Microbe-induced Innate Immune Responses in Human Dendritic Cells

Two types of antigen-presenting cells (APCs), macrophages and dendritic cells (DCs), function at the interface of innate and adaptive immunity. Through recognition of conserved microbial patterns, they are able to detect the invading pathogens. This leads to activation of signal transduction pathways that in turn induce gene expression of various molecules required for immune responses and eventually pathogen clearance. Cytokines are among the genes induced upon detection of microbes. They play an important role in regulating host immune responses during microbial infection. Chemotactic cytokines, chemokines, are involved in migratory events of immune cells. Cytokines also promote the differentiation of distinct T cell responses. Because of the multiple roles of cytokines in the immune system, the cytokine network needs to be tightly regulated. In this work, the induction of innate immune responses was studied using human primary macrophages or DCs as cell models. Salmonella enterica serovar Typhimurium served as a model for an intracellular bacterium, whereas Sendai virus was used in virus experiments. The starting point of this study was that DCs of mouse origin had recently been characterized as host cells for Salmonella. However, only little was known about the immune responses initiated in Salmonella-infected human DCs. Thus, cellular responses of macrophages and DCs, in particular the pattern of cytokine production, to Salmonella infection were compared. Salmonella-induced macrophages and DCs were found to produce multiple cytokines including interferon (IFN) -gamma, which is conventionally produced by T and natural killer (NK) cells. Both macrophages and DCs also promoted the intracellular survival of the bacterium. Phenotypic maturation of DCs as characterized by upregulation of costimulatory and human leukocyte antigen (HLA) molecules, and production of CCL19 chemokine, were also detected upon infection with Salmonella. Another focus of this PhD work was to unravel the regulatory events controlling the expression of cytokine genes encoding for CCL19 and type III IFNs, which are central to DC biology. We found that the promoters of CCL19 and type III IFNs contain similar regulatory elements that bind nuclear factor kappaB (NF-kappaB) and interferon regulatory factors (IRFs), which could mediate transcriptional activation of the genes. The regulation of type III IFNs in virus infection resembled that of type I IFNs a cytokine class traditionally regarded as antiviral. The induction of type I and type III IFNs was also observed in response to bacterial infection. Taken together, this work identifies new details about the interaction of Salmonella with its phagocytic host cells of human origin. In addition, studies provide information on the regulatory events controlling the expression of CCL19 and the most recently identified IFN family genes, type III IFN genes.

Local Politicizations : A Comparison of Finns and French Practicing Democracy

This study examines how do the processes of politicization differ in the Finnish and the French local contexts, and what kinds of consequences do these processes have on the local civic practices, the definitions and redefinitions of democracy and citizenship, the dynamics of power and resistance, and the ways of solving controversies in the public sphere. By means of comparative anthropology of the state , focusing on how democracy actually is practiced in different contexts, politicizations the processes of opening political arenas and recognizing controversy are analyzed. The focus of the study is on local activists engaged in different struggles on various levels of the local public spheres, and local politicians and civil servants participating in these struggles from their respective positions, in two middle-size European cities, Helsinki and Lyon. The empirical analyses of the book compare different political actors and levels of practicing democracy simultaneously. The study is empirically based on four different bodies of material: Ethnographic notes taken during a fieldwork among the activities of several local activist groups; 47 interviews of local activists and politicians; images representing different levels of public portrayals from activist websites (Helsinki N=274, Lyon N=232) and from city information magazines (Helsinki-info N=208, Lyon Citoyen N= 357); and finally, newspaper articles concerning local conflict issues, and reporting on the encounters between local citizens and representatives of the cities (January-June in 2005; Helsingin Sanomat N=96 and Le Progrès N= 102). The study makes three distinctive contributions to the study of current democratic societies: (1) a conceptual one by bringing politicization at the center of a comparison of political cultures, and by considering in parallel the ethnographic group styles theory by Nina Eliasoph and Paul Lichterman, the theory on counter-democracy by Pierre Rosanvallon and the pragmatist justification theory by Luc Boltanski and Laurent Thévenot; (2) an empirical one through the triangulation of ethnographic, thematic interview, visual, and newspaper data through which the different aspects of democratic practices are examined; and (3) a methodological one by developing new ways of analyzing comparative cases an application of Frame Analysis to visual material and the creation of Public Justification Analysis for analyzing morally loaded claims in newspaper reports thus building bridges between cultural, political, and pragmatic sociology. The results of the study indicate that the cultural tools the Finnish civic actors had at their disposal were prone to hinder more than support politicization, whereas the tools the French actors mainly relied on were frequently apt for making politicization possible. This crystallization is defined and detailed in many ways in the analyses of the book. Its consequences to the understanding and future research on the current developments of democracy are multiple, as politicization, while not assuring good results as such, is central to a functioning and vibrant democracy in which injustices can be fixed and new directions and solutions sought collectively.

