The ketogenic diet raises brain oxygen levels, attenuates postictal hypoxia, and protects against learning impairments.

OBJECTIVES: A prolonged vasoconstriction/hypoperfusion/hypoxic event follows self-terminating focal seizures. The ketogenic diet (KD) has demonstrated efficacy as a metabolic treatment for intractable epilepsy and other disorders but its effect on local brain oxygen levels is completely unknown. This study investigated the effects of the KD on tissue oxygenation in the hippocampus before and after electrically elicited (kindled) seizures and whether it could protect against a seizure-induced learning impairment. We also examined the effects of the ketone ß-hydroxybutyrate (BHB) as a potential underlying mechanism. METHODS: Male and female rats were given access to one of three diet protocols 2 weeks prior to the initiation of seizures: KD, caloric restricted standard chow, and ad libitum standard chow. Dorsal hippocampal oxygen levels were measured prior to initiation of diets as well as before and after a 10-day kindling paradigm. Male rats were then tested on a novel object recognition task to assess postictal learning impairments. In a separate cohort, BHB was administered 30 min prior to seizure elicitation to determine whether it influenced oxygen dynamics. RESULTS: The KD increased dorsal hippocampal oxygen levels, ameliorated postictal hypoxia, and prevented postictal learning impairments. Acute BHB administration did not alter oxygen levels before or after seizures. INTERPRETATION: The ketogenic diet raised brain oxygen levels and attenuated severe postictal hypoxia likely through a mechanism independent of ketosis and shows promise as a non-pharmacological treatment to prevent the postictal state.

Multicenter Evaluation of the Clinical Performance and the Neutralizing Antibody Activity Prediction Properties of 10 High-Throughput Serological Assays Used in Clinical Laboratories.

As the coronavirus disease 2019 (COVID-19) pandemic second wave is emerging, it is of the upmost importance to screen the population immunity in order to keep track of infected individuals. Consequently, immunoassays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with high specificity and positive predictive values are needed to obtain an accurate epidemiological picture. As more data accumulate about the immune responses and the kinetics of neutralizing-antibody (nAb) production in SARS-CoV-2-infected individuals, new applications are forecast for serological assays such as nAb activity prediction in convalescent-phase plasma from recovered patients. This multicenter study, involving six hospital centers, determined the baseline clinical performances, reproducibility, and nAb level correlations of 10 commercially available immunoassays. In addition, three lateral-flow chromatography assays were evaluated, as these devices can be used in logistically challenged areas. All assays were evaluated using the same patient panels in duplicate, thus enabling accurate comparison of the tests. Seven immunoassays examined in this study were shown to have excellent specificity (98 to 100%) and good to excellent positive predictive values (82 to 100%) when used in a low (5%)-seroprevalence setting. We observed sensitivities as low as 74% and as high as 95% at ≥15 days after symptom onset. The determination of optimized cutoff values through receiver operating characteristic (ROC) curve analyses had a significant impact on the diagnostic resolution of several enzyme immunoassays by increasing the sensitivity significantly without a large trade-off in specificity. We found that spike-based immunoassays seem to be better correlates of nAb activity. Finally, the results reported here will add to the general knowledge of the interlaboratory reproducibility of clinical performance parameters of immunoassays and provide new evidence about nAb activity prediction.

Insight into the Am-O Phase Equilibria: A Thermodynamic Study Coupling High-Temperature XRD and CALPHAD Modeling.

In the frame of minor actinide transmutation, americium can be diluted in UO2 and (U, Pu)O2 fuels burned in fast neutron reactors. The first mandatory step to foresee the influence of Am on the in-reactor behavior of transmutation targets or fuel is to have fundamental knowledge of the Am-O binary system and, in particular, of the AmO2-x phase. In this study, we coupled HT-XRD (high-temperature X-ray diffraction) experiments with CALPHAD thermodynamic modeling to provide new insights into the structural properties and phase equilibria in the AmO2-x-AmO1.61+x-Am2O3 domain. Because of this approach, we were able for the first time to assess the relationships between temperature, lattice parameter, and hypostoichiometry for fcc AmO2-x. We showed the presence of a hyperstoichiometric existence domain for the bcc AmO1.61+x phase and the absence of a miscibility gap in the fcc AmO2-x phase, contrary to previous representations of the phase diagram. Finally, with the new experimental data, a new CALPHAD thermodynamic model of the Am-O system was developed, and an improved version of the phase diagram is presented.

