Systemic effects of tissue plasminogen activator-associated fibrinolysis and its relation to thrombin generation in orthotopic liver transplantation

Orthotopic liver transplantation is frequently associated with hyperfibrinolysis, the origin and clinical relevance of which is largely unknown. In 20 orthotopic liver transplantations, we studied the occurrence and systemic effects of hyperfibrinolysis. Severe fibrinolysis was defined to be present when the euglobulin-clot lysis time and the whole-blood-clot lysis time, as measured by thrombelastography, were shorter than 60 and 90 min, respectively, at some time during the operation. Based on these criteria, 7 patients had minimal fibrinolysis (group I), and 13 patients had severe fibrinolysis (group II). In group II a gradual increase of tissue-type plasminogen activator (t-PA) activity was seen during the anhepatic stage, followed by an “explosive” increase immediately after graft reperfusion (P=0.0004, compared with group I), and a reduction of plasminogen activator inhibitor (PAI) activity. Plasma degradation products of fibrinogen and fibrin increased parallel to t-PA activity, and levels were significantly higher at 45 min after graft reperfusion in group II compared with group I (P<0.04). Thrombin-antithrombin III complexes showed an identical steady increase in both groups, indicating that increased t-PA activity was not related to thrombin formation. A combination of increased endothelial release and reduced hepatic clearance may have caused the increased t-PA activity. The t-PA—associated destruction of fibrinogen and fibrin after graft reperfusion is consistent with the clinical signs of severe oozing often seen in this period. These observations may have important clinical implications for the treatment of bleeding in patients undergoing orthotopic liver transplantation. © 1989 by The Williams and Wilkins Co

Ionic Mechanisms of Spinal Neuronal Cold Hypersensitivity in Ciguatera

Cold hypersensitivity is evident in a range of neuropathies and can evoke sensations of paradoxical burning cold pain. Ciguatoxin poisoning is known to induce a pain syndrome caused by consumption of contaminated tropical fish that can persist for months and include pruritus and cold allodynia; at present no suitable treatment is available. These studies for the first time examine neural substrates and molecular components of Pacific ciguatoxin-2 induced cold hypersensitivity. Electrophysiological recordings of dorsal horn lamina V/VI wide dynamic range neurones were made in non-sentient rats. Subcutaneous injection of 10 nM ciguatoxin-2 into the receptive field increased neuronal responses to innocuous and noxious cooling. In addition, neuronal responses to low threshold but not noxious punctate mechanical stimuli were also elevated. The resultant cold hypersensitivity was not reversed by M8-An, an antagonist of TRPM8. Both mechanical and cold hypersensitivity were completely prevented by co-injection with Nav1.8 antagonist A803467, whereas TRPA1 antagonist A967079 only prevented hypersensitivity to innocuous cooling and partially prevented hypersensitivity to noxious cooling. In naïve rats, neither innocuous nor noxious cold evoked neuronal responses were inhibited by antagonists of Nav1.8, TRPA1 or TRPM8 alone. Ciguatoxins may confer cold sensitivity to a subpopulation of cold-insensitive Nav1.8/TRPA1+ primary afferents, which could underlie cold allodynia reported in ciguatera. These data expand the understanding of central spinal cold sensitivity under normal conditions and the role of these ion channels in this translational rat model of ciguatoxin induced-hypersensitivity. This article is protected by copyright. All rights reserved

Modelling the functional genomics of Parkinson’s disease in Caenorhabditis elegans: LRRK2 and beyond

For decades, Parkinson’s disease (PD) cases have been genetically categorised into familial, when caused by mutations in single genes with a clear inheritance pattern in affected families, or idiopathic, in the absence of an evident monogenic determinant. Recently, genome-wide association studies (GWAS) have revealed how common genetic variability can explain up to 36% of PD heritability and that PD manifestation is often determined by multiple variants at different genetic loci. Thus, one of the current challenges in PD research stands in modelling the complex genetic architecture of this condition and translating this into functional studies. Caenorhabditis elegans provide a profound advantage as a reductionist, economical model for PD research, with a short lifecycle, straightforward genome engineering and high conservation of PD relevant neural, cellular and molecular pathways. Functional models of PD genes utilising C. elegans show many phenotypes recapitulating pathologies observed in PD. When contrasted with mammalian in vivo and in vitro models, these are frequently validated, suggesting relevance of C. elegans in the development of novel PD functional models. This review will discuss how the nematode C. elegans PD models have contributed to the uncovering of molecular and cellular mechanisms of disease, with a focus on the genes most commonly found as causative in familial PD and risk factors in idiopathic PD. Specifically, we will examine the current knowledge on a central player in both familial and idiopathic PD, Leucine-rich repeat kinase 2 (LRRK2) and how it connects to multiple PD associated GWAS candidates and Mendelian disease-causing genes

