@phdthesis{Schumann2013,
  author    = {Schumann, Sara},
  title     = {Influence of intestinal inflammation on bacterial protein expression in monoassociated mice},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-67757},
  school      = {Universit{\"a}t Potsdam},
  year      = {2013},
  abstract  = {Background: Increased numbers of intestinal E. coli are observed in inflammatory bowel disease, but the reasons for this proliferation and it exact role in intestinal inflammation are unknown. Aim of this PhD-project was to identify E. coli proteins involved in E. coli's adaptation to the inflammatory conditions in the gut and to investigate whether these factors affect the host. Furthermore, the molecular basis for strain-specific differences between probiotic and harmful E. coli in their response to intestinal inflammation was investigated. Methods: Using mice monoassociated either with the adherent-invasive E. coli (AIEC) strain UNC or the probiotic E. coli Nissle, two different mouse models of intestinal inflammation were analysed: On the one hand, severe inflammation was induced by treating mice with 3.5\% dextran sodium sulphate (DSS). On the other hand, a very mild intestinal inflammation was generated by associating interleukin 10-deficient (IL-10-/-) mice with E. coli. Differentially expressed proteins in the E. coli strains collected from caecal contents of these mice were identified by two-dimensional fluorescence difference gel electrophoresis. Results DSS-experiment: All DSS-treated mice revealed signs of a moderate caecal and a severe colonic inflammation. However, mice monoassociated with E. coli Nissle were less affected. In both E. coli strains, acute inflammation led to a downregulation of pathways involved in carbohydrate breakdown and energy generation. Accordingly, DSS-treated mice had lower caecal concentrations of bacterial fermentation products than the control mice. Differentially expressed proteins also included the Fe-S cluster repair protein NfuA, the tryptophanase TnaA, and the uncharacterised protein YggE. NfuA was upregulated nearly 3-fold in both E. coli strains after DSS administration. Reactive oxygen species produced during intestinal inflammation damage Fe-S clusters and thereby lead to an inactivation of Fe-S proteins. In vitro data indicated that the repair of Fe-S proteins by NfuA is a central mechanism in E. coli to survive oxidative stress. Expression of YggE, which has been reported to reduce the intracellular level of reactive oxygen species, was 4- to 8-fold higher in E. coli Nissle than in E. coli UNC under control and inflammatory conditions. In vitro growth experiments confirmed these results, indicating that E. coli Nissle is better equipped to cope with oxidative stress than E. coli UNC. Additionally, E. coli Nissle isolated from DSS-treated and control mice had TnaA levels 4- to 7-fold higher than E. coli UNC. In turn, caecal indole concentrations resulting from cleavage of tryptophan by TnaA were higher in E. coli Nissle- associated control mice than in the respective mice associated with E. coli UNC. Because of its anti-inflammatory effect, indole is hypothesised to be involved in the extension of the remission phase in ulcerative colitis described for E. coli Nissle. Results IL-10-/--experiment: Only IL-10-/- mice monoassociated with E. coli UNC for 8 weeks exhibited signs of a very mild caecal inflammation. In agreement with this weak inflammation, the variations in the bacterial proteome were small. Similar to the DSS-experiment, proteins downregulated by inflammation belong mainly to the central energy metabolism. In contrast to the DSS-experiment, no upregulation of chaperone proteins and NfuA were observed, indicating that these are strategies to overcome adverse effects of strong intestinal inflammation. The inhibitor of vertebrate C-type