Actinide Oxidation State and O/M Ratio in Hypostoichiometric Uranium-Plutonium-Americium U0.750Pu0.246Am0.004O2-x Mixed Oxides.

Innovative americium-bearing uranium-plutonium mixed oxides U1-yPuyO2-x are envisioned as nuclear fuel for sodium-cooled fast neutron reactors (SFRs). The oxygen-to-metal (O/M) ratio, directly related to the oxidation state of cations, affects many of the fuel properties. Thus, a thorough knowledge of its variation with the sintering conditions is essential. The aim of this work is to follow the oxidation state of uranium, plutonium, and americium, and so the O/M ratio, in U0.750Pu0.246Am0.004O2-x samples sintered for 4 h at 2023 K in various Ar + 5% H2 + z vpm H2O (z = ∼ 15, ∼ 90, and ∼ 200) gas mixtures. The O/M ratios were determined by gravimetry, XAS, and XRD and evidenced a partial oxidation of the samples at room temperature. Finally, by comparing XANES and EXAFS results to that of a previous study, we demonstrate that the presence of uranium does not influence the interactions between americium and plutonium and that the differences in the O/M ratio between the investigated conditions is controlled by the reduction of plutonium. We also discuss the role of the homogeneity of cation distribution, as determined by EPMA, on the mechanisms involved in the reduction process.

Biphasic MO2+x-M3O8-z domain of the U-Pu-O phase diagram.

The reduction of six mixed-oxide samples containing 14, 24, 35, 46, 54, and 62 mol % Pu was studied in situ by X-ray diffraction. The samples were first oxidized in air and subsequently reduced in a controlled atmosphere corresponding to a stoichiometric composition with an O/M = 2.00. After oxidation, we observed two structures, one cubic and one orthorhombic, MO2+x and M3O8-z. The two phases were subsequently reduced back to their stoichiometric O/M = 2.00 in a controlled atmosphere. The plutonium contents of the two resulting cubic structures differed from the initial one. We conclude that strong cation transport took place during oxidation, according to the shape of the tie lines in the biphasic MO2+x/M4O9-M3O8-z domain. The resulting overall O/M after oxidation was estimated. We propose the shape of the tie lines in the aforementioned biphasic domain and suggest a maximal plutonium solubility in the M3O8 structure at 8 ± 2 mol % (Pu/U + Pu) at 1573 K.

High temperature X-ray diffraction study of the oxidation products and kinetics of uranium-plutonium mixed oxides.

The oxidation products and kinetics of two sets of mixed uranium-plutonium dioxides containing 14%, 24%, 35%, 46%, 54%, and 62% plutonium treated in air were studied by means of in situ X-ray diffraction (XRD) from 300 to 1773 K every 100 K. The first set consisted of samples annealed 2 weeks before performing the experiments. The second one consisted of powdered samples that sustained self-irradiation damage. Results were compared with chosen literature data and kinetic models established for UO2. The obtained diffraction patterns were used to determine the temperature of the hexagonal M3O8 (M for metal) phase formation, which was found to increase with Pu content. The maximum observed amount of the hexagonal phase in wt % was found to decrease with Pu addition. We conclude that plutonium stabilizes the cubic phases during oxidation, but the hexagonal phase was observed even for the compositions with 62 mol % Pu. The results indicate that self-irradiation defects have a slight impact on the kinetics of oxidation and the lattice parameter even after the phase transformation. It was concluded that the lattice constant of the high oxygen phase was unaffected by the changes in the overall O/M when it was in equilibrium with small quantities of M3O8. We propose that the observed changes in the high oxygen cubic phase lattice parameter are a result of either cation migration or an increase in the miscibility of oxygen in this phase. The solubility of Pu in the hexagonal phase was estimated to be below 14 mol % even at elevated temperatures.

