Haemoglobin scavenging after subarachnoid haemorrhage

Rapid and effective clearance of cell-free haemoglobin after subarachnoid haemorrhage (SAH) is important to prevent vasospasm and neurotoxicity and improve long-term outcome. Haemoglobin is avidly bound by haptoglobin, and the complex is cleared by CD163 expressed on the membrane surface of macrophages. We studied the kinetics of haemoglobin and haptoglobin in cerebrospinal fluid after SAH. We show that haemoglobin levels rise gradually after SAH. Haptoglobin levels rise acutely with aneurysmal rupture as a result of injection of blood into the subarachnoid space. Although levels decline as haemoglobin scavenging occurs, complete depletion of haptoglobin does not occur and levels start rising again, indicating saturation of CD163 sites available for haptoglobin-haemoglobin clearance. In a preliminary neuropathological study we demonstrate that meningeal CD163 expression is upregulated after SAH, in keeping with a proinflammatory state. However, loss of CD163 occurs in meningeal areas with overlying blood compared with areas without overlying blood. Becauses ADAM17 is the enzyme responsible for shedding membrane-bound CD163, its inhibition may be a potential therapeutic strategy after SAH

Signal and System Approximation from General Measurements

In this paper we analyze the behavior of system approximation processes for stable linear time-invariant (LTI) systems and signals in the Paley-Wiener space PW_\pi^1. We consider approximation processes, where the input signal is not directly used to generate the system output, but instead a sequence of numbers is used that is generated from the input signal by measurement functionals. We consider classical sampling which corresponds to a pointwise evaluation of the signal, as well as several more general measurement functionals. We show that a stable system approximation is not possible for pointwise sampling, because there exist signals and systems such that the approximation process diverges. This remains true even with oversampling. However, if more general measurement functionals are considered, a stable approximation is possible if oversampling is used. Further, we show that without oversampling we have divergence for a large class of practically relevant measurement procedures.Comment: This paper will be published as part of the book "New Perspectives on Approximation and Sampling Theory - Festschrift in honor of Paul Butzer's 85th birthday" in the Applied and Numerical Harmonic Analysis Series, Birkhauser (Springer-Verlag). Parts of this work have been presented at the IEEE International Conference on Acoustics, Speech, and Signal Processing 2014 (ICASSP 2014

Rapid neuroinflammatory changes in human acute intracerebral hemorrhage

Objective Spontaneous intracerebral hemorrhage (ICH) is the commonest form of hemorrhagic stroke and is associated with a poor prognosis. Neurosurgical removal of intracerebral hematoma has limited benefit and no pharmacotherapies are available. In acute ICH, primary tissue damage is followed by secondary pathology, where the cellular and neuroinflammatory changes are poorly understood. Methods We studied histological changes in postmortem tissue from a cohort of spontaneous supra‐tentorial primary ICH cases (n = 27) with survival of 1–12 days, compared to a matched control group (n = 16) examined in corresponding regions. Hematoxylin–eosin and microglial (Iba1) immunolabelled sections were assessed at 0–2, 3–5, and 7–12 days post‐ICH. Results Peri‐hematoma, the observed ICH‐related changes include edema, tissue neutrophils and macrophages from day 1. Ischemic neurons and swollen endothelial cells were common at day 1 and universal after day 5, as were intramural erythrocytes within small vessel walls. Activated microglia were evident at day 1 post‐ICH. There was a significant increase in Iba1 positive area fraction at 0–2 (threefold), 3–5 (fourfold), and 7–12 days post ICH (ninefold) relative to controls. Giant microglia were detected peri‐hematoma from day 5 and consistently 7–12 days post‐ICH. Interpretation Our data indicate that neuroinflammatory processes commence from day 1 post‐ICH with changing microglial size and morphology following ICH and up to day 12. From day 5 some microglia exhibit a novel multiply nucleated morphology, which may be related to changing phagocytic function. Understanding the time course of neuroinflammatory changes, post‐ICH may reveal novel targets for therapy and brain restoration

Metaflammasome components in the human brain: a role in dementia with alzheimer's pathology?

