Synchronization and desynchronization in epilepsy: controversies and hypotheses

Epilepsy has been historically seen as a functional brain disorder associated with excessive synchronization of large neuronal populations leading to a hypersynchronous state. Recent evidence showed that epileptiform phenomena, particularly seizures, result from complex interactions between neuronal networks characterized by heterogeneity of neuronal firing and dynamical evolution of synchronization. Desynchronization is often observed preceding seizures or during their early stages; in contrast, high levels of synchronization observed towards the end of seizures may facilitate termination. In this review we discuss cellular and network mechanisms responsible for such complex changes in synchronization. Recent work has identified cell-type-specific inhibitory and excitatory interactions, the dichotomy between neuronal firing and the non-local measurement of local field potentials distant to that firing, and the reflection of the neuronal dark matter problem in non-firing neurons active in seizures. These recent advances have challenged long-established views and are leading to a more rigorous and realistic understanding of the pathophysiology of epilepsy.

Transcatheter Aortic Valve Replacement in Bicuspid Aortic Valve Disease.

BACKGROUND Limited information exists describing the results of transcatheter aortic valve (TAV) replacement in patients with bicuspid aortic valve (BAV) disease (TAV-in-BAV). OBJECTIVES This study sought to evaluate clinical outcomes of a large cohort of patients undergoing TAV-in-BAV. METHODS We retrospectively collected baseline characteristics, procedural data, and clinical follow-up findings from 12 centers in Europe and Canada that had performed TAV-in-BAV. RESULTS A total of 139 patients underwent TAV-in-BAV with the balloon-expandable transcatheter heart valve (THV) (n = 48) or self-expandable THV (n = 91) systems. Patient mean age and Society of Thoracic Surgeons predicted risk of mortality scores were 78.0 ± 8.9 years and 4.9 ± 3.4%, respectively. BAV stenosis occurred in 65.5%, regurgitation in 0.7%, and mixed disease in 33.8% of patients. Incidence of type 0 BAV was 26.7%; type 1 BAV was 68.3%; and type 2 BAV was 5.0%. Multislice computed tomography (MSCT)-based TAV sizing was used in 63.5% of patients (77.1% balloon-expandable THV vs. 56.0% self-expandable THV, p = 0.02). Procedural mortality was 3.6%, with TAV embolization in 2.2% and conversion to surgery in 2.2%. The mean aortic gradient decreased from 48.7 ± 16.5 mm Hg to 11.4 ± 9.9 mm Hg (p < 0.0001). Post-implantation aortic regurgitation (AR) grade ≥2 occurred in 28.4% (19.6% balloon-expandable THV vs. 32.2% self-expandable THV, p = 0.11) but was prevalent in only 17.4% when MSCT-based TAV sizing was performed (16.7% balloon-expandable THV vs. 17.6% self-expandable THV, p = 0.99). MSCT sizing was associated with reduced AR on multivariate analysis (odds ratio [OR]: 0.19, 95% confidence intervals [CI]: 0.08 to 0.45; p < 0.0001). Thirty-day device safety, success, and efficacy were noted in 79.1%, 89.9%, and 84.9% of patients, respectively. One-year mortality was 17.5%. Major vascular complications were associated with increased 1-year mortality (OR: 5.66, 95% CI: 1.21 to 26.43; p = 0.03). CONCLUSIONS TAV-in-BAV is feasible with encouraging short- and intermediate-term clinical outcomes. Importantly, a high incidence of post-implantation AR is observed, which appears to be mitigated by MSCT-based TAV sizing. Given the suboptimal echocardiographic results, further study is required to evaluate long-term efficacy.

Transcatheter aortic valve implantation in failed bioprosthetic surgical valves.

