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Runoff monitoring experiments are often conducted in remote sites. Sample collection and dispatch for analysis are often delayed due to sites' remoteness and limited local laboratory facilities. The standard method of dissolved organic carbon (DOC) and total organic carbon (TOC) analysis in water samples requires storage of the samples at 4 °C after collection and analysis with a minimum of delay. However, there is no freezing storage time limit specified to avoid degradation. To overcome the limitations of this approach, we investigated the method of storage, that is refrigeration (4 °C) versus freezing (-18 °C), and the effect of storage time on DOC and TOC fractions in runoff water. Storage of samples at 4 °C for more than a week resulted in a decline of TOC and DOC concentrations in runoff water.â¢Freezing unfiltered water samples immediately after collection minimized TOC losses during storage, however, it may lead to variable DOC results.â¢Filtering a subsample of runoff or irrigation water immediately after collection using a 0.45 µm filter and freezing both the filtered and unfiltered samples until analysis of DOC and TOC, respectively, can minimize losses during storage.
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Despite the potential for the chemokine class as therapeutic targets in immune mediated disease, success has been limited. Many chemokines can bind to multiple receptors and many receptors have multiple ligands, with few exceptions. One of those exceptions is CCL20, which exclusively pairs to CCR6 and is associated with several immunologic conditions, thus providing a promising therapeutic target. Following successful evaluation in a single dose, first time in human clinical study, GSK3050002-a humanized IgG1 monoclonal antibody against human CCL20-was evaluated in a 26-week cynomolgus monkey toxicology study. A high incidence of unexpected vascular and organ inflammation was observed microscopically, leading to the decision to halt clinical development. Here we report a dose-responsive increase in the incidence and severity of inflammation in multiple organs from monkeys receiving 30 and 300 mg/kg/week by either subcutaneous or intravenous injection. Histomorphological changes resembled an immune complex-mediated pathology, which is often due to formation of anti-drug antibodies in monkeys receiving a human protein therapeutic and thus not predictive of clinical outcome. However, the presentation was atypical in that there was a clear dose response with a very high incidence of inflammation with a low incidence of ADA that did not correlate well individually. Additionally, the immunohistologic presentation was atypical in that the severity and distribution of tissue inflammation was greater than the numbers of associated immune complexes (i.e., granular deposits). An extensive ex vivo analysis of large molecular weight protein complexes in monkey serum from this study and in human serum samples demonstrated a time-dependent aggregation of GSK3050002, that was not predicted by in vitro assays. The aggregates also contained complement components. These findings support the hypothesis that immune complexes of drug aggregates, not necessarily including anti-drug antibodies, can fix complement, accumulate over time, and trigger immune complex disease. A situation which may have increased clinical relevance than typical anti-drug antibody-associated immune complex disease in monkeys administered human antibody proteins.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Quimiocina CCL20/inmunología , Proteínas del Sistema Complemento/inmunología , Enfermedades del Complejo Inmune/tratamiento farmacológico , Enfermedades del Complejo Inmune/inmunología , Inmunoconjugados/uso terapéutico , Animales , Anticuerpos Monoclonales/toxicidad , Enfermedad Crónica , Cristalización , Determinación de Punto Final , Femenino , Humanos , Inflamación/inmunología , Inflamación/patología , Macaca fascicularisRESUMEN
Daprodustat (GSK1278863) is a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor in development for treatment of anemia of chronic kidney disease. Daprodustat's biological activity simulates components of the natural response to hypoxia; inhibition of PHDs results in HIF stabilization and modulation of HIF-controlled gene products, including erythropoietin. The carcinogenic potential of daprodustat was evaluated in 2-year carcinogenicity studies in Sprague-Dawley rats and CD-1 mice, where once-daily doses were administered. The mouse study also included evaluation of daprodustat's 3 major circulating human metabolites. There were no neoplastic findings that were considered treatment related in either study. Exaggerated pharmacology resulted in significantly increased red cell mass and subsequent multiorgan congestion and secondary non-neoplastic effects in both species, similar to those observed in chronic toxicity studies. In rats, these included aortic thrombosis and an exacerbation of spontaneous rodent cardiomyopathy, which contributed to a statistically significant decrease in survival in high-dose males (group terminated in week 94). Survival was not impacted in mice at any dose. Systemic exposures (area under the plasma concentration-time curve) to daprodustat at the high doses in rats and mice exceed predicted maximal human clinical exposure by ≥143-fold. These results suggest that daprodustat and metabolites do not pose a carcinogenic risk at clinical doses.
