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BackgroundPerinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia.MethodsThis study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age36weeks and a birth weight2500g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion.DiscussionThis trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia.Trial registrationNCT03162653, www.ClinicalTrials.gov, May 22, 2017.

Early intermittent cortical activity is thought to play a crucial role in the growth of neuronal network development, and large scale brain networks are known to provide the basis for higher brain functions. Yet, the early development of the large scale synchrony in cortical activations is unknown. Here, we tested the hypothesis that the early intermittent cortical activations seen in the human scalp EEG show a clear developmental course during the last trimester of pregnancy, the period of intensive growth of cortico-cortical connections. We recorded scalp EEG from altogether 22 premature infants at post-menstrual age between 30 and 44 weeks, and the early cortical synchrony was quantified using recently introduced activation synchrony index (ASI). The developmental correlations of ASI were computed for individual EEG signals as well as anatomically and mathematically defined spatial subgroups. We report two main findings. First, we observed a robust and statistically significant increase in ASI in all cortical areas. Second, there were significant spatial gradients in the synchrony in fronto-occipital and left-to-right directions. These findings provide evidence that early cortical activity is increasingly synchronized across the neocortex. The ASI-based metrics introduced in our work allow direct translational comparison to in vivo animal models, as well as hold promise for implementation as a functional developmental biomarker in future research on human neonates. ispartof: Neuroscience vol:322 pages:298-307 ispartof: location:United States status: published

BACKGROUND: Bortezomib and rituximab have shown additive activity in preclinical models of lymphoma, and have been shown to be active and generally well tolerated in a randomised phase 2 study in patients with follicular and marginal zone lymphoma. We compared the efficacy and safety of rituximab alone or combined with bortezomib in patients with relapsed or refractory follicular lymphoma in a phase 3 setting. METHODS: In this multicentre phase 3 trial, rituximab-naive or rituximab-sensitive patients aged 18 years or older with relapsed grade 1 or 2 follicular lymphoma were randomly assigned (1:1) to receive five 35-day cycles consisting of intravenous infusions of rituximab 375 mg/m(2) on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2-5, either alone or with bortezomib 1·6 mg/m(2), administered by intravenous injection on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. Treatment assignment was based on a computer-generated randomisation schedule prepared by the sponsor. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00312845. FINDINGS: Between April 10, 2006, and Aug 12, 2008, 676 patients were randomised to receive rituximab (n=340) or bortezomib plus rituximab (n=336). After a median follow-up of 33·9 months (IQR 26·4-39·7), median progression-free survival was 11·0 months (95% CI 9·1-12·0) in the rituximab group and 12·8 months (11·5-15·0) in the bortezomib plus rituximab group (hazard ratio 0·82, 95% CI 0·68-0·99; p=0·039). The magnitude of clinical benefit was not as large as the anticipated prespecified improvement of 33% in progression-free survival. Patients in both groups received a median of five treatment cycles (range 1-5); 245 of 339 (72%) and 237 of 334 (71%) patients in the rituximab and bortezomib plus rituximab groups, respectively, completed five cycles. Of patients who did not complete five cycles, most discontinued early because of disease progression (77 [23%] patients in the rituximab group, and 56 [17%] patients in the bortezomib plus rituximab group). Rates of adverse events of grade 3 or higher (70 [21%] of 339 rituximab-treated patients vs 152 [46%] of 334 bortezomib plus rituximab treated patients), and serious adverse events (37 [11%] patients vs 59 [18%] patients) were lower in the rituximab group than in the combination group. The most common adverse events of grade 3 or higher were neutropenia (15 [4%] patients in the rituximab group and 37 [11%] patients in the bortezomib plus rituximab group), infection (15 [4%] patients and 36 [11%] patients, respectively), diarrhoea (no patients and 25 [7%] patients, respectively), herpes zoster (one [

