OBJECTIVE:It was hypothesized that in encephalitides with autoantibodies directed to CNS surface antigens an antibody-removing intervention might speed up recovery.
METHODS:The outcome of autoimmune ...encephalitis in 19 patients with antibodies against surface antigens (leucine-rich, glioma inactivated 1 LGI1, n = 3; contactin-associated protein-2 CASPR2, n = 4; NMDA receptor NMDAR, n = 7) and intracellular antigens (glutamic acid decarboxylase GAD, n = 5) after immunoadsorption in addition to corticosteroid therapy was evaluated retrospectively. Modified Rankin scale (mRS) scores and data on seizures, memory, and antibody titers directly after immunoadsorption (early follow-up) and after a median of 4 months (late follow-up) were compiled.
RESULTS:Immediately after immunoadsorption, 9 of 14 patients with antibodies against LGI1, CASPR2, or NMDAR (64%), but none with GAD antibodies, had improved by at least one mRS point. Five of the 7 patients with LGI1 or CASRP2 antibodies had become seizure-free, and 2 patients with NMDAR antibodies had a memory improvement of more than 1 SD of a normal control population. At late follow-up, 12 of 14 patients with surface antibodies had improved (86%), and none of the patients with GAD antibodies.
CONCLUSIONS:It is suggested that addition of immunoadsorption to immunosuppression therapy in patients with surface antibodies may accelerate recovery. This supports the pathogenic role of surface antibodies.
CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that immunoadsorption combined with immunosuppression therapy is effective in patients with autoimmune encephalitis with surface antibodies.
Abstract We report on a 31-year-old, female patient who presented with somnolence due to an intoxication by the antiepileptic drug, mesuximide (MSM). The serum concentration of its metabolite ...n-desmethyl-mesuximide (85.7 mg/L) was above the so‐called therapeutic range (10–40 mg/L) but below the concentration range that led to an impairment of consciousness in previous cases according to the German SPC (> 150 mg/L). The symptoms remitted quickly under hemodialysis. In somnolent patients treated with MSM, the treating physicians should be aware of drug intoxication as a possible etiology. Therefore, the serum concentration should be measured early. Due to the, often, long latency until the results are available, treatment initiation may be necessary based on suspicion.
Low molecular weight heparin in hemodialysis and hemofiltration patients. Low molecular weight (LMW)-heparin was used as the sole anticoagulant during hemodialysis and hemofiltration in a pilot study ...on 32 patients. A LMW-heparin dose corresponding to 50% of the patients usual unfractionated, standard (UF)-heparin dose was found to produce comparable plasma heparin levels (anti-FXa-activity). No thrombosis of the extracorporal system and no bleeding complications occurred at this LMW-heparin dose. In contrast to UF-heparin, LMW-heparin produced only slight increases in PTT and thrombin time in all patients. Lipoprotein lipase was stimulated only marginally by LMW-heparin, with a correspondingly reduced release of free fatty acids. Both heparin species caused similar elevations in factor VIII and fibrin monomers, thus excluding a difference in coagulation activation. On the basis of these results, long-term studies have been started at four nephrology centers. To date, 26 patients have been treated with LMW-heparin for 6 months. A LMW-heparin dose was used that produced plasma anti-FXa-activity of 0.5 to 0.9 U/ml (initial dose: 30 to 40; dose/hr: 8 to 15 anti-FXa-units/kg body wt). PTT and thrombin time were only increased by 5sec on average. Surprisingly, the elevated pre-dialysis levels of factor VIII and fibrin monomers decreased during this 6-month period. Bleeding complications did not occur and thrombotic complications were not observed when the anti-FXa levels were above 0.5 U/ml. LMW-heparin, therefore, appears to be a good alternative to UF-heparin for dialysis patients and may present less risk of bleeding because of its reduced effect on PTT, thrombin time, and thrombocytes.
With the advent of multi-core processors, implementing parallel programming methods in application development is absolutely necessary in order to achieve good performance. Soon, 8-core and possibly ...16-core processors will be available, even for desktop machines. To support application developers in the various tasks involved in this process, several different tools need to be at his or her disposal. This workshop will give the users an overview of the existing tools in the area of integrated development environments for clusters, various parallel debuggers, and new-style performance analysis tools, as well as an update on the state of the art of long-term research tools, which have advanced to an industrial level. The proceedings of the 2nd Parallel Tools Workshop guide participants by providing a technical overview to help them decide upon which tool suits the requirements for the development task at hand. Additionally, through the hands-on sessions, the workshop will enable the user to immediately deploy the tools.
Monitoring the T cell receptor (TCR) repertoire in health and disease can provide key insights into adaptive immune responses, but the accuracy of current TCR sequencing (TCRseq) methods is unclear. ...In this study, we systematically compared the results of nine commercial and academic TCRseq methods, including six rapid amplification of complementary DNA ends (RACE)-polymerase chain reaction (PCR) and three multiplex-PCR approaches, when applied to the same T cell sample. We found marked differences in accuracy and intra- and inter-method reproducibility for T cell receptor α (TRA) and T cell receptor β (TRB) TCR chains. Most methods showed a lower ability to capture TRA than TRB diversity. Low RNA input generated non-representative repertoires. Results from the 5' RACE-PCR methods were consistent among themselves but differed from the RNA-based multiplex-PCR results. Using an in silico meta-repertoire generated from 108 replicates, we found that one genomic DNA-based method and two non-unique molecular identifier (UMI) RNA-based methods were more sensitive than UMI methods in detecting rare clonotypes, despite the better clonotype quantification accuracy of the latter.
