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Background Chronic intestinal inflammation results in tissue damage partly caused by an increase in matrix metalloproteinases (MMP) resulting in degradation of extracellular matrix (ECM) proteins. There is an unmet medical need for non-invasive ECM biomarkers of disease activity in inflammatory bowel disease (IBD) patients and for assessing mucosal healing and tissue turnover. We studied tissue remodelling by quantifying ECM protein fragments in serum from an animal model with chemically induced colitis (dextran sulphate sodium), to investigate the potential of ECM protein fragments as biomarkers of disease activity in IBD. Methods Disease was induced in male Sprague Dawley rats with 5% dextran sulphate sodium (DSS) for 5 days followed by a reversal period with regular water for 11 days. Disease activity index (DAI) was scored daily, combining weight loss, faecal consistency and blood in faeces. Serum was collected on day 0, 7, and 16 and retrieval of colon on day 7 and 16 for histological analysis. Competitive ELISAs were used to quantify MMP derived neo-epitope fragments of the basement membrane: Type IV collagen remodelling (C4M and P4NP7S) and interstitial matrix: Type III collagen remodelling (C3M and rPro-C3). Results In DSS rats, levels of C4M, P4NP7S, and C3M were significantly elevated (p = 0.001; p = 0.003; p = 0.0006) at day 6 compared with controls, and the levels declined at day 16. Levels of rPro-C3 were lower in DSS rats at day 7 and increased to normal levels at day 16. The ratio between C3M and rPro-C3 showed a significant overall degradation (p < 0.0001) of collagen type III in DSS rats compared with controls at day 7, which correlated to the DAI (r2=0.61, p < 0.0001). DAI increased with DSS dose and declined to normal levels during 11 days of regular water. Increased colonic tissue remodelling and inflammation was confirmed by histology.

Background Patients with inflammatory bowel disease (IBD) have varying disease courses with phases of inactive disease and flares of active disease with impairment of the intestinal epithelial barrier leading to tissue damage. Due to the large surface area, basement membrane is abundant in the intestinal tissue and its constituents, such as laminins, play an important role in the intestinal epithelial homeostasis. The laminin gamma 1 chain is highly abundant along the entire crypt-villus axis in the basement membrane. We investigated if a serum biomarker of the basement membrane (LG1M) could serve as surrogate biomarkers for disease activity in a rat in vivo colitis model and in IBD patients. Methods Serum from male Sprague Dawley rats that received 5–6% dextran sulfate sodium (DSS) (n = 21) or regular drinking water (n = 9) for 5 days was included and scored for disease activity index (DAI). In addition, serum from 44 Crohn’s disease (CD) patients with inactive (n = 20) or active (n = 24) disease and healthy subjects (n = 20) was included in this study. A competitive ELISA for matrix metalloproteinase (MMP) 9 mediated degradation of the laminin gamma 1 chain (LG1M) was used to estimate the level of laminin degradation in serum. Sections of the distal colon from the rats were assessed histologically for structural changes. Results LG1M were significantly elevated in CD patients serum compared with healthy subjects (p < 0.001; p < 0.001), but with lower levels in active CD compared inactive CD (Figure 1A). The findings of LG1M were confirmed in the in vivo colitis model, in which the levels of LG1M in DSS rat serum with high DAI were significantly lower (p = 0.004) compared with controls (Figure 1B). LG1M correlated negatively to DAI (r2 = 0.2153; p < 0.01) (Figure 1C). The structure of the distal colonic tissue in DSS rats was disrupted compared with controls with loss of crypt architecture and total surface area (Figure 1D–E).