IMPORTANCE Owing to a considerable shift toward bioprosthesis implantation rather than mechanical valves, it is expected that patients will increasingly present with degenerated bioprostheses in the next few years. Transcatheter aortic valve-in-valve implantation is a less invasive approach for patients with structural valve deterioration; however, a comprehensive evaluation of survival after the procedure has not yet been performed. OBJECTIVE To determine the survival of patients after transcatheter valve-in-valve implantation inside failed surgical bioprosthetic valves. DESIGN, SETTING, AND PARTICIPANTS Correlates for survival were evaluated using a multinational valve-in-valve registry that included 459 patients with degenerated bioprosthetic valves undergoing valve-in-valve implantation between 2007 and May 2013 in 55 centers (mean age, 77.6 [SD, 9.8] years; 56% men; median Society of Thoracic Surgeons mortality prediction score, 9.8% [interquartile range, 7.7%-16%]). Surgical valves were classified as small (≤21 mm; 29.7%), intermediate (>21 and <25 mm; 39.3%), and large (≥25 mm; 31%). Implanted devices included both balloon- and self-expandable valves. MAIN OUTCOMES AND MEASURES Survival, stroke, and New York Heart Association functional class. RESULTS Modes of bioprosthesis failure were stenosis (n = 181 [39.4%]), regurgitation (n = 139 [30.3%]), and combined (n = 139 [30.3%]). The stenosis group had a higher percentage of small valves (37% vs 20.9% and 26.6% in the regurgitation and combined groups, respectively; P = .005). Within 1 month following valve-in-valve implantation, 35 (7.6%) patients died, 8 (1.7%) had major stroke, and 313 (92.6%) of surviving patients had good functional status (New York Heart Association class I/II). The overall 1-year Kaplan-Meier survival rate was 83.2% (95% CI, 80.8%-84.7%; 62 death events; 228 survivors). Patients in the stenosis group had worse 1-year survival (76.6%; 95% CI, 68.9%-83.1%; 34 deaths; 86 survivors) in comparison with the regurgitation group (91.2%; 95% CI, 85.7%-96.7%; 10 deaths; 76 survivors) and the combined group (83.9%; 95% CI, 76.8%-91%; 18 deaths; 66 survivors) (P = .01). Similarly, patients with small valves had worse 1-year survival (74.8% [95% CI, 66.2%-83.4%]; 27 deaths; 57 survivors) vs with intermediate-sized valves (81.8%; 95% CI, 75.3%-88.3%; 26 deaths; 92 survivors) and with large valves (93.3%; 95% CI, 85.7%-96.7%; 7 deaths; 73 survivors) (P = .001). Factors associated with mortality within 1 year included having small surgical bioprosthesis (≤21 mm; hazard ratio, 2.04; 95% CI, 1.14-3.67; P = .02) and baseline stenosis (vs regurgitation; hazard ratio, 3.07; 95% CI, 1.33-7.08; P = .008). CONCLUSIONS AND RELEVANCE In this registry of patients who underwent transcatheter valve-in-valve implantation for degenerated bioprosthetic aortic valves, overall 1-year survival was 83.2%. Survival was lower among patients with small bioprostheses and those with predominant surgical valve stenosis.

Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination

BACKGROUND L-serine plays an essential role in neuronal development and function. Although a non-essential amino acid, L-serine must be synthesised within the brain because of its poor permeability by the blood-brain barrier. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1. METHODS AND RESULTS Using exome analysis we identified the recessive mutations, p.E256K, p.L315fs, and p.R457W, in SLC1A4, the gene encoding ASCT1, in patients with developmental delay, microcephaly and hypomyelination; seizure disorder was variably present. When expressed in a heterologous system, the mutations did not affect the protein level at the plasma membrane but abolished or markedly reduced L-serine transport for p.R457W and p.E256K mutations, respectively. Interestingly, p.E256K mutation displayed a lower L-serine and alanine affinity but the same substrate selectivity as wild-type ASCT1. CONCLUSIONS The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community.

Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement: The Randomized BRAVO-3 Trial.

