Convexity subarachnoid haemorrhage has a high risk of intracerebral haemorrhage in suspected cerebral amyloid angiopathy

The risk of future symptomatic intracerebral haemorrhage (sICH) remains uncertain in patients with acute convexity subarachnoid haemorrhage (cSAH) associated with suspected cerebral amyloid angiopathy (CAA). We assessed the risk of future sICH in patients presenting to our comprehensive stroke service with acute non-traumatic cSAH due to suspected CAA, between 2011 and 2016. We conducted a systematic search and pooled analysis including our cohort and other published studies including similar cohorts. Our hospital cohort included 20 patients (mean age 69 years; 60% male); 12 (60%) had probable CAA, and 6 (30%) had possible CAA according to the modified Boston criteria; two did not meet CAA criteria because of age <55 years, but were judged likely to be due to CAA. Fourteen patients (70%) had cortical superficial siderosis; 12 (60%) had cerebral microbleeds. Over a mean follow-up period of 19 months, 2 patients (9%) suffered sICH, both with probable CAA (annual sICH risk for probable CAA 8%). In a pooled analysis including our cohort and eight other studies (n = 172), the overall sICH rate per patient-year was 16% (95% CI 11-24%). In those with probable CAA (n = 104), the sICH rate per patient-year was 19% (95% CI 13-27%), compared to 7% (95% CI 3-15%) for those without probable CAA (n = 72). Patients with acute cSAH associated with suspected CAA are at high risk of future sICH (16% per patient-year); probable CAA might carry the highest risk

The Cerebral Haemorrhage Anatomical RaTing inStrument (CHARTS): Development and assessment of reliability.

PURPOSE: The causes, risk factors and prognosis of spontaneous intracerebral haemorrhage (ICH) are partly determined by anatomical location (specifically, lobar vs. non-lobar (deep and infratentorial) regions). We systematically developed a rating instrument to reliably classify ICH location. METHODS: We used a two-stage iterative Delphi-style method for instrument development. The resultant Cerebral Haemorrhage Anatomical RaTing inStrument (CHARTS) was validated on CT and MRI scans from a cohort of consecutive patients with acute spontaneous symptomatic ICH by three independent raters. We tested interrater and intrarater reliability using kappa statistics. RESULTS: Our validation cohort included 227 patients (58% male; median age: 72.4 (IQR: 67.1-74.6)). The interrater reliability for the main analyses (i.e. including any lobar ICH; all deep and infratentorial anatomical categories (lentiform, caudate thalamus; brainstem; cerebellum); and uncertain location) was excellent (all kappa values>0.80) both in pair-wise between-rater comparisons and across all raters. The intrarater reliability was substantial to almost perfect (k=0.83; 95%CI: 0.77-0.88 and k=0.95; 95%CI: 0.92-0.96 respectively). All kappa statistics remained consistent for individual cerebral lobar regions. CONCLUSIONS: The CHARTS instrument can be used to reliably and comprehensively map the anatomical location of spontaneous ICH, and may be helpful for studying important questions regarding causes, risk factors, prognosis, and for stratification in clinical trials

A gentle introduction to the functional renormalization group: the Kondo effect in quantum dots

The functional renormalization group provides an efficient description of the interplay and competition of correlations on different energy scales in interacting Fermi systems. An exact hierarchy of flow equations yields the gradual evolution from a microscopic model Hamiltonian to the effective action as a function of a continuously decreasing energy cutoff. Practical implementations rely on suitable truncations of the hierarchy, which capture nonuniversal properties at higher energy scales in addition to the universal low-energy asymptotics. As a specific example we study transport properties through a single-level quantum dot coupled to Fermi liquid leads. In particular, we focus on the temperature T=0 gate voltage dependence of the linear conductance. A comparison with exact results shows that the functional renormalization group approach captures the broad resonance plateau as well as the emergence of the Kondo scale. It can be easily extended to more complex setups of quantum dots.Comment: contribution to Les Houches proceedings 2006, Springer styl

Finite-size and correlation-induced effects in Mean-field Dynamics

The brain's activity is characterized by the interaction of a very large number of neurons that are strongly affected by noise. However, signals often arise at macroscopic scales integrating the effect of many neurons into a reliable pattern of activity. In order to study such large neuronal assemblies, one is often led to derive mean-field limits summarizing the effect of the interaction of a large number of neurons into an effective signal. Classical mean-field approaches consider the evolution of a deterministic variable, the mean activity, thus neglecting the stochastic nature of neural behavior. In this article, we build upon two recent approaches that include correlations and higher order moments in mean-field equations, and study how these stochastic effects influence the solutions of the mean-field equations, both in the limit of an infinite number of neurons and for large yet finite networks. We introduce a new model, the infinite model, which arises from both equations by a rescaling of the variables and, which is invertible for finite-size networks, and hence, provides equivalent equations to those previously derived models. The study of this model allows us to understand qualitative behavior of such large-scale networks. We show that, though the solutions of the deterministic mean-field equation constitute uncorrelated solutions of the new mean-field equations, the stability properties of limit cycles are modified by the presence of correlations, and additional non-trivial behaviors including periodic orbits appear when there were none in the mean field. The origin of all these behaviors is then explored in finite-size networks where interesting mesoscopic scale effects appear. This study leads us to show that the infinite-size system appears as a singular limit of the network equations, and for any finite network, the system will differ from the infinite system

Volume and functional outcome of intracerebral hemorrhage according to oral anticoagulant type

