipated changes in practice in the near future. METHODS: A survey questionnaire was developed to gather information about member demographics and practice, hours worked, full-time (FT) or part-time status, employment status, practice ownership, competition for referrals, proportion of endovascular vs open procedures, and anticipated changes in practice in the next 3 years. We used SurveyMonkey and distributed the survey to all active vascular surgeon (VS) members of the SVS. RESULTS: The response rate was 207 of 2230 (10.7%). Two thirds were in private practice, and 21% were in solo practice. Twenty-four percent were employed by hospitals/health systems. Those VS under the age of 50 years were more likely to exclusively practice vascular surgery compared with VS over the age of 50 years (P = .0003). Sixty-eight of the physicians (32.7%) were between 50 and 59 years old, 186 (90.3%) were men, 192 (92.8%) worked FT (>36 hours of patient care per week), and almost two thirds worked >60 hours per week. Those in physician-owned practices worked >40 hours of patient care per week more often than did FT employed VS (P = .012). Younger VS (age <50 years) more frequently reported >50% of their workload being endovascular compared with older VS (age ≥50 years; P < .001). Eighty percent of FT VS planned to continue their current practice over the next 3 years. Of the 43.6% indicating loss of referrals, 82% pointed to cardiologists as the competition. CONCLUSIONS: The current workforce is predominately male and works FT; one-third is between the ages of 50 and 59 years. Younger VS (age <50 years) are more likely to exclusively practice VS and have a higher caseload of endovascular procedures. Those in physician-owned practices are more likely to put in >40 hours of patient care per week than are FT employed VS. Longitudinal surveys of SVS members are imperative to help tailor educational, training, and practice management offerings, guide governmental activities, advocate for issues important to members, improve branding initiatives, and sponsor workforce analyses.


Assuntos
Procedimentos Endovasculares/tendências , Administração da Prática Médica/tendências , Padrões de Prática Médica/tendências , Procedimentos Cirúrgicos Vasculares/tendências , Adulto , Idoso , Distribuição de Qui-Quadrado , Competição Econômica/tendências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Propriedade/tendências , Admissão e Escalonamento de Pessoal/tendências , Prática Privada/tendências , Encaminhamento e Consulta/tendências , Sociedades Médicas , Inquéritos e Questionários , Fatores de Tempo , Carga de Trabalho
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