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The temporal consistency of the fAPAR GEOV2 full time series (constituted by data derived from SPOT-VGT1/2 and PROBA-V) is analyzed against the single-sensor MODIS dataset, with a particular focus on the most recent fAPAR anomalies (z-scores) produced from PROBA-V in the period 2014-2017. The intercomparison highlights a systematic overestimation of GEOV2 fAPAR z-scores when compared to MODIS fAPAR, likely related to the observed positive bias (over 90% of the domain) in the PROBA-V vs. SPOT-VGT1/2 relationship. A simple two-step harmonization procedure has been proposed to remove this discrepancy, based on two separate linear corrections of SPOT-VGT1/2 (2001-2013) and PROBA-V (2014-2017) data with respect to MODIS, followed by a time lag correction. The harmonized GEOV2 time series preserves the overall dynamic of fAPAR, while removing the sensor bias and improving the consistency with MODIS data. The fAPAR anomalies from the harmonized GEOV2 time series provide unbiased estimates of z-scores that are overall well correlated (R = 0.55 ± 0.25) with the MODIS fAPAR anomalies.
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We report on high resolution measurements of resonances in the spectrum of coherent synchrotron radiation (CSR) at the Canadian Light Source (CLS). The resonances permeate the spectrum at wave number intervals of 0.074 cm(-1), and are highly stable under changes in the machine setup (energy, bucket filling pattern, CSR in bursting or continuous mode). Analogous resonances were predicted long ago in an idealized theory as eigenmodes of a smooth toroidal vacuum chamber driven by a bunched beam moving on a circular orbit. A corollary of peaks in the spectrum is the presence of pulses in the wakefield of the bunch at well-defined spatial intervals. Through experiments and further calculations we elucidate the resonance and wakefield mechanisms in the CLS vacuum chamber, which has a fluted form much different from a smooth torus. The wakefield is observed directly in the 30-110 GHz range by rf diodes, and indirectly by an interferometer in the THz range. The wake pulse sequence found by diodes is less regular than in the toroidal model, and depends on the point of observation, but is accounted for in a simulation of fields in the fluted chamber. Attention is paid to polarization of the observed fields, and possible coherence of fields produced in adjacent bending magnets. Low frequency wakefield production appears to be mainly local in a single bend, but multibend effects cannot be excluded entirely, and could play a role in high frequency resonances. New simulation techniques have been developed, which should be invaluable in further work.
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We report on a 19-year-old patient who developed negative pressure pulmonary edema (NPPE) with respiratory insufficiency following abscess tonsillectomy. NPPE is an unpredictable and life-threatening postoperative complication characterized by respiratory insufficiency. It may arise immediately after extubation or later in the postoperative period. NPPE is frequently observed after laryngospasm or in combination with space-occupying lesions in the pharynx and larynx. Treatment comprises the immediate correction of hypoxemia, preferably by noninvasive respiratory support using continuous positive airway pressure (CPAP), although in some cases reintubation is necessary.
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Pressão Positiva Contínua nas Vias Aéreas , Abscesso Peritonsilar/complicações , Abscesso Peritonsilar/cirurgia , Edema Pulmonar/etiologia , Edema Pulmonar/terapia , Tonsilectomia/efeitos adversos , Humanos , Masculino , Edema Pulmonar/diagnóstico , Resultado do Tratamento , Adulto JovemRESUMO
Our aim was to study the ability of an immortalized cell line (AMJ2-C11) to sustain aerobic cell respiration at decreasing oxygen concentrations under continuous sulfide exposure. We assumed that the rate of elimination of sulfide through the pathway linked to the mitochondrial respiratory chain and therefore operating under aerobic conditions, should decrease with limiting oxygen concentrations. Thus, sulfide's inhibition of cellular respiration would occur faster under continuous sulfide exposure when the oxygen concentration is in the very low range. The experiments were performed with an O2K-oxygraph (Oroboros Instruments) by suspending 0.5-1×10(6) cells in 2 ml of continuously stirred respiration medium at 37 °C and calculating the oxygen flux (JO2) as the negative derivative of the oxygen concentration in the medium. The cells were studied in two different metabolic states, namely under normal physiologic respiration (1) and after uncoupling of mitochondrial respiration (2). Oxygen concentration was controlled by means of a titration-injection pump, resulting in average concentration values of 0.73±0.05 µM, 3.1±0.2 µM, and 6.2±0.2 µM. Simultaneously we injected a 2 mM Na2S solution at a continuous rate of 10 µl/s in order to quantify the titration-time required to reduce the JO2 to 50% of the initial respiratory activity. Under the lowest oxygen concentration this effect was achieved after 3.5 [0.3;3.5] and 11.7 [6.2;21.2]min in the uncoupled and coupled state, respectively. This time was statistically significantly shorter when compared to the intermediate and the highest O2 concentrations tested, which yielded values of 24.6 [15.5;28.1]min (coupled) and 35.9 [27.4;59.2]min (uncoupled), as well as 42.4 [27.5;42.4]min (coupled) and 51.5 [46.4;51.7]min (uncoupled). All data are medians [25%, and 75% percentiles]. Our results confirm that the onset of inhibition of cell respiration by sulfide occurs earlier under a continuous exposure when approaching the anoxic condition. This property may contribute to the physiological role of sulfide as an oxygen sensor.