The electroencephalogram (EEG) in states of awake, sleep, and seizure in a patient with intractable partial complex seizures was recorded through a 1 - x 1 -cm microgrid of 64 electrodes on the right inferior temporal gyrus during a week-long neurosurgical evaluation. Comparisons with a normal intracranial EEG were perforce from animals. Analytic phase and amplitude from the Hilbert transform gave the temporal resolution needed to resolve EEG spatiotemporal structure. The rest state revealed multiple overlapping patterns of high-frequency coherent oscillations resembling bubbles in boiling water. Bubble diameters gave estimates of the distances across the cortex over which the cortical oscillations were synchronized. Superimposed on these bubbles were large-sized epochs of phase locking with briefly constant frequency and high amplitude. These coordinated analytic phase differences occurred between short periods of high phase variance. The variance gave evidence for state transitions between transiently stable states with constant phase gradients. In sleep these phase patterns persisted with reduced amplitude, occasionally interrupted by long-lasting (similar to 1 s) epochs with no spatial textures in phase and amplitude despite a large increase in amplitude. Seizures had high amplitude 3/s spikes with steep spatial gradients. Onset occurred after pre-ictal reduction in bubble diameters as evidence for large-scale cortical disintegration preceding loss of stability. (c) 2006 Wiley Periodicals, Inc.

Objective: To transfer to the clinic for humans the technology and theory for high-resolution EEG analysis that have been developed in the laboratory with animals. Methods: EEGs were recorded at high spatial resolution from a 1 X 1 cm 8 X 8 electrode array on the right inferior temporal gyrus of a patient undergoing preoperative monitoring for epilepsy surgery. Cosines were fitted to EEG segments to measure frequency and phase and compute location, size, latency, phase velocity, duration, and recurrence rate of radially symmetric spatial patterns called phase cones. The Hilbert transform was also used to get high temporal resolution. Results: In the awake state, the power spectral density (PSD) showed power-law decrease in log power with log frequency at 1/f(alpha), alpha similar to 2, but with peaks in the standard empirical ranges. The phase in beta and gamma ranges had spatial gradients in conic form. Resetting of these stable spatial patterns of phase cones was spatially coincident at intermittent discontinuities ('phase slip') recurring at theta rates. Cones had half power diameters from 2 to 50+ mm; their durations had power-law distributions with values ranging from 6 to 300+ ms depending on length of the analysis window. In slow wave sleep PSD decreased at 1/f(alpha), alpha similar to 3,with loss of beta-gamma spectral peaks and diminished or absent oscillations and spatiotemporal phase structure. Conclusions: Spatiotemporal structures in awake human and rabbit EEG showed striking similarities. The only clear differences were ascribable to differing scales of measurement. These fine spatiotemporal structures of EEG were diminished or lost in slow wave sleep. Significance: The fine structure indicates that neocortical stability is sustained at self-organized criticality; that synaptic input in the awake state drives neocortex away from criticality causing beta-gamma oscillations in re-stabilizing 'neural avalanches'; and that diminished input in slow wave sleep allows return toward criticality but with some added risk of instability and seizure. (c) 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Objective: Evaluate spectral scaling properties of scalp electroencephalogram (EEG) and electromyogram (EMG), optimal spacing of electrodes, and strategies for mitigating EMG. Methods: EEG was recorded referentially from 9 subjects with a 64 channel linear array (electrodes 3 mm apart) placed parasagittally or transversely on forehead or occiput, at rest with eyes open or closed, or with deliberate EMG. Temporal (PSDt) and spatial (PSDx) power spectral densities were calculated with one-dimensional fast Fourier transform (FFT) for comparison with earlier analyses of intracranial EEG. Results: Scaling of PSDt from scalp resembled that from pia: near-linear decrease in log power with increasing log frequency (1/f(alpha)). Scalp PSDx decreased non-linearly and more rapidly than PSDx from pia. Peaks in PSDt (especially 4-12 Hz) and PSDx (especially 0.1-0.4 cycles/cm) revealed departures from 1/f(alpha). EMG power in PSDt was more "white" than 1/f(alpha). Conclusions: Smearing by dura-skull-scalp distorts PSDx more than PSDt of scalp EEG from 1/f(alpha) scaling at the pia. Spatial spectral peaks suggest that optimal scalp electrode spacing might be similar to I cm to capture non-local EEG components having the texture of gyri. Mitigation of EMG by filtering is unsatisfactory. A criterion for measuring EMG may support biofeedback for training subjects to reduce their EMG. Significance: High-density recording and log-log spectral display of EEG provide a foundation for holist studies of global human brain function, as an alternative to network approaches that decompose EEG into localized, modular signals for correlation and coherence. (C) 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Science Ireland Ltd. All rights reserved.