RESUMEN
Chronic obstructive pulmonary disease (COPD) is one of the most common causes of death worldwide. We report in an emphysema model of mice chronically exposed to tobacco smoke that pulmonary vascular dysfunction, vascular remodeling, and pulmonary hypertension (PH) precede development of alveolar destruction. We provide evidence for a causative role of inducible nitric oxide synthase (iNOS) and peroxynitrite in this context. Mice lacking iNOS were protected against emphysema and PH. Treatment of wild-type mice with the iNOS inhibitor N(6)-(1-iminoethyl)-L-lysine (L-NIL) prevented structural and functional alterations of both the lung vasculature and alveoli and also reversed established disease. In chimeric mice lacking iNOS in bone marrow (BM)-derived cells, PH was dependent on iNOS from BM-derived cells, whereas emphysema development was dependent on iNOS from non-BM-derived cells. Similar regulatory and structural alterations as seen in mouse lungs were found in lung tissue from humans with end-stage COPD.
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Modelos Animales de Enfermedad , Pulmón/patología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/patología , Fumar/patología , Animales , Humanos , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Pulmón/irrigación sanguínea , Pulmón/fisiopatología , Lisina/análogos & derivados , Lisina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo II/genética , Alveolos Pulmonares/patología , Alveolos Pulmonares/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfisema Pulmonar/inducido químicamente , Enfisema Pulmonar/tratamiento farmacológico , Enfisema Pulmonar/patología , Enfisema Pulmonar/fisiopatologíaRESUMEN
We investigate the parameters of global solar p-mode oscillations, namely damping width Γ , amplitude A , mean squared velocity ã v 2 ã , energy E , and energy supply rate d E / d t , derived from two solar cycles' worth (1996 - 2018) of Global Oscillation Network Group (GONG) time series for harmonic degrees l = 0 - 150 . We correct for the effect of fill factor, apparent solar radius, and spurious jumps in the mode amplitudes. We find that the amplitude of the activity-related changes of Γ and A depends on both frequency and harmonic degree of the modes, with the largest variations of Γ for modes with 2400 µ Hz ≤ ν ≤ 3300 µ Hz and 31 ≤ l ≤ 60 with a minimum-to-maximum variation of 26.6 ± 0.3 % and of A for modes with 2400 µ Hz ≤ ν ≤ 3300 µ Hz and 61 ≤ l ≤ 100 with a minimum-to-maximum variation of 27.4 ± 0.4 % . The level of correlation between the solar radio flux F 10.7 and mode parameters also depends on mode frequency and harmonic degree. As a function of mode frequency, the mode amplitudes are found to follow an asymmetric Voigt profile with ν max = 3073.59 ± 0.18 µ Hz . From the mode parameters, we calculate physical mode quantities and average them over specific mode frequency ranges. In this way, we find that the mean squared velocities ã v 2 ã and energies E of p modes are anticorrelated with the level of activity, varying by 14.7 ± 0.3 % and 18.4 ± 0.3 % , respectively, and that the mode energy supply rates show no significant correlation with activity. With this study we expand previously published results on the temporal variation of solar p-mode parameters. Our results will be helpful to future studies of the excitation and damping of p modes, i.e., the interplay between convection, magnetic field, and resonant acoustic oscillations.
