Cytosorb® haemoadsorption: a potential game changer for patients needing myocardial surgical revascularisation

Cytosorb, an extracorporeal blood purification system, utilises the principles of haemoadsorption to remove low molecular weight substances from the blood, including multiple cytokines such as interleukin (IL)-1b, IL-6, IL-8, and tumour necrosis factor-α, and anti-platelet drugs aiming to improve clinical outcomes. Given the prominent role of pro-inflammatory cytokines in various inflammatory states, Cytosorb has seen growing application as a therapeutic immunomodulator including surgery. This review focuses on the effects of the use of Cytosorb in patients undergoing coronary artery bypass grafting (CABG) and the indications of removal of cytokines and anti-platelet agents such as ticagrelor. The evidence supports the feasibility and safety profile of Cytosorb, with no device-related adverse events reported in all studies. Initial studies suggest significant potential for Cytosorb in urgent or emergency CABG surgery to remove anti-platelet medication with promising benefits on clinical outcomes including fewer blood product transfusions, decreased length of intensive care unit stay, and lower re-sternotomy rates. Furthermore, a cost saving analysis indicated that intraoperative removal of ticagrelor with Cytosorb would be cost effective in the setting of emergency cardiac surgery. However, the evidence remains inconclusive when Cytosorb is used in elective CABG surgery for cytokine removal. Definite high quality clinical trials for both indications for Cytosorb in CABG surgery are needed to clarify if there is a clinically significant benefit in clinical outcomes. There is substantial trial activity for the application of Cytosorb in higher risk cardiac surgery to establish the place of Cytosorb in future treatment pathways in cardiac surgery

Lindstrom theorems for fragments of first-order logic

Lindstr\"om theorems characterize logics in terms of model-theoretic conditions such as Compactness and the L\"owenheim-Skolem property. Most existing characterizations of this kind concern extensions of first-order logic. But on the other hand, many logics relevant to computer science are fragments or extensions of fragments of first-order logic, e.g., k-variable logics and various modal logics. Finding Lindstr\"om theorems for these languages can be challenging, as most known techniques rely on coding arguments that seem to require the full expressive power of first-order logic. In this paper, we provide Lindstr\"om theorems for several fragments of first-order logic, including the k-variable fragments for k>2, Tarski's relation algebra, graded modal logic, and the binary guarded fragment. We use two different proof techniques. One is a modification of the original Lindstr\"om proof. The other involves the modal concepts of bisimulation, tree unraveling, and finite depth. Our results also imply semantic preservation theorems.Comment: Appears in Logical Methods in Computer Science (LMCS

Antimalarial 4(1H)-pyridones bind to the Qisite of cytochromebc1

Cytochrome bc1 is a proven drug target in the prevention and treatment of malaria. The rise in drug-resistant strains of Plasmodium falciparum, the organism responsible for malaria, has generated a global effort in designing new classes of drugs. Much of the design/redesign work on overcoming this resistance has been focused on compounds that are presumed to bind the Qo site (one of two potential binding sites within cytochrome bc1) using the known crystal structure of this large membrane-bound macromolecular complex via in silico modeling. Cocrystallization of the cytochrome bc1 complex with the 4(1H)-pyridone class of inhibitors, GSK932121 and GW844520, that have been shown to be potent antimalarial agents in vivo, revealed that these inhibitors do not bind at the Qo site but bind at the Qi site. The discovery that these compounds bind at the Qi site may provide a molecular explanation for the cardiotoxicity and eventual failure of GSK932121 in phase-1 clinical trial and highlight the need for direct experimental observation of a compound bound to a target site before chemical optimization and development for clinical trials. The binding of the 4(1H)-pyridone class of inhibitors to Qi also explains the ability of this class to overcome parasite Qo-based atovaquone resistance and provides critical structural information for future design of new selective compounds with improved safety profiles

Spectrin-beta 2 facilitates the selective accumulation of GABAA receptors at somatodendritic synapses