lysozyme, Ivy, was 2- to 3-fold upregulated on mRNA and protein level in E. coli Nissle in comparison to E. coli UNC isolated from IL-10-/- mice. By overexpressing ivy, it was demonstrated in vitro that Ivy contributes to a higher lysozyme resistance observed for E. coli Nissle, supporting the role of Ivy as a potential fitness factor in this E. coli strain. Conclusions: The results of this PhD-study demonstrate that intestinal bacteria sense even minimal changes in the health status of the host. While some bacterial adaptations to the inflammatory conditions are equal in response to strong and mild intestinal inflammation, other reactions are unique to a specific disease state. In addition, probiotic and colitogenic E. coli differ in their response to the intestinal inflammation and thereby may influence the host in different ways.},
  language  = {en}
}
@article{GrisicEserHuisingaetal.2020,
  author    = {Grisic, Ana-Marija and Eser, Alexander and Huisinga, Wilhelm and Reinisch, Walter and Kloft, Charlotte},
  title     = {Quantitative relationship between infliximab exposure and inhibition of C-reactive protein synthesis to support inflammatory bowel disease management},
  series = {British journal of clinical pharmacology},
  volume    = {87},
  journal   = {British journal of clinical pharmacology},
  number    = {5},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {0306-5251},
  doi       = {10.1111/bcp.14648},
  pages     = {2374 -- 2384},
  year      = {2020},
  abstract  = {Aim Quantitative and kinetic insights into the drug exposure-disease response relationship might enhance our knowledge on loss of response and support more effective monitoring of inflammatory activity by biomarkers in patients with inflammatory bowel disease (IBD) treated with infliximab (IFX). This study aimed to derive recommendations for dose adjustment and treatment optimisation based on mechanistic characterisation of the relationship between IFX serum concentration and C-reactive protein (CRP) concentration. <br /> Methods Data from an investigator-initiated trial included 121 patients with IBD during IFX maintenance treatment. Serum concentrations of IFX, antidrug antibodies (ADA), CRP, and disease-related covariates were determined at the mid-term and end of a dosing interval. Data were analysed using a pharmacometric nonlinear mixed-effects modelling approach. An IFX exposure-CRP model was generated and applied to evaluate dosing regimens to achieve CRP remission. <br /> Results The generated quantitative model showed that IFX has the potential to inhibit up to 72\% (9\% relative standard error [RSE]) of CRP synthesis in a patient. IFX concentration leading to 90\% of the maximum CRP synthesis inhibition was 18.4 mu g/mL (43\% RSE). Presence of ADA was the most influential factor on IFX exposure. With standard dosing strategy, >= 55\% of ADA+ patients experienced CRP nonremission. Shortening the dosing interval and co-therapy with immunomodulators were found to be the most beneficial strategies to maintain CRP remission. <br /> Conclusions With the generated model we could for the first time establish a robust relationship between IFX exposure and CRP synthesis inhibition, which could be utilised for treatment optimisation in IBD patients.},
  language  = {en}
}
@article{DemarisWidigsonIlvemarketal.2022,
  author    = {D{\´e}maris, Alix and Widigson, Ella S. K. and Ilvemark, Johan F. K. F. and Steenholdt, Casper and Seidelin, Jakob B. and Huisinga, Wilhelm and Michelet, Robin and Aulin, Linda B. S. and Kloft, Charlotte},
  title     = {Ulcerative colitis and acute severe ulcerative colitis patients are overlooked in infliximab population pharmacokinetic models},
  series = {Pharmaceutics / Molecular Diversity Preservation International},
  volume    = {14},
  journal   = {Pharmaceutics / Molecular Diversity Preservation International},