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Evolución Clonal/genética , Dosificación de Gen/fisiología , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Proteína p53 Supresora de Tumor/genética , Alelos , Proliferación Celular/genética , Progresión de la Enfermedad , Eliminación de Gen , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Redes y Vías Metabólicas/genética , Mieloma Múltiple/metabolismo , Mieloma Múltiple/mortalidad , Mutación , Recurrencia , Análisis de Supervivencia , Células Tumorales CultivadasRESUMEN
BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disease characterized by vascular remodeling and increased pulmonary vascular resistance. Chronic alveolar hypoxia in animals is often used to decipher pathways being regulated in PH. Here, we aimed to investigate whether chronic hypoxia-induced PH in mice can be reversed by reoxygenation and whether possible regression can be used to identify pathways activated during the reversal and development of PH by genome-wide screening. METHODS AND RESULTS: Mice exposed to chronic hypoxia (21 days, 10% O2) were reoxygenated for up to 42 days. Full reversal of PH during reoxygenation was evident by normalized right ventricular pressure, right heart hypertrophy, and muscularization of small pulmonary vessels. Microarray analysis from these mice revealed s-adenosylmethionine decarboxylase 1 (AMD-1) as one of the most downregulated genes. In situ hybridization localized AMD-1 in pulmonary vessels. AMD-1 silencing decreased the proliferation of pulmonary arterial smooth muscle cells and diminished phospholipase Cγ1 phosphorylation. Compared with the respective controls, AMD-1 depletion by heterozygous in vivo knockout or pharmacological inhibition attenuated PH during chronic hypoxia. A detailed molecular approach including promoter analysis showed that AMD-1 could be regulated by early growth response 1, transcription factor, as a consequence of epidermal growth factor stimulation. Key findings from the animal model were confirmed in human idiopathic pulmonary arterial hypertension. CONCLUSIONS: Our study indicates that genome-wide screening in mice from a PH model in which full reversal of PH occurs can be useful to identify potential key candidates for the reversal and development of PH. Targeting AMD-1 may represent a promising strategy for PH therapy.
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Adenosilmetionina Descarboxilasa/metabolismo , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Pulmón/irrigación sanguínea , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Transducción de Señal/fisiología , Adenosilmetionina Descarboxilasa/deficiencia , Adenosilmetionina Descarboxilasa/genética , Adulto , Anciano , Animales , Apoptosis , Proliferación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Regulación hacia Abajo , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Factor de Crecimiento Epidérmico/metabolismo , Femenino , Humanos , Hipertensión Pulmonar/etiología , Hipoxia/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis por Micromatrices , Persona de Mediana Edad , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologíaRESUMEN
We used time-resolved shadowgraphy to characterize the pre-plasma formation in solid-target interaction experiments with micrometer-scale accuracy. We performed quantitative measurements of the plasma density for amplified spontaneous emission (ASE) levels ranging from 2 · 10(-7) to 10(-10) backed with 2-dimensional hydrodynamic simulations. We find that ASE levels above 10(-9) are able to create a significant pre-plasma plume that features a plasma canal driving a self-focusing of the laser beam. For ASE levels of 10(-10), no ASE pre-plasma could be detected.
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Electricidad , Rayos Láser , Gases em Plasma/química , Simulación por Computador , Procesamiento de Imagen Asistido por Computador , Electricidad Estática , Factores de TiempoRESUMEN
Neutron diffraction beamlines have traditionally relied on deploying large detector arrays of 3He tubes or neutron-sensitive scintillators coupled with photomultipliers to efficiently probe crystallographic and microstructure information of a given material. Given the large upfront cost of custom-made data acquisition systems and the recent scarcity of 3He, new diffraction beamlines or upgrades to existing ones demand innovative approaches. This paper introduces a novel Timepix3-based event-mode imaging neutron diffraction detector system as well as first results of a silicon powder diffraction measurement made at the HIPPO neutron powder diffractometer at the Los Alamos Neutron Science Center. Notably, these initial measurements were conducted simultaneously with the 3He array on HIPPO, enabling direct comparison. Data reduction for this type of data was implemented in the MAUD code, enabling Rietveld analysis. Results from the Timepix3-based setup and HIPPO were benchmarked against McStas simulations, showing good agreement for peak resolution. With further development, systems such as the one presented here may substantially reduce the cost of detector systems for new neutron instrumentation as well as for upgrades of existing beamlines.
