Immune thrombocytopenia (ITP) results from platelet destruction and production suppression. Eltrombopag belongs to a new class of thrombopoietin-mimetic drugs that raise platelet counts in ITP ...patients. We performed a single-arm study to assess the response to a single course of dexamethasone (40 mg by mouth, days 1-4) in combination with eltrombopag (50 mg, days 5-32) in 12 adults with newly diagnosed ITP in an outpatient setting. Median follow-up was 12.5 months. After therapy (day 33), 100% of patients achieved at least ≥30 × 109/L platelets. Four patients relapsed. Complete response at 6 months (platelets ≥100 × 109/L) was achieved in 50% of patients and response at 6 months (platelets ≥30 <100 × 109/L) was achieved in another 25%; relapse-free survival was 66.7% at 12 months (median response duration of 8.3 months). In conclusion, eltrombopag/dexamethasone is a feasible frontline therapy for ITP. This trial is registered at www.clinicaltrials.gov as NCT01652599.
•Eltrombopag/dexamethasone is a safe and effective combination for treating newly diagnosed ITP patients.•This treatment may prove useful in achieving lasting responses without additional immunosuppression in some patients.
Abstract
Dialysis-related amyloidosis (DRA), a serious complication among long-term hemodialysis patients, is caused by amyloid fibrils of β2-microglobulin (β2m). Although high serum β2m levels and a ...long dialysis vintage are the primary and secondary risk factors for the onset of DRA, respectively, patients with these do not always develop DRA, indicating that there are additional risk factors. To clarify these unknown factors, we investigate the effects of human sera on β2m amyloid fibril formation, revealing that sera markedly inhibit amyloid fibril formation. Results from over 100 sera indicate that, although the inhibitory effects of sera deteriorate in long-term dialysis patients, they are ameliorated by maintenance dialysis treatments in the short term. Serum albumin prevents amyloid fibril formation based on macromolecular crowding effects, and decreased serum albumin concentration in dialysis patients is a tertiary risk factor for the onset of DRA. We construct a theoretical model assuming cumulative effects of the three risk factors, suggesting the importance of monitoring temporary and accumulated risks to prevent the development of amyloidosis, which occurs based on supersaturation-limited amyloid fibril formation in a crowded milieu.
El Lago Titicaca, en la actualidad, es considerado una maravilla natural del mundo. Es el habitad de muchas especies nativas únicas y en extinción, con flora y fauna de gran diversidad, sitio de ...anidamiento de muchas aves migratorias, fuente de agua dulce filtrada, por su volumen, regula la temperatura del aire de la región permitiendo condiciones del clima menos agresivas para la vida. Sin embargo en las últimas décadas, la influencia antropogénica afectó su conservación. Los problemas que presenta el Lago Titicaca, están concentradas en la zona litoral, las bahías y el Lago Menor. Grandes cantidades de agua residuales que ingresan directamente o deficientemente tratadas, en particular a las Bahías de Puno y Copacabana, están generando procesos de eutrofización. El efecto de las descargas son el incremento de sedimentos acumulados en el fondo, floración explosiva de algas Lemna sp. en la superficie, reducción en los niveles de oxígeno disuelto, y disminución de la calidad del agua. Sin embargo, los procesos de contaminación no pueden entenderse solo en función de la carga de materia orgánica que recibe, ya que están bien acoplados a una amplia gama de procesos físicos que van a vincular la dinámica entre la zona litoral y la cuenca principal. Se ha demostrado en grandes lagos, que mueven nutrientes, calor, carbono orgánico, y otros trazadores a través de isóbaras, desde el borde del lago a la plataforma interna, y viceversa. Estos procesos físicos determinan en gran medida el tiempo promedio en que los contaminantes permanecen en las zonas cercanas a la costa y, por tanto, es necesario estimar su concentración y el nivel de variabilidad en la zona costera. En regiones con fuerte intercambio, los flujos de nutrientes a través de la zona costera parecen estar todavía dominados por grandes entradas de agua, y hay poca evidencia de perturbaciones antropogénicas. En zonas de intercambio restringido, a su vez, existen fuertes evidencias del impacto humano, en términos de cantidad de toplancton y abundancia relativa de especies, o zonas profundas del lago donde el oxígeno disminuye. La zona costera del lago Titicaca, y en particular, la bahía interior de Puno, es un ejemplo paradigmático de contaminación causada por la acción humana sin control sobre el entorno cercano a la costa. La Bahía Interior está unido a la Bahía Exterior de Puno por dos canales y una región con mucha totora que genera restricciones al intercambio. Desafortunadamente, poco se sabe sobre el tipo de intercambio o de los procesos físicos que controlan los flujos de sustancias entre la bahía de Puno y el cuerpo principal del lago. Este, también es el caso de muchas bahías en lagos de todo el mundo, en el que los procesos de intercambio se