Postsurgical Prophylaxis in Crohn's Disease: Which Patients, Which Agents?

NlmCategory="UNASSIGNED">Crohn's disease (CD) evolution is characterized by increasing proportions of patients developing complications such as strictures, abscesses and fistulas that require surgical management. After resection of a diseased intestinal segment, CD recurrence concerns up to 60% of patients within a year post surgery. The mucosa just above the site of the intestinal anastomosis is at particularly high risk of relapse. Prophylactic medical therapy to prevent recurrence has been shown to be effective with a variety of medications, but the recurrence rate remains high, demanding that a better risk stratification of patients be achieved. Recognized risk factors for postsurgical CD recurrence include young age at diagnosis and at surgery, smoking, need for repeated surgeries and penetrating disease. These patients require full dose immunosuppressive or anti-tumor necrosis factor (anti-TNF) therapy, which should be initiated in the immediate postoperative period, to prevent the onset of an inflammatory activity in the bowel. Systematic follow-up by endoscopy to monitor treatment benefit should also be part of the management, as endoscopic recurrence heralds clinical relapse in these patients. The role of noninvasive markers of mucosal inflammation, such as stool calprotectin levels, show promise to complete this monitoring. Although the efficacy of mesalazine and imidazole antibiotics has been long recognized, more aggressive approaches, such as thiopurines and anti-TNF antibodies, have shown higher efficacies in direct comparison trials. The potential place of anti-homing agents is not yet defined, but these agents should in principle be of interest for this prophylactic indication due to their mode of action and interesting side-effect profile. The current recommendations are based on a step-up approach that includes immunosuppressors and/or imidazole antibiotics, followed by an anti-TNF agent, such as infliximab and adalimumab, both already tested in randomized trials in this indication. When endoscopic recurrence is identified during follow-up, upscaling to anti-TNF or dose escalation is advocated.

Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized (13)C magnetic resonance.

BACKGROUND: The heart relies on continuous energy production and imbalances herein impair cardiac function directly. The tricarboxylic acid (TCA) cycle is the primary means of energy generation in the healthy myocardium, but direct noninvasive quantification of metabolic fluxes is challenging due to the low concentration of most metabolites. Hyperpolarized (13)C magnetic resonance spectroscopy (MRS) provides the opportunity to measure cellular metabolism in real time in vivo. The aim of this work was to noninvasively measure myocardial TCA cycle flux (VTCA) in vivo within a single minute. METHODS AND RESULTS: Hyperpolarized [1-(13)C]acetate was administered at different concentrations in healthy rats. (13)C incorporation into [1-(13)C]acetylcarnitine and the TCA cycle intermediate [5-(13)C]citrate was dynamically detected in vivo with a time resolution of 3s. Different kinetic models were established and evaluated to determine the metabolic fluxes by simultaneously fitting the evolution of the (13)C labeling in acetate, acetylcarnitine, and citrate. VTCA was estimated to be 6.7±1.7μmol·g(-1)·min(-1) (dry weight), and was best estimated with a model using only the labeling in citrate and acetylcarnitine, independent of the precursor. The TCA cycle rate was not linear with the citrate-to-acetate metabolite ratio, and could thus not be quantified using a ratiometric approach. The (13)C signal evolution of citrate, i.e. citrate formation was independent of the amount of injected acetate, while the (13)C signal evolution of acetylcarnitine revealed a dose dependency with the injected acetate. The (13)C labeling of citrate did not correlate to that of acetylcarnitine, leading to the hypothesis that acetylcarnitine formation is not an indication of mitochondrial TCA cycle activity in the heart. CONCLUSIONS: Hyperpolarized [1-(13)C]acetate is a metabolic probe independent of pyruvate dehydrogenase (PDH) activity. It allows the direct estimation of VTCA in vivo, which was shown to be neither dependent on the administered acetate dose nor on the (13)C labeling of acetylcarnitine. Dynamic (13)C MRS coupled to the injection of hyperpolarized [1-(13)C]acetate can enable the measurement of metabolic changes during impaired heart function.