Objective: To compare intracerebral hemorrhage (ICH) volume and clinical outcome of non–vitamin K oral anticoagulants (NOAC)–associated ICH to warfarin-associated ICH. Methods: In this multicenter cross-sectional observational study of patients with anticoagulant-associated ICH, consecutive patients with NOAC-ICH were compared to those with warfarin-ICH selected from a population of 344 patients with anticoagulant-associated ICH. ICH volume was measured by an observer blinded to clinical details. Outcome measures were ICH volume and clinical outcome adjusted for confounding factors. Results: We compared 11 patients with NOAC-ICH to 52 patients with warfarin-ICH. The median ICH volume was 2.4 mL (interquartile range [IQR] 0.3–5.4 mL) for NOAC-ICH vs 8.9 mL (IQR 4.0–21.3 mL) for warfarin-ICH (p = 0.0028). In univariate linear regression, use of warfarin (difference in cube root volume 1.61; 95% confidence interval [CI] 0.69 to 2.53) and lobar ICH location (compared with nonlobar ICH; difference in cube root volume 1.52; 95% CI 2.20 to 0.85) were associated with larger ICH volumes. In multivariable linear regression adjusting for confounding factors (sex, hypertension, previous ischemic stroke, white matter disease burden, and premorbid modified Rankin Scale score [mRS]), warfarin use remained independently associated with larger ICH (cube root) volumes (coefficient 0.64; 95% CI 0.24 to 1.25; p = 0.042). Ordered logistic regression showed an increased odds of a worse clinical outcome (as measured by discharge mRS) in warfarin-ICH compared with NOAC-ICH: odds ratio 4.46 (95% CI 1.10 to 18.14; p = 0.037). Conclusions: In this small prospective observational study, patients with NOAC-associated ICH had smaller ICH volumes and better clinical outcomes compared with warfarin-associated ICH

Gain control network conditions in early sensory coding

Gain control is essential for the proper function of any sensory system. However, the precise mechanisms for achieving effective gain control in the brain are unknown. Based on our understanding of the existence and strength of connections in the insect olfactory system, we analyze the conditions that lead to controlled gain in a randomly connected network of excitatory and inhibitory neurons. We consider two scenarios for the variation of input into the system. In the first case, the intensity of the sensory input controls the input currents to a fixed proportion of neurons of the excitatory and inhibitory populations. In the second case, increasing intensity of the sensory stimulus will both, recruit an increasing number of neurons that receive input and change the input current that they receive. Using a mean field approximation for the network activity we derive relationships between the parameters of the network that ensure that the overall level of activity of the excitatory population remains unchanged for increasing intensity of the external stimulation. We find that, first, the main parameters that regulate network gain are the probabilities of connections from the inhibitory population to the excitatory population and of the connections within the inhibitory population. Second, we show that strict gain control is not achievable in a random network in the second case, when the input recruits an increasing number of neurons. Finally, we confirm that the gain control conditions derived from the mean field approximation are valid in simulations of firing rate models and Hodgkin-Huxley conductance based models

Multi-Timescale Perceptual History Resolves Visual Ambiguity

When visual input is inconclusive, does previous experience aid the visual system in attaining an accurate perceptual interpretation? Prolonged viewing of a visually ambiguous stimulus causes perception to alternate between conflicting interpretations. When viewed intermittently, however, ambiguous stimuli tend to evoke the same percept on many consecutive presentations. This perceptual stabilization has been suggested to reflect persistence of the most recent percept throughout the blank that separates two presentations. Here we show that the memory trace that causes stabilization reflects not just the latest percept, but perception during a much longer period. That is, the choice between competing percepts at stimulus reappearance is determined by an elaborate history of prior perception. Specifically, we demonstrate a seconds-long influence of the latest percept, as well as a more persistent influence based on the relative proportion of dominance during a preceding period of at least one minute. In case short-term perceptual history and long-term perceptual history are opposed (because perception has recently switched after prolonged stabilization), the long-term influence recovers after the effect of the latest percept has worn off, indicating independence between time scales. We accommodate these results by adding two positive adaptation terms, one with a short time constant and one with a long time constant, to a standard model of perceptual switching

Evidence for Two Modes of Synergistic Induction of Apoptosis by Mapatumumab and Oxaliplatin in Combination with Hyperthermia in Human Colon Cancer Cells

Colorectal cancer is the third leading cause of cancer-related mortality in the world-- the main cause of death from colorectal cancer is hepatic metastases, which can be treated with isolated hepatic perfusion (IHP). Searching for the most clinically relevant approaches for treating colorectal metastatic disease by isolated hepatic perfusion (IHP), we developed the application of oxaliplatin concomitantly with hyperthermia and humanized death receptor 4 (DR4) antibody mapatumumab (Mapa), and investigated the molecular mechanisms of this multimodality treatment in human colon cancer cell lines CX-1 and HCT116 as well as human colon cancer stem cells Tu-12, Tu-21 and Tu-22. We showed here, in this study, that the synergistic effect of the multimodality treatment-induced apoptosis was caspase dependent and activated death signaling via both the extrinsic apoptotic pathway and the intrinsic pathway. Death signaling was activated by c-Jun N-terminal kinase (JNK) signaling which led to Bcl-xL phosphorylation at serine 62, decreasing the anti-apoptotic activity of Bcl-xL, which contributed to the intrinsic pathway. The downregulation of cellular FLICE inhibitory protein long isoform (c-FLIPL) in the extrinsic pathway was accomplished through ubiquitination at lysine residue (K) 195 and protein synthesis inhibition. Overexpression of c-FLIPL mutant (K195R) and Bcl-xL mutant (S62A) completely abrogated the synergistic effect. The successful outcome of this study supports the application of multimodality strategy to patients with colorectal hepatic metastases who fail to respond to standard chemoradiotherapy that predominantly targets the mitochondrial apoptotic pathway. © 2013 Song et al