Objectives
Cerebrospinal fluid (CSF) from some patients with amyotrophic lateral sclerosis (ALS) has been demonstrated to significantly reduce the neuronal viability of primary cell cultures of motor ...neurons. We aimed to study the potential clinical consequences associated with the cytotoxicity of CSF in a cohort of patients with ALS.
Methods
We collected CSF from thirty‐one patients with ALS. We analysed cytotoxicity by incubating it into the primary cultures of motor cortex neurons. Neural viability was quantified after 24 hours using the colorimetric MTT reduction assay. All patients were followed up from the moment of diagnosis to death, and a complete evaluation during disease progression and survival was performed, including gastrostomy and respiratory assistance.
Results
Twenty‐one patients (67.7%) presented a cytotoxic CSF. There were no significant differences between patients with and without cytotoxicity regarding mean time from symptom onset to the diagnosis, from the diagnosis to death, from the diagnosis to respiratory assistance with BIPAP, from diagnosis to gastrostomy and from the onset of symptoms to death. In Cox regression analysis, bulbar onset, but not cytotoxicity, gender or age at onset, was associated with a lower risk of survival.
Conclusions
Cerebrospinal fluid cytotoxicity was not associated with differential survival rates. This suggests that the presence of cytotoxicity in CSF, measured through neuronal viability in primary cultures of motor cortex neurons, could reflect different mechanisms of the disease, but it does not predict disease outcome.
Resumen Introducción La exposición de líquido cefalorraquídeo (LCR) de pacientes con esclerosis lateral amiotrófica (ELA) induce efectos citotóxicos en cultivos celulares de neuronas motoras in ...vitro. Material y métodos Se seleccionó LCR de 32 pacientes con ELA que previamente habían demostrado efectos citotóxicos. Se implantaron con minibombas osmóticas intracerebroventriculares (ICV) en 28 ratas macho adultas y se dividieron en 3 grupos: 9 ratas de LCR de pacientes no-ELA, 15 ratas de ELA-LCR citotóxico y 4 ratas de una solución salina fisiológica. El LCR se administró por vía ICV de forma continua durante periodos de 20 o 43 días. Se realizó la evaluación clínica, electromiográfica y análisis de tejidos después de sacrificio a los 20, 45 y 82 días tras la cirugía. Resultados Los estudios inmunohistoquímicos muestran daño en los tejidos con características similares a las encontradas en formas esporádicas de ELA, tales como sobre expresión de cistatina C, transferrina y la proteína en el TDP-43 citoplasmática. Los primeros cambios observados parecían jugar un papel protector por la sobreexpresión de periferina, panAKT, fosfoAKT y metalotioneínas; esta expresión habría disminuido al momento de analizar las ratas que se sacrificaron al día 82, en el que hay un aumento de apoptosis. Los primeros cambios celulares identificados fueron la constatación de activación de la microglía seguido por astrogliosis con sobreexpresión de GFAP y proteína S100B. Conclusiones Nuestros datos parecen indicar que la ELA podría propagarse a través del LCR, y que la administración ICV de ELA-LCR citotóxico produce cambios similares a los encontrados en las formas esporádicas de la enfermedad.
Cerebrospinal fluid (CSF) from amyotrophic lateral sclerosis (ALS) patients induces cytotoxic effects in in vitro cultured motor neurons.
We selected CSF with previously reported cytotoxic effects ...from 32 ALS patients. Twenty-eight adult male rats were intracerebroventricularly implanted with osmotic mini-pumps and divided into 3 groups: 9 rats injected with CSF from non-ALS patients, 15 rats injected with cytotoxic ALS-CSF, and 4 rats injected with a physiological saline solution. CSF was intracerebroventricularly and continuously infused for periods of 20 or 43days after implantation. We conducted clinical assessments and electromyographic examinations, and histological analyses were conducted in rats euthanised 20, 45, and 82days after surgery.