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Hipóxia Celular/fisiologia , Oxigênio/metabolismo , Sulfetos/metabolismo , Animais , Linhagem Celular , Respiração Celular/fisiologia , Camundongos , Mitocôndrias/metabolismo , Quinona RedutasesRESUMO
Due to the increased frequency of human-tick encounters and expanding ranges of ticks in the United States, there is a critical need to identify environmental conditions associated with tick populations and their likelihood to contact human hosts. In a passive tick surveillance partnership with the US Department of Agriculture Forest Inventory and Analysis (FIA) program, we identified environmental variables associated with tick encounters by forestry personnel. Ticks were identified by species and life stage, and site-specific variables were associated with each tick using FIA forest inventory datasets and generalized linear models with negative binomial distributions. Of the 55 FIA variables available, we identified biotic and abiotic environmental variables associated with Amblyomma americanum L. (carbon in litter material and standing dead tree aboveground dry biomass), Dermacentor variabilis Say (seedling species unevenness and elevation), and Ixodes scapularis L. (carbon in dead woody material and seedling species unevenness). We propose conducting future treatment-control studies using these forestry-related environmental variables to test their ability to alter tick abundance at sites. Land management decisions not only affect common flora and fauna, but changes to these habitats can also alter the way ticks parasitize hosts and use vegetation to find those hosts. These results can be used with land management decisions to prevent future human-tick encounters and highlight risk areas.
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Ixodes , Humanos , Estados Unidos , Animais , Sudeste dos Estados Unidos , Ecossistema , Florestas , CarbonoRESUMO
BACKGROUND: Anastomotic leakage after esophageal surgery is a significant cause of morbidity and mortality. Postoperative leakage of esophagogastric anastomosis has been reported in 2-30% of surgical patient, resulting in an increased need for reoperation and a high risk of subsequent esophageal stricture formation and fistula. So far, experimental investigations on major factors influencing the healing of esophageal anastomoses, e.g. neovascularization and collagen deposition, have been hindered by the lack of a functional rodent model. METHODS: We developed a novel technique of gastric tube formation followed by end-to-end esophagogastric anastomosis in a rat model. Standardized anastomoses were carried out in 18 Brown-Norway rats and normal esophagogastric healing was studied by measuring anastomotic breaking strength 5 days after surgery. RESULTS: Five animals showed an insufficiency of the esophagogastric anastomosis as determined by anastomotic leakage testing. Normal anastomotic healing was found in 10 animals. The anastomotic breaking strength was 1.93 ± 0.45 N. CONCLUSION: The rat model for performing esophagogastric anastomoses after gastric tube formation may serve as a functional and useful model in future research studies on microvascular and molecular processes of anastomotic healing.