RESUMEN
Laser-driven ion beams have gained considerable attention for their potential use in multidisciplinary research and technology. Preclinical studies into their radiobiological effectiveness have established the prospect of using laser-driven ion beams for radiotherapy. In particular, research into the beneficial effects of ultrahigh instantaneous dose rates is enabled by the high ion bunch charge and uniquely short bunch lengths present for laser-driven ion beams. Such studies require reliable, online dosimetry methods to monitor the bunch charge for every laser shot to ensure that the prescribed dose is accurately applied to the biological sample. In this paper, we present the first successful use of an Integrating Current Transformer (ICT) for laser-driven ion accelerators. This is a noninvasive diagnostic to measure the charge of the accelerated ion bunch. It enables online estimates of the applied dose in radiobiological experiments and facilitates ion beam tuning, in particular, optimization of the laser ion source, and alignment of the proton transport beamline. We present the ICT implementation and the correlation with other diagnostics, such as radiochromic films, a Thomson parabola spectrometer, and a scintillator.
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Rayos Láser , Aceleradores de Partículas , Radiometría/métodos , Radiobiología , AceleraciónRESUMEN
Neutrons are a valuable tool for non-destructive material investigation as their interaction cross sections with matter are isotope sensitive and can be used complementary to x-rays. So far, most neutron applications have been limited to large-scale facilities such as nuclear research reactors, spallation sources, and accelerator-driven neutron sources. Here we show the design and optimization of a laser-driven neutron source in the epi-thermal and thermal energy range, which is used for non-invasive material analysis. Neutron resonance spectroscopy, neutron radiography, and neutron resonance imaging with moderated neutrons are demonstrated for investigating samples in terms of isotope composition and thickness. The experimental results encourage applications in non-destructive and isotope-sensitive material analysis and pave the way for compact laser-driven neutron sources with high application potential.
RESUMEN
RATIONALE: Hypoxic pulmonary vasoconstriction (HPV) is an important mechanism by which pulmonary gas exchange is optimized by the adaptation of blood flow to alveolar ventilation. In chronic hypoxia, in addition to HPV a vascular remodeling process leads to pulmonary hypertension. A complex of heme oxygenase-2 (HO-2) and the BK channel has been suggested as a universal oxygen sensor system. OBJECTIVES: We investigated whether this complex serves as an oxygen sensor for the vascular effects of alveolar hypoxia in the lung. METHODS: The investigations were performed in chronically hypoxic mice, in isolated perfused and ventilated lungs, and on the cellular level, including HO-2- and BK-channel deficient mice. MEASUREMENTS AND MAIN RESULTS: Immunohistochemical analysis of mouse lungs identified HO-2 mainly in pulmonary arteries, the bronchial epithelium, and alveolar epithelial cells. BK channel alpha-subunit (BKalpha) immunoreactivity was found primarily in the bronchial and vascular smooth muscle layer. Immunofluorescence staining and coimmunoprecipitation suggested only a weak complexation of HO-2 and BKalpha in pulmonary arterial smooth muscle cells. The strength of acute and sustained HPV, determined in isolated perfused and ventilated lungs, was not different among wild-type, HO-2-deficient, and BKalpha-deficient mice. Exposure of mice to 3 weeks of chronic hypoxia resulted in a slight down-regulation of HO-2 and no alteration in BKalpha expression. The degree of pulmonary hypertension that developed, quantified on the basis of right ventricular pressure, right-heart hypertrophy, and the degree of muscularization of precapillary pulmonary arteries, was not different among wild-type, HO-2-deficient, and BKalpha-deficient mice. CONCLUSIONS: It is demonstrated that neither deletion of HO-2 nor BK channels affect acute, sustained, and chronic vascular responses to alveolar hypoxia in the lung.