Developing supply chain performance measurement metrics, case Halton Oy

Tämä tutkimus pyrkii selvittämään, miten toimitusketjun suorituskykyä voidaan mitata kohdeyrityksessä. Supply Chain Council (SCC) on vuonna 1996 kehittänyt Supply Chain Operations Reference (SCOR) – mallin, joka mahdollistaa myös suorituskyvyn mittaamisen. Tämän tutkimuksen tarkoituksena on soveltaa SCOR-mallin suorituskyvyn mittausmallia kohdeyrityksessä. Työ on kvalitatiivinen tapaustutkimus. Työn teoriaosassa on pääasiallisesti käsitelty toimitusketjua ja suorituskyvyn mittaamista koskevaa kirjallisuutta. Mittausjärjestelmän luominen alkaa kohdeyrityksen esittelyllä. SCOR – mallin mittarit on kohdeyrityksessä rakennettu SCC:n ehdotusten mukaisesti, jotta mittareiden tulokset olisivat käyttökelpoisia myös benchmarkkausta varten. Malli sisältää 10 SCOR – mittaria, sekä muutamia muita Haltonin omia mittareita. Lopputuloksena voidaan nähdä, että SCOR – malli antaa hyvän yleiskuvan toimitusketjun suorituskyvystä, mutta kohdeyrityksessä on silti tarvetta kehittää edelleen informatiivisempia mittareita, jotka antaisivat yksityiskohtaisempaa tietoa kohdeyrityksen johdolle.

Direct tumor recognition by a human CD4(+) T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses.

Tumor antigen-specific CD4(+) T cells generally orchestrate and regulate immune cells to provide immune surveillance against malignancy. However, activation of antigen-specific CD4(+) T cells is restricted at local tumor sites where antigen-presenting cells (APCs) are frequently dysfunctional, which can cause rapid exhaustion of anti-tumor immune responses. Herein, we characterize anti-tumor effects of a unique human CD4(+) helper T-cell subset that directly recognizes the cytoplasmic tumor antigen, NY-ESO-1, presented by MHC class II on cancer cells. Upon direct recognition of cancer cells, tumor-recognizing CD4(+) T cells (TR-CD4) potently induced IFN-γ-dependent growth arrest in cancer cells. In addition, direct recognition of cancer cells triggers TR-CD4 to provide help to NY-ESO-1-specific CD8(+) T cells by enhancing cytotoxic activity, and improving viability and proliferation in the absence of APCs. Notably, the TR-CD4 either alone or in collaboration with CD8(+) T cells significantly inhibited tumor growth in vivo in a xenograft model. Finally, retroviral gene-engineering with T cell receptor (TCR) derived from TR-CD4 produced large numbers of functional TR-CD4. These observations provide mechanistic insights into the role of TR-CD4 in tumor immunity, and suggest that approaches to utilize TR-CD4 will augment anti-tumor immune responses for durable therapeutic efficacy in cancer patients.

Judicialisation and Direct Democracy. Switzerland's Ban on Minaret Construction

Launched by representatives from the Union démocratique du centre (UDC) with the aim of circumventing political and judicial decisions made at both local and national levels, the 2009 federal popular initiative calling for a ban on the construction of minarets rekindled the stigmatisation of Muslims living in Switzerland. Within the prevalent institutional configuration it moreover revived controversies surrounding issues such as direct democracy versus fundamental rights, or "the will of the people" versus "the power of the judges", whether national or international. "Judicialisation" is a polysemous concept. It is not understood here as the transfer to the courts of matters of political significance - in this instance the public regulation of religion - but as a process of juridification (or juridicalisation) in which court rulings were constantly anticipated in the political debate provoked by the popular initiative.

Creatine deficiency syndomes : a new model of partial GAMT deficiency affecting brain cell development