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Anastomose Cirúrgica , Esôfago/cirurgia , Estômago/cirurgia , Cicatrização , Anastomose Cirúrgica/efeitos adversos , Anastomose Cirúrgica/métodos , Animais , Masculino , Modelos Animais , Ratos , Ratos Endogâmicos BNRESUMO
European forests are an important source for timber production, human welfare, income, protection and biodiversity. During the last two decades, Europe has experienced a number of droughts which have been exceptional within the last 500 years, both in terms of duration and intensity. These droughts seem to leave remarkable imprints on the mortality dynamics of European forests. However, systematic observations on tree decline, with emphasis on a single species, has been scarce so far so that our understanding of mortality dynamics and drought occurrence is still limited at a continental scale. Here, we make use of the ICP Forest crown defoliation dataset, permitting us to retrospectively monitor tree mortality for all major conifers, major broadleaves, as well as a pooled dataset of minor tree species in Europe. In total, we analysed more than three million observations gathered during the last 25 years and employed a high-resolution drought index which can assess soil moisture anomaly based on a hydrological water-balance and runoff model. We found overall and species-specific increasing trends in mortality rates, accompanied by decreasing soil moisture. A generalized linear mixed model identified a previous-year soil moisture anomaly as the most important driver of mortality patterns in conifers, but the response was not uniform across the numerous analysed plots. We conclude that mortality patterns in European forests are currently reaching a concerning upward trend which could be further accelerated by global change-type droughts in the near future.
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Florestas , Árvores , Humanos , Estudos Retrospectivos , Árvores/fisiologia , Secas , Solo , Mudança ClimáticaRESUMO
Haemaphysalis longicornis Neumann, Asian longhorned tick, was collected in Madison County, Kentucky, United States as part of an ongoing collaborative-tick surveillance project. This is the first collection of this invasive tick that includes ancillary data on habitat and landscape features derived from the USDA Forest Service, Forest Inventory and Analysis program.
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Distribuição Animal , Ecossistema , Ixodidae , Animais , Monitoramento Epidemiológico , KentuckyRESUMO
OBJECTIVE: To examine the effect of marine n-3 polyunsaturated fatty acids (PUFA) supplementation in a low to moderate and a high dose on plasma levels of myeloperoxidase (MPO) in healthy individuals. BACKGROUND: Atherosclerosis is a chronic inflammatory disease and MPO, which is secreted primarily from activated neutrophils and monocytes, has pro-inflammatory properties and has been linked with both initiation and propagation of atherosclerosis. Marine n-3 PUFA have anti-inflammatory properties, but whether n-3 PUFA affect plasma levels of MPO is largely unknown. METHODS: Sixty healthy adults were randomized to three groups receiving either 6.6 g PUFA/day, 2.0 g PUFA/day or a control oil (olive oil) for 12 weeks. Blood samples were drawn at baseline and after exposure. Plasma levels of MPO were measured using a MPO ELISA-kit (from Mercodia, Uppsala, Sweden) with specific mouse monoclonal antibodies. RESULTS: Plasma MPO concentrations (microg/L) at baseline were 36.9 +/- 9.4; 36.2 +/- 7.1 and 35.4 +/- 11.3 (for high dose-, low dose- and control-group, respectively). After 12 weeks of supplementation we found no significant changes in plasma MPO in any of the groups nor between groups, with values after intervention of 36.1 +/- 8.6; 37.0 +/- 8.2 and 34.4 +/- 11.1, respectively. CONCLUSION: Supplementation with n-3 PUFA has no effect on plasma levels of MPO in healthy adults with low baseline levels of MPO.
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Ácidos Graxos Ômega-3/farmacologia , Peroxidase/sangue , Administração Oral , Adulto , Suplementos Nutricionais , Esquema de Medicação , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Azeite de Oliva , Óleos de Plantas/farmacologiaRESUMO
OBJECTIVE: Extracellular matrix modification by matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) and alpha2-macroglobulin may affect the stability of atherosclerotic plaques. Marine n-3 polyunsaturated fatty acids (n-3 PUFA) may protect against plaque rupture. The aim was to investigate the effect of marine n-3 PUFA supplementation on serum levels of MMP-9, TIMP-1, and alpha2-macroglobulin. METHODS: Healthy volunteers were randomized to receive capsules contributing either 6.6 g marine n-3 PUFA/day, 2.0 g marine n-3 PUFA/day or 6.6 g of olive oil (control). Serum MMP-9, TIMP-1 and alpha2-macroglobulin was measured at baseline and after 12 weeks of supplementation. One way ANOVA or Kruskal-Wallis test was used to compare groups. RESULTS: 60 healthy volunteers were enrolled and no subjects dropped out of the 12 week study. There were no statistically significant changes in serum levels of MMP-9, TIMP-1, and alpha2-macroglobulin in any of the three treatment groups (P=0.85, P=0.23 and P=0.87, respectively). CONCLUSION: Supplementation with marine n-3 PUFA had no effect on serum levels of MMP-9, TIMP-1 and alpha2-macroglobulin in healthy subjects. The possible protection offered by marine n-3 PUFA against plaque rupture is therefore unlikely to be mediated through a change in serum levels of MMP-9, TIMP-1 and alpha2-macroglobulin.