mantienen en gran parte inexplorados. Por lo tanto, existe una necesidad urgente de comprender los procesos físicos que controlan el intercambio entre zona litoral y pelágico, esto permitiría tratar mejor los problemas de calidad del agua en las zonas costeras. Nuestro objetivo es entender los mecanismos físicos que intervienen en el intercambio de agua y sustancias entre zona litoral y pelágica en grandes lagos tropicales. Utilizamos la bahía de Puno y el lago Grande, como un ejemplo del caso. Estimamos el caudal de salida o entrada a través de la boca de la Bahía de Puno, debido a tres procesos físicos que consideramos de mayor importancia que serían los responsables del flujo de agua y sustancias. En particular, se presta atención al intercambio horizontal impulsado por ondas barotrópicas, baroclínicas y procesos de difusión, temas que en la actualidad siguen sin explorarse. Para cumplir con este objetivo se utiliza una combinación de argumentos de escala, basados en datos de campo existentes que apareció principalmente en informes científicos y profesionales, y simulaciones que se realizaron con un modelo de transporte hidrodinámico tridimensional y, originalmente desarrollado por el Servicio Geológico de Estados Unidos, en la Universidad de California, Davis, USA, ampliado y adaptado en la Universidad de Granada para ejecutarse en arquitecturas paralelas. Se estimó los caudales de intercambio y tiempo de residencia de la Bahía de Puno, así como la tasa de difusión para una sustancia, entre el Lago Grande y la Bahía de Puno.
Energy harvesting is a technology that can be applied to IoT systems to eliminate the need for batteries. Many types of energy sources are available for energy harvesting, such as light, thermal, ...vibration, and electromagnetic energy. Indoors, where most IoT devices are located, artificial light, such as from LED lamps, can be used for energy harvesting in circuits with very ultra-low power consumption. Integrated switch-capacitor DC-DC converters are required for this type of system to convert the harvested energy into a constant output voltage suitable for powering an electronic circuit. The idea of this work is to use a hysteretic feedback control consisting of comparators and a logic system to adjust the switching frequency and the voltage conversion ratio (VCR) of the converter. With this, the equivalent output resistance is tuned to a value that results in a constant output voltage. A new method for modeling the equivalent output resistance based on charge flow analysis is proposed, which also considers the effects of source resistance. An integrated energy-harvesting system consisting of a switched-capacitor DC-DC converter is implemented to obtain an output voltage of 400 mV using a small photovoltaic cell for energy harvesting from indoor light. The proposed system can power an ultra-low-power device between 20 μW and 40 μW with a minimum input voltage of 230 mV. Electrical simulation results show that the implemented converter can achieve a peak efficiency of 81.24% at an input voltage of 260 mV for a 20 μW load.
Yellow rust (YR) or stripe rust, caused by
Puccinia striformis
f. sp
tritici
Eriks (
Pst
), is a major challenge to resistance breeding in wheat. A genome wide association study (GWAS) was performed ...using 22,415 single nucleotide polymorphism (SNP) markers and 591 haplotypes to identify genomic regions associated with resistance to YR in a subset panel of 419 pre-breeding lines (PBLs) developed at International Center for Maize and Wheat Improvement (CIMMYT). The 419 PBLs were derived from an initial set of 984 PBLs generated by a three-way crossing scheme (exotic/elite1//elite2) among 25 best elites and 244 exotics (synthetics, landraces) from CIMMYT’s germplasm bank. For the study, 419 PBLs were characterized with 22,415 high-quality DArTseq-SNPs and phenotyped for severity of YR disease at five locations in Mexico. A population structure was evident in the panel with three distinct subpopulations, and a genome-wide linkage disequilibrium (LD) decay of 2.5 cM was obtained. Across all five locations, 14 SNPs and 7 haplotype blocks were significantly (
P
< 0.001) associated with the disease severity explaining 6.0 to 14.1% and 7.9 to 19.9% of variation, respectively. Based on average LD decay of 2.5 cM, identified 14 SNP–trait associations were delimited to seven quantitative trait loci in total. Seven SNPs were part of the two haplotype blocks on chromosome 2A identified in haplotypes-based GWAS.
In silico
analysis of the identified SNPs showed hits with interesting candidate genes, which are related to pathogenic process or known to regulate induction of genes related to pathogenesis such as those coding for glunolactone oxidase, quinate O-hydroxycinnamoyl transferase, or two-component histidine kinase. The two-component histidine kinase, for example, acts as a sensor in the perception of phytohormones ethylene and cytokinin. Ethylene plays a very important role in regulation of multiple metabolic processes of plants, including induction of defense mechanisms mediated by jasmonate. The SNPs linked to the promising genes identified in the study can be used for marker-assisted selection.