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Hemo Oxigenasa (Desciclizante)/genética , Hemo Oxigenasa (Desciclizante)/fisiología , Hipoxia/fisiopatología , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/genética , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/fisiología , Pulmón/irrigación sanguínea , Alveolos Pulmonares/irrigación sanguínea , Vasoconstricción/fisiología , Animales , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Hipoxia/patología , Técnicas In Vitro , Pulmón/patología , Ratones , Microscopía Fluorescente , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiopatología , Reacción en Cadena de la Polimerasa , Alveolos Pulmonares/patología , Presión Esfenoidal Pulmonar/fisiología , ARN Mensajero/genéticaRESUMEN
Nonphagocytic NADPH oxidases have recently been suggested to play a major role in the regulation of physiological and pathophysiological processes, in particular, hypertrophy, remodeling, and angiogenesis in the systemic circulation. Moreover, NADPH oxidases have been suggested to serve as oxygen sensors in the lung. Chronic hypoxia induces vascular remodeling with medial hypertrophy leading to the development of pulmonary hypertension. We screened lung tissue for the expression of NADPH oxidase subunits. NOX1, NOXA1, NOXO1, p22phox, p47phox, p40phox, p67phox, NOX2, and NOX4 were present in mouse lung tissue. Comparing mice maintained for 21 days under hypoxic (10% O(2)) or normoxic (21% O(2)) conditions, an upregulation exclusively of NOX4 mRNA was observed under hypoxia in homogenized lung tissue, concomitant with increased levels in microdissected pulmonary arterial vessels. In situ hybridization and immunohistological staining for NOX4 in mouse lungs revealed a localization of NOX4 mRNA and protein predominantly in the media of small pulmonary arteries, with increased labeling intensities after chronic exposure to hypoxia. In isolated pulmonary arterial smooth muscle cells (PASMCs), NOX4 was localized primarily to the perinuclear space and its expression levels were increased after exposure to hypoxia. Treatment of PASMCs with siRNA directed against NOX4 decreased NOX4 mRNA levels and reduced PASMC proliferation as well as generation of reactive oxygen species. In lungs from patients with idiopathic pulmonary arterial hypertension (IPAH), expression levels of NOX4, which was localized in the vessel media, were 2.5-fold upregulated. These results support an important role for NOX4 in the vascular remodeling associated with development of pulmonary hypertension.
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Hipertensión Pulmonar/enzimología , Hipoxia/enzimología , NADPH Oxidasas/fisiología , Animales , División Celular , Células Cultivadas/efectos de los fármacos , Células Cultivadas/enzimología , Enfermedad Crónica , Diseño de Fármacos , Retículo Endoplásmico/enzimología , Inducción Enzimática , Femenino , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Hipertrofia , Hipoxia/complicaciones , Hipoxia/fisiopatología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Pulmón/irrigación sanguínea , Masculino , Glicoproteínas de Membrana/análisis , Miocitos del Músculo Liso/enzimología , Miocitos del Músculo Liso/patología , NADPH Oxidasa 2 , NADPH Oxidasa 4 , NADPH Oxidasas/análisis , NADPH Oxidasas/biosíntesis , NADPH Oxidasas/genética , Óxido Nítrico/fisiología , Especificidad de Órganos , Oxígeno/metabolismo , Oxígeno/farmacología , Subunidades de Proteína , Arteria Pulmonar/citología , Arteria Pulmonar/enzimología , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Interferente Pequeño/farmacología , Superóxidos/metabolismo , Factor de Crecimiento Transformador beta1/fisiología , Túnica Media/enzimología , Túnica Media/patologíaRESUMEN
Recent advances in molecular diagnostics have shown that lesions affecting both copies of the gene for tumor suppressor protein 53 (TP53) count among the most powerful predictors for high-risk disease in multiple myeloma (MM). However, the functional relevance and potential therapeutic implications of single hits to TP53 remain less well understood. Here, we have for the first time approximated the different constellations of mono- and bi-allelic TP53 lesions observed in MM patients within the frame of a single MM cell line model and assessed their potential to disrupt p53 system functionality and to impart drug resistance. Both types of common first hit: point mutation with expression of mutant p53 protein or complete loss of contribution from one of two wildtype alleles strongly impaired p53 system functionality and increased resistance to melphalan. Second hits abolished remaining p53 activity and increased resistance to genotoxic drugs even further. These results fit well with the clinical drive to TP53 single- and double-hit disease in MM patients, provide a rationale for the most commonly observed double-hit constellation (del17p+ TP53 point mutation), and underscore the potential increases in MM cell malignancy associated with any type of initial TP53 lesion.