Les syndromes de déficiences cérébrales en créatine (CCDS) sont dus à des mutations dans les gènes GATM et G AMT (codant pour les enzymes AGAT et G AMT de la voie de synthèse de créatine) ainsi que SLC6A8 (transporteur de créatine), et génèrent une absence ou une très forte baisse de créatine (Cr) dans le cerveau, mesurée par spectroscopic de résonance magnétique. Les patients CCDS développent des handicaps neurologiques sévères. Les patients AGAT et GAMT peuvent être traités avec des doses importantes de Cr, mais gardent dans la plupart des cas des séquelles neurologiques irréversibles. Aucun traitement efficace n'existe à ce jour pour la déficience en SLC6A8. Bien que de nombreux modèles aient été développés pour comprendre la Cr cérébrale en conditions physiologiques, les pathomécanismes des CCDS ne sont pas encore compris. Des souris transgéniques pour les gènes Gatm, Gamt et Slc6a8 ont été générées, mais elles ne miment que partiellement la pathologie humaine. Parmi les CCDS, la déficience en GAMT est la plus sévère, en raison de l'accumulation cérébrale de l'intermédiaire guanidinoacétate (GAA). Alors que la toxicité cérébrale du GAA a été étudiée par exposition directe au GAA d'animaux adultes sains, les mécanismes de la toxicité du GAA en condition de déficience en GAMT dans le cerveau en développement sont encore inconnus. Le but de ce projet était donc de développer un modèle de déficience en GAMT dans des cultures 3D primaires de cellules nerveuses de rat en agrégats par knock-down du gène GAMT, en utilisant un virus adéno-associé (AAV) induisant le mécanisme d'interférence à l'ARN (RNAi). Le virus scAAV2, à la multiplicité d'infection de 1000, s'est révélé le plus efficace pour transduire tous les types de cellules nerveuses des cultures (neurones, astrocytes, oligodendrocytes), et générer un knock-down maximal de la protéine GAMT de 85% (jour in vitro 18). Cette déficience partielle en GAMT s'est révélée insuffisante pour générer une déficience en Cr, mais a causé l'accumulation attendue de GAA, à des doses comparables aux niveaux observés dans le LCR des patients GAMT. Le GAA a induit une croissance axonale anarchique accompagnée d'une baisse de l'apoptose naturelle, suivis par une induction tardive de mort cellulaire non-apoptotique. Le co-traitement par la Cr a prévenu tous les effets toxiques du GAA. Ce travail montre que l'accumulation de GAA en absence de déficience en Cr est suffisante pour affecter le développement du tissu nerveux, et suggère que des formes de déficiences en GAMT supplémentaires, ne présentant pas de déficiences en Cr, pourraient être découvertes par mesure du GAA, en particulier à travers les programmes récemment proposés de dépistage néonatal de la déficience en GAMT. -- Cerebral creatine deficiency syndromes (CCDS) are caused by mutations in the genes GATM and GAMT (respectively coding for the two enzymes of the creatine synthetic pathway, AGAT and GAMT) as well as SLC6A8 (creatine transporter), and lead to the absence or very strong decrease of creatine (Cr) in the brain when measured by magnetic resonance spectroscopy. Affected patients show severe neurological impairments. While AGAT and GAMT deficient patients can be treated with high dosages of Cr, most remain with irreversible brain sequelae. No treatment has been successful so far for SLC6A8 deficiency. While many models have helped understanding the cerebral Cr pathways in physiological conditions, the pathomechanisms underlying CCDS are yet to be elucidated. Transgenic mice carrying mutations in the Gatm, Gamt and Slc6a8 genes have been developed, but only partially mimic the human pathology. Among CCDS, GAMT deficiency is the most severe, due to the CNS accumulation of the guanidinoacetate (GAA) intermediate. While brain toxicity of GAA has been explored through direct GAA exposure of adult healthy animals, the mechanisms underlying GAA toxicity in GAMT deficiency conditions on the developing CNS are yet unknown. The aim of this project was thus to develop and characterize a GAMT deficiency model in developing brain cells by gene knockdown, by adeno-associated virus (AAV)-driven RNA interference (RNAi) in rat 3D organotypic primary brain cell cultures in aggregates. scAAV2 with a multiplicity of infection of 1000 was shown as the most efficient serotype, was able to transduce all brain cell types (neurons, astrocytes, oligodendrocytes) and to induce a maximal GAMT protein knockdown of 85% (day in vitro 18). Metabolite analysis showed that partial GAMT knockdown was insufficient to induce Cr deficiency but generated the awaited GAA accumulation at concentrations comparable to the levels observed in cerebrospinal fluid of GAMT-deficient patients. Accumulated GAA induced axonal hypersprouting paralleled with inhibition of natural apoptosis, followed by a later induction in non-apoptotic cell death. Cr supplementation led to the prevention of all GAA-induced toxic effects. This work shows that GAA accumulation without Cr deficiency is sufficient to affect CNS development, and suggests that additional partial GAMT deficiencies, which may not show the classical brain Cr deficiency, may be discovered through GAA measurement including by recently proposed neonatal screening programs for GAMT deficiency.