Epidemiological and genetic studies have identified metabolic disorders and inflammation as risk factors for Alzheimer's disease (AD). Evidence in obesity and type-2 diabetes suggests a role for a metabolic inflammasome (“metaflammasome”) in mediating chronic inflammation in peripheral organs implicating IKKβ (inhibitor of nuclear factor kappa-B kinase subunit beta), IRS1 (insulin receptor substrate 1), JNK (c-jun N-terminal kinase), and PKR (double-stranded RNA protein kinase). We hypothesized that these proteins are expressed in the brain in response to metabolic risk factors in AD. Neocortex from 299 participants from the MRC Cognitive Function and Ageing Studies was analysed by immunohistochemistry for the expression of the phosphorylated (active) form of IKKβ [pSer176/180], IRS1 [pS312], JNK [pThr183/Tyr185] and PKR [pT451]. The data were analyzed to investigate whether the proteins were expressed together and in relation with metabolic disorders, dementia, Alzheimer's pathology and APOE genotype. We observed a change from a positive to a negative association between the proteins and hypertension according to the dementia status. Type-2 diabetes was negatively related with the proteins among participants without dementia; whereas participants with dementia and AD pathology showed a positive association with JNK. A significant association between IKKβ and JNK in participants with dementia and AD pathology was observed, but not in those without dementia. Otherwise, weak to moderate associations were observed among the protein loads. The presence of dementia was significantly associated with JNK and negatively associated with IKKβ and IRS1. Cognitive scores showed a significant positive relationship with IKKβ and a negative with IRS1, JNK and PKR. The proteins were significantly associated with pathology in Alzheimer's participants with the relationship being inverse or not significant in participants without dementia. Expression of the proteins was not related to APOE genotype. These findings highlight a role for these proteins in AD pathophysiology but not necessarily as a complex

Secrecy Results for Compound Wiretap Channels

We derive a lower bound on the secrecy capacity of the compound wiretap channel with channel state information at the transmitter which matches the general upper bound on the secrecy capacity of general compound wiretap channels given by Liang et al. and thus establishing a full coding theorem in this case. We achieve this with a stronger secrecy criterion and the maximum error probability criterion, and with a decoder that is robust against the effect of randomisation in the encoding. This relieves us from the need of decoding the randomisation parameter which is in general not possible within this model. Moreover we prove a lower bound on the secrecy capacity of the compound wiretap channel without channel state information and derive a multi-letter expression for the capacity in this communication scenario.Comment: 25 pages, 1 figure. Accepted for publication in the journal "Problems of Information Transmission". Some of the results were presented at the ITW 2011 Paraty [arXiv:1103.0135] and published in the conference paper available at the IEEE Xplor

Entanglement transmission and generation under channel uncertainty: Universal quantum channel coding

We determine the optimal rates of universal quantum codes for entanglement transmission and generation under channel uncertainty. In the simplest scenario the sender and receiver are provided merely with the information that the channel they use belongs to a given set of channels, so that they are forced to use quantum codes that are reliable for the whole set of channels. This is precisely the quantum analog of the compound channel coding problem. We determine the entanglement transmission and entanglement-generating capacities of compound quantum channels and show that they are equal. Moreover, we investigate two variants of that basic scenario, namely the cases of informed decoder or informed encoder, and derive corresponding capacity results.Comment: 45 pages, no figures. Section 6.2 rewritten due to an error in equation (72) of the old version. Added table of contents, added section 'Conclusions and further remarks'. Accepted for publication in 'Communications in Mathematical Physics

Quantum capacity under adversarial quantum noise: arbitrarily varying quantum channels

We investigate entanglement transmission over an unknown channel in the presence of a third party (called the adversary), which is enabled to choose the channel from a given set of memoryless but non-stationary channels without informing the legitimate sender and receiver about the particular choice that he made. This channel model is called arbitrarily varying quantum channel (AVQC). We derive a quantum version of Ahlswede's dichotomy for classical arbitrarily varying channels. This includes a regularized formula for the common randomness-assisted capacity for entanglement transmission of an AVQC. Quite surprisingly and in contrast to the classical analog of the problem involving the maximal and average error probability, we find that the capacity for entanglement transmission of an AVQC always equals its strong subspace transmission capacity. These results are accompanied by different notions of symmetrizability (zero-capacity conditions) as well as by conditions for an AVQC to have a capacity described by a single-letter formula. In he final part of the paper the capacity of the erasure-AVQC is computed and some light shed on the connection between AVQCs and zero-error capacities. Additionally, we show by entirely elementary and operational arguments motivated by the theory of AVQCs that the quantum, classical, and entanglement-assisted zero-error capacities of quantum channels are generically zero and are discontinuous at every positivity point.Comment: 49 pages, no figures, final version of our papers arXiv:1010.0418v2 and arXiv:1010.0418. Published "Online First" in Communications in Mathematical Physics, 201