Searching (the) FIRST radio arcs near ACO clusters

Gravitational lensing (GL) of distant radio sources by galaxy clusters should produce radio arc(let)s. We extracted radio sources from the FIRST survey near Abell cluster cores and found their radio position angles to be uniformly distributed with respect to the cluster centres. This result holds even when we restrict the sample to the richest or most centrally condensed clusters, and to sources with high S/N and large axial ratio. Our failure to detect GL with statistical methods may be due to poor cluster centre positions. We did not find convincing candidates for arcs either. Our result agrees with theoretical estimates predicting that surveys much deeper than FIRST are required to detect the effect. This is in apparent conflict with the detection of such an effect claimed by Bagchi & Kapahi (1995).Comment: 6 pages; 8 figures and 1 style file are included; to appear in Proc. "Observational Cosmology with the New Radio Surveys", eds. M. Bremer, N. Jackson & I. Perez-Fournon, Kluwer Acad. Pres

Measurements of Rate Coefficients for Reactions of OH with Ethanol and Propan-2-ol at Very Low Temperatures.

The low temperature kinetics of the reactions of OH with ethanol and propan-2-ol have been studied using a pulsed Laval nozzle apparatus coupled with pulsed laser photolysis-laser-induced fluorescence (PLP-LIF) spectroscopy. The rate coefficients for both reactions have been found to increase significantly as the temperature is lowered, by approximately a factor of 18 between 293 and 54 K for ethanol, and by ∼10 between 298 and 88 K for OH + propan-2-ol. The pressure dependence of the rate coefficients provides evidence for two reaction channels: a zero pressure bimolecular abstraction channel leading to products and collisional stabilization of a weakly bound OH-alcohol complex. The presence of the abstraction channel at low temperatures is rationalized by a quantum mechanical tunneling mechanism, most likely through the barrier to hydrogen abstraction from the OH moiety on the alcohol

High-threshold mechanosensitive ion channels blocked by a novel conopeptide mediate pressure-evoked pain

Little is known about the molecular basis of somatosensory mechanotransduction in mammals. We screened a library of peptide toxins for effects on mechanically activated currents in cultured dorsal root ganglion neurons. One conopeptide analogue, termed NMB-1 for noxious mechanosensation blocker 1, selectively inhibits (IC50 1 µM) sustained mechanically activated currents in a subset of sensory neurons. Biotinylated NMB-1 retains activity and binds selectively to peripherin-positive nociceptive sensory neurons. The selectivity of NMB-1 was confirmed by the fact that it has no inhibitory effects on voltage-gated sodium and calcium channels, or ligand-gated channels such as acid-sensing ion channels or TRPA1 channels. Conversely, the tarantula toxin, GsMTx-4, which inhibits stretch-activated ion channels, had no effects on mechanically activated currents in sensory neurons. In behavioral assays, NMB-1 inhibits responses only to high intensity, painful mechanical stimulation and has no effects on low intensity mechanical stimulation or thermosensation. Unexpectedly, NMB-1 was found to also be an inhibitor of rapid FM1-43 loading (a measure of mechanotransduction) in cochlear hair cells. These data demonstrate that pharmacologically distinct channels respond to distinct types of mechanical stimuli and suggest that mechanically activated sustained currents underlie noxious mechanosensation. NMB-1 thus provides a novel diagnostic tool for the molecular definition of channels involved in hearing and pressure-evoked pain

Antagonistic interaction networks are structured independently of latitude and host guild

Peer reviewe

A massive reservoir of low-excitation molecular gas at high redshift

Molecular hydrogen is an important component of galaxies because it fuels star formation and accretion onto AGN, the two processes that generate the large infrared luminosities of gas-rich galaxies. Observations of spectral-line emission from the tracer molecule CO are used to probe the properties of this gas. But the lines that have been studied in the local Universe, mostly the lower rotational transitions of J = 1-0 and J = 2-1, have hitherto been unobservable in high-redshift galaxies. Instead, higher transitions have been used, although the densities and temperatures required to excite these higher transitions may not be reached by much of the gas. As a result, past observations may have underestimated the total amount of molecular gas by a substantial amount. Here we report the discovery of large amounts of low-excitation molecular gas around the infrared-luminous quasar, APM 08279+5255 at z = 3.91, using the two lowest excitation lines of 12CO (J = 1-0 and J = 2-1). The maps confirm the presence of hot and dense gas near the nucleus, and reveal an extended reservoir of molecular gas with low excitation that is 10 to 100 times more massive than the gas traced by higher-excitation observations. This raises the possibility that significant amounts of low-excitation molecular gas may lurk in the environments of high-redshift (z > 3) galaxies.Comment: To appear as a Letter to Nature, 4th January 200