BACKGROUND Anticoagulation is required during transcatheter aortic valve replacement (TAVR) procedures. Although an optimal regimen has not been determined, heparin is mainly used. Direct thrombin inhibition with bivalirudin may be an effective alternative to heparin as the procedural anticoagulant agent in this setting. OBJECTIVES The goal of this study was to determine whether bivalirudin offers an alternative to heparin as the procedural anticoagulant agent in patients undergoing TAVR. METHODS A total of 802 patients with aortic stenosis were randomized to undergo transfemoral TAVR with bivalirudin versus unfractionated heparin during the procedure. The 2 primary endpoints were major bleeding within 48 h or before hospital discharge (whichever occurred first) and 30-day net adverse clinical events, defined as the combination of major adverse cardiovascular events (all-cause mortality, myocardial infarction, or stroke) and major bleeding. RESULTS Anticoagulation with bivalirudin versus heparin did not meet superiority because it did not result in significantly lower rates of major bleeding at 48 h (6.9% vs. 9.0%; relative risk: 0.77; 95% confidence interval [CI]: 0.48 to 1.23; p = 0.27) or net adverse cardiovascular events at 30 days (14.4% vs. 16.1%; relative risk: 0.89; 95% CI: 0.64 to 1.24; risk difference: -1.72; 95% CI: -6.70 to 3.25; p = 0.50); regarding the latter, the prespecified noninferiority hypothesis was met (pnoninferiority < 0.01). Rates of major adverse cardiovascular events at 48 h were not significantly different (3.5% vs. 4.8%; relative risk: 0.73; 95% CI: 0.37 to 1.43; p = 0.35). At 48 h, the bivalirudin group had significantly fewer myocardial infarctions but more acute kidney injury events than the heparin group; at 30 days, these differences were no longer significant. CONCLUSIONS In this randomized trial of TAVR procedural pharmacotherapy, bivalirudin did not reduce rates of major bleeding at 48 h or net adverse cardiovascular events within 30 days compared with heparin. Although superiority was not shown, the noninferiority hypothesis was met with respect to the latter factor. Given the lower cost, heparin should remain the standard of care, and bivalirudin can be an alternative anticoagulant option in patients unable to receive heparin in TAVR. (International, Multi-center, Open-label, Randomized Controlled Trial in Patients Undergoing TAVR to Determine the Treatment Effect [Both Safety and Efficacy] of Using Bivalirudin Instead of UFH [BRAVO-2/3]; NCT01651780).

Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.

Na 1 Nachlass Max Horkheimer, 45 - Korrespondenzen u.a. mit der Familie Rabinowitsch, Friedrich Pollock und Franz Neumann (p. I 21, A, 1-218)

37 Briefe zwischen Fritz Rabinowitsch, Gregor Rabinowitsch, Fred Roberts und Max Horkheimer, 1936-1943; 14 Briefe und Beilagen zwischen Finley Parker, Benjamin Parker und dem American General Consulat, 1937-1939; 4 Brief zwischen dem National Council of Jewish Women New York und Max Horkheimer, 1937; 31 Briefe und Beilagen zwischen Finley Parker, Benjamin Parker und Max Horkheimer, 1937-1939; 7 Briefe zwischen Franz L. Neumann und Finley Parker, Benjamin Parker, 09.10.1937, 1937; 2 Briefe zwischen dem American Conulat, General und dem National Council of Jewish Women, 27.07.1937, 16.08.1937; 1 Brief von Finley und Benjamin Parker an Gregor Rabinowitsch, 22.10.1937; 3 Briefe von Max Horkheimer an das United States Consulate Berlin, 1937; 1 Brief von Finley und Benjamin Parker an Hans-Heinrich Schulz, 21.09.1937; 1 Brief von Finley und Benjamin Parker an Eberhard Roethe, 21.09.1937; 6 Briefe zwischen Friedrich Pollock und Max Horkheimer, 1937-1943; 2 Briefe zwischen dem Schweizerischer Buchhändlerverein und Max Horkheimer, 31.07.1937, 10.09.1937; 2 Briefe zwischen Robert Hilb und Max Horkheimer, 07.09.1937; 2 Briefe zwischen Franz Neumann und Max Horkheimer, 29.08.1937, 31.08.1937; 11 Briefe zwischen Alexander Farquharson und Max Horkheimer, 1937; 1 Brief von Girsberger an Max Horkheimer, 29.08.1937; 1 Brief von Abner J. Rubien an Max Horkheimer, 29.07.1937; 1 Brief von Brill an Max Horkheimer, 29.07.1937; 2 Briefe zwischen Otto Nathan und Max Horkheimer, 28.07.1937, 25.04.1939; 5 Briefe zwischen dem Germany Emergency Committee London und Max Horkheimer, 1937; 2 Briefe von der National City Bank New York an das American Consul, New York, 1937; 1 Brief von John G. Jenkins an Paul F. Lazarsfeld, 05.04.1937; 3 Briefe zwischen Frank H. Bowles und Max Horkheimer, 23.03.1937, 1937;