High-temperature X-ray diffraction study of uranium-neptunium mixed oxides.

Incorporating minor actinides (MAs = Am, Np, Cm) in UO2 fertile blankets is a viable option to recycle them. Despite this applied interest, phase equilibria between uranium and MAs still need to be thoroughly investigated, especially at elevated temperatures. In particular, few reports on the U-Np-O system are available. In the present work, we provide for the first time in situ high-temperature X-ray diffraction results obtained during the oxidation of (U1-yNpy)O2 uranium-neptunium mixed oxides up to 1373 K and discuss subsequent phase transformations. We show that (i) neptunium stabilizes the UO2-type fluorite structure at high temperature and that (ii) the U3O8-type orthorhombic structure is observed in a wide range of compositions. We clearly demonstrate the incorporation of neptunium in this phase, which was a controversial question in previous studies up to now. We believe it is the particular stability of the tetravalent state of neptunium that is responsible for the observed phase relationships.

Role of cation interactions in the reduction process in plutonium-americium mixed oxides.

The oxygen to metal ratio (O/M) is directly related to oxygen potential, which strongly influences the sintering and irradiation performance of nuclear fuels. A better understanding of these two parameters is therefore of major interest. To further ascertain the correlation between O/M ratio and oxygen potential in Am-bearing MOX, several thermodynamic descriptions are being developed. Despite their differences, they all involve the valence of actinide cations (e.g., U, Pu, and Am) as essential parameters. However, as no experimental data on their valence are available, these models rely on assumptions. In the present work, we coupled X-ray diffraction and X-ray absorption spectroscopy to follow the behavior of Pu and Am in three hypo-stoichiometric, U-free Pu(1-y)Am(y)O(2-x) compounds. We provide for the first time a quantitative determination of Pu and Am valences, demonstrating that plutonium reduction from Pu(4+) to Pu(3+) starts only when americium reduction from Am(4+) to Am(3+) is completed. This result fills in an important gap in experimental data, thereby improving the thermodynamic description of nuclear fuels. At last, we suggest that the O/M ratio may evolve at room temperature, especially for high Am content, which is of main concern for the fabrication of Am-loaded MOX and their storage prior to irradiation.

Caffeine exacerbates seizure-induced death via postictal hypoxia.

Sudden unexpected death in epilepsy (SUDEP) is the leading epilepsy-related cause of premature mortality in people with intractable epilepsy, who are 27 times more likely to die than the general population. Impairment of the central control of breathing following a seizure has been identified as a putative cause of death, but the mechanisms underlying this seizure-induced breathing failure are largely unknown. Our laboratory has advanced a vascular theory of postictal behavioural dysfunction, including SUDEP. We have recently reported that seizure-induced death occurs after seizures invade brainstem breathing centres which then leads to local hypoxia causing breathing failure and death. Here we investigated the effects of caffeine and two adenosine receptors in two models of seizure-induced death. We recorded local oxygen levels in brainstem breathing centres as well as time to cessation of breathing and cardiac activity relative to seizure activity. The administration of the non-selective A1/A2A antagonist caffeine or the selective A1 agonist N6-cyclopentyladenosine reveals a detrimental effect on postictal hypoxia, providing support for caffeine modulating cerebral vasculature leading to brainstem hypoxia and cessation of breathing. Conversely, A2A activation with CGS-21680 was found to increase the lifespan of mice in both our models of seizure-induced death.

Sudden unexpected death in epilepsy is prevented by blocking postictal hypoxia.

