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Control Analysis (control + analysis)
Kinds of Control Analysis Selected AbstractsMetabolic Control Analysis of Monoclonal Antibody SynthesisBIOTECHNOLOGY PROGRESS, Issue 2 2001Ramon Gonzalez A general route for protein synthesis in eukaryotic cells has been proposed and applied to monoclonal antibody (MAb) synthesis. It takes into account transcription of the gene, binding of ribosomes to mRNA, and polypeptide elongation including binding to SRP (signal recognition particles) and SRP-receptor, competing translocation, folding and glycosylation, assembly of the heavy and light chains in a tetrameric protein and Golgi processing and secretion. A comprehensive model was built on the basis of the proposed pathway. The model takes into account the mechanism of each step. Metabolic control analysis (MCA) principles were applied to the general pathway using the proposed model, and control coefficients were calculated. The results show a shared flux control (of both pathway flux and flux ratio at the branch) among different steps, i.e., transcription, folding, glycosylation, translocation and building blocks synthesis. The steps sharing the control depend on the concentration of building blocks, pathway flux and levels of OST (oligosacharyl transferase), BiP (heavy chain binding protein) and PDI (protein disulfide isomerase). Model predictions compare well with experimental data for MAb synthesis, explaining the control structure of the route and the heterogeneity of the product and also addressing future targets for improvement of the production rate of MAbs. [source] A new evaluation technique for the detection of impurities in purified proteins via CE with native UV-LIFELECTROPHORESIS, Issue 2 2010Audrey Rodat Abstract An analytical methodology for quality control analyses of IgG and their impurities is presented using a new UV-LIF (266,nm) detector inside the cassette of a CE instrument and its performance was evaluated. The observed sensitivity was very close to that obtained by silver staining of slab gels (LOD of 25,ng/mL), while the sensitivity of the analysis is 80 times better than with CE/UV absorption (214,nm). Examples of the analysis of pharmaceutical and other commercial IgGs are provided and the kinetics of the reduction of IgG by ,-mercaptoethanol is reported, demonstrating the ease of performing the analysis. [source] Epidemiologic evaluation of pharmaceuticals with limited evidence of carcinogenicityINTERNATIONAL JOURNAL OF CANCER, Issue 9 2009Gary D. Friedman Abstract Thorough review by the International Agency for Research on Cancer (IARC) has resulted in classifying many substances, including pharmaceuticals, as probably or possibly carcinogenic to humans, based on experiments on animals or limited data on humans. We evaluated 9 such pharmaceuticals for evidence of carcinogenicity in patients receiving them in a large medical care program with automated pharmacy records and a cancer registry. Nested case,control analyses were performed in a cohort of 6.5 million subscribers with up to 12 years of follow-up, focusing on cancer sites suggested by previous evidence and other sites with odds ratio of at least 1.50, p < 0.01 and some evidence of dose,response. Unmeasured confounding was estimated in sensitivity analyses. We found some supportive evidence for carcinogenicity of griseofulvin, metronidazole and phenytoin and for the known carcinogen, cyclophosphamide, which was added for validation of our data and analyses. Findings for chloramphenicol, iron-dextran complex, phenoxybenzamine and phenobarbital were essentially non-contributory. Confounding by cigarette smoking and prior thyroid disease could account, respectively, for associations of oxazepam with lung cancer and propylthiouracil with thyroid cancer. Although not definitive, these findings should be considered in the evaluations of these pharmaceuticals. © 2009 UICC [source] Co-twin control and cohort analyses of body mass index and height in relation to breast, prostate, ovarian, corpus uteri, colon and rectal cancer among Swedish and Finnish twinsINTERNATIONAL JOURNAL OF CANCER, Issue 4 2007Ellen Lundqvist Abstract Associations between anthropometric measures and cancer have been studied previously, but relatively few studies have had the opportunity to control for genetic and early shared environmental factors. In this study, we analyzed 2 twin cohorts from Sweden born 1886,1925 (n = 21,870) and 1926,1958 (n = 30,279) and 1 from Finland born 1880,1958 (n = 25,882) including in total 78,031 twins, and studied the association between BMI and height and risk of prostate, breast, ovarian, corpus uteri, colon and rectal cancer. The cohorts were both analyzed through a co-twin control method and as traditional cohorts. In co-twin control analyses, older obese (BMI , 30 kg/m2) subjects (median age 56 years at baseline) were at higher risk of cancer of the corpus uteri (OR = 3.0; 95% CI 0.9,10.6), colon (OR = 1.9; 95% CI 0.8,4.5) and breast (OR = 2.5; 95% CI 1.3,4.2). For younger obese women (median age 30 years at baseline), an inverse tendency was observed for breast cancer (OR = 0.6; 95% CI 0.3,1.5, p for trend = 0.05). The tallest women had an increased risk of breast (OR = 1.8; 95% CI 1.3,2.7) and ovarian cancer (OR = 1.7; 95% CI 0.8,3.5). No consistent associations were found for prostate cancer either for BMI or height. There are some suggestions in our study that uncontrolled genetic or early shared environmental factors may affect risk estimates in studies of anthropometric measures and cancer risk, but do not explain observations of increased cancer risks related to BMI or height. © 2007 Wiley-Liss, Inc. [source] A rapid screening LC-MS/MS method based on conventional HPLC pumps for the analysis of low molecular weight xenobiotics: application to doping control analysisDRUG TESTING AND ANALYSIS, Issue 7 2010Monica Mazzarino Abstract This study presents a fast multi-analyte screening method specifically developed for the detection of xenobiotics in urine. The proposed method allows the screening of several classes of substance in a single chromatographic method with a run-time of 11 min, inclusive of post-run and reconditioning times. Chromatographic separation is achieved in 7.2 min using a reversed-phase 2.7 µm fused-core particle column, generating a back-pressure not