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Ácidos Graxos Ômega-3/farmacologia , Metaloproteinase 9 da Matriz/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , alfa-Macroglobulinas/análise , Adulto , Análise de Variância , Suplementos Nutricionais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The adsorbate structure of the first layer acetylene on the NaCl(100) single-crystal surface is investigated using polarization infrared spectroscopy in combination with low-energy electron diffraction (LEED) experiments, and potential calculations on the basis of pair potentials. In agreement with a previous study, a triplet of infrared absorptions in the region of the asymmetric stretch vibration of C(2)H(2) was observed and assigned to an adsorbate phase with (3 square root 2 x square root 2)R45 degrees translational symmetry determined in the LEED experiment. The polarization dependence of the infrared spectra is consistent with a parallel orientation of the molecules with respect to the surface. The number of molecules per unit cell is four to six as determined by photometric considerations. Total energy minimizations support a new structure model which contains five inequivalent molecules per unit cell in a herringbone arrangement. The application of a vibrational exciton approach demonstrates that this new structure model can reproduce the triplet spectrum observed in the infrared experiments.
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BACKGROUND: Fetal akinesia deformation sequence syndrome (FADS) is a heterogeneous disorder characterised by fetal akinesia and developmental defects including, in some case, pterygia. Multiple pterygium syndromes (MPS) are traditionally divided into prenatally lethal and non-lethal (such as Escobar) types. Previously, we and others reported that homozygous mutations in the fetal acetylcholine receptor gamma subunit (CHRNG) can cause both lethal and non-lethal MPS, demonstrating that pterygia resulted from fetal akinesia, and that mutations in the acetylcholine receptor subunits CHRNA1, CHRND, and Rapsyn (RAPSN) can also result in a MPS/FADS phenotype. METHODS: We hypothesised that mutations in other acetylcholine receptor related genes may interfere with neurotransmission at the neuromuscular junction and so we analysed 14 cases of lethal MPS/FADS without CHRNG, CHRNA1, CHRNB1, CHRND, or RAPSN mutations for mutations in DOK7. RESULTS: A homozygous DOK7 splice site mutation, c.331+1G>T, was identified in a family with three children affected with lethal FADS. Previously DOK7 mutations have been reported to underlie a congenital myaesthenic syndrome with a characteristic "limb girdle" pattern of muscle weakness. CONCLUSION: This finding is consistent with the hypothesis that whereas incomplete loss of DOK7 function may cause congenital myasthenia, more severe loss of function can result in a lethal fetal akinesia phenotype.
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Anormalidades Múltiplas/genética , Mutação em Linhagem Germinativa , Proteínas Musculares/genética , Anormalidades Múltiplas/patologia , Processamento Alternativo/genética , Sequência de Bases , Criança , Consanguinidade , Análise Mutacional de DNA , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Índia , Masculino , Sítios de Splice de RNA/genética , SíndromeRESUMO
Capabilities of highly sensitive surface-enhanced infrared absorption (SEIRA) spectroscopy are demonstrated by exploiting large-area templates (cm2) based on self-organized (SO) nanorod antennas. We engineered highly dense arrays of gold nanorod antennas featuring polarization-sensitive localized plasmon resonances, tunable over a broadband near- and mid-infrared (IR) spectrum, in overlap with the so-called "functional group" window. We demonstrate polarization-sensitive SEIRA activity, homogeneous over macroscopic areas and stable in time, by exploiting prototype self-assembled monolayers of IR-active octadecanthiol (ODT) molecules. The strong coupling between the plasmonic excitation and molecular stretching modes gives rise to characteristic Fano resonances in SEIRA. The SO engineering of the active hotspots in the arrays allows us to achieve signal amplitude improved up to 5.7%. This figure is competitive to the response of lithographic nanoantennas and is stable when the optical excitation spot varies from the micro- to macroscale, thus enabling highly sensitive SEIRA spectroscopy with cost-effective nanosensor devices.
