Long-term safety and efficacy of Eculizumab in Aquaporin-4 IgG-positive NMOSD

Objective During PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open-label extension (OLE; NCT02003144) evaluating eculizumab's long-term safety and efficacy. Methods Patients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis. Results Across PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1–276.9 weeks), for a combined total of 362.3 patient-years (PY). Treatment-related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab-treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6–97.3) of patients remained adjudicated relapse-free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013–0.048) in all eculizumab-treated patients versus 0.350 (95% CI = 0.199–0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use. Interpretation This analysis demonstrates that eculizumab's long-term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long-term eculizumab treatment to reduce relapse risk in patients with AQP4-IgG+ NMOSD. ANN NEUROL 2021;89:1088–109

Cortical alterations in a model for absence epilepsy and febrile seizures: In vivo findings in mice carrying a human GABA(A)R gamma2 subunit mutation

Full text embargoed until: 2016-05-31Childhood absence epilepsy (CAE) is one of the most common forms of epilepsy among children. The study of a large Australian family demonstrated that a point mutation in the gene encoding the gamma2 subunit of the GABA(A) receptor (G2R43Q) leads to an autosomal dominantly inherited form of CAE and febrile seizures (FS). In a transgenic mouse model carrying the gamma2 (R43Q) mutation heterozygous animals recapitulate the human phenotype. In-vitro experiments indicated that this point mutation impairs cortical inhibition and thus increases the likelihood of seizures. Here, using whole-cell (WC) and extracellular (EC) recordings as well as voltage-sensitive dye imaging (VSDI), we systematically searched for an in vivo correlate of cortical alterations caused by the G2R43Q mutation, as suggested by the mentioned in vitro results. We measured spontaneous and whisker-evoked activity in the primary somatosensory cortex and ventral posteriomedial nucleus of the thalamus (VPM) before and after intraperitoneal injection of the ictogenic substance pentylenetetrazol (PTZ) in urethane-anesthetized G2R43Q mice and controls in a blinded setting. Compared to wildtype controls in G2R43Q mice after PTZ injection we found 1.) Increased cortical spontaneous activity in layer 2/3 and layer 5/6 pyramidal neurons (increased standard deviation of the mean membrane potential in WC recordings), 2.) Increased variance of stimulus evoked cortical responses in VSDI experiments. 3.) The cortical effects are not due to increased strength or precision of thalamic output. In summary our findings support the hypothesis of a cortical pathology in this mouse model of human genetic absence epilepsy. Further study is needed to characterize underlying molecular mechanisms

Electron Beam Generation Using a Ferroelectric Cathode

Abstract. Data is presented on the production of electron beams from a ferroelectric cathode at voltages of order 0.5 MV and current densities of order 100 A/cm 2 . In comparison with data at lower voltages the beam current scales as the three halves power of the voltage. An interpretation of the voltage dependent scaling, based on the coupling of electrostatic energy from the ferroelectric to the gun, is presented

Proximity biotinylation to define the local environment of the protein kinase A catalytic subunit in adrenal cells

Summary: Mutant protein kinase A catalytic subunit (PKAc) drives adrenal Cushing’s syndrome, though its signaling interactions remain unclear. This protocol details steps to use live-cell proximity labeling to identify subcellular compartments and proteins closely associated with variants of PKAc in human adrenal cells. We include instructions for clonal cell line generation, live biotin labeling of proximal proteins, isolation of biotinylated proteins, and sample processing for proteomic analysis using the biotin ligase miniTurbo with wild-type and mutant PKAc.1,2For complete details on the use and execution of this protocol, please refer to Omar et al. (2022).3 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics

Active Precipitation of Radiation Belt Electrons Using Rocket Exhaust Driven Amplification (REDA) of Man‐Made Whistlers

Ground-based very low frequency (VLF) transmitters located around the world generate signals that leak through the bottom side of the ionosphere in the form of whistler mode waves. Wave and particle measurements on satellites have observed that these man-made VLF waves can be strong enough to scatter trapped energetic electrons into low pitch angle orbits, causing loss by absorption in the lower atmosphere. This precipitation loss process is greatly enhanced by intentional amplification of the whistler waves using a newly discovered process called rocket exhaust driven amplification (REDA). Satellite measurements of REDA have shown between 30 and 50 dB intensification of VLF waves in space using a 60 s burn of the 150 g/s thruster on the Cygnus satellite that services the International Space Station. This controlled amplification process is adequate to deplete the energetic particle population on the affected field lines in a few minutes rather than the multi-day period it would take naturally. Numerical simulations of the pitch angle diffusion for radiation belt particles use the UCLA quasi-linear Fokker Planck model to assess the impact of REDA on radiation belt remediation of newly injected energetic electrons. The simulated precipitation fluxes of energetic electrons are applied to models of D-region electron density and bremsstrahlung X-rays for predictions of the modified environment that can be observed with satellite and ground-based sensors