Parkinson's disease is a neurodegenerative disease characterized by the formation of neuronal inclusions of α-synuclein in patient brains. As the disease progresses, toxic α-synuclein aggregates ...transmit throughout the nervous system. No effective disease-modifying therapy has been established, and preventing α-synuclein aggregation is thought to be one of the most promising approaches to ameliorate the disease. In this study, we performed a two-step screening using the thioflavin T assay and a cell-based assay to identify α-synuclein aggregation inhibitors. The first screening, thioflavin T assay, allowed the identification of 30 molecules, among a total of 1262 FDA-approved small compounds, which showed inhibitory effects on α-synuclein fibrilization. In the second screening, a cell-based aggregation assay, seven out of these 30 candidates were found to prevent α-synuclein aggregation without causing substantial toxicity. Of the seven final candidates, tannic acid was the most promising compound. The robustness of our screening method was validated by a primary neuronal cell model and a Caenorhabditis elegans model, which demonstrated the effect of tannic acid against α-synuclein aggregation. In conclusion, our two-step screening system is a powerful method for the identification of α-synuclein aggregation inhibitors, and tannic acid is a promising candidate as a disease-modifying drug for Parkinson's disease.
Machine failure in modern industry leads to lost production and reduced competitiveness. Maintenance costs represent between 15% and 60% of the manufacturing cost of the final product, and in heavy ...industry, these costs can be as high as 50% of the total production cost. Predictive maintenance is an efficient technique to avoid unexpected maintenance stops during production in industry. Vibration measurement is the main non-invasive method for locating and predicting faults in rotating machine components. This paper reviews the techniques and tools used to collect and analyze vibration data, as well as the methods used to interpret and diagnose faults in rotating machinery. The main steps of this technique are discussed, including data acquisition, data transmission, signal processing, and fault detection. Predictive maintenance through vibration analysis is a key strategy for cost reduction and a mandatory application in modern industry.
Haploidentical hematopoietic can be conducted on an outpatient basis but the two main reasons to accept into the hospital a patient in this setting are complications of the hematological toxicity ...and/or the cytokine-release syndrome. With the aim of reducing the post-transplant cyclophosphamide-dependent toxicity without compromising its effectivity, attempts to reduce the dose of post-transplant cyclophosphamide have been made: Decreases from the conventional total dose of post-transplant cyclophosphamide (100 mg/Kg) have been explored worldwide, showing that decreasing the total dose to even 50 mg/Kg significantly decreases the toxicity of the procedure without compromising its efficacy, safety and results. We present here the salient data of the attempts to diminish the doses of post-transplant cyclophosphamide which have been done and published worldwide, information that suggests that the conventional doses of post-transplant cyclophosphamide can be significantly reduced thus decreasing the toxicity, without compromising the effectiveness of the procedure, mainly the development of graft
host disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The neuron-to-neuron propagation of misfolded α-synuclein (αSyn) aggregates is thought to be key to the pathogenesis of synucleinopathies. Recent studies have shown that extracellular αSyn aggregates ...taken up by the endosomal-lysosomal system can rupture the lysosomal vesicular membrane; however, it remains unclear whether lysosomal rupture leads to the transmission of αSyn aggregation. Here, we applied cell-based αSyn propagation models to show that ruptured lysosomes are the pathway through which exogenous αSyn aggregates transmit aggregation, and furthermore, this process was prevented by lysophagy, i.e., selective autophagy of damaged lysosomes. αSyn aggregates accumulated predominantly in lysosomes, causing their rupture, and seeded the aggregation of endogenous αSyn, initially around damaged lysosomes. Exogenous αSyn aggregates induced the accumulation of LC3 on lysosomes. This LC3 accumulation was not observed in cells in which a key regulator of autophagy, RB1CC1/FIP200, was knocked out and was confirmed as lysophagy by transmission electron microscopy. Importantly, RB1CC1/FIP200-deficient cells treated with αSyn aggregates had increased numbers of ruptured lysosomes and enhanced propagation of αSyn aggregation. Furthermore, various types of lysosomal damage induced using lysosomotropic reagents, depletion of lysosomal enzymes, or more toxic species of αSyn fibrils also exacerbated the propagation of αSyn aggregation, and impaired lysophagy and lysosomal membrane damage synergistically enhanced propagation. These results indicate that lysophagy prevents exogenous αSyn aggregates from escaping the endosomal-lysosomal system and transmitting aggregation to endogenous cytosolic αSyn via ruptured lysosomal vesicles. Our findings suggest that the progression and severity of synucleinopathies are associated with damage to lysosomal membranes and impaired lysophagy.
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