Immunohistochemical studies revealed tissue damage with similar characteristics to those found in the sporadic forms of ALS, such as overexpression of cystatin C, transferrin, and TDP-43 protein in the cytoplasm. The earliest changes observed seemed to play a protective role due to the overexpression of peripherin, AKTpan, AKTphospho, and metallothioneins; this expression had diminished by the time we analysed rats euthanised on day 82, when an increase in apoptosis was observed. The first cellular changes identified were activated microglia followed by astrogliosis and overexpression of GFAP and S100B proteins.
Our data suggest that ALS could spread through CSF and that intracerebroventricular administration of cytotoxic ALS-CSF provokes changes similar to those found in sporadic forms of the disease.
La exposición de líquido cefalorraquídeo (LCR) de pacientes con esclerosis lateral amiotrófica (ELA) induce efectos citotóxicos en cultivos celulares de neuronas motoras in vitro.
Se seleccionó LCR de 32 pacientes con ELA que previamente habían demostrado efectos citotóxicos. Se implantaron con minibombas osmóticas intracerebroventriculares (ICV) en 28 ratas macho adultas y se dividieron en 3 grupos: 9 ratas de LCR de pacientes no-ELA, 15 ratas de ELA-LCR citotóxico y 4 ratas de una solución salina fisiológica. El LCR se administró por vía ICV de forma continua durante periodos de 20 o 43días. Se realizó la evaluación clínica, electromiográfica y análisis de tejidos después de sacrificio a los 20, 45 y 82días tras la cirugía.
Los estudios inmunohistoquímicos muestran daño en los tejidos con características similares a las encontradas en formas esporádicas de ELA, tales como sobreexpresión de cistatinaC, transferrina y la proteína en el TDP-43 citoplasmática. Los primeros cambios observados parecían jugar un papel protector por la sobreexpresión de periferina, panAKT, fosfoAKT y metalotioneínas; esta expresión habría disminuido al momento de analizar las ratas que se sacrificaron al día 82, en el que hay un aumento de apoptosis. Los primeros cambios celulares identificados fueron la constatación de activación de la microglía seguido por astrogliosis con sobreexpresión de GFAP y proteína S100B.
Nuestros datos parecen indicar que la ELA podría propagarse a través del LCR, y que la administración ICV de ELA-LCR citotóxico produce cambios similares a los encontrados en las formas esporádicas de la enfermedad.
Cerebrospinal fluid (CSF) from amyotrophic lateral sclerosis (ALS) patients induces cytotoxic effects in in vitro cultured motor neurons.
We selected CSF with previously reported cytotoxic effects ...from 32 ALS patients. Twenty-eight adult male rats were intracerebroventricularly implanted with osmotic mini-pumps and divided into 3 groups: 9 rats injected with CSF from non-ALS patients, 15 rats injected with cytotoxic ALS-CSF, and 4 rats injected with a physiological saline solution. CSF was intracerebroventricularly and continuously infused for periods of 20 or 43days after implantation. We conducted clinical assessments and electromyographic examinations, and histological analyses were conducted in rats euthanised 20, 45, and 82days after surgery.
Immunohistochemical studies revealed tissue damage with similar characteristics to those found in the sporadic forms of ALS, such as overexpression of cystatinC, transferrin, and TDP-43 protein in the cytoplasm. The earliest changes observed seemed to play a protective role due to the overexpression of peripherin, AKTpan, AKTphospho, and metallothioneins; this expression had diminished by the time we analysed rats euthanised on day 82, when an increase in apoptosis was observed. The first cellular changes identified were activated microglia followed by astrogliosis and overexpression of GFAP and S100B proteins.
Our data suggest that ALS could spread through CSF and that intracerebroventricular administration of cytotoxic ALS-CSF provokes changes similar to those found in sporadic forms of the disease.
The diradical acceptor–donor–acceptor triad 1 ••, based on two polychlorotriphenylmethyl (PTM) radicals connected through a tetrathiafulvalene(TTF)–vinylene bridge, has been synthesized. The ...generation of the mixed-valence radical anion, 1 •–, and triradical cation species, 1•••+, obtained upon electrochemical reduction and oxidation, respectively, was monitored by optical and ESR spectroscopy. Interestingly, the modification of electron delocalization and magnetic coupling was observed when the charged species were generated and the changes have been rationalized by theoretical calculations.
