Object Oriented Tool for Modelling, Simulation and Production Planning in Petrochemical Industries

http://www.cs.hut.fi/~framling/Publications/RPO93.pdfInternational audienceThe subject of this work is to study the use of object oriented models of petrochemical plants in order to si mplify simulation and production planning. A prototype system for an existing plant was developed to achieve this goal. The prototype system was made using the object oriented programming language Smalltalk/V. The system is generic and allows creating graphical simulation models for most kinds of petrochemical plants main ly as a simple drawing operation. The models can be used for simulating production plans as well as for generating them automatically. The results obtained prove that object ori ented methods allow the creation of very flexible models. These models are shown to facilitate simulation and automatic scheduling, when used together with artificial intelligence methods

Lymph node tissue kallikrein-related peptidase 6 mRNA: a progression marker for colorectal cancer

BACKGROUND: A most important characteristic feature for poor prognosis in colorectal cancer (CRC) is the presence of lymph node metastasis. Determination of carcinoembryonic antigen (CEA) mRNA levels in lymph nodes has proven powerful for quantification of disseminated tumour cells. Here, we investigate the utility of human tissue kallikrein-related peptidase 6 (KLK6) mRNA as a progression biomarker to complement CEA mRNA, for improved selection of patients in need of adjuvant therapy and intensified follow-up after surgery. METHODS: Lymph nodes of pTNM stage I-IV CRC-(166 patients/503 lymph nodes) and control (23/108) patients were collected at surgery and analysed by quantitative RT-PCR. RESULTS: Lymph node KLK6 positivity was an indicator of poor outcome (hazard ratio 3.7). Risk of recurrence and cancer death increased with KLK6 lymph node levels. Patients with KLK6 lymph node levels above the 90th percentile had a hazard ratio of 6.5 and 76 months shorter average survival time compared to patients with KLK6 negative nodes. The KLK6 positivity in lymph nodes with few tumour cells, that is, low CEA mRNA levels, also indicated poor prognosis (hazard ratio 2.8). CONCLUSION: In CRC patients, lymph node KLK6 positivity indicated presence of aggressive tumour cells associated with poor prognosis and high risk of tumour recurrence. British Journal of Cancer (2012) 107, 150-157. doi: 10.1038/bjc.2012.220 www.bjcancer.com Published online 14 June 2012 (C) 2012 Cancer Research U

Predictive markers for humoral influenza vaccine response in patients with common variable immunodeficiency (CVID)

BACKGROUND: A subgroup of patients with common variable immunodeficiencies (CVID) responds to vaccination. The aim of the study was to try to identify predictive markers for those who developed a humoral immune response after influenza vaccination. METHODS: 48 patients with CVID (29 females, 19 males, mean age 59.4 years) were vaccinated with the A(H1N1) influenza vaccine Pandemrix® and boosted after one month. Blood samples were collected prior to each vaccination and two months later. Patients with a 4-fold titer increase of the hemagglutinin inhibition test (≥ 1:40) were considered responders and compared to non-responders for clinical, immunological and genetic markers. RESULTS: Eight (16.7%) patients responded to the vaccination. A significantly higher proportion of the responders, who showed a Euroclass SmB-Trnorm21norm profile (p=0.03) with a post-germinal center B cell pattern (p=0.04) in blood, suffered from enteropathies (p=0.04) as compared to non-responders. Bronchiectasis on the other hand, was exclusively found among non-responders (n=7), as was autoimmune cytopenia (n=5). Non-responders with a Euroclass SmB-21lowTrnorm profile (p=0.02), had a significantly higher prevalence of progressive antibody deficiency (p=0.048) and, at diagnosis, a higher mean serum IgM level (p=0.03), a lower mean serum IgG1 level (p=0.007), an expansion of absolute counts of cytotoxic CD8+ T-cells (p=0.033) and an increased proportion of memory CD8+ T-cells (p=0.044) in blood. CVID associated HLA markers were not detected in non-responders (p=0.03). CONCLUSION: About one-fifth of the CVID patients achieved protective antibody levels after A(H1N1) vaccination and selected clinical and immunological markers were identified that may predict a positive outcome of influenza vaccination

Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation

13 pages, 3 figures, 4 tables.-- et al.Class switch recombination (CSR) and somatic hypermutation (SHM) are mechanistically related processes initiated by activation-induced cytidine deaminase. Here, we have studied the role of ataxia telangiectasia and Rad3-related protein (ATR) in CSR by analyzing the recombinational junctions, resulting from in vivo switching, in cells from patients with mutations in the ATR gene. The proportion of cells that have switched to immunoglobulin (Ig)A and IgG in the peripheral blood seems to be normal in ATR-deficient (ATRD) patients and the recombined S regions show a normal “blunt end-joining,” but impaired end joining with partially complementary (1–3 bp) DNA ends. There was also an increased usage of microhomology at the μ-α switch junctions, but only up to 9 bp, suggesting that the end-joining pathway requiring longer microhomologies (≥10 bp) may be ATR dependent. The SHM pattern in the Ig variable heavy chain genes is altered, with fewer mutations occurring at A and more mutations at T residues and thus a loss of strand bias in targeting A/T pairs within certain hotspots. These data suggest that the role of ATR is partially overlapping with that of ataxia telangiectasia–mutated protein, but that the former is also endowed with unique functional properties in the repair processes during CSR and SHM.This work was supported by the Swedish Research Council, the Swedish Society for Medical Research (SSMF), and the Swedish Doctors Association.Peer reviewe

Newborn screening for primary immunodeficiency diseases: the past, the present and the future