Epilepsy is at times a fatal disease. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in people with intractable epilepsy and is defined by exclusion; non-accidental, non-toxicologic, and non-anatomic causes of death. While SUDEP often follows a bilateral tonic-clonic seizure, the mechanisms that ultimately lead to terminal apnea and then asystole remain elusive and there is a lack of preventative treatments. Based on the observation that discrete seizures lead to local and postictal vasoconstriction, resulting in hypoperfusion, hypoxia and behavioural disturbances in the forebrain we reasoned those similar mechanisms may play a role in SUDEP when seizures invade the brainstem. Here we tested this neurovascular-based hypothesis of SUDEP in awake non-anesthetized mice by pharmacologically preventing seizure-induced vasoconstriction, with cyclooxygenase-2 or L-type calcium channel antagonists. In both acute and chronic mouse models of seizure-induced premature mortality, ibuprofen and nicardipine extended life while systemic drug levels remained high enough to be effective. We also examined the potential role of spreading depolarization in the acute model of seizure-induced premature mortality. These data provide a proof-of-principle for the neurovascular hypothesis of SUDEP rather than spreading depolarization and the use of currently available drugs to prevent it.

170 GHz Uni-Traveling Carrier Photodiodes for InP-based photonic integrated circuits.

We demonstrate the capability of fabricating extremely high-bandwidth Uni-Traveling Carrier Photodiodes (UTC-PDs) using techniques that are suitable for active-passive monolithic integration with Multiple Quantum Well (MQW)-based photonic devices. The devices achieved a responsivity of 0.27 A/W, a 3-dB bandwidth of 170 GHz, and an output power of -9 dBm at 200 GHz. We anticipate that this work will deliver Photonic Integrated Circuits with extremely high bandwidth for optical communications and millimetre-wave applications.

146-GHz millimeter-wave radio-over-fiber photonic wireless transmission system.

We report the experimental implementation of a wireless transmission system with a 146-GHz carrier frequency which is generated by optical heterodyning the two modes from a monolithically integrated quantum dash dual-DFB source. The monolithic structure of the device and the inherent low noise characteristics of quantum dash gain material allow us to demonstrate the transmission of a 1 Gbps ON-OFF keyed data signal with the two wavelengths in a free-running state at 146-GHz carrier wave frequency. The tuning range of the device fully covers the W-band (75 - 110 GHz) and the F-band (90 - 140 GHz).

High-speed photodiodes for InP-based photonic integrated circuits.

We demonstrate the feasibility of monolithic integration of evanescently coupled Uni-Traveling Carrier Photodiodes (UTC-PDs) having a bandwidth exceeding 100 GHz with Multimode Interference (MMI) couplers. This platform is suitable for active-passive, butt-joint monolithic integration with various Multiple Quantum Well (MQW) devices for narrow linewidth millimeter-wave photomixing sources. The fabricated devices achieved a high 3-dB bandwidth of up to 110 GHz and a generated output power of more than 0 dBm (1 mW) at 120 GHz with a flat frequency response over the microwave F-band (90-140 GHz).

Genetic dissection of fruit quality traits in the octoploid cultivated strawberry highlights the role of homoeo-QTL in their control.

Fruit quality traits are major breeding targets in the Rosaceae. Several of the major Rosaceae species are current or ancient polyploids. To dissect the inheritance of fruit quality traits in polyploid fleshy fruit species, we used a cultivated strawberry segregating population comprising a 213 full-sibling F1 progeny from a cross between the variety 'Capitola' and the genotype 'CF1116'. We previously developed the most comprehensive strawberry linkage map, which displays seven homoeology groups (HG), including each four homoeology linkage groups (Genetics 179:2045-2060, 2008). The map was used to identify quantitative trait loci (QTL) for 19 fruit traits related to fruit development, texture, colour, anthocyanin, sugar and organic acid contents. Analyses were carried out over two or three successive years on field-grown plants. QTL were detected for all the analysed traits. Because strawberry is an octopolyploid species, QTL controlling a given trait and located at orthologous positions on different homoeologous linkage groups within one HG are considered as homoeo-QTL. We found that, for various traits, about one-fourth of QTL were putative homoeo-QTL and were localised on two linkage groups. Several homoeo-QTL could be detected the same year, suggesting that several copies of the gene underlying the QTL are functional. The detection of some other homoeo-QTL was year-dependent. Therefore, changes in allelic expression could take place in response to environmental changes. We believe that, in strawberry as in other polyploid fruit species, the mechanisms unravelled in the present study may play a crucial role in the variations of fruit quality.