Background Endoscopy is a mainstay in Crohn′s Disease (CD) monitoring. However, endoscopic evaluation of the intestinal mucosa is time-consuming and inconvenient for the patients. Therefore biomarkers that can substitute the need for endoscopic examinations are warranted. Currently, the best validated biomarker for endoscopic disease activity in CD is faecal calprotectin (fCalp). We investigated, whether circulating levels of the tissue-remodelling biomarkers VICM, basement membrane turnover (P4NP, C4M) and Pro-C3, reflects endoscopic disease activity in CD. Methods We investigated blood samples from 9 CD patients before and after 4 weeks of adalimumab treatment (n = 18) along with serum from male Sprague Dawley rats treated with 1–3% DSS for 7 days (n = 42) and the disease activity index (DAI: faecal consistency, visible blood in faeces and weight loss) was applied. CD patients underwent colonoscopy before and after adalimumab treatment. Endoscopic disease activity was scored by the Simple Endoscopic Activity Score in CD (SES-CD). We measured levels of the biomarkers VICM, P4NP, C4M and Pro-C3 by ELISA. The serum levels of the biomarkers were combined in a backwards multivariate regression model. This model was correlated with the SES-CD score compared with fCalp and C-reactive protein (CRP) levels. Results In the samples from CD patients (n = 18) the only biomarkers that contributed significantly to the multivariate analysis model were VICM, P4NP/C4M and Pro-C3. fCalp and CRP did not contribute and was therefore excluded. This model (VICM; p = 0.003, P4NP/C4M; p = 0.025, and Pro-C3; p = 0.022) correlated significantly with the SES-CD score (overall model; r2 = 0.53, p < 0.001). fCalp had a moderate correlation with the SES-CD score alone (r2 = 0.30, p = 0.016), and CRP did not correlate with SES-CD (r2 = 0.03, p = 0.40). Finally, only the combination of the tissue remodelling biomarkers (VICM, P4NP/C4M, Pro-C3) could separate patients with mild (SES-CD< 7) from patients with moderate to severe endoscopic disease activity (SES-CD >6) (p < 0.01, AUC: 0.89 [CI:0.75–1.0]), fCalp did not demonstrate significant discriminative power (p = 0.12, AUC:0.76 [CI:0.43–1.0]). At day 7 the DSS rats with DAI >7 had significantly elevated serum levels of C4M and P4NP compared with controls (p < 0.05). C4M (r2 = 0.29, p < 0.001) and P4NP (r2 = 0.21, p = 0.005) correlated with DAI score in DSS treated rats. Conclusions The combined tissue-remodelling biomarkers correlated significantly with the endoscopic disease activity in CD. These data were supported by findings from the DSS model. These biomarkers performed better than the established biomarkers fCalp and CRP, and may be used as surrogate markers for endoscopic disease activity assessment.

Background Stricturing disease remains one of the biggest complications leading to intestinal resection in Crohn’s disease (CD), and affecting 30–50% of patients with CD. Intestinal strictures are caused by fibrosis development, as a result of increased collagen deposition. Intestinal fibroblasts and myofibroblasts are the main effector cells for intestinal fibrosis development and intestinal subepithelial myofibroblasts have shown to produce significantly elevated levels of type XVI collagen in CD patients. Thus, we investigated a novel serum biomarker, quantifying type XVI collagen (C16-C), as a biomarker for intestinal fibrosis in CD patients. Methods Serum from CD patients (n = 44) and healthy subjects (n = 50) was included. The Montreal classification for CD disease behaviour (B1, non-stricturing/non-penetrating: n = 20; B2: stricturing, n = 11; B3: penetrating n = 13) and disease location (L1, ileum: n = 14; L2, colon: n = 5; L3, ileum + colon: n = 25) was applied. The patients were classified as having inactive disease (n = 20) or active disease (n = 24) based on the Crohn’s disease Activity Index (CDAI) score. Competitive ELISA was applied for the quantification of C16-C in serum from CD patients (total serum samples: n = 94). Results The biomarker C16-C was significantly elevated in patients with CD compared with healthy donors (p < 0.001, AUC: 0.81). CD patients with strictures (B2) demonstrated significantly elevated serum levels of C16-C compared with CD patient without strictures (B1 and B3), and healthy donors. Furthermore, the diagnostic accuracy to separate CD patients with strictures (B2) from CD patient without strictures (B1 and B3) was 76% (p < 0.01, AUC: 0.76) and healthy donors 96% (p < 0.001, AUC 0.82). In addition, C16-C was also elevated in CD patients with ileum or ileum+colon disease involvement compared with only colon involvement and healthy donors (p < 0.05). There was no significant difference between patients with active or inactive disease.