Primary immunodeficiency diseases (PID) are a heterogeneous group of disorders caused by inborn errors of immunity, with affected children presenting with severe, recurrent or unusual infections. Over 300 distinct genetic molecular abnormalities resulting in PID have been identified, and this number continues to rise. Newborn screening for PID has been established in many countries, with the majority of centers using a PCR-based T cell receptor excision circle (TREC) assay to screen for severe combined immunodeficiency (SCID) and other forms of T cell lymphopenia. Multiplexed screening including quantitation of kappa-recombining exclusion circles (KREC) has also been described, offering advantages over TREC screening alone. Screening technologies are also expanding to include protein-based assays to identify complement deficiencies and granulocyte disorders. Given the rapid advances in genomic medicine, a potential future direction is the application of next-generation sequencing (NGS) technologies to screen infants for a panel of genetic mutations, which would enable identification of a wide range of diseases. However, several ethical and economic issues must be considered before moving towards this screening strategy.Jovanka King, Jonas F. Ludvigsson and Lennart Hammarströ

Biomarker selection for detection of occult tumour cells in lymph nodes of colorectal cancer patients using real-time quantitative RT–PCR

Accurate identification of lymph node involvement is critical for successful treatment of patients with colorectal carcinoma (CRC). Real-time quantitative RT–PCR with a specific probe and RNA copy standard for biomarker mRNA has proven very powerful for detection of disseminated tumour cells. Which properties of biomarker mRNAs are important for identification of disseminated CRC cells? Seven biomarker candidates, CEA, CEACAM1-S/L, CEACAM6, CEACAM7-1/2, MUC2, MMP7 and CK20, were compared in a test-set of lymph nodes from 51 CRC patients (Dukes' A–D) and 10 controls. Normal colon epithelial cells, primary tumours, and different immune cells were also analysed. The biomarkers were ranked according to: (1) detection of haematoxylin/eosin positive nodes, (2) detection of Dukes' A and B patients, who developed metastases during a 54 months follow-up period and (3) identification of patients with Dukes' C and D tumours using the highest value of control nodes as cutoff. The following properties appear to be of importance; (a) no expression in immune cells, (b) relatively high and constant expression in tumour tissue irrespective of Dukes' stage and (c) no or weak downregulation in tumours compared to normal tissue. CEA fulfilled these criteria best, followed by CK20 and MUC2

Structure of HI-6•Sarin-Acetylcholinesterase Determined by X-Ray Crystallography and Molecular Dynamics Simulation: Reactivator Mechanism and Design

Organophosphonates such as isopropyl metylphosphonofluoridate (sarin) are extremely toxic as they phosphonylate the catalytic serine residue of acetylcholinesterase (AChE), an enzyme essential to humans and other species. Design of effective AChE reactivators as antidotes to various organophosphonates requires information on how the reactivators interact with the phosphonylated AChEs. However, such information has not been available hitherto because of three main challenges. First, reactivators are generally flexible in order to change from the ground state to the transition state for reactivation; this flexibility discourages determination of crystal structures of AChE in complex with effective reactivators that are intrinsically disordered. Second, reactivation occurs upon binding of a reactivator to the phosphonylated AChE. Third, the phosphorous conjugate can develop resistance to reactivation. We have identified crystallographic conditions that led to the determination of a crystal structure of the sarinnonaged-conjugated mouse AChE in complex with [(E)-[1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl]-oxoazanium dichloride (HI-6) at a resolution of 2.2 Å. In this structure, the carboxyamino-pyridinium ring of HI-6 is sandwiched by Tyr124 and Trp286, however, the oxime-pyridinium ring is disordered. By combining crystallography with microsecond molecular dynamics simulation, we determined the oxime-pyridinium ring structure, which shows that the oxime group of HI-6 can form a hydrogen-bond network to the sarin isopropyl ether oxygen, and a water molecule is able to form a hydrogen bond to the catalytic histidine residue and subsequently deprotonates the oxime for reactivation. These results offer insights into the reactivation mechanism of HI-6 and design of better reactivators

Inequalities of quality of life in unemployed young adults: A population-based questionnaire study

BACKGROUND: It is well known that unemployment is a great problem both to the exposed individual and to the whole society. Unemployment is reported as more common among young people compared to the general level of unemployment. Inequity in health status and life-satisfaction is related to unemployment. The purpose of this population-based study was to describe QOL among unemployed young people compared to those who are not unemployed, and to analyse variables related to QOL for the respective groups. METHODS: The sample consisted of 264 young unemployed individuals and 528 working or studying individuals as a reference group. They all received a questionnaire about civil status, educational level, immigration, employment status, self-reported health, self-esteem, social support, social network, spare time, dwelling, economy and personal characteristics. The response rate was 72%. The significance of differences between proportions was tested by Fisher's exact test or by χ(2 )test. Multivariate analysis was carried out by means of a logistic regression model. RESULTS: Our results balance the predominant picture of youth unemployment as a principally negative experience. Although the unemployed reported lower levels of QOL than the reference group, a majority of unemployed young adults reported good QOL, and 24% even experienced higher QOL after being unemployed. Positive QOL related not only to good health, but also to high self-esteem, satisfaction with spare time and broad latitude for decision-making. CONCLUSION: Even if QOL is good among a majority of unemployed young adults, inequalities in QOL were demonstrated. To create more equity in health, individuals who report reduced subjective health, especially anxiety need extra attention and support. Efforts should aim at empowering unemployed young adults by identifying their concerns and resources, and by creating individual programmes in relation not only to education and work, but also to personal development