The ABCG transporter PEC1/ABCG32 is required for the formation of the developing leaf cuticle in Arabidopsis.

The cuticle is an essential diffusion barrier on aerial surfaces of land plants whose structural component is the polyester cutin. The PERMEABLE CUTICLE1/ABCG32 (PEC1) transporter is involved in plant cuticle formation in Arabidopsis. The gpat6 pec1 and gpat4 gapt8 pec1 double and triple mutants are characterized. Their PEC1-specific contributions to aliphatic cutin composition and cuticle formation during plant development are revealed by gas chromatography/mass spectrometry and Fourier-transform infrared spectroscopy. The composition of cutin changes during rosette leaf expansion in Arabidopsis. C16:0 monomers are in higher abundance in expanding than in fully expanded leaves. The atypical cutin monomer C18:2 dicarboxylic acid is more prominent in fully expanded leaves. Findings point to differences in the regulation of several pathways of cutin precursor synthesis. PEC1 plays an essential role during expansion of the rosette leaf cuticle. The reduction of C16 monomers in the pec1 mutant during leaf expansion is unlikely to cause permeability of the leaf cuticle because the gpat6 mutant with even fewer C16:0 monomers forms a functional rosette leaf cuticle at all stages of development. PEC1/ABCG32 transport activity affects cutin composition and cuticle structure in a specific and non-redundant fashion.

Developing Launching Processes — A Case Study

New product launches are becoming more and more important to companies around the globe. Being first on the market is a good place to be, and it will mostly likely bring the best profits. Gaining that desired position requires a lot of work where cooperation inside as well as outside of the company need to be in line. This thesis discusses launching processes in a pharmaceutical firm. The topic is looked at from supply chain management's point of view where purchasing department's role is emphasized. Additionally, launching strategies related to launches are investigated and the idea of internal alignment is introduced. Moreover, the topic is examined in project and process management perspective; how with the tools of project and process management the launching processes could be improved. The main findings reveal that there are many improvement points in the current launching process. Problems in the areas of information exchange, leadership and internal alignment were discovered yet trust and confidence for the better future compound the interviewees. This study presents what are the most important factors for a successful product launch and how the current processes could be streamlined.

Developing service offering of an air freight carrier

The thesis examined service offering development of an air freight carrier from the customers' point of view. The study was limited to the biggest business clients of the carrier. Service offering development can be divided into service concept, process and system. The thesis was based on these three themes and quality. Compared to product development, systematic and well-structured service development has been studied little, especially in business market. However, service development is a current issue. Due to growing competition companies should carefully listen to their clients' needs and respond to them by offering right services. Methodology of the thesis is qualitative and representatives of three forwarding companies were interviewed. It was found out that the forwarding companies consider themselves as partners of the airline. In addition to general reliability, the customers value the most fluent terminal processes and electronic communication.

Developing of the Variable Speed Drive -control in simulated parallel pumping systems

This thesis presents briefly the basic operation and use of centrifugal pumps and parallel pumping applications. The characteristics of parallel pumping applications are compared to circuitry, in order to search analogy between these technical fields. The purpose of studying circuitry is to find out if common software tools for solving circuit performance could be used to observe parallel pumping applications. The empirical part of the thesis introduces a simulation environment for parallel pumping systems, which is based on circuit components of Matlab Simulink —software. The created simulation environment ensures the observation of variable speed controlled parallel pumping systems in case of different controlling methods. The introduced simulation environment was evaluated by building a simulation model for actual parallel pumping system at Lappeenranta University of Technology. The simulated performance of the parallel pumps was compared to measured values of the actual system. The gathered information shows, that if the initial data of the system and pump perfonnance is adequate, the circuitry based simulation environment can be exploited to observe parallel pumping systems. The introduced simulation environment can represent the actual operation of parallel pumps in reasonably accuracy. There by the circuitry based simulation can be used as a researching tool to develop new controlling ways for parallel pumps.