exceeding 400 bar and therefore enabling the use of traditional high performance liquid chromatography (HPLC) instruments. The effectiveness of this approach was evaluated, by liquid-chromatography tandem mass spectrometry (LC-MS/MS) in positive electrospray ionization, using 20 blank urine samples spiked with 45 compounds prohibited in sport: 11 diuretics, 16 glucocorticoids, 9 stimulants, 5 anti-oestrogens, as well as formoterol, carboxy-finasteride (previously prohibited by the World Anti-Doping Agency (WADA) in 2008), gestrinone and tetrahydrogestrinone. Qualitative validation shows the proposed method to be specific with no significant interference. All of the analytes considered in this study were clearly distinguishable in urine, with limits of detection ranging from 5 ng/mL to 350 ng/mL, significantly below the Minimum Required Performance Levels (MRPL) set by WADA for the accredited sports anti-doping laboratories. All compounds of interest were separated, including synthetic and endogenous glucocorticoids with similar retention times and fragmentation patterns. Copyright © 2010 John Wiley & Sons, Ltd. [source] Screening for the calstabin-ryanodine receptor complex stabilizers JTV-519 and S-107 in doping control analysisDRUG TESTING AND ANALYSIS, Issue 1 2009Mario Thevis Abstract Recent studies outlined the influence of exercise on the stability of the skeletal muscle calstabin1-ryanodine receptor1-complex, which represents a major Ca2+ release channel. The progressive modification of the type-1 skeletal muscle ryanodine receptor (RyR1) combined with reduced levels of calstabin1 and phosphodiesterase PDE4D3 resulted in a Ca2+ leak that has been a suggested cause of muscle damage and impaired exercise capacity. The use of 1,4-benzothiazepine derivatives such as the drug candidates JTV-519 and S-107 enhanced rebinding of calstabin1 to RyR1 and resulted in significantly improved skeletal muscle function and exercise performance in rodents. Due to the fact that the mechanism of RyR1 remodelling under exercise conditions were proven to be similar in mice and humans, a comparable effect of JTV-519 and S-107 on trained athletes is expected, making the compounds relevant for doping controls. After synthesis of JTV-519, S-107, and a putative desmethylated metabolite of S-107, target compounds were characterized using nuclear magnetic resonance spectroscopy and electrospray ionization (ESI),high-resolution/high-accuracy Orbitrap mass spectrometry. Collision-induced dissociation pathways were suggested based on the determination of elemental compositions of product ions and H/D-exchange experiments. The most diagnostic product ion of JTV-519 was found at m/z 188 (representing the 4-benzyl-1-methyl piperidine residue), and S-107 as well as its desmethylated analog yielded characteristic fragments at m/z 153 and 138 (accounting for 1-methoxy-4-methylsulfanyl-benzene and 4-methoxy-benzenethiol residues, respectively). The analytes were implemented in existing doping control screening procedures based on liquid chromatography, multiple reaction monitoring and simultaneous precursor ion scanning modes using a triple quadrupole mass spectrometer. Validation items such as specificity, recovery (68,92%), lower limit of detection (0.1,0.2 ng/mL), intraday (5.2,18.5%) and interday (8.7,18.8%) precision as well as ion suppression/enhancement effects were determined. Copyright © 2009 John Wiley & Sons, Ltd. [source] Probabilistic seismic demand analysis of controlled steel moment-resisting frame structuresEARTHQUAKE ENGINEERING AND STRUCTURAL DYNAMICS, Issue 12 2002Luciana R. Barroso Abstract This paper describes a proposed methodology, referred to as probabilistic seismic control analysis, for the development of probabilistic seismic demand curves for structures with supplemental control devices. The resulting curves may be used to determine the probability that any response measure, whether for a structure or control device, exceeds a pre-determined allowable limit. This procedure couples conventional probabilistic seismic hazard analysis with non-linear dynamic structural analyses to provide system specific information. This method is performed by evaluating the performance of specific controlled systems under seismic excitations using the SAC Phase II structures for the Los Angeles region, and three different control-systems: (i) base isolation; (ii) linear viscous brace dampers; and (iii) active tendon braces. The use of a probabilistic format allows for consideration of structural response over a range of seismic hazards. The resulting annual hazard curves provide a basis for comparison between the different control strategies. Results for these curves indicate that no single control strategy is the most effective at all hazard levels. For example, at low return periods the viscous system has the lowest drift demands. However, at higher return periods, the isolation system becomes the most effective strategy. Copyright © 2002 John Wiley & Sons, Ltd. [source] Ecological control analysis: being(s) in control of mass flux and metabolite concentrations in anaerobic degradation processesENVIRONMENTAL MICROBIOLOGY, Issue 2 2007Wilfred F. M. Röling Summary Identification of the functional groups of microorganisms that are predominantly in control of fluxes through, and concentrations in, microbial networks would benefit microbial ecology and environmental biotechnology: the properties of those controlling microorganisms could be studied or monitored specifically or their activity could be modulated in attempts to manipulate the behaviour of such networks. Herein we present ecological control analysis (ECA) as a versatile mathematical framework that allows for the quantification of the control of each functional group in a microbial network on its process rates and concentrations of intermediates. In contrast to current views, we show that rates of flow of matter are not always limited by a single functional group; rather flux control can be distributed over several groups. Also, control over intermediate concentrations is always shared. Because of indirect interactions, through other functional groups, the concentration of an intermediate can also be controlled by functional groups not producing or consuming it. Ecological control analysis is illustrated by a case study on the anaerobic degradation of organic