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Barbitúricos/toxicidad , Carcinogénesis/inducido químicamente , Pruebas de Carcinogenicidad , Evaluación Preclínica de Medicamentos , Glicina/análogos & derivados , Animales , Glicina/toxicidad , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Ratones , Ratas , Ratas Sprague-DawleyRESUMEN
Evidence for helium excimers (He2*) in the lowest allowed rotational quantum state in liquid helium is presented. He2* was generated by a corona discharge in the gas and normal liquid phases. Fluorescence spectra recorded in the visible region between 3.8 and 5.0 K and 0.2 and 5.6 bar showed the rotationally resolved d3Σu+ â b3Πg transition of He2*. Analysis of the pressure and temperature dependence of lineshifts and line intensities showed features of solvated He2* superimposed on its gas-phase spectrum and, in the liquid phase only, pressure-induced rotational cooling. These findings suggest that He2* can be used to investigate bulk helium in different phases at the nanoscale.
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We show that rotational line spectra of molecular clusters with near zero permanent dipole moments can be observed using impulsive alignment. Aligned rotational wavepackets were generated by non-resonant interaction with intense femtosecond laser pump pulses and then probed using Coulomb explosion by a second, time-delayed femtosecond laser pulse. By means of a Fourier transform a rich spectrum of rotational eigenstates was derived. For the smallest cluster, C(2)H(2)-He, we were able to establish essentially all rotational eigenstates up to the dissociation threshold on the basis of theoretical level predictions. The C(2)H(2)-He complex is found to exhibit distinct features of large amplitude motion and very early onset of free internal rotor energy level structure.
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Rotational wave packets of the weakly bound C(2)H(2)-He complex have been created using impulsive alignment. The coherent rotational dynamics were monitored for 600 ps enabling extraction of a frequency spectrum showing multiple rotational energy levels up to J = 4. spectrum has been combined with ab initio calculations to show that the complex has a highly delocalized structure and is bound only by ca. 7 cm(-1). The experiments demonstrate how highly featured rotational spectra can be obtained from an extremely cold environment where only the lowest rotational energy states are initially populated.
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Wastewater samples were taken from an aerobic bioreactor, operated by a dairy processor in southeastern Australia to reduce nutrient and pollutant loads. Samples were taken over a two-year period, to determine whether trace organic compounds or physicochemical analyses of the wastewater could be used to discriminate the water taken before, during and after processing of the wastewater in the bioreactor. Multivariate analyses of the physicochemical data suggested that nitrate, pH and total dissolved nitrogen best described the infeed wastewater entering the bioreactor, while organic and particulate phosphorus concentrations where predominantly responsible for describing the composition of the content of the bioreactor. Gas chromatography-mass spectrometry data of organic compounds within the wastewater samples were also analysed via multivariate analyses. The analyses found that the compound 4-nitrophenol was associated with ammonia concentrations and mixed liquor wastewater. Therefore, 4-nitrophenol may possibly be used to act as an indicator of anaerobicity in aerobic bioreactors.
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Reactores Biológicos , Industria Lechera , Compuestos Orgánicos/análisis , Aerobiosis , Cromatografía de Gases y Espectrometría de Masas , Concentración de Iones de Hidrógeno , Análisis Multivariante , Análisis de Componente PrincipalRESUMEN
Bioreactors are often an integral part of dairy factory efforts to reduce the biological oxygen demand of their wastewater. In this study, infeed, mixed liquor and supernatant samples of an aerobic bioreactor used by a dairy factory in South-Eastern Australia were analyzed for nutrients and organic compounds using gas chromatography-mass spectrometry and physicochemical analyses. Despite different concentrations of organic inputs into the bioreactor, nutrients and trace organic compounds were reduced significantly (i.e. average concentration of trace organic compounds: infeed=1681 µg/L; mixed liquor=257 µg/L; supernatant=23 µg/L). However, during one sampling period the bioreactor was adversely affected by the organic loading. Trace organic compounds in the samples were predominantly fatty acids associated with animal products. The analyses suggest that it is possible to trace a disruptive input (i.e. infeed with high organic carbon concentrations) into an aerobic bioreactor by measuring concentrations of fatty acids or ammonia.
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Reactores Biológicos , Industria Lechera , Compuestos Orgánicos/análisis , Estaciones del Año , Contaminantes Químicos del Agua/análisis , Aerobiosis , Australia , Cromatografía de Gases y Espectrometría de MasasRESUMEN
Wastewater from a dairy processor is being reused and recycled both within the plant and for irrigation. Flash pyrolysis GC-MS was used to examine nitrogen and phenol containing compounds (M.W.=35 to 450 g/mol) in the particulate fraction of the milk condensate, combined clean wastewater and aerobic bioreactor effluent. For comparison, the particulates were also prepared for standard GC-MS analyses using conventional solvent extraction methods. Compounds detected by pyrolysis GC-MS were found mostly in the bioreactor with the amino acid arginine (220 mg/kg) and the amino acid derivative 1-methyl-5-oxo-L-proline methyl ester (130 mg/kg) found at the highest concentrations. In comparison, sterols detected in the effluent were found at higher concentrations when using solvent extraction indicating some degradation with pyrolysis GC-MS. However, with few exceptions, particulates were generally found not to act as passive collectors capable of concentrating less water soluble chemicals.
