Targeting Neuroinflammation to Treat Alzheimer's Disease.

Over the past few decades, research on Alzheimer's disease (AD) has focused on pathomechanisms linked to two of the major pathological hallmarks of extracellular deposition of beta-amyloid peptides and intra-neuronal formation of neurofibrils. Recently, a third disease component, the neuroinflammatory reaction mediated by cerebral innate immune cells, has entered the spotlight, prompted by findings from genetic, pre-clinical, and clinical studies. Various proteins that arise during neurodegeneration, including beta-amyloid, tau, heat shock proteins, and chromogranin, among others, act as danger-associated molecular patterns, that-upon engagement of pattern recognition receptors-induce inflammatory signaling pathways and ultimately lead to the production and release of immune mediators. These may have beneficial effects but ultimately compromise neuronal function and cause cell death. The current review, assembled by participants of the Chiclana Summer School on Neuroinflammation 2016, provides an overview of our current understanding of AD-related immune processes. We describe the principal cellular and molecular players in inflammation as they pertain to AD, examine modifying factors, and discuss potential future therapeutic targets.

A full subtraction approach for finite element method based source analysis using constrained Delaunay tetrahedralisation.

A mathematical dipole is widely used as a model for the primary current source in electroencephalography (EEG) source analysis. In the governing Poisson-type differential equation, the dipole leads to a singularity on the right-hand side, which has to be treated specifically. In this paper, we will present a full subtraction approach where the total potential is divided into a singularity and a correction potential. The singularity potential is due to a dipole in an infinite region of homogeneous conductivity. The correction potential is computed using the finite element (FE) method. Special care is taken in order to evaluate the right-hand side integral appropriately with the objective of achieving highest possible convergence order for linear basis functions. Our new approach allows the construction of transfer matrices for fast computation of the inverse problem for anisotropic volume conductors. A constrained Delaunay tetrahedralisation (CDT) approach is used for the generation of high-quality FE meshes. We validate the new approach in a four-layer sphere model with a highly conductive cerebrospinal fluid (CSF) and an anisotropic skull compartment. For radial and tangential sources with eccentricities up to 1 mm below the CSF compartment, we achieve a maximal relative error of 0.71% in a CDT-FE model with 360 k nodes which is not locally refined around the source singularity and therefore useful for arbitrary dipole locations. The combination of the full subtraction approach with the high quality CDT meshes leads to accuracies that, to the best of the author's knowledge, have not yet been presented before.

Accuracy and run-time comparison for different potential approaches and iterative solvers in finite element method based EEG source analysis.

Accuracy and run-time play an important role in medical diagnostics and research as well as in the field of neuroscience. In Electroencephalography (EEG) source reconstruction, a current distribution in the human brain is reconstructed noninvasively from measured potentials at the head surface (the EEG inverse problem). Numerical modeling techniques are used to simulate head surface potentials for dipolar current sources in the human cortex, the so-called EEG forward problem.In this paper, the efficiency of algebraic multigrid (AMG), incomplete Cholesky (IC) and Jacobi preconditioners for the conjugate gradient (CG) method are compared for iteratively solving the finite element (FE) method based EEG forward problem. The interplay of the three solvers with a full subtraction approach and two direct potential approaches, the Venant and the partial integration method for the treatment of the dipole singularity is examined. The examination is performed in a four-compartment sphere model with anisotropic skull layer, where quasi-analytical solutions allow for an exact quantification of computational speed versus numerical error. Specifically-tuned constrained Delaunay tetrahedralization (CDT) FE meshes lead to high accuracies for both the full subtraction and the direct potential approaches. Best accuracies are achieved by the full subtraction approach if the homogeneity condition is fulfilled. It is shown that the AMG-CG achieves an order of magnitude higher computational speed than the CG with the standard preconditioners with an increasing gain factor when decreasing mesh size. Our results should broaden the application of accurate and fast high-resolution FE volume conductor modeling in source analysis routine.

Application of the chirp z-transform to MRI data.

A version of the chirp z-transform (CZT) enabling signal intensity and phase-preserving field-of-view scaling has been programmed. The algorithm is important for all single-point imaging sequences such as SPRITE when used with multiple data acquisition for T2* mapping or signal averaging. CZT has particular utility for SPRITE imaging of nuclei with short relaxation times such as sodium at high field. Here, a complete theory of the properties of CZT is given. This method operates entirely in k-space. It is compared with a conventional interpolation approach that works in image space after the application of a fast Fourier transformation.

Total synthesis of (-)-salicylihalamide.

A concise total synthesis of the potent cytotoxic marine natural products salicylihalamide A and B (la, b) is reported. Key steps of our approach were the asymmetric hydrogenation reactions of beta-keto esters 18 and 32 catalyzed by [((S)-BINAP)Ru-Cl2]2. NEt3 and the cyclization of the macrolide core by ring closing olefin metathesis (RCM) using the "second-generation" ruthenium carbene complex 24 as the catalyst which bears an imidazol-2-ylidene ligand. The EIZ ratio obtained in this macrocyclization reaction was determined by the protecting groups at the remote phenolic OH group of the cyclization precursor. The elaboration of the resulting cycloalkene 37 into the final target involved a CrCl2-mediated synthesis of vinyliodide 49 which, after deprotection, did undergo a copper-catalyzed cross-coupling process with the (Z,Z)-configurated carboxamide 42 to form the labile enamide moiety of 1. Compound 42 was derived from a palladium-catalyzed Negishi coupling between butynylzinc chloride and 3-iodoacrylate 39 followed by a Lindlar reduction of enyne 40 thus obtained and a final aminolysis of the ester group.

Concise synthesis of (S,S)-(+)-dehydrohomoancepsenolide.

A concise total synthesis of the bis-butenolide 3 in optically active form is reported. Key steps are a zinc-mediated "three-component coupling" with formation of dienyne 9 which undergoes ring closing metathesis (RCM) on treatment with (PCy(3))(2)Cl(2)Ru=CHPh. Dimerization of the resulting butenolide 11 is then achieved via alkyne metathesis using (tBuO)(3)W&tbd1;CCMe(3) as the catalyst. A Lindlar reduction completes this synthesis which delivers product 3 in only five steps with an overall yield of 25%.

[Neonatal seizures: the beginning and interruption of the treatment]. / Convulsiones neonatales: inicio e interrupción del tratamiento.

Opinions vary as to which 'neonatal seizures' should be treated and which should not be. There is also controversy as to when therapy of seizures should be discontinued. A poll taken among a group of eleven experts in these matters concurred in the opinion that classical neonatal seizures, those well established by clinical and EEG criteria, can be treated before confirmatory EEG support is obtained. They also agreed that those movements known as subtle seizures should await EEG or video/EEG confirmation before commencing therapy. Nine of these experts now believe that therapy for seizures should be terminated at an early time. Most will stop the therapy while the patient is still in the nursery with the exception of 3 who would treat the babies for 3 months.