Bioavailability of intravenous fosphenytoin sodium in healthy Japanese volunteers

To compare and evaluate the bioavailability for intravenous fosphenytoin sodium with that of intravenous phenytoin sodium in Japanese subjects. In study 1, healthy Japanese male volunteers received a 30-min infusion of 375 mg fosphenytoin sodium or an equimolar dose of 250 mg phenytoin by a double-blind, crossover method. In study 2, other healthy Japanese male volunteers received a 30-min or 10-min infusion of 563 mg fosphenytoin sodium, followed by a dose of 750 mg after 2 weeks in an unblinded manner. Comparing with 250 mg phenytoin sodium, 375 mg fosphenytoin sodium exhibited lower total plasma phenytoin C(max), whereas the geometric mean ratio of the AUC of total and free phenyotoin for fosphenytoin sodium at a dose of 375 mg was very similar to phenytoin sodium at a equimolar dose of 250 mg (AUC(0–t) ratio: 0.98 and 1.02, respectively). Therefore, fosphenytoin is almost completely converted to phenytoin in subjects. Fosphenytoin sodium was rapidly converted to phenytoin at doses of 375, 563, and 750 mg. The maximum concentration (C(max)) of total plasma phenytoin increased in a dose-dependent manner. The area under the plasma concentration–time curve (AUC) increased slightly more than proportionally with the administered dose, and clearance (CL) decreased with increasing dose. Pain and other infusion-site reactions were reported by all 12 subjects with phenytoin sodium, whereas very few symptoms were observed with fosphenytoin sodium. In conclusion, fosphenytoin sodium is considered to be a useful substitute for phenytoin sodium with almost no associated injection-site reactions

Successful Treatment of Epilepsy by Resection of Periventricular Nodular Heterotopia

We report on a case of successful surgical treatment of drug-resistant epilepsy associated with a solitary lesion of periventricular nodular heterotopia (PNH). In the reported patient, intracranial ictal electroencephalography disclosed that seizures did not originate from the heterotopic nodules. However, the seizures were completely suppressed by lesionectomy of PNH alone. Epileptogenesis associated with PNH likely involves a very complex network between PNH and the surrounding cortex, and the disruption of this network may be an effective means of curing intractable, PNH-associated epilepsy

Ictal direct current shifts contribute to defining the core ictal focus in epilepsy surgery

難治てんかん焦点の新しいバイオマーカー「発作時DC電位」 --国内5施設の共同研究での世界初の成果--. 京都大学プレスリリース. 2022-09-05.Identifying the minimal and optimal epileptogenic area to resect and cure is the goal of epilepsy surgery. To achieve this, EEG analysis is recognized as the most direct way to detect epileptogenic lesions from spatiotemporal perspectives. Although ictal direct-current shifts (icDCs; below 1 Hz) and ictal high-frequency oscillations (icHFOs; above 80 Hz) have received increasing attention as good indicators that can add more specific information to the conventionally defined seizure-onset zone, large cohort studies on postoperative outcomes are still lacking. This work aimed to clarify whether this additional information, particularly icDCs which is assumed to reflect extracellular potassium concentration, really improve postoperative outcomes. To assess the usefulness in epilepsy surgery, we collected unique EEG datasets recorded with a longer time constant of 10 sec using an alternate current amplifier. 61 patients [15 with mesial temporal lobe epilepsy and 46 with neocortical epilepsy] who had undergone invasive presurgical evaluation for medically refractory seizures at five institutes in Japan, were retrospectively enrolled in this study. Among intracranially implanted electrodes, the two core electrodes of both icDCs and icHFOs were independently identified by board-certified clinicians based on unified methods. The occurrence patterns, such as their onset time, duration, and amplitude (power) were evaluated to extract the features of both icDCs and icHFOs. Additionally, we examined whether the resection ratio of the core electrodes of icDCs and icHFOs independently correlated with favorable outcomes. A total of 53 patients with 327 seizures were analyzed for wide-band EEG analysis, and 49 patients were analyzed for outcome analysis. icDCs were detected in the seizure-onset zone more frequently than icHFOs among both patients (92% vs. 71%) and seizures (86% vs. 62%). Additionally, icDCs significantly preceded icHFOs in patients exhibiting both biomarkers, and icDCs occurred more frequently in neocortical epilepsy patients than in mesial temporal lobe epilepsy patients. Finally, although a low corresponding rate was observed for icDCs and icHFOs (39%) at the electrode level, complete resection of the core area of icDCs significantly correlated with favorable outcomes, similar to icHFO outcomes. Our results provide a proof of concept that the independent significance of icDCs from icHFOs should be considered as reliable biomarkers to achieve favorable outcomes in epilepsy surgery. Moreover, the different distribution of the core areas of icDCs and icHFOs may provide new insights into the underlying mechanisms of epilepsy, in which not only neurons but also glial cells may be actively involved via extracellular potassium levels

A history of mild shocks experienced by the regolith particles on hydrated asteroid Ryugu

Micrometeorites, a possible major source of Earth’s water, are thought to form from explosive dispersal of hydrated chondritic materials during impact events on their parental asteroids. However, this provenance and formation mechanism have yet to be directly confirmed using asteroid returned samples. Here, we report evidence of mild shock metamorphism in the surface particles of asteroid Ryugu based on electron microscopy. All particles are dominated by phyllosilicates but lack dehydration textures, which are indicative of shock-heating temperatures below ~500 °C. Microfault-like textures associated with extensively shock-deformed framboidal magnetites and a high-pressure polymorph of Fe–Cr–sulfide have been identified. These findings indicate that the average peak pressure was -2 GPa. The vast majority of ejecta formed during impact on Ryugu-like asteroids would be hydrated materials, larger than a millimetre, originating far from the impact point. These characteristics are inconsistent with current micrometeorite production models, and consequently, a new formation mechanism is required