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Antineoplásicos Alquilantes/farmacología , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple/genética , Proteína p53 Supresora de Tumor/genética , Alelos , Antineoplásicos Alquilantes/uso terapéutico , Sistemas CRISPR-Cas/genética , Línea Celular Tumoral , Edición Génica , Heterocigoto , Homocigoto , Humanos , Melfalán/farmacología , Melfalán/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Mutación Puntual , Transducción de Señal/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Progression of pulmonary hypertension is associated with increased proliferation and migration of pulmonary vascular smooth muscle cells. PDGF is a potent mitogen and involved in this process. We now report that the PDGF receptor antagonist STI571 (imatinib) reversed advanced pulmonary vascular disease in 2 animal models of pulmonary hypertension. In rats with monocrotaline-induced pulmonary hypertension, therapy with daily administration of STI571 was started 28 days after induction of the disease. A 2-week treatment resulted in 100% survival, compared with only 50% in sham-treated rats. The changes in RV pressure, measured continuously by telemetry, and right heart hypertrophy were reversed to near-normal levels. STI571 prevented phosphorylation of the PDGF receptor and suppressed activation of downstream signaling pathways. Similar results were obtained in chronically hypoxic mice, which were treated with STI571 after full establishment of pulmonary hypertension. Moreover, expression of the PDGF receptor was found to be significantly increased in lung tissue from pulmonary arterial hypertension patients compared with healthy donor lung tissue. We conclude that STI571 reverses vascular remodeling and cor pulmonale in severe experimental pulmonary hypertension regardless of the initiating stimulus. This regimen offers a unique novel approach for antire-modeling therapy in progressed pulmonary hypertension.
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Hipertensión Pulmonar/tratamiento farmacológico , Piperazinas/administración & dosificación , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Animales , Benzamidas , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Humanos , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Mesilato de Imatinib , Pulmón/irrigación sanguínea , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Ratas , Ratas Sprague-Dawley , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismoRESUMEN
Dynamic cerebral autoregulation assessed from blood pressure transients can be considerably impaired in severe internal carotid artery (ICA) obstruction. It is unknown whether impaired autoregulation indicates an increased risk of subsequent ischemic events in this situation. 165 patients with ICA stenosis (> 70 %) or occlusion were prospectively followed until anterior circulation stroke, transient ischemic attack, carotid recanalization without prior event, death or study end. Transcranial Doppler sonography was used to determine autoregulation in both middle cerebral arteries from spontaneous blood pressure fluctuations (correlation coefficient indices Dx and Mx) and respiratory- induced 0.1 Hz oscillations (phase). Standard CO(2) reactivity (CO(2)R) was additionally assessed. All indices were classified as impaired vs. preserved according to reference values from 79 agematched controls. During median follow-up of 24.5 months, there were 16 ischemic events over ipsilateral sides. Competing risk analysis revealed a significant predictive effect on ipsilateral ischemic events for impaired Dx (rate ratio 8.2 [95 % confidence interval 1.7-39], p = 0.0079), phase (5.0 [2-13], p = 0.0007) and CO(2)R (9.4 [2.2-40], p = 0.0025). Restricting analysis to severe stenosis alone (n = 103), only impaired phase (rate ratio 8.6 [1.6-45], p = 0.01) remained as a significant predictor. In a continuous statistical model, only Dx and Mx were significant predictors of ischemic events (p = 0.012 and p = 0.016). In conclusion, impaired dynamic cerebral autoregulation indicates an increased risk of subsequent ischemic events in severe obstructive ICA disease. Its clinical application might thus be of help in identifying higher risk patients.