matter, using experimental data obtained from the literature. During anaerobic degradation, fermenting microorganisms interact with terminal electron-accepting microorganisms (e.g. halorespirers, methanogens). The analysis indicates that flux control mainly resides with fermenting microorganisms, but can shift to the terminal electron-accepting microorganisms under less favourable redox conditions. Paradoxically, halorespiring microorganisms do not control the rate of perchloroethylene and trichloroethylene degradation even though they catalyse those processes themselves. [source] Experimental validation of metabolic pathway modelingFEBS JOURNAL, Issue 13 2008An illustration with glycolytic segments from Entamoeba histolytica In the search for new drug targets in the human parasite Entamoeba histolytica, metabolic control analysis was applied to determine, experimentally, flux control distribution of amebal glycolysis. The first (hexokinase, hexose-6-phosphate isomerase, pyrophosphate-dependent phosphofructokinase (PPi -PFK), aldolase and triose-phosphate isomerase) and final (3-phosphoglycerate mutase, enolase and pyruvate phosphate dikinase) glycolytic segments were reconstituted in vitro with recombinant enzymes under near-physiological conditions of pH, temperature and enzyme proportion. Flux control was determined by titrating flux with each enzyme component. In parallel, both glycolytic segments were also modeled by using the rate equations and kinetic parameters previously determined. Because the flux control distribution predicted by modeling and that determined by reconstitution were not similar, kinetic interactions among all the reconstituted components were experimentally revised to unravel the causes of the discrepancy. For the final segment, it was found that 3-phosphoglycerate was a weakly competitive inhibitor of enolase, whereas PPi was a moderate inhibitor of 3-phosphoglycerate mutase and enolase. For the first segment, PPi was both a strong inhibitor of aldolase and a nonessential mixed-type activator of amebal hexokinase; in addition, lower Vmax values for hexose-6-phosphate isomerase, PPi -PFK and aldolase were induced by PPi or ATP inhibition. It should be noted that PPi and other metabolites were absent from the 3-phosphoglycerate mutase and enolase or aldolase and hexokinase kinetics experiments, but present in reconstitution experiments. Only by incorporating these modifications in the rate equations, modeling predicted values of flux control distribution, flux rate and metabolite concentrations similar to those experimentally determined. The experimentally validated segment models allowed ,in silico experimentation' to be carried out, which is not easy to achieve in in vivo or in vitro systems. The results predicted a nonsignificant effect on flux rate and flux control distribution by adding parallel routes (pyruvate kinase for the final segment and ATP-dependent PFK for the first segment), because of the much lower activity of these enzymes in the ameba. Furthermore, modeling predicted full flux-control by 3-phosphoglycerate mutase and hexokinase, in the presence of low physiological substrate and product concentrations. It is concluded that the combination of in vitro pathway reconstitution with modeling and enzyme kinetics experimentation permits a more comprehensive understanding of the pathway behavior and control properties. [source] Expression of the pyrG gene determines the pool sizes of CTP and dCTP in Lactococcus lactisFEBS JOURNAL, Issue 12 2004Casper M. Jørgensen The pyrG gene from Lactococcus lactis encodes CTP synthase (EC 6.4.3.2), an enzyme converting UTP to CTP. A series of strains were constructed with different levels of pyrG expression by insertion of synthetic constitutive promoters with different strengths in front of pyrG. These strains expressed pyrG levels in a range from 3 to 665% relative to the wild-type expression level. Decreasing the level of CTP synthase to 43% had no effect on the growth rate, showing that the capacity of CTP synthase in the cell is in excess in a wild-type strain. We then studied how pyrG expression affected the intracellular pool sizes of nucleotides and the correlation between pyrG expression and nucleotide pool sizes was quantified using metabolic control analysis in terms of inherent control coefficients. At the wild-type expression level, CTP synthase had full control of the CTP concentration with a concentration control coefficient close to one and a negative concentration control coefficient of ,0.28 for the UTP concentration. Additionally, a concentration control coefficient of 0.49 was calculated for the dCTP concentration. Implications for the homeostasis of nucleotide pools are discussed. [source] The effect of thiamine supplementation on tumour proliferationFEBS JOURNAL, Issue 15 2001A metabolic control analysis study Thiamine deficiency frequently occurs in patients with advanced cancer and therefore thiamine supplementation is used as nutritional support. Thiamine (vitamin B1) is metabolized to thiamine pyrophosphate, the cofactor of transketolase, which is involved in ribose synthesis, necessary for cell replication. Thus, it is important to determine whether the benefits of thiamine supplementation outweigh the risks of tumor proliferation. Using oxythiamine (an irreversible inhibitor of transketolase) and metabolic control analysis (MCA) methods, we measured an in vivo tumour growth control coefficient of 0.9 for the thiamine-transketolase complex in mice with Ehrlich's ascites tumour. Thus, transketolase enzyme and thiamine clearly determine cell proliferation in the Ehrlich's ascites tumour model. This high control coefficient allows us to predict that in advanced tumours, which are commonly thiamine deficient, supplementation of thiamine could significantly increase tumour growth through transketolase activation. The effect of thiamine supplementation on tumour proliferation was demonstrated by in vivo experiments in mice with the ascites tumour. Thiamine supplementation in doses between 12.5 and 250 times the recommended dietary allowance (RDA) for mice were administered starting on day four of tumour inoculation. We observed a high stimulatory effect on tumour growth of 164% compared to controls at a thiamine dose of 25 times the RDA. This growth stimulatory effect was predicted on the basis of correction of