Smoke particles ejected into the atmosphere from biomass burning can modify the atmospheric composition around and even far from the sources. In late winter and early spring, biomass burning ...emissions from inland regions can be efficiently transported to urban areas in southeastern South America, thus affecting air quality in those areas. In this study, the Weather Research and Forecasting with Chemistry model was applied in order to investigate the impact of biomass burning sources on aerosol loadings and properties over the São Paulo Metropolitan Area (SPMA), in southeastern Brazil, during the period from 19 August to 3 September 2014. The model performance was evaluated using available aerosol measurements from the Narrowing the Uncertainties on Aerosol and Climate Change in São Paulo State project. The combined application of aerosol data and Weather Research and Forecasting with Chemistry simulations made it possible to represent some of the most important aerosol properties, such as particle number concentration and cloud condensation nuclei activation, in addition to evaluation of the impact of biomass burning by analyzing a 5‐day transport event, from 22 to 26 August 2014. During this transport event, differences in the average predicted PM2.5 concentration reached 15 μg/m3 (peaking at 20 μg/m3 during the nighttime hours) over the SPMA, compared with 35 μg/m3 over inland areas northwest and north of the SPMA. Biomass burning accounted for up to 20% of the baseline particle number concentration‐ and cloud condensation nuclei‐weighted relative differences over the SPMA (2,300 and 1,400 cm−3, respectively).
Key Points
The fully coupled WRF‐Chem model was applied and evaluated for the atmosphere over the metropolitan area of São Paulo
The WRF‐Chem can reproduce observed temporal variations in meteorological conditions and chemical species
Inclusion of biomass burning emissions improves predictions of aerosol properties
The understanding of the crystal structure of organic compounds, and its relationship to their physical properties, have become essential to design new advanced molecular materials. In this context, ...we present a computational study devoted to rationalize the different crystal packing displayed by two closely related organic systems based on the TTF-PTM dyad (TTF = tetrathiafulvalene, PTM = polychlorotriphenylmethane) with almost the same molecular structure but a different electronic one. The radical species (1), with an enhanced electronic donor–acceptor character, exhibits a herringbone packing, whereas the nonradical protonated analogue (2) is organized forming dimers. The stability of the possible polymorphs is analyzed in terms of the cohesion energy of the unit cell, intermolecular interactions between pairs, and molecular flexibility of the dyad molecules. It is observed that the higher electron delocalization in radical compound 1 has a direct influence on the geometry of the molecule, which seems to dictate its preferential crystal structure.
We report on observations of the pulsar/Be star binary system PSR J2032+4127/MT91 213 in the energy range between and with the Very Energetic Radiation Imaging Telescope Array and Major Atmospheric ...Gamma Imaging Cherenkov telescope arrays. The binary orbit has a period of approximately 50 years, with the most recent periastron occurring on 2017 November 13. Our observations span from 18 months prior to periastron to one month after. A new point-like gamma-ray source is detected, coincident with the location of PSR J2032+4127/MT91 213. The gamma-ray light curve and spectrum are well characterized over the periastron passage. The flux is variable over at least an order of magnitude, peaking at periastron, thus providing a firm association of the TeV source with the pulsar/Be star system. Observations prior to periastron show a cutoff in the spectrum at an energy around . This result adds a new member to the small population of known TeV binaries, and it identifies only the second source of this class in which the nature and properties of the compact object are firmly established. We compare the gamma-ray results with the light curve measured with the X-ray Telescope on board the Neil Gehrels Swift Observatory and with the predictions of recent theoretical models of the system. We conclude that significant revision of the models is required to explain the details of the emission that we have observed, and we discuss the relationship between the binary system and the overlapping steady extended source, TeV J2032+4130.
PDF
