The relationship of systemic hemodynamics and oxygen consumption to early allograft failure after liver transplantation.

The early postoperative hemodynamic data of 88 patients who underwent primary liver transplantation between July 1989 and October 1990 at the University Health Center of Pittsburgh were analyzed to establish the relationship of systemic hemodynamics and oxygen consumption to perioperative allograft function. The 15 patients whose allografts failed within the 1st month following transplantation were designated as group 1, while 73 patients who retained adequate graft function constituted group 2. Although the cardiac index and oxygen delivery did not differ significantly between the groups, group 1 consistently demonstrated a lower mean arterial pressure, oxygen consumption, arteriovenous oxygen content difference, and arterial ketone body ratio. The etiology of reduced oxygen consumption in group 1 patients is speculative, but the data support the notion that oxygen consumption is a useful, predictive indicator for liver allograft function after transplantation

A proteinase 3 contribution to juvenile idiopathic arthritis-associated cartilage damage

A full understanding of the molecular mechanisms implicated in the etiopathogenesis of juvenile idiopathic arthritis (JIA) is lacking. A critical role for leukocyte proteolytic activity (e.g., elastase and cathepsin G) has been proposed. While leukocyte elastase’s (HLE) role has been documented, the potential contribution of proteinase 3 (PR3), a serine protease present in abundance in neutrophils, has not been evaluated. In this study we investigated: (1) PR3 concentrations in the synovial fluid of JIA patients using ELISA and (2) the cartilage degradation potential of PR3 by measuring the hydrolysis of fluorescently labeled collagen II in vitro. In parallel, concentrations and collagen II hydrolysis by HLE were assessed. Additionally, the levels of the co-secreted primary granule protein myeloperoxidase (MPO) were assessed in synovial fluid of patients diagnosed with JIA. We report the following levels of analytes in JIA synovial fluid: PR3—114 ± 100 ng/mL (mean ± SD), HLE—1272 ± 1219 ng/mL, and MPO—1129 ± 1659 ng/mL, with a very strong correlation between the PR3 and HLE concentrations (rs = 0.898, p \u3c 1 × 10–6 ). Importantly, PR3 hydrolyzed fluorescently labeled collagen II as efficiently as HLE. Taken together, these novel findings suggest that PR3 (in addition to HLE) contributes to JIA-associated joint damage

Discovery of the Central Excess Brightness in Hard X-rays in the Cluster of Galaxies Abell 1795

Using the X-ray data from \ASCA, spectral and spatial properties of the intra-cluster medium (ICM) of the cD cluster Abell 1795 are studied, up to a radial distance of $\sim 12'$ ($\sim 1.3$ $h_{50}^{-1}$ kpc). The ICM temperature and abundance are spatially rather constant, although the cool emission component is reconfirmed in the central region. The azimuthally- averaged radial X-ray surface brightness profiles are very similar between soft (0.7--3 keV) and hard (3--10 keV) energy bands, and neither can be fitted with a single-$\beta$ model due to a strong data excess within $\sim5'$ of the cluster center. In contrast, double-$\beta$ models can successfully reproduce the overall brightness profiles both in the soft and hard energy bands, as well as that derived with the \ROSAT PSPC. Properties of the central excess brightness are very similar over the 0.2--10 keV energy range spanned by \ROSAT and \ASCA. Thus, the excess X-ray emission from the core region of this cluster is confirmed for the first time in hard X-rays above 3 keV. This indicates that the shape of the gravitational potential becomes deeper than the King-type one towards the cluster center. Radial profiles of the total gravitating matter, calculated using the double-$\beta$ model, reveal an excess mass of $\sim 3 \times 10^{13}~ M_{\odot}$ within $\sim 150 h^{-1}_{50}$ kpc of the cluster center. This suggests a hierarchy in the gravitational potential corresponding to the cD galaxy and the entire cluster.Comment: 27 pages, 8 figures; to appear ApJ 500 (June 20, 1998

Dust Destruction in the High-Velocity Shocks Driven by Supernovae in the Early Universe

We investigate the destruction of dust grains by sputtering in the high-velocity interstellar shocks driven by supernovae (SNe) in the early universe to reveal the dependence of the time-scale of dust destruction on the gas density $n_{{\rm H}, 0}$ in the interstellar medium (ISM) as well as on the progenitor mass $M_{\rm pr}$ and explosion energy $E_{\rm 51}$ of SN. The sputtering yields for the combinations of dust and ion species of interest to us are evaluated by applying the so-called universal relation with a slight modification. The dynamics of dust grains and their destruction by sputtering in shock are calculated by taking into account the size distribution of each dust species, together with the time evolution of temperature and density of gas in spherically symmetric shocks. The results of calculations show that the efficiency of dust destruction depends not only on the sputtering yield but also on the initial size distribution of each grain species. The efficiency of dust destruction increases with increasing $E_{\rm 51}$ and/or increasing $n_{{\rm H}, 0}$, but is almost independent of $M_{\rm pr}$ as long as $E_{\rm 51}$ is the same. The mass of gas swept up by shock is the increasing function of $E_{\rm 51}$ and the decreasing function of $n_{{\rm H}, 0}$. Combining these results, we present the approximation formula for the time-scale of destruction for each grain species in the early universe as a function of $E_{\rm 51}$ and $n_{{\rm H}, 0}$. This formula is applicable for investigating the evolution of dust grains at the early epoch of the universe with the metallicity of Z \la 10^{-3} $Z_\odot$. The effects of the cooling processes of gas on the destruction of dust are briefly discussed.Comment: 49 pages including 7 tables and 25 figures, accepted for publication in Ap

Design and Mechanism of (S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic Acid, a Highly Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Addiction

© 2018 American Chemical Society. γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. Inhibition of GABA aminotransferase (GABA-AT), a pyridoxal 5′-phosphate (PLP)-dependent enzyme that degrades GABA, has been established as a possible strategy for the treatment of substance abuse. The raised GABA levels that occur as a consequence of this inhibition have been found to antagonize the rapid release of dopamine in the ventral striatum (nucleus accumbens) that follows an acute challenge by an addictive substance. In addition, increased GABA levels are also known to elicit an anticonvulsant effect in patients with epilepsy. We previously designed the mechanism-based inactivator (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (2), now called CPP-115, that is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved drug that is an inactivator of GABA-AT. CPP-115 was found to have high therapeutic potential for the treatment of cocaine addiction and for a variety of epilepsies, has successfully completed a Phase I safety clinical trial, and was found to be effective in the treatment of infantile spasms (West syndrome). Herein we report the design, using molecular dynamics simulations, synthesis, and biological evaluation of a new mechanism-based inactivator, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (5), which was found to be almost 10 times more efficient as an inactivator of GABA-AT than CPP-115. We also present the unexpected crystal structure of 5 bound to GABA-AT, as well as computational analyses used to assist the structure elucidation process. Furthermore, 5 was found to have favorable pharmacokinetic properties and low off-target activities. In vivo studies in freely moving rats showed that 5 was dramatically superior to CPP-115 in suppressing the release of dopamine in the corpus striatum, which occurs subsequent to either an acute cocaine or nicotine challenge. Compound 5 also attenuated increased metabolic demands (neuronal glucose metabolism) in the hippocampus, a brain region that encodes spatial information concerning the environment in which an animal receives a reinforcing or aversive drug. This multidisciplinary computational design to preclinical efficacy approach should be applicable to the design and improvement of mechanism-based inhibitors of other enzymes whose crystal structures and inactivation mechanisms are known