Fast synaptic inhibition is dependent on targeting specific GABAAR subtypes to dendritic and axon initial segment (AIS) synapses. Synaptic GABAARs are typically assembled from α1-3, β and γ subunits. Here, we isolate distinct GABAARs from the brain and interrogate their composition using quantitative proteomics. We show that α2-containing receptors co-assemble with α1 subunits, whereas α1 receptors can form GABAARs with α1 as the sole α subunit. We demonstrate that α1 and α2 subunit-containing receptors co-purify with distinct spectrin isoforms; cytoskeletal proteins that link transmembrane proteins to the cytoskeleton. β2-spectrin was preferentially associated with α1-containing GABAARs at dendritic synapses, while β4-spectrin was associated with α2-containing GABAARs at AIS synapses. Ablating β2-spectrin expression reduced dendritic and AIS synapses containing α1 but increased the number of synapses containing α2, which altered phasic inhibition. Thus, we demonstrate a role for spectrins in the synapse-specific targeting of GABAARs, determining the efficacy of fast neuronal inhibition

Effects of intrauterine exposure to synthetic glucocorticoids on fetal, newborn, and infant hypothalamic-pituitary-adrenal axis function in humans : a systematic review

BACKGROUND: Synthetic glucocorticoids are commonly used in reproductive medicine. Fetal organ systems are highly sensitive to changes in the intrauterine environment, including overexposure to glucocorticoids. Structural and functional alterations resulting from such changes may persist throughout life and have been associated with diverse diseases. One system that could be particularly sensitive to fetal glucocorticoid overexposure is the hypothalamic-pituitary-adrenal (hpa) axis. Many human studies have investigated this possibility, but a systematic review to identify consistent, emergent findings is lacking. METHODS: We systematically review 49 human studies, assessing the effects of intrauterine exposure to synthetic glucocorticoids on fetal, neonate, and infant hpa function. RESULTS: Study quality varied considerably, but the main findings held true after restricting the analyses to higher-quality studies: intrauterine exposure to synthetic glucocorticoids reduces offspring hpa activity under unstimulated conditions after pain but not pharmacological challenge. Although reduced unstimulated hpa function appears to recover within the first 2 wk postpartum, blunted hpa reactivity to pain is likely to persist throughout the first 4 months of life. There is some evidence that the magnitude of the effects is correlated with the total amount of glucocorticoids administered and varies with the time interval between glucocorticoid exposure and hpa assessment. CONCLUSIONS: This systematic review has allowed the demonstration of the way in which intrauterine exposure to various regimens of synthetic glucocorticoids affects various forms of hpa function. As such, it guides future studies in terms of which variables need to be focused on in order to further strengthen the understanding of such therapy, whilst continuing to profit from its clinical benefits

KCC2 is required for the survival of mature neurons but not for their development

The K+/Cl- co-transporter KCC2 (SLC12A5) allows mature neurons in the CNS to maintain low intracellular Cl- levels that are critical in mediating fast hyperpolarizing synaptic inhibition via type A γ-aminobutyric acid receptors (GABAARs). In accordance with this, compromised KCC2 activity results in seizures, but whether such deficits directly contribute to the subsequent changes in neuronal structure and viability that lead to epileptogenesis, remains to be assessed. Canonical hyperpolarizing GABAAR currents develop postnatally which reflect a progressive increase in KCC2 expression levels and activity. To investigate the role that KCC2 plays in regulating neuronal viability and architecture we have conditionally ablated KCC2 expression in developing and mature neurons. Decreasing KCC2 expression in mature neurons resulted in the rapid activation of the extrinsic apoptotic pathway. Intriguingly, direct pharmacological inhibition of KCC2 in mature neurons was sufficient to rapidly induce apoptosis, an effect that was not abrogated via blockade of neuronal depolarization using Tetrodotoxin (TTX). In contrast, ablating KCC2 expression in immature neurons had no discernable effects on their subsequent development, arborization or dendritic structure. However, removing KCC2 in immature neurons was sufficient to ablate the subsequent postnatal development of hyperpolarizing GABAAR currents. Collectively, our results demonstrate that KCC2 plays a critical role in neuronal survival by limiting apoptosis, and mature neurons are highly sensitive to the loss of KCC2 function. In contrast, KCC2 appears to play a minimal role in mediating neuronal development or architecture