Coding Theorem for a Class of Quantum Channels with Long-Term Memory

In this paper we consider the transmission of classical information through a class of quantum channels with long-term memory, which are given by convex combinations of product channels. Hence, the memory of such channels is given by a Markov chain which is aperiodic but not irreducible. We prove the coding theorem and weak converse for this class of channels. The main techniques that we employ, are a quantum version of Feinstein's Fundamental Lemma and a generalization of Helstrom's Theorem.Comment: Some typos correcte

Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins

Glioblastoma is a devastating brain cancer for which effective treatments are required. Tumour-associated microglia and macrophages promote glioblastoma growth in an immune-suppressed microenvironment. Most recurrences occur at the invasive margin of the surrounding brain, yet the relationships between microglia/macrophage phenotypes, T cells and programmed death-ligand 1 (an immune checkpoint) across human glioblastoma regions are understudied. In this study, we performed a quantitative immunohistochemical analysis of 15 markers of microglia/macrophage phenotypes (including anti-inflammatory markers triggering receptor expressed on myeloid cells 2 and CD163, and the low-affinity-activating receptor CD32a), T cells, natural killer cells and programmed death-ligand 1, in 59 human IDH1-wild-type glioblastoma multi-regional samples (n = 177; 1 sample at tumour core, 2 samples at the margins: the infiltrating zone and leading edge). Assessment was made for the prognostic value of markers; the results were validated in an independent cohort. Microglia/macrophage motility and activation (Iba1, CD68), programmed death-ligand 1 and CD4+ T cells were reduced, and homeostatic microglia (P2RY12) were increased in the invasive margins compared with the tumour core. There were significant positive correlations between microglia/macrophage markers CD68 (phagocytic)/triggering receptor expressed on myeloid cells 2 (anti-inflammatory) and CD8+ T cells in the invasive margins but not in the tumour core (P < 0.01). Programmed death-ligand 1 expression was associated with microglia/macrophage markers (including anti-inflammatory) CD68, CD163, CD32a and triggering receptor expressed on myeloid cells 2, only in the leading edge of glioblastomas (P < 0.01). Similarly, there was a positive correlation between programmed death-ligand 1 expression and CD8+ T-cell infiltration in the leading edge (P < 0.001). There was no relationship between CD64 (a receptor for autoreactive T-cell responses) and CD8+/CD4+ T cells, or between the microglia/macrophage antigen presentation marker HLA-DR and microglial motility (Iba1) in the tumour margins. Natural killer cell infiltration (CD335+) correlated with CD8+ T cells and with CD68/CD163/triggering receptor expressed on myeloid cells 2 anti-inflammatory microglia/macrophages at the leading edge. In an independent large glioblastoma cohort with transcriptomic data, positive correlations between anti-inflammatory microglia/macrophage markers (triggering receptor expressed on myeloid cells 2, CD163 and CD32a) and CD4+/CD8+/programmed death-ligand 1 RNA expression were validated (P < 0.001). Finally, multivariate analysis showed that high triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the leading edge were significantly associated with poorer overall patient survival (hazard ratio = 2.05, 3.42 and 2.11, respectively), independent of clinical variables. In conclusion, anti-inflammatory microglia/macrophages, CD8+ T cells and programmed death-ligand 1 are correlated in the invasive margins of glioblastoma, consistent with immune-suppressive interactions. High triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the human glioblastoma leading edge are predictors of poorer overall survival. Given substantial interest in targeting microglia/macrophages, together with immune checkpoint inhibitors in cancer, these data have major clinical implications

On Quantum Capacity of Compound Channels

In this paper we address the issue of universal or robust communication over quantum channels. Specifically, we consider memoryless communication scenario with channel uncertainty which is an analog of compound channel in classical information theory. We determine the quantum capacity of finite compound channels and arbitrary compound channels with informed decoder. Our approach in the finite case is based on the observation that perfect channel knowledge at the decoder does not increase the capacity of finite quantum compound channels. As a consequence we obtain coding theorem for finite quantum averaged channels, the simplest class of channels with long-term memory. The extension of these results to quantum compound channels with uninformed encoder and decoder, and infinitely many constituents remains an open problem.Comment: 16 pages, no figure