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Virtually all climate monitoring and forecasting efforts concentrate on hazards rather than on impacts, while the latter are a priority for planning emergency activities and for the evaluation of mitigation strategies. Effective disaster risk management strategies need to consider the prevailing "human terrain" to predict who is at risk and how communities will be affected. There has been little effort to align the spatiotemporal granularity of socioeconomic assessments with the granularity of weather or climate monitoring. The lack of a high-resolution socioeconomic baseline leaves methodical approaches like machine learning virtually untapped for pattern recognition of extreme climate impacts on livelihood conditions. While the request for "better" socioeconomic data is not new, we highlight the need to collect and analyze environmental and socioeconomic data together and discuss novel strategies for coordinated data collection via mobile technologies from a drought risk management perspective. A better temporal, spatial, and contextual understanding of socioeconomic impacts of extreme climate conditions will help to establish complex causal pathways and quantitative proof about climate-attributable livelihood impacts. Such considerations are particularly important in the context of the latest big data-driven initiatives, such as the World Bank's Famine Action Mechanism (FAM).
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Tick surveillance provides essential information on distributions and encounter frequencies; it is a component of operational activities in public health practice. Our research objectives were a proof-of-concept for collaborative surveillance, which involved establishing an academic and government partnership to enhance tick surveillance efforts. The University of Tennessee (UT) collaborated with United States Department of Agriculture Forest Service, Southern Research Station Forest Inventory Analysis (FIA) in an Occupational Health and Safety partnership. UT provided FIA crews in the southeastern United States with vials containing 80% ethanol (July 2014-November 2017). Crew members were instructed to put all encountered ticks into the vials and return them to FIA headquarters. UT identified all submitted ticks to species and life stage, and screened Amblyomma americanum (L.) for Ehrlichia bacteria using a nested-PCR assay. From the 198 returned vials, 1,180 ticks were submitted, including A. americanum (90.51%; 202 larvae, 503 nymphs, and 363 adults), Dermacentor variabilis Say (7.12%; 1 nymph, 83 adults), Ixodes scapularis (Say) (1.61%; 19 adults), Amblyomma maculatum Koch (0.59%; 1 nymph, 6 adults), and Amblyomma cajennense (Fabricius) (0.17%; 1 nymph, 1 adult). FIA crews encountered A. americanum with Ehrlichia and collection information was used to generate baseline occurrence data of tick encounters. Results indicate that this collaborative-tick surveillance can be improved and used to generate useful data including pathogen detection, and because crews revisit these sites, changes in tick encounters can be monitored.
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Distribuição Animal , Monitoramento Epidemiológico , Ixodidae/microbiologia , Ixodidae/fisiologia , Parcerias Público-Privadas , Animais , Região dos Apalaches , Ehrlichia/isolamento & purificação , Feminino , Ixodidae/crescimento & desenvolvimento , Larva/microbiologia , Larva/fisiologia , Masculino , Ninfa/microbiologia , Ninfa/fisiologia , Estações do Ano , Sudeste dos Estados Unidos , Manejo de Espécimes , TexasRESUMO
Mutations in the Saccharomyces cerevisiae SNF1 gene affect a number of cellular processes, including the expression of genes involved in carbon source utilization and phospholipid biosynthesis. To identify targets of the Snf1 kinase that modulate expression of INO1, a gene required for an early, rate-limiting step in phospholipid biosynthesis, we performed a genetic selection for suppressors of the inositol auxotrophy of snf1Delta strains. We identified mutations in ACC1 and FAS1, two genes important for fatty acid biosynthesis in yeast; ACC1 encodes acetyl coenzyme A carboxylase (Acc1), and FAS1 encodes the beta subunit of fatty acid synthase. Acc1 was shown previously to be phosphorylated and inactivated by Snf1. Here we show that snf1Delta strains with increased Acc1 activity exhibit decreased INO1 transcription. Strains carrying the ACC1 suppressor mutation have reduced Acc1 activity in vitro and in vivo, as revealed by enzymatic assays and increased sensitivity to the Acc1-specific inhibitor soraphen A. Moreover, a reduction in Acc1 activity, caused by addition of soraphen A, provision of exogenous fatty acid, or conditional expression of ACC1, suppresses the inositol auxotrophy of snf1Delta strains. Together, these findings indicate that the inositol auxotrophy of snf1Delta strains arises in part from elevated Acc1 activity and that a reduction in this activity restores INO1 expression in these strains. These results reveal a Snf1-dependent connection between fatty acid production and phospholipid biosynthesis, identify Acc1 as a Snf1 target important for INO1 transcription, and suggest models in which metabolites that are generated or utilized during fatty acid biosynthesis can significantly influence gene expression in yeast.