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Bacterias/metabolismo , Industria Lechera , Leche , Material Particulado/química , Reciclaje/métodos , Eliminación de Residuos Líquidos/métodos , Purificación del Agua/métodos , Aerobiosis , Animales , Fenómenos Químicos , Cromatografía de Gases y Espectrometría de Masas , Ríos/química , Solventes/química , Temperatura , Abastecimiento de AguaRESUMEN
We report electronic spectra of the Au-Xe complex for the first time. The transitions are recorded in the vicinity of the Au atomic 6p<-- 6s transitions. Structured spectra are found close to both the 6(2)P(1/2) and 6(2)P(3/2) states. The former is assigned as a (2)Pi(1/2) state in line with previous work on Au-Ar and Au-Kr; the possible assignment of the second spectrum is discussed. In addition, a large basis set extrapolated RCCSD(T) potential energy curve for the ground state, X(2)Sigma(+), is presented and derived spectroscopic parameters reported. More qualitative calculations are presented for electronically-excited states which arise from the Au(5(2)D) + Xe and Au(6(2)P) + Xe asymptotes, as well as some higher-lying states. The ab initio results are employed in the assignment of the reported spectra.
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We report electronic absorption spectra, recorded using one- and two-color resonance-enhanced multiphoton ionization spectroscopy, of the Au-Kr complex. The transition is localized on the gold atom, and corresponds to a 6p<--6s atomic excitation; we observe transitions to the D (2)Pi(1/2) and D (2)Pi(3/2) spin-orbit states. In addition, we report the results of ab initio calculations, which consider electronic states arising from the 6 (2)S, 5 (2)D, and 6 (2)P atomic energy levels of Au. Further, we also report an accurate value for the dissociation energy of the ground state of Au-Kr, based on basis set extrapolated RCCSD(T) calculations. The experimental results are discussed in the light of the theoretical ones.
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OBJECTIVE: To report the case of a neonate presenting with nonautoimmune thyrotoxicosis and failure to thrive in whom an activating TSHR mutation was suspected. METHODS: We describe the clinical and laboratory findings in a neonate who presented with nonautoimmune thyrotoxicosis and failure to thrive, including results of DNA analysis of TSHR, which encodes the thyroid-stimulating hormone receptor (TSHR). Relevant literature is also reviewed. RESULTS: The proband was born spontaneously at 35 weeks' gestation, and his early neonatal period was remarkable for meconium aspiration, pneumothorax, hepatomegaly with associated elevated transaminases, and direct hyperbilirubinemia. On days 9 and 11 of life, thyroid function studies revealed hyperthyroidism, which remained persistent on day 26 of life. On day 44 of life, the infant was admitted to the hospital. The mother reported he had an increased activity level, disturbed sleep, jitteriness, and exaggerated startle response. Weight was at the third percentile. After additional workup, Lugol's iodine solution, propanolol, and propylthiouracil were prescribed, which led to improvement in thyroid function. No TSHR antibodies were detected in the mother's or patient's sera. Analysis of the patient's DNA revealed a heterozygous T-to-C substitution at amino acid 568 in exon 10 (Ile568Thr), which predicts an isoleucine to threonine conversion in the second extracellular loop of TSHR. The mutation was not identified in the parents' DNA. CONCLUSIONS: A mutation causing constitutive activation of TSHR was confirmed in this patient, a finding that has implications for genetic counseling and consideration of total thyroidectomy or long-term thionamide therapy followed by radioiodide ablation as treatment options. Although rare, TSHR mutations should be considered in an infant presenting with thyrotoxicosis in absence of demonstrable TSHR antibodies in serum.
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Mutación Missense , Receptores de Tirotropina/genética , Tirotoxicosis/genética , Análisis Mutacional de ADN , Humanos , Recién Nacido , Masculino , Tirotoxicosis/patologíaRESUMEN
The Au-Ar complex is reinvestigated employing resonance-enhanced multiphoton ionization spectroscopy. Spectra are reported, corresponding to the atomic transition Au(6p<--6s). This electronic excitation yields (2)Pi and (2)Sigma(+) states of Au-Ar, which interact under the influence of spin-orbit coupling. The spectra are consistent with strong sigma-pi mixing induced by the large spin-orbit coupling of Au, leading to strong interaction of the two Omega=12 states, which arise from the Ar((1)S(0))+Au((2)P(12,32)) asymptotes, and the consequent formation of a "shelf" on the outer wall of the lowest Omega=12 state. In addition, high-level ab initio calculations are reported on the ground electronic state, X (2)Sigma(+), including extrapolation to the basis set limit.