the pre-existing level of thiamine deficiency (42%), as assayed by the cofactor/enzyme ratio. Interestingly, at very high overdoses of thiamine, ,,2500 times the RDA, thiamine supplementation had the opposite effect and caused 10% inhibition of tumour growth. This effect was heightened, resulting in a 36% decrease, when thiamine supplementation was administered from the 7th day prior to tumour inoculation. Our results show that thiamine supplementation sufficient to correct existing thiamine deficiency stimulates tumour proliferation as predicted by MCA. The tumour inhibitory effect at high doses of thiamine is unexplained and merits further study. [source] A variant of the Cockayne syndrome B gene ERCC6 confers risk of lung cancer,,HUMAN MUTATION, Issue 1 2008Zhongning Lin Abstract Cockayne syndrome B protein (ERCC6) plays an essential role in DNA repair. However, the Cockayne syndrome caused by the ERCC6 defect has not been linked to cancer predisposition; likely due to the fact that cells with severe disruption of the ERCC6 function are sensitive to lesion-induced apoptosis, thus reducing the chance of tumorigenesis. The biological function and cancer susceptibility of a common variant rs3793784:C>G (c.,6530C>G) in the ERCC6 was examined. We show that the c.,6530C allele has lower binding affinity of Sp1 by EMSA and displays a lower transcriptional activity in vitro and in vivo. We then examined the contribution of this polymorphism to the risk of lung cancer in a case,control study with 1,000 cases and 1,000 controls. The case,control analysis revealed a 1.76-fold (P= × 10,9) excess risk of developing lung cancer for the c.,6530CC carriers compared with noncarriers. The c.,6530CC interacts with smoking to intensify lung cancer risk, with the odds ratio (OR)=9 for developing lung cancer among heavy smokers. Our data constituted strong evidence that ERCC6 rs3793784:C>G alters its transcriptional activity and may confer personalized susceptibility to lung cancer. Hum Mutat 29(1), 113,122, 2008. Published 2007, Wiley-Liss, Inc. [source] A population- and family-based study of Canadian families reveals association of HLA DRB1*0103 with colonic involvement in inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 1 2003Dr. Mark S. Silverberg Abstract The aim of this study was to identify major histocompatibility complex alleles associated with the development and clinical features of inflammatory bowel disease (IBD). Genotyping at the human leukocyte antigen (HLA) DRB1 and DQB1 loci was performed on individuals from 118 Caucasian IBD sibling pair families and on 216 healthy controls. Both population- and family-based association tests were used to analyze data obtained on the entire study population and on clinical subgroups stratified by diagnosis, ethnicity, and disease distribution. HLA DRB1*0103 was significantly associated with IBD (OR = 6.0, p = 0.0001) in a case,control analysis of non-Jewish IBD-affected individuals. This association was apparent among both Crohn's disease (OR = 5.23, p = 0.0007) and ulcerative colitis (OR = 7.9, p = 0.0001) patients and was confirmed in the non-Jewish IBD population by results of family-based association analysis using the transmission disequilibrium test. HLA DQB1*0501 was also associated with IBD (OR = 1.64, p = 0.02) in the non-Jewish population, but statistically significant association of this allele with disease was not detected for Crohn's disease and ulcerative colitis separately. No significant associations were identified among the Jewish patients. In the non-Jewish IBD families, IBD was as strongly associated with the DRB1*0103 DQB1*0501 haplotype as with the DRB1*0103 allele alone. The carrier frequency of the DRB1*0103 allele was found to be 10-fold higher in Crohn's disease patients with pure colonic involvement than in healthy controls (38.5% vs. 3.2%; p = 0.0002). These data demonstrate the association of the HLA DRB1*0103 allele with both Crohn's disease and ulcerative colitis and with large intestine,restricted disease in non-Jewish IBD patients and therefore identify HLA DRB1*0103 as a potentially important contributor to disease susceptibility and to expression of colonic involvement in IBD. [source] A control analysis of interaction problem by fluid forceINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING, Issue 7 2001Shoichiro Kato Abstract This paper presents a control analysis of displacement for a building. To control the vertical displacement of the building, control device of multi-balloons with water inside is introduced on the friction piles. Coupling through the water, soil, balloon and pile, the interaction problem is numerically solved. The soil is assumed to be a linear elastic body. The balloon and pile are also modelled as linear elastic truss and rigid-frame components. The water is assumed to be the two-dimensional incompressible Navier,Stokes flow. All components are discretized by the finite element method in space. The control analysis of vertical displacement by fluid force is performed for the purpose of keeping the building horizontal. One of the optimal control theory, the so-called Sakawa,Shindo method, is applied for the control analysis. Using this method, control flux of the water is determined so that position at the top of the balloon comes to be close to the objective position. Copyright © 2001 John Wiley & Sons, Ltd. [source] Analysis of candidate genes on chromosome 19 in coeliac disease: an association study of the KIR and LILR gene clustersINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 4 2002S. J. Moodie Summary Coeliac disease is strongly heritable, with more than half of the genetic susceptibility estimated to come from genes outside the HLA region. Several candidate regions have been suggested from genome-wide linkage studies including chromosome 19q13.4 where linkage has been replicated between populations. The natural killer (NK) cell immunoglobulin-like receptors (KIRs) and leukocyte immunoglobulin-like receptor (LILR, also known as ILT and LIR) gene clusters lie within this region in the leukocyte receptor cluster (LRC). KIR molecules are involved in cytotoxic lymphocyte function and expressed by intraepithelial T and NK cells in the duodenum. We studied 132 unrelated UK Caucasian coeliac patients and their parents together with a control group of 171 UK Caucasians. PCR-SSP for KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5, LILRA3 (ILT6), LILRA3 deletion and an LILRA3 exon 3 single nucleotide polymorphism (SNP) allowed classification of KIR genotypes into five categories and determination of homozygosity or heterozygosity for the common A and B type KIR haplotypes (as defined in the text) and for the LILRA3 deletion. Case,control analysis found no association of the five KIR genotype categories, the A or B KIR haplotypes, the LILRA3 gene deletion or the LILRA3 exon 3 SNP with coeliac disease. A transmission disequilibrium test also found no association of the A and B KIR haplotypes or the LILRA3 gene deletion with coeliac disease. [source] Emerging drugs: mechanism of action, mass spectrometry and doping control analysisJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 4 2009Mario Thevis Abstract The number of compounds and doping methods in sports is in a state of constant flux. In addition to ,traditional' doping agents, such as anabolic androgenic steroids or erythropoietin, new therapeutics and emerging drugs have considerable potential for misuse in elite sport. Such compounds are commonly based on new chemical structures, and the mechanisms underlying their modes of action represent new therapeutic approaches arising from recent advances in medical research; therefore, sports drug testing procedures need to be continuously modified and complementary methods developed, preferably based on mass spectrometry, to enable comprehensive doping controls. This tutorial not only discusses emerging drugs that can be categorized as anabolic agents (selective androgen receptor modulators, SARMs), gene doping [hypoxia-inducible factor stabilizers, peroxisome-proliferator-activated receptor (PPAR),-agonists] and erythropoietin-mimetics (Hematide) but also compounds with potentially performance-enhancing properties that are not classified in the current list of the World Anti-Doping Agency. Compounds such as ryanodine-calstabin-complex modulators (benzothiazepines) are included, their mass spectrometric properties discussed, and current approaches in sports drug testing outlined. Copyright © 2009 John Wiley & Sons, Ltd. [source] Two outbreaks of Burkholderia cepacia nosocomial infection in a neonatal intensive care unitJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 1-2 2008Jimmy KF Lee Background: An outbreak of Burkholderia cepacia septicaemia occurred in our neonatal unit over a 9-week period in 2001, affecting 23 babies and two died. A second outbreak lasting 8 days occurred a year later, affecting five babies. Setting: Neonatal Intensive Care Unit, Kuala Terengganu Hospital. Aim: To review the patient characteristics and the risk factors for septicaemia in the first outbreak. Methods: Retrospective review of records and in the first outbreak a case,control analysis with 23 matched controls for risk factors for septicaemia. Results: In the first outbreak, median birthweight was 1670 g (range 860,3760) and median gestational age was 32 weeks (range 27,41). There were 32 episodes of septicaemia, and five and two patients had two and three episodes, respectively. The mortality rate was 6.3% per septicaemic episode. Multiple logistic regression showed the presence of a prior long line was associated with first septicaemic episode (OR 7.07, 95% CI 1.37,36.47 with P = 0.019) but not prior assisted ventilation. The organism was isolated from the water of an oxygen humidifier in the delivery room, three ventilator water traps and one humidifier water trap in the neonatal unit. In the second outbreak, six episodes of septicaemia occurred in five neonates with median birthweight 2060 g and median gestational age 32.5 weeks. The organism was isolated from two ventilator water traps. Conclusion: These two outbreaks of Burkholderia cepacia subsided with general infection control measures. The sources of these two outbreaks were not identified. [source] Is the hepatitis C virus epidemic over in Egypt?LIVER INTERNATIONAL, Issue 4 2010Incidence, risk factors of new hepatitis C virus infections Abstract Objectives: To estimate hepatitis C virus (HCV) incidence rates and identify risk factors for current HCV transmission with emphasis on the role of living with infected household family members in rural Egypt. Methods: A 4-year population-based, cohort study of seronegative villagers was conducted to identify incident HCV seroconversion cases. A risk factor questionnaire and blood samples for anti-HCV EIA-3 and HCV RNA polymerase chain reaction testing were collected at two rounds of follow-up. Incidence rates, relative risks and 95% confidence interval (CI) were calculated based on a Poisson distribution. A matched case,control analysis to explore specific behavioural predictors of infection was conducted and odds ratios were obtained by conditional logistic regression. Results: Twenty-five participants (11 females) seroconverted in 10 578 person years of follow-up (PY), (incidence rate of 2.4/1000 PY; 95% CI: 1.6,3.5). The median age at seroconversion was 26 years [interquartile range (IQR) 19,35] among males and 20 years (IQR 13,24) among females. The only significant risk factor identified for these cases was receiving injections [adjusted odds ratio (ORadj)=3.3; 95% CI: 1.1,9.8]. Two of the 17 viraemic seroconvertors were infected with the same strain as at least one of their family members. Conclusion: This study identified the important role of injections in spreading HCV infection in this rural community. National healthcare awareness and infection control programmes should be strengthened to prevent further transmission. Screening of families of infected HCV subjects should be an essential part of case management for early detection and management. [source] ABO-incompatible deceased donor liver transplantation in the United States: A national registry analysis,LIVER TRANSPLANTATION, Issue 8 2009Zoe A. Stewart In the United States, ABO-incompatible liver transplantation (ILT) is limited to emergent situations when ABO-compatible liver transplantation (CLT) is unavailable. We analyzed the United Network for Organ Sharing database of ILT performed from 1990-2006 to assess ILT outcomes for infant (0-1 years; N = 156), pediatric (2-17 years; N = 170), and adult (> 17 years; N = 667) patients. Since 2000, the number of ILT has decreased annually, and there has been decreased use