  number    = {10},
  publisher = {MDPI},
  address   = {Basel},
  issn      = {1999-4923},
  doi       = {10.3390/pharmaceutics14102095},
  pages     = {32},
  year      = {2022},
  abstract  = {Ulcerative colitis (UC) is part of the inflammatory bowels diseases, and moderate to severe UC patients can be treated with anti-tumour necrosis alpha monoclonal antibodies, including infliximab (IFX). Even though treatment of UC patients by IFX has been in place for over a decade, many gaps in modelling of IFX PK in this population remain. This is even more true for acute severe UC (ASUC) patients for which early prediction of IFX pharmacokinetic (PK) could highly improve treatment outcome. Thus, this review aims to compile and analyse published population PK models of IFX in UC and ASUC patients, and to assess the current knowledge on disease activity impact on IFX PK. For this, a semi-systematic literature search was conducted, from which 26 publications including a population PK model analysis of UC patients receiving IFX therapy were selected. Amongst those, only four developed a model specifically for UC patients, and only three populations included severe UC patients. Investigations of disease activity impact on PK were reported in only 4 of the 14 models selected. In addition, the lack of reported model codes and assessment of predictive performance make the use of published models in a clinical setting challenging. Thus, more comprehensive investigation of PK in UC and ASUC is needed as well as more adequate reports on developed models and their evaluation in order to apply them in a clinical setting.},
  language  = {en}
}
@phdthesis{Berding2017,
  author    = {Berding, Anja},
  title     = {Kurz-, mittel- und langfristige Effekte einer Schulung f{\"u}r Patienten mit chronisch entz{\"u}ndlichen Darmerkrankungen auf krankheitsbezogene {\"A}ngste und Gesundheitskompetenzen},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-401063},
  school      = {Universit{\"a}t Potsdam},
  pages     = {V, 118},
  year      = {2017},
  abstract  = {Menschen mit chronisch entz{\"u}ndlichen Darmerkrankungen (CED) leiden unter vielf{\"a}ltigen k{\"o}rperlichen und psychosozialen Einschr{\"a}nkungen. Wie auch bei anderen chronischen Erkrankungen k{\"o}nnten Patientenschulungen ihr psychisches Befinden verbessern (z.B. De Ridder \& Schreurs, 2001; Faller, Reusch \& Meng, 2011a; K{\"u}ver, Becker \& Ludt, 2008; Sch{\"u}ssler, 1998; Warsi, Wang, LaValley, Avorn \& Solomon, 2004). F{\"u}r CED liegen jedoch nur wenige Schulungsevaluationen vor (z.B. Bregenzer et al., 2005; Mussell, B{\"o}cker, Nagel, Olbrich \& Singer, 2003; Oxelmark, Magnusson, L{\"o}fberg \& Hiller{\aa}s, 2007), deren Aussagekraft i.d.R. durch methodische M{\"a}ngel eingeschr{\"a}nkt ist. Daher ist die Bedeutung von Schulungsprogrammen f{\"u}r CED-Betroffene weiterhin offen. {\"U}berdies gibt es f{\"u}r den deutschen Sprachraum noch keine Schulung, die zu psychischen Verbesserungen f{\"u}hrt. Aus diesem Grunde wurde ein 1,5-t{\"a}giges Wochenend-Seminar mit medizinischen und psychologischen Inhalten konzeptionalisiert, manualisiert und in der vorliegenden Studie evaluiert. Zur summativen Evaluation nahmen 181 ambulante CED-Patienten an einer prospektiven, multizentrischen, randomisierten, kontrollierten Studie mit vier Messzeitpunkten teil: vor (T1), zwei Wochen (T2) und drei Monate (T3) nach dem Seminar. Zur 12-Monatskatamnese (T4EG) wurde die Stabilit{\"a}t der Effekte in der Experimentalgruppe (EG; n = 86) {\"u}berpr{\"u}ft. Die Wartekontrollgruppe (n = 95) erhielt zun{\"a}chst die Standardbehandlung, also keine Patientenschulung, und konnte an dieser nach der dritten Datenerhebung ebenfalls teilnehmen. Kovarianzanalysen (ANCOVAs) mit Kontrolle f{\"u}r die jeweilige Ausgangslage wurden durchgef{\"u}hrt. Weitere Analysen