Proceedings of the 23rd Annual Biochemical Engineering Symposium

The 23rd Annual Biochemical Engineering Symposium was held at the University of Oklahoma on April 17, 1993. The objectives of the symposium were to provide 1) a forum for informal discussion of biochemical engineering research being carried at the participating universities and 2) an opportunity for students to present and publish their work. Thirteen papers presented at the symposium are included in the proceedings. Because final publication usually takes place in refereed journals, the articles included here are typically brief and often cover work in progress. The program of the symposium and a list of participants are included in the proceedings. ContentsA Low-Cost Bioreactor Strategy for RNA Synthesis, H. Anthony Marble, Eleni Chrisikos, and Robert H. Davis Development of a CELSS Bioreactor: Oxygen Transfer and Micromixing in Parabolic Flight, P.E. Villeneuve, K.S. Wenger, B.G. Thompson, T. Kedar, and E.H. Dunlop Scale-up of Dexter Murine Bone Marrow Cultures Utilizing a Three-Dimensional Fiberglass Support Matrix, John G. Highfill, Paul Todd, Steve Haley, and Dhinaker Kompala Modeling and Estimation of States of Recombinant Fermentations Using Nonlinear Input/Output Models, Vicotr M. Saucedo and M. Nazmul Karim Deadent Microfiltration of Bovine Serum Albumin Suspension Through Yeast Cake Layers and Assymetric Polymeric Membranes, Naveen Arora and Robert H. Davis Monitoring the Fate of Toluene and Phenol in the Rhizosphere, N. Muralidharan, Lawrence C. Davis, and Larry E. Erickson Hydrodynamic Motions Associated with Bubble Coalescence and Breakup, T.Y. Yiin, L.A. Glasgow, and L.E. Erickson Expression and Purification of a-Human Atrial Natriuretic Peptide in Escherichia coli by Fusion with L-Asparaginase, Nien-Tung Ma and Roger G. Harrison High Pressure Crystallization of Proteins, Mungara V. Saikumar, Charles E. Glatz, and Maurice A. Larson Structure/Function Relationships in the Catalytic and Starch Binding Domains of Glucoamylase, Pedro M. Coutinho, Clark Ford, Peter J. Reilly Cellular Responses of Insect Cell Spodoptera frugiperda to Environmental Stresses, Paul Yeh, Grace Y. Sun, Gary A. Weisman, Rakesh Bajpai A Novel Approach to Understanding the Antimicrobial Activity of Peptides, Naveen Pathak, Marie-Helene Janna, Gael Ruche, David McCarthy, and Roger Harrison Mass Transfer in the Bioremediation of Soils Contaminated with Trapped Non-Aqueous Phase Liquids, Xiaoqing Yang, Larry E. Jacobson, and L.T. Fan

Potassium and argon concentrations and age determination of ODP Site 125-782 and 125-786

K-Ar whole-rock ages have been obtained for 30 samples from Sites 782 and 786, Ocean Drilling Program Leg 125 in the Izu-Bonin (Ogasawara) forearc region. They form a trimodal spread of ages between 9 Ma and 44 Ma and are, with a few exceptions, consistent with the inferred lithostratigraphy. The ages have been interpreted in terms of at least two distinct episodes of magmatic and/or hydrothermal activity. A group of ten samples, including the lava flows, gave an isochron age of 41.3 ± 0.5 Ma (middle-late Eocene). This is thought to represent the age of the principal magmatic development of the volcanic forearc basement, and is comparable to published ages on equivalent rocks from other parts of the forearc basement high (e.g., the Ogasawara Islands). It may be significant that this age is slightly younger than the timing of major plate reorganization in the Western Pacific at about 43 Ma. This was followed by a minor episode of intrusive magmatism at 34.6 ± 0.7 Ma (early Oligocene) which appears to have reset the ages of some of the earlier units. This event probably corresponds to the initiation of rifting of the "proto-arc" to form the Parece Vela Basin. Boninitic samples were erupted during both episodes of magmatism, the earlier being of low-Ca boninite type and the later being of medium- and high-Ca types. It is also possible that a third episode of intrusive magmatism affected the Izu-Bonin forearc region at both Sites 782 and 786 at about 17 Ma. This would be consistent with magmatic activity elsewhere in the region during the Miocene, associated with the end of active spreading in the Parece Vela Basin and the start of arc activity in the West Mariana Ridge.