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Acetil-CoA Carboxilase/antagonistas & inibidores , Proteínas de Transporte , Proteínas Fúngicas/fisiologia , Regulação Enzimológica da Expressão Gênica , Regulação Fúngica da Expressão Gênica , Mio-Inositol-1-Fosfato Sintase/genética , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas de Saccharomyces cerevisiae , Proteínas Quinases Ativadas por AMP , Acetil-CoA Carboxilase/genética , Proteínas Fúngicas/genética , Inositol/metabolismo , Fenótipo , Fosfolipídeos/metabolismo , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Repressoras/genética , Saccharomyces cerevisiae , Fatores de Transcrição/genética , Transcrição GênicaRESUMO
Gastric emptying can be assessed by an oral administration of a 13C labeled substrate and its response in the expiratory release of the oxidation product [Formula: see text]. Impaired gut function, reflected, for example, in an intolerance against enteral nutrition may delay or discontinue gastric emptying, potentially leading to multiple peaks in the time profile of expiration. The resulting profile cannot be analyzed by the usual data evaluation that is based on a 'beta exponential' (BEX) function. We developed a new approach that better reflects the underlying physiology. It allows a flexible time profile of gastric release and considers a transient [Formula: see text] retention in different compartments as well as an incomplete recovery of [Formula: see text] in the expiration. Parameters that describe the distribution/retention kinetics cannot be determined based on the same breath data that were used to estimate emptying. To enable the determination of the kinetic parameters, they were constrained to match published data using a Bayesian statistical analysis. The applicability of the new model was compared with BEX for healthy subjects. BEX fails to explain the observed data and, compared to the new approach, overestimates the speed of emptying. Predictive accuracy under impaired gastric motility was explored using synthetic data. Only the new approach can reproduce a multiphase absorption profile. When routine benchtop equipment was used for measurements, then the rate-limiting step for precision in the estimate of emptying is the quality in the a priori estimate for kinetic parameters rather than precision in measurements. Only about 80% of the absorbed [Formula: see text] has to be released by expiration. With these features, the new approach promises to widen the applicability of breath tests for gastric emptying.
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Testes Respiratórios/métodos , Dióxido de Carbono/análise , Esvaziamento Gástrico/fisiologia , Estômago/fisiopatologia , Administração Oral , Adulto , Teorema de Bayes , Isótopos de Carbono , Simulação por Computador , Expiração , Feminino , Humanos , Absorção Intestinal , Cinética , Masculino , Pessoa de Meia-Idade , IncertezaRESUMO
Bioactive lipids contribute to the pathophysiology of multiple sclerosis. Here, we show that lysophosphatidic acids (LPAs) are dysregulated in multiple sclerosis (MS) and are functionally relevant in this disease. LPAs and autotaxin, the major enzyme producing extracellular LPAs, were analyzed in serum and cerebrospinal fluid in a cross-sectional population of MS patients and were compared with respective data from mice in the experimental autoimmune encephalomyelitis (EAE) model, spontaneous EAE in TCR1640 mice, and EAE in Lpar2 -/- mice. Serum LPAs were reduced in MS and EAE whereas spinal cord LPAs in TCR1640 mice increased during the 'symptom-free' intervals, i.e. on resolution of inflammation during recovery hence possibly pointing to positive effects of brain LPAs during remyelination as suggested in previous studies. Peripheral LPAs mildly re-raised during relapses but further dropped in refractory relapses. The peripheral loss led to a redistribution of immune cells from the spleen to the spinal cord, suggesting defects of lymphocyte homing. In support, LPAR2 positive T-cells were reduced in EAE and the disease was intensified in Lpar2 deficient mice. Further, treatment with an LPAR2 agonist reduced clinical signs of relapsing-remitting EAE suggesting that the LPAR2 agonist partially compensated the endogenous loss of LPAs and implicating LPA signaling as a novel treatment approach. Graphical summary of lysophosphatidic signaling in multiple sclerosis.