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Isquemia Encefálica/etiología , Encéfalo/fisiopatología , Enfermedades de las Arterias Carótidas/complicaciones , Circulación Cerebrovascular/fisiología , Riesgo , Anciano , Análisis de Varianza , Velocidad del Flujo Sanguíneo/fisiología , Encéfalo/patología , Isquemia Encefálica/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Lateralidad Funcional , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Valores de Referencia , Análisis de Regresión , Análisis Espectral , Ultrasonografía Doppler Transcraneal/métodosRESUMEN
BACKGROUND: To investigate whether there is: (1) a specific temporal course of cerebral dysautoregulation in acute ischemic stroke, and (2) a separate detrimental effect of recombinant tissue plasminogen activator (rtPA) on autoregulation dynamics in this situation. METHODS: We studied 16 patients with acute middle cerebral artery (MCA) occlusion and rtPA thrombolysis (intra-arterial or intravenous application, or both). Controls were 71 healthy adults and 11 patients with minor stroke not receiving rtPA. Dynamic autoregulation was recorded from spontaneous fluctuations of blood pressure and MCA flow velocity (transcranial Doppler) using two well-described approaches (index Mx, phase shift). Three measurements were performed (study 1: 20 +/- 9 h of ictus; study 2: 64 +/- 10 h; study 3: 112 +/- 7 h). RESULTS: Two groups of clinical outcome were identified: good (modified Rankin scale
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Circulación Cerebrovascular/efectos de los fármacos , Fibrinolíticos/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Terapia Trombolítica , Activador de Tejido Plasminógeno/uso terapéutico , Enfermedad Aguda , Anciano , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Femenino , Fibrinolíticos/administración & dosificación , Fibrinolíticos/efectos adversos , Homeostasis , Humanos , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/fisiopatología , Infusiones Intraarteriales , Infusiones Intravenosas , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Terapia Trombolítica/efectos adversos , Factores de Tiempo , Activador de Tejido Plasminógeno/administración & dosificación , Activador de Tejido Plasminógeno/efectos adversos , Resultado del Tratamiento , Ultrasonografía Doppler TranscranealRESUMEN
Walking along a beach one may notice debris being washed ashore from the vast oceans. Then, turning your head up at night you even might noticed a shooting star or a bright spot passing by. Chances are, that you witnessed space debris, endangering future space flight in lower earth orbit. If it was possible to turn cm-sized debris into shooting stars the problem might be averted. Unfortunately, these fragments counting in the 100 thousands are not controllable. To possibly regain control we demonstrate how to exert forces on a free falling debris object from a distance by ablating material with a high energy ns-laser-system. Thrust effects did scale as expected from simulations and led to speed gains above 0.3 m/s per laser pulse in an evacuated micro-gravity environment.