The capability to perform fast load changes has been an important issue in the power market, and will become increasingly more so due to the incresing commercialisation of the European power market. An optimizing control system for improving the load-following capability of power-plant units has therefore been developed. The system is implemented as a complement, producing control signals to be added to those of the existing boiler control system, a concept which has various practical advantages in terms of implementation and commissioning. The optimizing control system takes account of the multivariable and load-de*pendent nonlinear characteristics of the boiler process, as a scheduled LQG controller with feedforward action is utilized. The LQG controller improves the control of critical pro*cess variables, making it possible to increase the load-following capability of a specific plant. Field tests on a 265 MW coal-fired power-plant unit reveals that the maximum allowable load gradient that can be imposed on the plant, can be increased from 4 MW/min. to 8 MW/min.

An optimizing control system for improving the load following capabilities of power plant units has been developed. The system is implemented as a complement producing additive control signals to the existing boiler control system, a concept which has various practical advantages in terms of implementation and commissioning. The optimizing control system takes into account the multivariable and nonlinear characteristics of the boiler process as a gain-scheduled LQG-controller is utilized. For the purpose of facilitating the control concept development a dynamic simulation model of the boiler process and the existing control system has been developed and validated. The optimizing control system has been developed and tested by extensive use of the simulation model. Simulation results indicate that a reduction of steam temperature deviations of about 75% can be obtained. The advantages of using a simulation model when designing a new control concept are discussed.