Activation of a novel natriuretic endocrine system in humans with heart failure

Proguanylin and prouroguanylin are the inactive precursors of guanylin and uroguanylin, natriuretic peptides involved in the regulation of sodium balance. Urinary uroguanylin levels have been found previously to be elevated in patients with HF (heart failure). The aim of the present study was to investigate whether plasma proguanylin and prouroguanylin levels are increased in patients with HF and to evaluate their relationship with cardiac and renal function. In this prospective observational study, we recruited 243 patients with HF (151 men) and 72 healthy controls. In patients with HF, plasma levels of proguanylin [median, 7.2 (range, 0.9–79.0) μg/l] and prouroguanylin [8.3 (1.7–53.0 μg/l)] were both significantly (P<0.0005) higher compared with levels in healthy controls [5.5 (0.4–22.3 μg/l) for proguanylin and 6.3 (2.5–16.9) μg/l for prouroguanylin]. In patients with HF, increased age, a history of hypertension, diabetes and atrial fibrillation, use of diuretics, a higher NYHA (New York Heart Association) class and a lower eGFR (estimated glomerular filtration rate) were significant univariate predictors of proguanylin and prouroguanylin levels. In multivariate analysis, a history of hypertension and low eGFR both had strong independent associations with proguanylin and prouroguanylin levels. Proguanylin and prouroguanylin varied significantly between NYHA class with a trend of increasing plasma concentrations with worsening severity of symptoms. In conclusion, plasma proguanylin and prouroguanylin are elevated in patients with HF. Elevated plasma proguanylin and prouroguanylin levels are associated with hypertension, renal impairment and increasing severity of HF. This novel endocrine system may contribute to the pathophysiology of HF

Photo-antagonism of the GABAA receptor

Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation. These compounds are based on the competitive antagonist gabazine and incorporate a variety of photoactive groups. By using site-directed mutagenesis and ligand-docking studies, they reveal new areas of the GABA binding site at the interface between receptor β and α subunits. These compounds enable the selected inactivation of native GABAA receptor populations providing new insight into the function of inhibitory synapses and extrasynaptic receptors in controlling neuronal excitation

Glycogen Synthase Kinase (GSK) 3β phosphorylates and protects nuclear myosin 1c from proteasome-mediated degradation to activate rDNA transcription in early G1 cells

Nuclear myosin 1c (NM1) mediates RNA polymerase I (pol I) transcription activation and cell cycle progression by facilitating PCAF-mediated H3K9 acetylation, but the molecular mechanism by which NM1 is regulated remains unclear. Here, we report that at early G1 the glycogen synthase kinase (GSK) 3β phosphorylates and stabilizes NM1, allowing for NM1 association with the chromatin. Genomic analysis by ChIP-Seq showed that this mechanism occurs on the rDNA as active GSK3β selectively occupies the gene. ChIP assays and transmission electron microscopy in GSK3β-/- mouse embryonic fibroblasts indicated that at G1 rRNA synthesis is suppressed due to decreased H3K9 acetylation leading to a chromatin state incompatible with transcription. We found that GSK3β directly phosphorylates the endogenous NM1 on a single serine residue (Ser-1020) located within the NM1 C-terminus. In G1 this phosphorylation event stabilizes NM1 and prevents NM1 polyubiquitination by the E3 ligase UBR5 and proteasome-mediated degradation. We conclude that GSK3β-mediated phosphorylation of NM1 is required for pol I transcription activation

The factors driving evolved herbicide resistance at a national scale

Repeated use of xenobiotic chemicals has selected for the rapid evolution of resistance threatening health and food security at a global scale. Strategies for preventing the evolution of resistance include cycling and mixtures of chemicals and diversification of management. We currently lack large-scale studies that evaluate the efficacy of these different strategies for minimizing the evolution of resistance. Here we use a national scale dataset of occurrence of the weed Alopecurus myosuroides (Blackgrass) in the UK to address this. Weed densities are correlated with assays of evolved resistance, supporting the hypothesis that resistance is driving weed abundance at a national scale. Resistance was correlated with the frequency of historical herbicide applications suggesting that evolution of resistance is primarily driven by intensity of exposure to herbicides, but was unrelated directly to other cultural techniques. We find that populations resistant to one herbicide are likely to show resistance to multiple herbicide classes. Finally, we show that the economic costs of evolved resistance are considerable: loss of control through resistance can double the economic costs of weeds. This research highlights the importance of managing threats to food production and healthcare systems using an evolutionarily informed approach in a proactive not reactive manner