Paediatric moyamoya in mainland France: a comprehensive survey of academic neuropaediatric centres.

BACKGROUND: Epidemiological data of paediatric moyamoya disease/syndrome (MMD/MMS) in non-Asian populations are scarce. METHODS: A questionnaire was sent to every French neuropaediatric academic centre to estimate the prevalence, incidence, familial form rate and location of paediatric MMD/MMS cases. Specific paediatric data were also retrieved from the most recent nationwide Japanese study. RESULTS: A 100% response rate was obtained. The prevalence of paediatric MMD/MMS was estimated at 0.39/100,000 children (95% CI: 0.28-0.49), and the incidence was estimated at 0.065/100,000 children/year (95% CI: 0.025-0.12), with 7.5% familial cases. The prevalence was homogenous within the different administrative areas. CONCLUSIONS: This comprehensive survey of MMD/MMS in academic neuropaediatric centres suggests that the prevalence of the disease in children in France is approximately 1/20th of that estimated in Asia.

In situ study of the solid-state formation of U(1-x)Am(x)O(2±Î´) solid solution.

In order to reduce the nuclear waste inventory and radiotoxicity, U(1-x)Am(x)O(2±Î´) materials are promising fuels for heterogeneous transmutation. In this context, they are generally fabricated from UO(2+δ) and AmO(2-δ) dioxide powders. In the subsequent solid solution, americium is assumed to be trivalent whereas uranium exhibits a mixed-valence (+IV/+V) state. However, no formation mechanisms were ever evidenced and, more particularly, it was not possible to know whether the reduction of Am(IV) to Am(III) occurs before the solid-solution formation, or only once it is established. In this study, we used high-temperature X-ray diffraction on a UO(2±Î´)/AmO(2-δ) (15 mol %) mixture to observe in situ the formation of the U(1-x)Am(x)O(2±Î´) solid solution. We show that UO(2+δ) is, at relatively low temperature (<700 K), oxidized to U(4)O(9-δ), which is likely to be caused by oxygen release from the simultaneous AmO(2-δ) reduction to cubic Am(2)O(3±Î´). Cubic Am(2)O(3+δ) then transforms to hexagonal Am(2)O(3) at 1300 K. Thus, the initial Am(IV) is fully reduced to Am(III) before the solid solution starts forming at 1740 K. The UO(2) fluorite phase vanishes after 4 h at 1970 K, indicating that the formation of the solid solution is completed, which proves that this solid solution is formed after the complete reduction of Am(IV) to Am(III).

Early emergence of an H275Y mutation in a hematopoietic cell transplant recipient treated with intravenous peramivir.

Oseltamivir resistance in pandemic 2009 influenza A/H1N1 is caused by the neuraminidase mutation H275Y. This mutation has also been associated with in vitro resistance to peramivir, but few clinical cases have been described to date. Using allele-specific real-time reverse transcriptase polymerase chain reaction assay for the H275Y mutation, we were able to identify resistant H1N1 in a hematopoietic cell transplant recipient receiving intravenous peramivir therapy, and through serial testing we determined the molecular evolution of resistance. This case demonstrates that an H275Y mutant population can emerge early and replicate in vivo under peramivir antiviral pressure to become the major viral population.

Experimental insight into the radiation resistance of zirconia-based americium ceramics.

Our works shows that the americium pyrochlore (241)Am(2)Zr(2)O(7) undergoes a phase transition to a defect-fluorite structure along with an unusual volume contraction when subjected to internal radiation from alpha-emitting actinides. Disorder relaxation proceeds through the simultaneous formation of cation antisites and oxygen Frenkel pairs. X-ray absorption spectroscopy at the Am-L(II) and the Zr-K edges reveals that Am-O polyhedra show an increasing disorder with increasing exposure. In contrast, the Zr-O polyhedral units remain highly ordered, while rotating along edges and corners, thereby reducing the structural strain imposed by the growing disorder around americium. We believe it is this particular property of the compound that provides the remarkable resistance to radiation (>9.4 x 10(18) alpha-decay events g(-1) or 0.80 dpa).