Relationship between splanchnic, peripheral and cardiac haemodynamics in liver cirrhosis of different degrees of severity

OBJECTIVE: To investigate the relationships between changes in splanchnic and systemic haemodynamics in liver cirrhosis. DESIGN AND METHODS: Abdominal and peripheral duplex-Doppler sonography and Doppler echocardiography were performed in 42 cirrhotic patients with (group A, ascitic) or without ascites (group NA, non-ascitic) and in a control group of 36 healthy volunteers. RESULTS: There were significant differences (P < 0.05 at ANOVA) between the three groups in portal vein flow velocity (controls, groups NA and A, respectively, 29.2, 21.4 and 20.0 cm/s), portal diameter (9.3, 12.2 and 12.0 mm), superior mesenteric artery (SMA) resistance index (RI) (0.889, 0.854 and 0.816), femoral artery RI (0.988, 0.974 and 0.945), mean arterial pressure (MAP) (101.4, 102.0 and 87.3 mmHg), peripheral vascular resistance (1579, 1404 and 1094 dyn/cm5/s) and cardiac index (CI) (2.91, 3.46 and 3.77 l/min/m2). Multiple regression analysis identified renal interlobular- and SMA RI (respectively, r = -0.58 and r = 0.51) in group A as the two regional vascular beds correlated to MAP. CONCLUSION: The deterioration of the cirrhotic hyperdynamic circulation in the presence of ascites and the correlation between MAP and mesenteric and renal resistances are consistent with the peripheral arterial vasodilation hypothesis. The positive correlation between MAP and SMA RI in ascitic patients shows a link between this region and the general circulation. This seems to suggest that splanchnic hyperafflux plays a part in the formation of ascites.     

A multi-objective evolutionary approach to the protein structure prediction problem

The protein structure prediction (PSP) problem is concerned with the prediction of the folded, native, tertiary structure of a protein given its sequence of amino acids. It is a challenging and computationally open problem, as proven by the numerous methodological attempts and the research effort applied to it in the last few years. The potential energy functions used in the literature to evaluate the conformation of a protein are based on the calculations of two different interaction energies: local (bond atoms) and non-local (non-bond atoms). In this paper, we show experimentally that those types of interactions are in conflict, and do so by using the potential energy function Chemistry at HARvard Macromolecular Mechanics. A multi-objective formulation of the PSP problem is introduced and its applicability studied. We use a multi-objective evolutionary algorithm as a search procedure for exploring the conformational space of the PSP problem.     

Targeting of interleukin 2 to human ovarian carcinoma by fusion with a single-chain Fv of antifolate receptor antibody

To provide a new tool for the immunotherapy of human ovarian carcinoma, we constructed a fusion protein between interleukin-2 (IL-2) and the single-chain Fv (scFv) of MOV19, a monoclonal antibody directed against alpha-folate receptor (alpha-FR), known to be overexpressed on human nonmucinous ovarian carcinoma. This was accomplished by fusing the coding sequences in a single open reading frame and expressing the IL-2/MOV19 scFv chimera under the control of the murine immunoglobulin K promoter in J558L plasmacytoma cells. The design allowed the construction of a small molecule combining the specificity of MOV19 with the immunostimulatory activity of IL-2. This might improve the tissue penetration and distribution of the fusion protein within the tumor, reduce its immunogenicity, and avoid the toxicity related to the systemic administration of IL-2. The IL-2/MOV19 fusion protein was stable on purification from the cell supernatant and was biologically active. Importantly, this construct was able to target IL-2 onto the surface of alpha-FR-overexpressing tumor cells and stimulated the proliferation of the IL-2-dependent CTLL-2 cell line as well as that of human resting peripheral blood lymphocytes. In a syngeneic mouse model, IL-2/MOV19 scFv specifically targeted a-FR gene-transduced metastatic tumor cells without accumulating in normal tissues, due to its fast clearance from the body. Prolonged release of IL-2/MOV19 scFv by in vivo transplanted J558-EF6.1 producer cells protected 60% of mice from the development of lung metastases caused by an i.v. injection of a-FR gene-transduced tumor cells. Moreover, treatment with IL-2/MOV19 scFv, but not with recombinant IL-2, significantly reduced the volume of s.c. tumors. The pharmacokinetics and biological characteristics of IL-2/NMOV19 scFv might allow us to combine the systemic administration of this molecule with the adoptive transfer of in vitro retargeted T lymphocytes for the treatment of ovarian cancer, thereby providing local delivery of IL-2 without toxicity.     