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The structural properties of phenylacetylene have been investigated in the S(0)((1)A(1)) neutral ground and S(1)((1)B(2)) and S(2)((1)A(1)) singlet excited states and the D(0)((2)B(1)) cationic state using both rovibronic and multidimensional Franck-Condon simulations from data determined via correlated ab initio methods. Results are compared to experimental and ab initio data reported in the literature. (10,10)-CASSCF and a hybrid CASSCF/SACCI frequency analysis using the cc-pVDZ Dunning basis set have been employed to produce vibronic simulations of REMPI/FES, dispersed fluorescence, TPES and MATI spectra. Calculated rotational constants are used where appropriate to compare to rotationally resolved experimental studies. Whilst the simulations are of generally good quality, it is apparent that the distortion of the ring along the long axis upon electronic excitation is underestimated, resulting in smaller predicted changes in ipso and para CCC bond angles and weaker activities in the 6a and 9a modes compared with experiment. Simulations of one-photon MATI spectra on the other hand, which do not rely on excited state methodologies, compare very well with experiment, suggesting that the neutral and cationic ground state geometries are quite accurate, as are the predicted changes in geometry accompanying ionisation. Simulated rotational and vibrational profiles, as well as other calculated physical data, show good agreement with the numerous experimental and computational studies of phenylacetylene in the literature.
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OBJECTIVE: We sought to determine whether, in a specialty referral clinic, parental perceptions of their child's obesity were commensurate with the child's body mass index z score. Secondarily, we examined the impact of birth weight and parental body mass index on their child's body mass index z score and review results of an intake questionnaire. DESIGN: Cross-sectional study SETTING: University of Michigan from March 21, 2003 through June 30, 2004 PARTICIPANTS: Eighty-two children ages 1-20.2 years of age INTERVENTION: Body mass index z score for all participants was calculated. An intake questionnaire was completed by caregivers in which they were asked to describe their child as little overweight, overweight, very overweight or obese. OUTCOME MEASURES: Mean body mass index z score was compared to each parental descriptor. Regression analysis related body mass index z score to birthweight and parental body mass index. RESULTS: Body mass index z score was not related to parental descriptors. Maternal body mass index and child birthweight were predictors of the child's body mass index z score (r2=0.15, p<0.05; and r2=0.11, p<0.05, respectively). Both together produced a better model than either alone (r2=0.23, p<0.05). There was no relationship between paternal and child body mass index z score (p>0.05). CONCLUSIONS: There is a divergence between the parental perception of childhood obesity and the clinical definition that persists even in the context of an explicit referral. Given the significant impact of maternal weight on childhood overweight, education for prevention of overweight youth should encompass prenatal, early childhood and adolescent health maintenance.
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Peso al Nacer , Índice de Masa Corporal , Peso Corporal , Obesidad , Padres/psicología , Percepción , Adolescente , Adulto , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Estilo de Vida , Masculino , Relaciones Padres-Hijo , Derivación y Consulta , Análisis de Regresión , Encuestas y CuestionariosRESUMEN
The 1,4-diazabicyclo[2.2.2]octane-Arn (n = 1,2,3) van der Waals complexes (DABCO-Arn) have been investigated using a combination of (1 + 1') resonance enhanced multiphoton ionization (REMPI) and zero electron kinetic energy (ZEKE) spectroscopy. The additivity of the spectral shifts observed in both REMPI and ZEKE spectra, taken together with analysis of vibrational structure, suggest that in both DABCO-Ar and DABCO-Ar2 the argon atoms bind in equivalent equatorial (face) locations between two adjacent (CH2)2 bridges. However, the cumulative evidence from both REMPI and ZEKE spectra, together with ab initio results, suggests that the DABCO-Ar3 complex does not revert to D3h symmetry, but rather adopts a C2v structure in which all three argon atoms bind to one side of the DABCO framework. The exceptionally low wave-number vibrational structure observed in the REMPI spectra suggest that the van der Waals interaction in the excited state is extremely weak. However, ionization necessarily increases the strength of the interaction by virtue of the introduction of charge-induced dipole forces, as revealed by a consistent increase in vibrational wave numbers of the modes observed in the resultant ZEKE spectra.
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The complementary threshold ionization techniques of MATI and ZEKE spectroscopy have been used to reveal well-resolved, long-lived (>10 micros) hydrogenic Rydberg series (50< or =n< or =98) in a van der Waals complex formed between a polyatomic molecule and a diatomic molecule for the first time. The series are observed within 50 cm(-1) of the adiabatic ionization threshold as well as two core-excited thresholds corresponding to excitation of up to two quanta in the van der Waals vibrational mode.