legten eine Adjustierung f{\"u}r die Krankheitsaktivit{\"a}t zu T1 nahe, weshalb diese als zus{\"a}tzliche Kovariate in die ANCOVAs aufgenommen wurde. Krankheitsbezogene {\"A}ngste und Sorgen (PS-CEDE Gesamtwert zu T3; Krebs, Kachel \& Faller, 1998) fungierten als prim{\"a}rer Zielparameter. Zu den sekund{\"a}ren Zielkriterien geh{\"o}rten Progredienzangst und Angstbew{\"a}ltigung (PA-F-KF und PA-F; Mehnert, Herschbach, Berg, Henrich \& Koch, 2006 bzw. Dankert et al., 2003; Herschbach et al., 2005) sowie die Gesundheitskompetenzen Positive Grundhaltung, Aktive Lebensgestaltung und Erwerb von Fertigkeiten und Handlungsstrategien (heiQ; Osborne, Elsworth \& Whitfield, 2007; Schuler et al., 2013). Weitere sekund{\"a}re Zielparameter waren gesundheitsbezogene Lebensqualit{\"a}t (SF-12; Bullinger \& Kirchberger, 1998), Symptome einer Angstst{\"o}rung oder Depression (PHQ-4; Kroenke, Spitzer, Williams \& L{\"o}we, 2009; L{\"o}we et al., 2010), Wissen, der Umgang mit der CED bzw. von ihr ausgel{\"o}sten negativen Gef{\"u}hlen sowie die Zufriedenheit der Teilnehmenden mit dem Seminar. Von Interesse war außerdem, ob Geschlecht, Alter, Art, Dauer oder Aktivit{\"a}t der Erkrankung vor der Schulung einen Einfluss auf die genannten Variablen hatten und ob f{\"u}r sie differentielle Wirksamkeitseffekte bestanden. Dar{\"u}ber hinaus wurden krankheitsbezogene {\"A}ngste und Sorgen von ungeschulten Studienteilnehmern untersucht. Zwei Wochen und drei Monate nach der Schulung ließen sich im Vergleich von Experimental- und Kontrollgruppe signifikante, mittlere bis große Effekte auf krankheitsbezogene {\"A}ngste und Sorgen, Progredienzangst und deren Bew{\"a}ltigung sowie eine Positive Grundhaltung der CED gegen{\"u}ber erzielen (stets p ≤ .001). Außerdem kam es zu beiden Messzeitpunkten zu signifikanten, großen Interventionseffekten auf den Erwerb von Fertigkeiten und Handlungsstrategien im Umgang mit der Erkrankung, das Wissen um sie und den Umgang mit ihr (stets p < .001) sowie zu moderaten Effekten auf den Umgang mit CED-bedingten negativen Gef{\"u}hlen (T2: p = .001; T3: p = .008). Alle beschriebenen Effekte waren auch nach zw{\"o}lf Monaten noch stabil. F{\"u}r Aktive Lebensgestaltung, gesundheitsbezogene Lebensqualit{\"a}t sowie Angst- und Depressionssymptomatik konnten keine Schulungseffekte nachgewiesen werden. Die zus{\"a}tzliche Kontrolle f{\"u}r die Krankheitsaktivit{\"a}t zu T1 f{\"u}hrte zu keinen wesentlichen {\"A}nderungen in den Ergebnissen. Auch bei den Subgruppenanalysen hatte die Krankheitsaktivit{\"a}t keinen relevanten Einfluss auf die Wirksamkeit der Schulung. Gleiches gilt f{\"u}r Geschlecht, Alter, Art und Dauer der CED. Mit Ausnahme der Krankheitsaktivit{\"a}t deuteten dies bereits die zur Baseline durchgef{\"u}hrten t-Tests an, bei denen insgesamt nur sehr wenige signifikante, h{\"o}chstens moderate Unterschiede zwischen den einzelnen Subgruppen auftraten. Sowohl bei der formativen als auch der summativen Evaluation zeigte sich {\"u}berdies die hohe Zufriedenheit der Teilnehmenden mit der Schulung. Neben der Akzeptanz konnte außerdem die Durchf{\"u}hrbarkeit best{\"a}tigt werden. Die Auswertung der {\"A}ngste und Sorgen der Studienteilnehmenden lieferte zudem Hinweise f{\"u}r die Entwicklung und Modifikation von Interventionen f{\"u}r CED-Betroffene. Es l{\"a}sst sich festhalten, dass f{\"u}r die hier evaluierte Schulung f{\"u}r CED-Patienten ein Wirksamkeitsnachweis erbracht werden konnte und sie sehr positiv von den Teilnehmenden bewertet wurde. Sie f{\"u}hrte sowohl kurz-, mittel- als auch langfristig zu substantiellen Verbesserungen in psychischer Belastung, Selbstmanagement-F{\"a}higkeiten, der Bew{\"a}ltigung der Erkrankung sowie im Wissen und war gleichermaßen wirksam bei Betroffenen, die sich in Geschlecht, Alter, Art, Dauer oder Aktivit{\"a}t ihrer CED unterschieden.},
  language  = {de}
}