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Encefalomielite Autoimune Experimental/metabolismo , Lisofosfolipídeos/metabolismo , Esclerose Múltipla/metabolismo , Adolescente , Adulto , Animais , Biomarcadores/metabolismo , Estudos de Coortes , Estudos Transversais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Feminino , Humanos , Fatores Imunológicos/farmacologia , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Receptores de Ácidos Lisofosfatídicos/agonistas , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Adulto JovemRESUMO
Extracellular ATP might act as a trophic factor on growing axons during development of the CNS via P2 receptors. In the present study the postnatal presence of selected P2 receptor subtypes was analyzed and their putative trophic capacity in entorhino-hippocampal slice co-cultures of mouse brain was tested. The effect of the P2 receptor ligands 2-methylthioadenosine-5'-triphosphate (P2X/Y receptor agonist) and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (P2X/Y receptor antagonist) on axonal growth and fiber density of biocytin-labeled hippocampal projections was compared both with untreated cultures and with cultures treated with artificial cerebrospinal fluid. After 10 days in vitro, double immunofluorescence labeling revealed the expression of P2X(1), P2X(2), P2X(4) as well as P2Y(1) and P2Y(2) receptors in the examined regions of entorhinal fiber termination. Further, quantitative analysis of identified biocytin-traced entorhinal fibers showed a significant increase in fiber density in the dentate gyrus after incubation of the slices with the P2 receptor agonist 2-methylthioadenosine-5'-triphosphate. This neurite outgrowth promoting effect was completely abolished by the P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid. Our in vitro data indicate that ATP via its P2X and P2Y receptors can shape hippocampal connectivity during development.
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Axônios/fisiologia , Hipocampo/crescimento & desenvolvimento , Agonistas do Receptor Purinérgico P2 , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Animais , Axônios/efeitos dos fármacos , Contagem de Células , Técnicas de Cocultura , Giro Denteado/citologia , Giro Denteado/efeitos dos fármacos , Córtex Entorrinal/fisiologia , Técnica Indireta de Fluorescência para Anticorpo , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Fibras Nervosas/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacologia , Estimulação Química , Tionucleotídeos/farmacologiaRESUMO
AIM: Cardiac resynchronization therapy (CRT) has been shown to improve haemodynamics and clinical symptoms in heart failure patients. The present study evaluated the effects of a 4-month CRT on myocardial blood flow (MBF) at rest, after vasodilation and on myocardial oxygen consumption (MVO(2)). PATIENTS, METHODS: We studied 16 patients with idiopathic dilated cardiomyopathy prior to and during CRT performed as biventricular pacing. Resting MBF and MVO(2) were determined from an (11)C-acetate PET study and vasodilator MBF from a (13)N-ammonia study. RESULTS: MBF at rest (0.55 +/- 0.10 ml/min/g), after vasodilation (1.20 +/- 0.45 ml/min/g), and MVO2 (0.082 +/- 0.014/min) did not change by mid-term CRT at a global level (0.57 +/- 0.11 ml/min/g; 1.32 +/- 0.49 ml/min/g; 0.085 +/- 0.018/min), whereas the rate pressure product (RPP) normalised MVO(2) decreased from 0.104 +/- 0.024 to 0.086 +/- 0.018/min (p = 0.02). At baseline, the regional analysis revealed significantly higher values for all parameters in the lateral wall than for those in the other walls. Under CRT the regional differences between the resting parameters equalized and all parameters showed significant lower coefficients of variation. CONCLUSION: Effects of mid-term CRT on resting MBF, vasodilator MBF and MVO(2) occur at a regional level. The resynchronization is associated with a more homogenous distribution pattern of these parameters among the myocardial walls. Substantial alterations to global MBF at rest, after vasodilation or to MVO(2) are not detectable. Regarding the RPP normalised MVO(2), there is evidence of improved ventricular efficiency through CRT.