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OBJECTIVES: Chronic alveolar hypoxia induces pulmonary hypertension, evident from elevated pulmonary artery pressure (PAP), pulmonary vascular resistance, right ventricular hypertrophy (RVH), and increased muscularization of the pulmonary vasculature. Additionally, the vasoconstrictor response to acute hypoxia (HPV) may be reduced in the remodeled vasculature. However, no direct comparison of different treatments on the various parameters characterizing pulmonary hypertension has been performed yet. Against this background, we compared the effects of inhaled NO, infused iloprost, a stable prostacyclin analogue, and oral sildenafil, a phosphodiesterase 5 inhibitor, on hypoxia-induced pulmonary hypertension. METHODS: Exposure of rabbits to chronic hypoxia (FiO(2)=0.10) for 42 days. Treatment with infused iloprost, oral sildenafil, and inhaled nitric oxide. RESULTS: We quantified PAP, pulmonary vascular resistance, RVH, vascular remodeling, vasoreactivity, and the strength of HPV. Chronic hypoxia resulted in an increase in (a) the right ventricle/(left ventricle+septum) ratio from 0.26+/-0.01 to 0.44+/-0.01, (b) PAP, and (c) the degree of muscularization from 14.0+/-4.0% to 43.5+/-5.3%. Treatment with iloprost and sildenafil, but not with NO, prevented the increase in muscularization. In contrast, RVH was strongly inhibited by sildenafil, whereas NO had some minor, and iloprost had no effect. Only iloprost reduced PAP compared to NO and sildenafil. The downregulation of HPV was abrogated only by NO. CONCLUSION: We demonstrated (a) that the parameters characterizing hypoxia-induced pulmonary hypertension are not functionally linked, (b) that the downregulation of HPV under chronic hypoxia can be prevented by inhaled NO but not by sildenafil and iloprost, and (c) that iloprost is particularly effective in preventing vascular remodeling and sildenafil in preventing RVH.
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Hipertensión Pulmonar/tratamiento farmacológico , Hipoxia/complicaciones , Resistencia Vascular/efectos de los fármacos , Vasodilatadores/farmacología , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Iloprost/administración & dosificación , Iloprost/farmacología , Óxido Nítrico/administración & dosificación , Óxido Nítrico/farmacología , Piperazinas/administración & dosificación , Piperazinas/farmacología , Purinas/administración & dosificación , Purinas/farmacología , Conejos , Citrato de Sildenafil , Sulfonas/administración & dosificación , Sulfonas/farmacología , Resultado del Tratamiento , Vasodilatadores/administración & dosificaciónRESUMEN
A technique for the creation of free-standing cryogenic targets for laser-driven ion acceleration is presented, which allows us to create solid state targets consisting of initially gaseous materials. In particular, the use of deuterium and the methods for its preparation as a target material for laser-driven ion acceleration are discussed. Moving in the phase diagram through the liquid phase leads to the substance covering an aperture on a cooled copper frame where it is solidified through further cooling. An account of characterization techniques for target thickness is given, with a focus on deducing thickness values from distance values delivered by chromatic confocal sensors.
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Laser-plasma interactions in the novel regime of relativistically induced transparency (RIT) have been harnessed to generate intense ion beams efficiently with average energies exceeding 10 MeV/nucleon (>100 MeV for protons) at "table-top" scales in experiments at the LANL Trident Laser. By further optimization of the laser and target, the RIT regime has been extended into a self-organized plasma mode. This mode yields an ion beam with much narrower energy spread while maintaining high ion energy and conversion efficiency. This mode involves self-generation of persistent high magnetic fields (â¼104 T, according to particle-in-cell simulations of the experiments) at the rear-side of the plasma. These magnetic fields trap the laser-heated multi-MeV electrons, which generate a high localized electrostatic field (â¼0.1 T V/m). After the laser exits the plasma, this electric field acts on a highly structured ion-beam distribution in phase space to reduce the energy spread, thus separating acceleration and energy-spread reduction. Thus, ion beams with narrow energy peaks at up to 18 MeV/nucleon are generated reproducibly with high efficiency (≈5%). The experimental demonstration has been done with 0.12 PW, high-contrast, 0.6 ps Gaussian 1.053 µm laser pulses irradiating planar foils up to 250 nm thick at 2-8 × 1020 W/cm2. These ion beams with co-propagating electrons have been used on Trident for uniform volumetric isochoric heating to generate and study warm-dense matter at high densities. These beam plasmas have been directed also at a thick Ta disk to generate a directed, intense point-like Bremsstrahlung source of photons peaked at â¼2 MeV and used it for point projection radiography of thick high density objects. In addition, prior work on the intense neutron beam driven by an intense deuterium beam generated in the RIT regime has been extended. Neutron spectral control by means of a flexible converter-disk design has been demonstrated, and the neutron beam has been used for point-projection imaging of thick objects. The plans and prospects for further improvements and applications are also discussed.