of blood type B donors and increased use of blood type A donors. Furthermore, ILT graft survival has improved for all age groups in recent years, beyond the improved graft survival attributable to era effect based on comparison to respective age group CLT. On matched control analysis, graft survival was significantly worse for adult ILT as compared to adult CLT. However, infant and pediatric ILTs did not have worse graft survival versus age-matched CLT. Adjusted analyses identified age-specific characteristics impacting ILT graft loss. For infants, transplant after 2000 and donor age < 9 years were associated with reduced risk of ILT graft loss. For pediatric patients, female recipient sex and donor age > 50 years were associated with increased risk of ILT graft loss. For adults, life support, repeat transplant, split grafts, and hepatocellular carcinoma were associated with increased risk of ILT graft loss. The current study identifies important trends in ILT in the United States in the modern immunosuppression era, as well as specific recipient, donor, and graft characteristics impacting ILT graft survival that could be utilized to guide ILT organ allocation in exigent circumstances. Liver Transpl 15:883,893, 2009. © 2009 AASLD. [source] Ascites after liver transplantation,A mysteryLIVER TRANSPLANTATION, Issue 5 2004Charmaine A. Stewart Ascites after liver transplantation, although uncommon, presents a serious clinical dilemma. The hemodynamic changes that support the development of ascites before liver transplantation are resolved after transplant; therefore, persistent ascites (PA) after liver transplantation is unexpected and poorly characterized. The aim of this study was to define the clinical factors associated with PA after liver transplantation. This was a retrospective case,control analysis of patients who underwent liver transplantation at the University of Pennsylvania. PA occurring for more than 3 months after liver transplantation was confirmed by imaging studies. PA was correlated with multiple recipient and donor variables, including etiology of liver disease, preoperative ascites, prior portosystemic shunt (PS), donor age, and cold ischemic (CI) time. There were 2 groups: group 1, cases with PA transplanted from November 1990 to July 2001, and group 2, consecutive, control subjects who underwent liver transplantation between September 1999 and December 2001. Both groups were followed to censoring, May 2002, or death. Twenty-five from group 1 had ascites after liver transplantation after a median follow-up of 2.6 years. In group 1 vs group 2 (n = 106), there was a male predominance 80% vs 61% (P = .10) with similar age 52 years; chronic hepatitis C virus (HCV) was diagnosed in 88% vs 44% (P < .0001); preoperative ascites and ascites refractory to treatment were more prevalent in group 1 (P = .0004 and P =.02, respectively), and CI was higher in group 1, (8.5 hours vs 6.3 hours, P = .002). Eight of the 25 (group 1) had portal hypertension with median portosystemic gradient 16.5 mm Hg (range, 16,24). PS was performed in 7 of 25 cases, which resulted in partial resolution of ascites. The development of PA after liver transplantation is multifactorial; HCV, refractory ascites before liver transplantation, and prolonged CI contribute to PA after liver transplantation. (Liver Transpl 2004;10:654,660.) [source] (203) Manufacturing Process for a Highly Purified, Stable Liquid Formulation of Botulinum Toxin Type B (MyoblocÔ)PAIN MEDICINE, Issue 3 2001Andrew Grethlein Botulinum toxin type B (BoNT-B; MyoblocÔ) is a new botulinum toxin with demonstrated efficacy in patients with cervical dystonia, and has been found to decrease neck pain associated with this disorder. Developmental work has led to the commercial-scale production of a uniform, highly purified toxin complex in a liquid formulation. Production of BoNT-B involves fermentation, recovery and purification from Clostridium botulinum. The reliability and robustness of the process were tested by altering critical process parameters (eg, pH, temperature) and showing that a high-quality product resulted even in conditions detrimental to C botulinum fermentation. Consistency and key quality attributes (purity, complex integrity, percent nicking, specific activity) of the toxin were assessed using a series of biochemical tests, which were validated as precise and accurate and are now routinely used in quality control analysis. Results confirmed production of an intact, uniform toxin complex with consistent purity, percentage nicking (a measure of toxin activation) of over 70%, and specific activity over 90 U/ng in three manufacturing runs. BoNT-B is manufactured as a slightly acidic liquid formulation that maintains complex integrity, reducing the potential for generating neutralizing antibodies. The potency of drug substance, dilute bulk solution, and finished product was shown to be reliable using the validated mouse intraperitoneal LD50 potency assay. The liquid formulation of BoNT-B was found to be stable for at least 9 months at 25°C and at least 3 years at 2,8°C. BoNT-B has a long shelf-life and may be produced on a commercial scale reliably and reproducibly, making it readily available and convenient to store and use. Support of Elan Pharmaceuticals is gratefully acknowledged. [source] Changes in prescribed drug doses after market introductionPHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 6 2002Eibert R. Heerdink PhD Abstract Purpose The establishment of recommended dosing regimens has always been a difficult aspect of drug development. This paper examines the extent to which postmarketing prescribing deviates from initially recommended dosing regimens. We used the World Health Organization's (WHO) periodically updated compilation of the ,Defined Daily Dose' (DDD) to reflect prevailing patterns of prescribing in national markets. The aim of this study was to evaluate DDD changes over time (1982,2000) and to identify possible determinants of these changes. Methods Data on DDD changes were obtained from the WHO's Oslo Collaborating Centre. We performed a case,control analysis in which we compared drugs with (cases) and without (controls) postmarketing changes in DDD on possible determinants associated with DDD change. Results We found 115 instances of a change of DDD in the period 1982,2000 (45 (39.1%) increases and 70 (60.9%) decreases). Antibiotics showed the greatest number of changes in DDD: predominantly increases in the 1980s, while the 1990s were dominated by decreases in DDD of mostly cardiovascular drugs. Conclusion Changes in DDD reflect the outcome of a melange of forces, including misconceptions of dose requirements during pre-market development of drug and postmarketing changes in pharmacotherapeutic knowledge, clinical concepts, economic forces, and, in the case of anti-infective agents, changing patterns of resistance/sensitivity of target microorganisms to the anti-infective agent(s) in question. Copyright © 2002 John Wiley & Sons, Ltd. [source] Rapid method for determining malondialdehyde as secondary oxidation product in palm olein system by Fourier transform infrared spectroscopyPHYTOCHEMICAL ANALYSIS, Issue 4 2002M. E. S. Mirghani Abstract A simple and rapid Fourier transform infrared (FTIR) spectroscopic method has been developed for the quantitative determination of malondialdehyde as secondary oxidation product in a palm olein system. The FTIR method was based on a sodium chloride transmission cell and utilised a partial least square statistical approach to derive a calibration model. The frequency region combinations that gave good calibration were 2900,2800, and 1800,1600,cm,1. The precision and accuracy, in the range 0,60,µmol malondialdehyde/kg oil, were comparable to those of the modified distillation method with a coefficient of determination (r2) of 0.9891 and standard error of calibration of 1.49. The calibration was cross-validated and produced an r2 of 0.9786 and standard error of prediction of 2.136. The results showed that the FTIR method is versatile, efficient and accurate, and suitable for routine quality control analysis with the result obtainable in about 2,min from a sample of less than 2,mL. Copyright © 2002 John Wiley & Sons, Ltd. [source] Predictors of delayed return to work after back injury: A case,control analysis of union carpenters in Washington StateAMERICAN JOURNAL OF INDUSTRIAL MEDICINE, Issue 11 2009Kristen L. Kucera PhD Abstract Methods Union administrative records identified 20,642 union carpenters who worked in Washington State from 1989 to 2003. The Department of Labor and Industries provided records of workers' compensation claims and associated medical care. Work-related back claims (n,=,4,241) were identified by ANSI codes (back, trunk, or neck/back) or ICD-9 codes relevant to medical care consistent with a back injury. Cases (n,=,738) were defined as back injury claims with >90 days of paid lost time; controls (n,=,699) resulted in return to work within 30 days. Logistic regression models estimated odds ratios and 95% confidence intervals (OR, 95% CI) of delayed return to work (DRTW). Results Thirty percent of case claims and 8% of control claims were identified by an ICD-9 code. DRTW after back injury was associated with being female (2.7, 95% CI: 1.3,5.5), age 30,44 (1.2, 95% CI: 0.9,1.7) and age over 45 (1.6, 95% CI: 1.1,2.3), four or more years union experience (1.4, 95% CI: 1.1,1.8), previous paid time loss back claim (1.8, 95% CI: 1.3,2.5), and ,30-day delay to medical care (3.6, 95% CI: 2.1, 6.1). Evidence of more acute trauma was also associated with DRTW. Conclusions Use of ICD-9 codes identified claims with multiple injuries that would otherwise not be captured by ANSI codes alone. Though carpenters of younger age and inexperience were at increased risk for a paid lost time back injury claim, older carpenters and more experienced workers, once injured, were more likely to have DRTW as were those who experienced acute events. Am. J. Ind. Med. 52:821,830, 2009. © 2009 Wiley-Liss, Inc. [source] Direct quantification of 11-nor-,9 -tetrahydrocannabinol-9-carboxylic acid in urine by liquid chromatography/tandem mass spectrometry in relation to doping control analysisRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 8 2010C. Chebbah An accurate and precise method for the quantification of 11-nor-,9 -tetrahydrocannabinol-9-carboxylic acid (THCA) in urine by liquid chromatography/tandem mass spectrometry (LC/MS/MS) for doping analysis purposes has been developed. The method involves the use of only 200,µL of urine and the use of D9 -THCA as internal standard. No extraction procedure is used. The urine samples are hydrolysed using sodium hydroxide and diluted with a mixture of methanol/glacial acetic acid (1:1). Chromatographic separation is achieved using a C8 column with gradient elution. All MS and MS/MS parameters were optimised in both positive and negative electrospray ionisation modes. For the identification and the quantification of THCA three product ions are monitored in both ionisation modes. The method is linear over the studied range (5,40,ng/mL), with satisfactory intra-and inter-assay precision, and the relative standard deviations (RSDs) are lower than 15%. Good accuracy is achieved with bias less than 10% at all levels tested. No significant matrix effects are observed. The selectivity and specificity are satisfactory, and no interferences are detected. The LC/MS/MS method was applied for the analysis of 48 real urine samples previously analysed with a routine gas chromatography/mass spectrometry (GC/MS) method. A good correlation between the two methods was obtained (r2,>,0.98) with a slope close to 1. Copyright © 2010 John Wiley & Sons, Ltd. [source] Electrospray ionization mass spectrometric characterization and quantitation of xanthine derivatives using isotopically labelled analogues: an application for equine doping control analysisRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 14 2004Mario Thevis Isotope-dilution mass spectrometry has been employed successfully in numerous fields of analytical chemistry enabling the establishment of fast and reliable procedures. In equine sports, xanthine derivatives such as caffeine and theobromine are prohibited, and doping control laboratories analyze horse urine specimens regarding these illicit performance-enhancing drugs. Theobromine has to exceed a threshold level of 2,,g/mL, hence a robust and reliable quantitation is required. Stably deuterated theobromine and caffeine were synthesized by the reaction of xanthine or theobromine with iodomethane-d3 in the presence of N -methyl- N -trimethylsilyltrifluoroacetamide or potassium carbonate in acetonitrile, respectively. Both compounds were