Oxygen isotope evidence from Ryugu samples for early water delivery to Earth by CI chondrites

The delivery of water to the inner Solar System, including Earth, is still a debated topic. A preferential role for hydrated asteroids in this process is supported by isotopic measurements. Carbonaceous chondrite (CC) meteorites represent our main source of information about these volatile-rich asteroids. However, the destruction of weaker materials during atmospheric entry creates a bias in our CC data. The return of surface materials from the C-type asteroid 162173 Ryugu by the Hayabusa2 spacecraft provides a unique opportunity to study high-porosity, low-density, primitive materials, unrepresented in the meteorite record. We measured the bulk oxygen isotope composition from four Ryugu particles and show that they most closely resemble the rare CI (CC Ivuna-type) chondrites, but with some differences that we attribute to the terrestrial contamination of the CI meteorites. We suggest that CI-related material is widespread among carbonaceous asteroids and a more important source of Earth’s water and other volatiles than its limited presence in our meteoritic collection indicates

Influx of nitrogen-rich material from the outer Solar System indicated by iron nitride in Ryugu samples

Large amounts of nitrogen compounds, such as ammonium salts, may be stored in icy bodies and comets, but the transport of these nitrogen-bearing solids into the near-Earth region is not well understood. Here, we report the discovery of iron nitride on magnetite grains from the surface of the near-Earth C-type carbonaceous asteroid Ryugu, suggesting inorganic nitrogen fixation. Micrometeoroid impacts and solar wind irradiation may have caused the selective loss of volatile species from major iron-bearing minerals to form the metallic iron. Iron nitride is a product of nitridation of the iron metal by impacts of micrometeoroids that have higher nitrogen contents than the CI chondrites. The impactors are probably primitive materials with origins in the nitrogen-rich reservoirs in the outer Solar System. Our observation implies that the amount of nitrogen available for planetary formation and prebiotic reactions in the inner Solar System is greater than previously recognized

Four‐dimensional‐STEM analysis of the phyllosilicate‐rich matrix of Ryugu samples

Ryugu asteroid grains brought back to the Earth by the Hayabusa2 space mission are pristine samples containing hydrated minerals and organic compounds. Here, we investigate the mineralogy of their phyllosilicate-rich matrix with four-dimensional scanning transmission electron microscopy (4D-STEM). We have identified and mapped the mineral phases at the nanometer scale (serpentine, smectite, pyrrhotite), observed the presence of Ni-bearing pyrrhotite, and identified the serpentine polymorph as lizardite, in agreement with the reported aqueous alteration history of Ryugu. Furthermore, we have mapped the d-spacings of smectite and observed a broad distribution of values, ranging from 1 to 2 nm, with an average d-spacing of 1.24 nm, indicating significant heterogeneity within the sample. Such d-spacing variability could be the result of either the presence of organic matter trapped in the interlayers or the influence of various geochemical conditions at the submicrometer scale, suggestive of a range of organic compounds and/or changes in smectite crystal chemistry

A pristine record of outer Solar System materials from asteroid Ryugu’s returned sample

Volatile and organic-rich C-type asteroids may have been one of the main sources of Earth’s water. Our best insight into their chemistry is currently provided by carbonaceous chondritic meteorites, but the meteorite record is biased: only the strongest types survive atmospheric entry and are then modified by interaction with the terrestrial environment. Here we present the results of a detailed bulk and microanalytical study of pristine Ryugu particles, brought to Earth by the Hayabusa2 spacecraft. Ryugu particles display a close compositional match with the chemically unfractionated, but aqueously altered, CI (Ivuna-type) chondrites, which are widely used as a proxy for the bulk Solar System composition. The sample shows an intricate spatial relationship between aliphatic-rich organics and phyllosilicates and indicates maximum temperatures of ~30 °C during aqueous alteration. We find that heavy hydrogen and nitrogen abundances are consistent with an outer Solar System origin. Ryugu particles are the most uncontaminated and unfractionated extraterrestrial materials studied so far, and provide the best available match to the bulk Solar System composition

A dehydrated space-weathered skin cloaking the hydrated interior of Ryugu

Without a protective atmosphere, space-exposed surfaces of airless Solar System bodies gradually experience an alteration in composition, structure and optical properties through a collective process called space weathering. The return of samples from near-Earth asteroid (162173) Ryugu by Hayabusa2 provides the first opportunity for laboratory study of space-weathering signatures on the most abundant type of inner solar system body: a C-type asteroid, composed of materials largely unchanged since the formation of the Solar System. Weathered Ryugu grains show areas of surface amorphization and partial melting of phyllosilicates, in which reduction from Fe3+ to Fe2+ and dehydration developed. Space weathering probably contributed to dehydration by dehydroxylation of Ryugu surface phyllosilicates that had already lost interlayer water molecules and to weakening of the 2.7 µm hydroxyl (–OH) band in reflectance spectra. For C-type asteroids in general, this indicates that a weak 2.7 µm band can signify space-weathering-induced surface dehydration, rather than bulk volatile loss