Dette projekt omhandler forbedring af eksisterende kraftværkers reguleringsevne med det formål at forbedre deres konkurrenceevne i det forestående liberaliserede elmarked samt for at bibeholde den høje forsyningssikkerhed i forbindelse med udbygningen med vindmøller og andre uregulerbare enheder. Kedlen er den del af et kraftværk, der har den langsomste dynamik og er derfor oftest den be*græn*sende faktor for hele kraftværksblokkens reguleringsevne. Med bagrund i dette er det søgt at forbedre kedlens reguleringsevne ved i højere grad ad reguleringsteknisk vej at tage mere hensyn til kedelprocessens multivariable og ulineære karakteristika end hidtil. For at forøge systemets robusthed samt for at gøre idriftsætning og ind-/udkobling af regulatoren simplere, opbygges regulatoren som en optimerende overbygning til det eksisterende reguleringssystem. Dette er gjort på en sådan måde at der bl.a. ud fra fejlsignalerne i det eksisterende reguleringssystem beregnes styresignaler, der adderes til styresignalerne fra de eksisterende regulatorer. Denne specielle opkobling har resulteret i at der ud fra måledata identificeres en model be*stå*ende af kedelprocessen samt det eksisterende reguleringssystem. En i forhold til lasten scheduleret multivariabel LQG-regulator er blevet anvendt. Schedulering er anvendt da det har vist sig at de dominerende ulineariteter er lastafhængige. To forskellige metoder til indføring af feedforward-kompensering er blevet behandlet. I den ene metode er feedforward-kompensatoren integreret i LQG-regulatoren, i den anden er den separeret fra LQG-regulatoren, men koordineret via tilstandsestimatoren. På grund af, at LQG-regulatoren er indført som en optimerende overbygning til en allerede reguleret proces, så har processen set fra LQG-regulatoren (bestående af kedelproces og eksisterende reguleringsystem) en DC-forstærkning på nul. Denne specielle karakteristikum er eksplicit blevet taget i betragtning i forbindelse med modelopstillingen samt regulatordesignet. Til afprøvning af de opstillede metoder er I/S SKÆRBÆKVÆRKET, blok 2 (SVS2) blevet anvendt som testeksempel. For bl.a. at have et sikkert miljø til udvikling af det optimerende reguleringssystem er der blevet udviklet en dynamisk simuleringsmodel af kedel, turbiner og eksisterende reguleringssystem på SVS2. Denne kaldes for SVS2-simulatoren og er opbygget ud fra de grundlæggende love om masse- og energibevarelse, samt sammenhænge for varmeovergang, fluiddynamik osv. Sammenligninger mellem SVS2-simulatoren og SVS2 viser at SVS2-simulatoren afspejler den virkelige procesdynamik på tilfredsstillende vis. Den begrænsende faktor for kedlens reguleringsevne på SVS2 har vist sig at være udsving i damptemperaturen før 1. sprøjte. Styrbare input er valgt til fødevandsmængden og brændselsmængden, hvilke kobler kraftigt til HT-damptrykket, hvorfor denne er medtaget i regulerings-strategien for ikke at forværre reguleringen af HT-damptrykket. Yderligere er der indført feedforward-kompensering fra lasten. Dette er tydeligvist et multivariabelt reguleringsproblem. Afprøvninger af en LQG-regulator med integreret feedforward-kompensator på SVS2-simulato*ren viser at udsvingene i damptemperaturen før 1. sprøjte kan reduceres betragteligt un*der lastændringer samtidig med at en mindre reduktion i udsving i HT-damptrykket er op*nået. Sta*biliteten af det schedulerede system designet til SVS2-simulatoren er blevet behandlet. Der er blevet opstillet en metode til beregning af den maksimalt tilladelige lastgradient for hvilken det samlede systems stabilitet kan garanteres. Metoden viser sig dog i praksis at være me*get kon*se*rativ, idet en grænse opnåes der er langt under den det ved simuleringer viser sig mu*lig at ope*rere med. Afprøvninger på SVS2 resulterer i,at LQG-regulatoren må tunes meget sløvt af hensyn til feedback-delens stabilitet. Dette resulterer i at feedforward-delen også bliver meget sløv, hvor*for de samme forbedringer ikke kan opnås i praksis. Til løsning af dette problem er LQG-regulatoren med koordineret LQ-feedforward-kompensator blevet udviklet, hvilket muliggør en seperat tuning af feedback-delen og feedforward-delen. Der er blevet designet og implementeret en LQ-feedforward-kompensator i fire forskellige lastpunkter dækkende hele normal*drifts*område for kedlen. De praktiske afprøvninger viser at det er muligt næsten at ud*kom*pen*sere udsvingene i damptemperaturen før 1. sprøjte samtidig med at der er status quo på HT-damptrykket. LQ-feedforward-kompensatoren har med gode resultater været lang*tids**testet på SVS2. Afprøvninger af LQG-feedback-regulatoren har vist, at det er muligt at undertrykke forstyrrelser fra fyrrummet med op til 37%. Disse forbedringer af kedel*sta*biliteten under lastændringer forventes at kunne øge SVS2's reguleringevne betragteligt. Der er blevet opstillet en generel implementeringsstrategi for det udviklede koncept på and*re kraftværksblokke. Genereliteten af konceptet er vist ved opstilling af en reguleringsstrategi for I/S FYNSVÆRKET, blok 7, der er en noget nyere blok end SVS2 samt procesmæssigt er lidt anderledes opbygget (bl.a. på grund af røggasrecirkulation). Ana*ly*se- og strukturspecifikationsdelen af den generelle implementeringsstrategi er anvendt på I/S FYNS*VÆRKET, blok 7, med det formål at anskueliggøre at det udviklede koncept kan an*vendes til forbedring af reguleringsevnen af denne blok. Koncept for en LQ-feedforward-kom*pen*sator er opstillet med det mål at mindske udsving i damptemperaturen efter udskiller samt i damptemperaturen før 1. sprøjte. På baggrund af de opnåede resultater på I/S SKÆRBÆKVÆRKET, blok 2 forventes det som nævnt ovenfor at blokkens reguleringsevne kan øges væsentligt. På grund af konceptets generelitet vil et tilsvarende system kunne opbygges på andre blokke. Dette vil kunne bidrage til at forbedre kraftværkernes konkurrenceevne i det forestående liberaliserede elmarked samt til at bibeholde den høje forsyningssikkerhed i forbindelse med udbygningen med vindmøller og andre uregulerbare enheder.

An An optimizing control system for improving the load following capabilities of power plant units has been developed. The system is implemented as a complement producing additive control signals to the existing boiler control system, a concept which has various practical advantages in terms of implementation and commissioning. The optimizing control system takes into account the multivariable and nonlinear characteristics of the boiler process as a gain-scheduled LQG-controller is utilized. Simulation results indicate that a reduction of steam temperature deviations of about 75% can be obtained.optimizing control system for improving the load following capabilities of power plant units has been developed. The system is implemented as a complement producing additive control signals to the existing boiler control system, a concept which has various practical advantages in terms of implementation and commissioning. The optimizing control system takes into account the multivariable and nonlinear characteristics of the boiler process as a gain-scheduled LQG-controller is utilized. Simulation results indicate that a reduction of steam temperature deviations of about 75% can be obtained.