Pharmacological characterization of the cysteinyl-leukotriene antagonists CGP 45715A (iralukast) and CGP 57698 in human airways in vitro

1. Cysteinyl-leukotrienes (cysteinyl-LTs) are important mediators in the pathogenesis of asthma. They cause bronchoconstriction, mucus hypersecretion, increase in microvascular permeability, plasma extravasation and eosinophil recruitment. 2. We investigated the pharmacological profile of the cysteinyl-LT antagonists CGP 45715A (iralukast), a structural analogue of LTD4 and CGP 57698, a quinoline type antagonist, in human airways in vitro, by performing binding studies on human lung parenchyma membranes and functional studies on human isolated bronchial strips. 3. Competition curves vs [3H]-LTD4 on human lung parenchyma membranes demonstrated that: (a) both antagonists were able to compete for the two sites labelled by [3H]-LTD4; (b) as in all the G-protein coupled receptors, iralukast and CGP 57698 did not discriminate between the high and the low affinity states of the CysLT receptor labelled by LTD4 (Ki1=Ki2= 16.6 nM+/-36% CV and Ki1= Ki2 = 5.7 nM+/-19% CV, respectively); (c) iralukast, but not CGP 57698, displayed a slow binding kinetic, because preincubation (15 min) increased its antagonist potency. 4. In functional studies: (a) iralukast and CGP 57698 antagonized LTD4-induced contraction of human bronchi, with pA2 values of 7.77+/-4.3% CV and 8.51+/-1.6% CV, respectively, and slopes not significantly different from unity; (b) the maximal LTD4 response in the presence of CGP 57698 was actually increased, thus clearly deviating from apparent simple competition. 5. Both antagonists significantly inhibited antigen-induced contraction of human isolated bronchial strips in a concentration-dependent manner, lowering the upper plateau of the anti-IgE curves. 6. In conclusion, the results of the present in vitro investigation indicate that iralukast and CGP 57698 are potent antagonists of LTD4 in human airways, with affinities in the nanomolar range, similar to those obtained for ICI 204,219 and ONO 1078, two of the most clinically advanced CysLT receptor antagonists. Thus, these compounds might be useful drugs for the therapy of asthma and other allergic diseases.     

Sexual Harassment Under Social Identity Threat: The Computer Harassment Paradigm.

Two laboratory experiments investigated the hypothesis that threat to male identity would increase the likelihood of gender harassment. In both experiments, using the computer harassment paradigm, male university students (N=80 in Experiment 1, N=90 in Experiment 2) were exposed to different types of identity threat (legitimacy threat and threat to group value in Experiment 1 and distinctiveness threat and prototypicality threat in Experiment 2) or to no threat and were then given the opportunity to send pornographic material to a virtual female interaction partner. Results show that (a) participants harassed the female interaction partner more when they were exposed to a legitimacy, distinctiveness, or prototypicality threat than to no threat; (b) this was mainly true for highly identified males; and (c) harassment enhanced postexperimental gender identification. Results are interpreted as supporting a social identity account of gender harassment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Heterogeneous platelet-activating factor (PAF) receptors and calcium increase in platelets and macrophages

We used the increase in cytosolic Ca2+ levels, [Ca2+]i, as a way to characterize PAF (platelet-activating factor, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) receptors in human platelets and rat and human macrophages. [Ca2+] was measured by means of the fluorescent probe fura-2/acetoxymethylester. PAF recognized heterogeneous receptors in human macrophages only (curve slope <1). The PAF antagonist SCH 37370 (1-acetyl-4(8-chloro-5,6-dihydro-11H-benzo[5.6]cyclohepta[1,2-b]pyridine -11-ylidine)piperidine) abolished [Ca2+]i elevation in human platelets, while in rat and human macrophages the maximal inhibition was 76% and 85%, respectively. On the contrary, the antagonist WEB 2086 (3-[4-(2-chlorophenyl)-9-methyl-6Hthieno[3,2-f] [1,2,4]triazolo-[4,3-a] [1,4]-diazepin-2-yl]-1-(4-morpholiny)-1-propanon, apafant) totally inhibited the effect of PAF in both platelets and macrophages. The WEB 2086 concentration-response curves had a slope <1 in the three cell types, indicating interaction with heterogeneous receptors. Accordingly, 3H-WEB 2086 bound to two different classes of sites. Both phases of [Ca2+]i elevation (influx or release) were equally affected by the antagonists. These data support the notions that: 1) PAF receptors are heterogeneous; 2) the two antagonists have a different selectivity toward the receptor subtypes: WEB 2086 recognizes two different receptors both in platelets and in macrophages, while SCH 37370 does not discriminate between receptor subtypes in platelets, and only interacts with one subtype in macrophages; and 3) both SCH 37370 and WEB 2086 display different potencies in rat and human macrophages.     

Basic investigation of the chemical deactivation of V2O5/WO3-TiO2 SCR catalysts by potassium,calcium, and phosphate

Topics in Catalysis - The influence of the combustion products of different lubrication oil additives and impurities in fuel or urea solution on the activity and selectivity of V2O5/WO3-TiO2...     

Erratum to: Anionic liposomes for small interfering ribonucleic acid (siRNA) delivery to primary neuronal cells: Evaluation of alpha-synuclein knockdown efficacy

Nano Research - The name of the fourth author in the original version of this article was unfortunately wrongly written on the first page. Instead of Caitriona M. O’iscoll It should read...     

A heuristic approach to batching and scheduling a single machine to minimize setup costs

In this paper we consider the problem of creating batches of parts, to be processed in a flexible manufacturing cell, and scheduling their operations. We consider the case in which the system consists of one machine and at most k parts may be present in the system at the same time. Given that each part requires a sequence of operations, and each operation requires a given tool, the objective is to minimize the total number of setups. We develop a heuristic algorithm for its solution and we present an extensive computational experience.