RESUMEN
The phase shift between oscillations of blood pressure (BP) and Doppler middle cerebral artery flow velocity (MCAFV) reflects continuous cerebral autoregulatory action. It is not known whether a similar phase shift exists for cortical hemodynamics ('microvascular level') assessed by near infrared spectroscopy (NIRS) and what the effects are of pathological conditions. This study investigates the phase relations between oscillations of BP, MCAFV and NIRS parameters in 38 healthy older adults and 28 patients with unilateral severe obstructive carotid disease. BP was recorded noninvasively by finger plethysmography. Stable 0.1 Hz oscillations of all hemodynamic parameters were induced by regular breathing at a rate of 6/min. Basic results were that: (1) BP-induced cortical microvascular oscillations (NIRS) follow those of macrovascular oscillations (MCAFV) with a phase of 80-90 degrees (corresponding to 2-2.5 s at 0.1 Hz), most likely reflecting a transit time phenomenon; (2) oxy- and deoxyhemoglobin thereby oscillate in counterphase; (3) hemodynamic compromise in carotid obstruction leads to (a) delayed NIRS oscillations in comparison to BP which are highly correlated to a shorter phase lead of MCAFV against BP and (b) a decoupling of the oxy-/deoxyhemoglobin counterphase to 240 degrees . Cortical hemodynamic responses to BP oscillations follow specific phase relationships due to cerebral autoregulatory action and circulatory transit times. With hemodynamic impairment, as in unilateral carotid obstruction, these phases are significantly changed reflecting disturbed autoregulation.
Asunto(s)
Relojes Biológicos/fisiología , Presión Sanguínea/fisiología , Circulación Cerebrovascular/fisiología , Microcirculación/fisiología , Arteria Cerebral Media/fisiología , Telencéfalo/irrigación sanguínea , Anciano , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/fisiopatología , Trastornos Cerebrovasculares/diagnóstico por imagen , Trastornos Cerebrovasculares/fisiopatología , Femenino , Homeostasis/fisiología , Humanos , Flujometría por Láser-Doppler/métodos , Masculino , Microcirculación/diagnóstico por imagen , Persona de Mediana Edad , Arteria Cerebral Media/diagnóstico por imagen , Pletismografía , Valor Predictivo de las Pruebas , Factores de Riesgo , Telencéfalo/diagnóstico por imagen , Telencéfalo/fisiología , UltrasonografíaRESUMEN
Hydrothermal oxidation (HTO) provides an efficient technique to completely destroy wet organic wastes. In this study, HTO was applied to treat fecal sludge at well-defined experimental conditions. Four different kinetic models were adjusted to the obtained data. Among others, a distributed activation energy model (DAEM) was applied. A total of 33 experiments were carried out in an unstirred batch reactor with pressurized air as the oxidant at temperatures of <470 °C, oxygen-to-fuel equivalence ratios between 0 and 1.9, feed concentrations between 3.9 and 9.8 molTOC L-1 (TOC = total organic carbon), and reaction times between 86 and 1572 s. Decomposition of the fecal sludge was monitored by means of the conversion of TOC to CO2 and CO. In the presence of oxygen, ignition of the reaction was observed around 300 °C, followed by further rapid decomposition of the organic material. The TOC was completely decomposed to CO2 within 25 min at 470 °C and an oxygen-to-fuel equivalence ratio of 1.2. CO was formed as an intermediate product, and no other combustible products were found in the gas. At certain reaction conditions, the formation of unwanted coke and tarlike products occurred. The reaction temperature and oxygen-to-fuel equivalence ratio showed a significant influence on TOC conversion, while the initial TOC concentration did not. Conversion of TOC to CO2 could be well described with a first-order rate law and an activation energy of 39 kJ mol-1.