characterized by nuclear magnetic resonance spectroscopy and electrospray ionization tandem mass spectrometry, and a robust and fast assay for the qualitative and quantitative analysis of theobromine in equine urine samples was validated. Urine specimens were extracted by means of solid-phase extraction cartridges, and concentrated extracts were analyzed by liquid chromatography interfaced to a triple-quadrupole mass spectrometer. In addition, the dissociation behavior of deuterated analogues to caffeine and theobromine allowed proposals for fragmentation routes of xanthine derivatives after atmospheric pressure ionization and collisionally activated dissociation. Copyright © 2004 John Wiley & Sons, Ltd. [source] Reduced Mortality Rate Associated with Annual Mammograms after Breast Cancer TherapyTHE BREAST JOURNAL, Issue 1 2006Timothy L. Lash DSc Abstract: Guidelines have been developed for appropriate posttherapy surveillance for breast cancer recurrence. One purpose of posttherapy surveillance is to detect potentially curable local recurrences and new cancers in the opposite breast. The objective of this investigation was to assess the impact of annual mammography on all-cause mortality in breast cancer survivors. We conducted a case,control analysis nested in a cohort of 865 stage I or II breast cancer patients diagnosed from 1996 to 1999. The exposure variable was the number of mammograms received after completing primary therapy. Cases were decedents and we used risk-set sampling to match eight controls to each case on follow-up time. The mortality rate declined with an increasing number of mammograms (p for trend = 0.007). The age- and therapy-adjusted odds ratio associating receipt of an additional mammogram, compared with receipt of no mammogram, equaled 0.77 (95% confidence interval [CI] 0.53,1.1). These results are consistent with a protective effect of regular surveillance mammography after completing therapy for early stage breast cancer. [source] An INSIG2 Polymorphism Affects Glucose Homeostasis in Sardinian Obese Children and AdolescentsANNALS OF HUMAN GENETICS, Issue 5 2010Patrizia Zavattari Summary Allelic variants of a single nucleotide polymorphism (SNP), rs7566605, located approximately 10 kb upstream of the INSIG2 gene have been found in association with body weight and with other clinical features related to obesity in some populations but not in others. Our objective was to test the association of this SNP in obese children and adolescents from the genetically isolated population of Sardinia. We tested the association of rs7566605 with body mass index (BMI) and with serum glucose and insulin concentrations and a surrogate measure of insulin resistance (HOMA-IR) in a cohort of 747 Sardinian obese children and adolescents. A case control analysis was performed using 548 ethnically-matched healthy controls. Allelic frequencies of the SNP were similar between patients and controls. Mean glucose and insulin concentration and mean HOMA-IR values were significantly higher in patients carrying the CC genotype than in the CG and GG carriers. In the patients with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), allele C was significantly more frequent than in controls. Although INSIG2 polymorphisms do not consistently associate with BMI, the observation of an association with glucose concentration would support a role for this gene in the metabolic complications of obesity. [source] Risk of tuberculosis is higher with anti,tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three-year prospective french research axed on tolerance of biotherapies registry,ARTHRITIS & RHEUMATISM, Issue 7 2009F. Tubach Objective Tuberculosis (TB) is associated with anti,tumor necrosis factor (anti-TNF) monoclonal antibody (mAb) therapy, but whether this association is drug-specific remains a concern. Our objective was to describe cases of TB associated with anti-TNF mAb therapy, identify risk factors, and estimate the incidence. Methods We conducted an incidence study and a case,control analysis to investigate the risk of newly diagnosed TB associated with the use of anti-TNF agents. As part of the French Research Axed on Tolerance of Biotherapies (RATIO) registry, for 3 years we collected cases of TB among French patients receiving anti-TNF mAb therapy for any indication; for each case, 2 patients treated with anti-TNF agents served as control subjects. Results We collected 69 cases of TB in patients treated for rheumatoid arthritis (n = 40), spondylarthritides (n = 18), inflammatory colitis (n = 9), psoriasis (n = 1) and Behçet's disease (n = 1) with infliximab (n = 36), adalimumab (n = 28), and etanercept (n = 5). None of the patients had received correct chemoprophylactic treatment. The sex- and age-adjusted incidence rate of TB was 116.7 per 100,000 patient-years. The standardized incidence ratio (SIR) was 12.2 (95% confidence interval [95% CI] 9.7,15.5) and was higher for therapy with infliximab and adalimumab than for therapy with etanercept (SIR 18.6 [95% CI 13.4,25.8] and SIR 29.3 [95% CI 20.3,42.4] versus SIR 1.8 [95% CI 0.7,4.3], respectively). In the case,control analysis, exposure to infliximab or adalimumab versus etanercept was an independent risk factor for TB (odds ratio [OR] 13.3 [95% CI 2.6,69.0] and OR 17.1 [95% CI 3.6,80.6], respectively). Other risk factors were age, the first year of anti-TNF mAb treatment, and being born in an endemic area. Conclusion The risk of TB is higher for patients receiving anti-TNF mAb therapy than for those receiving soluble TNF receptor therapy. The increased risk with early anti-TNF treatment and the absence of correct chemoprophylactic treatment favor the reactivation of latent TB. [source] ROBUST H, CONTROL AND QUADRATIC STABILIZATION OF DISCRETE-TIME SWITCHED SYSTEMS WITH NORM-BOUNDED TIME-VARYING UNCERTAINTIESASIAN JOURNAL OF CONTROL, Issue 3 2007Zhijian Ji ABSTRACT We focus on robust H, control analysis and synthesis for discretetime switched systems with norm-bounded time-varying uncertainties. Sufficient conditions are derived to guarantee quadratic stability along with a prescribed H, -norm bound. Each of them can be dealt with as a linear matrix inequality (LMI) which can be tested with efficient algorithms. All the switching rules are constructively designed, and do not rely on any uncertainties. [source] | |||||||||||||||||||||||||||||||