To design, construct and validate radiofrequency (RF) transmit and receive phased array coils for high-resolution visual cortex imaging at 7 Tesla.
A 4 channel transmit and 16 channel receive array ...was constructed on a conformal polycarbonate former. Transmit field efficiency and homogeneity were simulated and validated, along with the Specific Absorption Rate, using Formula: see text mapping techniques and electromagnetic simulations. Receiver signal-to-noise ratio (SNR), temporal SNR (tSNR) across EPI time series, g-factors for accelerated imaging and noise correlations were evaluated and compared with a commercial 32 channel whole head coil. The performance of the coil was further evaluated with human subjects through functional MRI (fMRI) studies at standard and submillimeter resolutions of upto 0.8mm isotropic.
The transmit and receive sections were characterized using bench tests and showed good interelement decoupling, preamplifier decoupling and sample loading. SNR for the 16 channel coil was ∼ 1.5 times that of the commercial coil in the human occipital lobe, and showed better g-factor values for accelerated imaging. fMRI tests conducted showed better response to Blood Oxygen Level Dependent (BOLD) activation, at resolutions of 1.2mm and 0.8mm isotropic.
The 4 channel phased array transmit coil provides homogeneous excitation across the visual cortex, which, in combination with the dual row 16 channel receive array, makes for a valuable research tool for high resolution anatomical and functional imaging of the visual cortex at 7T.
The ability to measure functional brain responses non-invasively with ultra high field MRI (7 T and above) represents a unique opportunity in advancing our understanding of the human brain. Compared ...to lower fields (3 T and below), ultra high field MRI has an increased sensitivity, which can be used to acquire functional images with greater spatial resolution, and greater specificity of the blood oxygen level dependent (BOLD) signal to the underlying neuronal responses.
Together, increased resolution and specificity enable investigating brain functions at a submillimeter scale, which so far could only be done with invasive techniques. At this mesoscopic spatial scale, perception, cognition and behavior can be probed at the level of fundamental units of neural computations, such as cortical columns, cortical layers, and subcortical nuclei. This represents a unique and distinctive advantage that differentiates ultra high from lower field imaging and that can foster a tighter link between fMRI and computational modeling of neural networks.
So far, functional brain mapping at submillimeter scale has focused on the processing of sensory information and on well-known systems for which extensive information is available from invasive recordings in animals. It remains an open challenge to extend this methodology to uniquely human functions and, more generally, to systems for which animal models may be problematic. To succeed, the possibility to acquire high-resolution functional data with large spatial coverage, the availability of computational models of neural processing as well as accurate biophysical modeling of neurovascular coupling at mesoscopic scale all appear necessary.
•Increasing field strength provides advantages in studying brain function in vivo.•High fields allow imaging functional subdivisions of sub-cortical regions.•At high fields functional imaging can be performed at the mesoscopic scale.•At the mesoscale brain inspired computational models can be tested and developed.•Laminar neourvascular coupling models need updating to extend applications.
Drug-like molecules are known to contain many different building blocks with great potential as pharmacophores for drug discovery. The continued search for unique scaffolds in our laboratory led to ...the isolation of a novel Ghanaian soil bacterium,
. MA37. This strain produces many bioactive molecules, most of which belong to carbazoles, pyrrolizidines, and fluorinated metabolites. Further probing of the metabolites of MA37 has led to the discovery of a new naphthacene-type aromatic natural product, which we have named accramycin A
. This molecule was isolated using an HPLC-photodiode array (PDA) guided isolation process and MS/MS molecular networking. The structure of
was characterized by detailed analysis of LC-MS, UV, 1D, and 2D NMR data. Preliminary studies on the antibacterial properties of
using Group B
(GBS) produced a minimum inhibitory concentration (MIC) of 27 µg/mL. This represents the first report of such bioactivity amongst the naphthacene-type aromatic polyketides, and also suggests the possibility for the further development of potent molecules against GBS based on the accramycin scaffold. A putative
biosynthetic pathway for accramycin, featuring a tridecaketide-specific type II polyketide synthase, was proposed.
Multivalency is a key principle in reinforcing reversible molecular interactions through the formation of multiple bonds. The influenza A virus deploys this strategy to bind strongly to cell surface ...receptors. We performed single-molecule force spectroscopy (SMFS) to investigate the rupture force required to break individual and multiple bonds formed between synthetic sialic acid (SA) receptors and the two principal spike proteins of the influenza A virus (H3N2): hemagglutinin (H3) and neuraminidase (N2). Kinetic parameters such as the rupture length (χβ) and dissociation rate (k off) are extracted using the model by Friddle, De Yoreo, and Noy. We found that a monovalent SA receptor binds to N2 with a significantly higher bond lifetime (270 ms) compared to that for H3 (36 ms). By extending the single-bond rupture analysis to a multibond system of n protein-receptor pairs, we provide an unprecedented quantification of the mechanistic features of multivalency between H3 and N2 with SA receptors and show that the stability of the multivalent connection increases with the number of bonds from tens to hundreds of milliseconds. Association rates (k on) are also provided, and an estimation of the dissociation constants (K D) between the SA receptors to both proteins indicate a 17-fold higher binding affinity for the SA–N2 bond with respect to that of SA–H3. An optimal designed multivalent SA receptor showed a higher binding stability to the H3 protein of the influenza A virus than to the monovalent SA receptor. Our study emphasizes the influence of the scaffold on the presentation of receptors during multivalent binding.
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