Monetary Policy Implementation in the Interbank Market

The liquidity crisis that swept through the financial markets in 2007 triggered multi-billion losses and forced buyouts of some large banks. The resulting credit crunch is sometimes compared to the great recession in the early twentieth century. But the crisis also serves as a reminder of the significance of the interbank market and of proper central bank policy in this market. This thesis deals with implementation of monetary policy in the interbank market and examines how central bank tools affect commercial banks' decisions. I answer the following questions: • What is the relationship between the policy setup and interbank interest rate volatility? (averaging reserve requirement reduces the volatility) • What can explain a weak relationship between market liquidity and the interest rate? (high reserve requirement buffer) • What determines banks' decisions on when to satisfy the reserve requirement? (market frictions) • How did the liquidity crisis that began in 2007 affect interbank market behaviour? (resulted in higher credit risk and trading frictions as well as expected liquidity shortage)

Critical leg ischaemia with tissue loss : a challenge for the vascular surgeon

There is a widespread reporting habit of combining the outcomes for patients with rest pain (Fontaine III) and tissue loss (Fontaine IV) under the single category of critical leg ischaemia (CLI). This study focused on patients with ischaemic tissue loss treated with infrainguinal bypass surgery (IBS). All patients included in the study were treated at Helsinki University Central Hospital in 2000-2007. First, ulcer healing time after IBS and factors influencing healing time were prospectively assessed in 2 studies including 148 and 110 patients, respectively. Second,the results of redo IBS were retrospectively evaluated in 593 patients undergoing primary IBS for CLI with tissue loss . Third,long-term outcome were retrospectively analysed in 636 patients who underwent IBS for CLI with tissue loss . Fourth, the outcome of IBS was retrospectively compared with endovascular treatment (PTA) of the infrapopliteal arteries in 1023 CLI patients. Fifth, the influence multidrug resistant Pseudomans aeruginosa (MDR Pa) bacteria contamination in CLI patients treated with IBS was retropectively assessed. Sixty-four patients with positive MDR Pa -culture were matched with 64 MDR Pa - negative controls. Complete ulcer healing rate, including the ischemic ulcers and incisional wounds, was 40% at 6 months after IBS and 75% at one year. Diabetes was a risk factor for prolonged complete ulcer healing time. Ischaemic tissue lesions located in mid-and hindfoot healed poorly. At one year after IBS 50% of the patients were alive with salvaged leg and completely healed ulcers. The absence of gap between tertiary graft patency and leg salvage rates indicates the importance of a patent infrainguinal graft to save a leg with ischaemic tissue loss. Long-term survival for patients with ischaemic tissue loss was poor, 38% at 5 years. Only 30% of the patients were alive without amputation at 5 years. Several of the patient comorbidities increased independently the mortality risk; coronary artery disease, renal insufficiency, chronic obstructive lung disease and high age. When both PTA and bypass is feasible, infrapopliteal PTA as a first-line strategy is expected to achieve similar long-term results to bypass surgery in CLI when redo surgery is actively utilized. MDR Pa in a patient with CLI should be considered as a serious event with increased risk of early major amputation or death. Conclusion: Despite a successful infrainguinal bypass healing of the ischaemic ulcers and incisional wounds ulcer healing is a slow process especially in diabetics. Bypass surgery and PTA improve the outcome of the ischaemic leg but the mortality rate of the patients is high due to their severe comorbidities.

Eri maitohappobakteerien ja niiden annostustason vaikutus säilörehun käymislaatuun ja aerobiseen stabiilisuuteen

Tämän maisterin tutkielman tarkoituksena oli testata eri maitohappobakteerien ja niiden annostustason vaikutusta säilörehun käymislaatuun ja aerobiseen stabiilisuuteen. Biologisilla säilöntäaineilla eli ympeillä säilöttyjen rehujen laatua verrattiin kontrolleina toimiviin painorehuun ja muurahaishapolla tehtyyn rehuun. Koerehut tehtiin Helsingin yliopiston Maataloustieteiden laitoksella 7.6.2010. Timotei (Phleum pratense) - nurminata (Festuca pratensis) kasvusto korjattiin tähkimisen alkuvaiheessa D-arvon ollessa 711 g/kg ka. Nurmikasvuston kuiva-ainepitoisuus oli 170 g/kg heti niiton jälkeen määritettäessä ja neljän tunnin esikuivauksen jälkeen 208 g/kg. Rehuraaka-aine jaettiin kuuteen erään, joihin lisättiin säilöntäaine. Säilöntäainekäsittelyt olivat: 1) ei säilöntäainetta (painorehu), 2) muurahaishappo (100 %:na 4 l/t), 3) Lactobacillus plantarum ja Pediococcus acidilactici 1x10? pmy/g sekä pektinaasi-, ksylanaasi- ja sellulaasientsyymi, 4) L. plantarum 1x10? pmy/g, 5) L. plantarum 1x10? pmy/g ja 6) L. plantarum ja L. buchneri 2x10? pmy/g. Rehut säilöttiin laboratoriosiiloissa kolmena rinnakkaisena. Laboratoriosiilojen lisäksi rehua säilöttiin jokaisesta säilöntäainekäsittelystä kuuteen rinnakkaiseen minisiiloon säilönnän alkuajan fermentaation ja rehujen pH:n muutoksen seuraamiseksi. Minisiiloista seurattiin kaasuntuotantoa 21 päivän ajan. Raaka-aineen koostumus ja rehujen säilönnällinen laatu sekä aerobinen stabiilisuus määritettiin. Säilörehujen kuiva-ainepitoisuus oli suhteellisen pieni (n. 210 g/kg), jotta voitiin testata biologisten säilöntäaineiden tehoa märässä rehussa. Kosteassa rehussa biologisten säilöntäaineiden toiminnan onnistuminen on haastavaa. Koska raaka-aineen sokeripitoisuus oli kuitenkin erittäin suuri (196 g/kg ka), onnistui ymppirehujen säilöntä hyvin. Kaikkien koerehujen pH oli alle 4:n. Painorehu ei täyttänyt hyvän rehun kriteerejä ammoniumtypen osalta. Muurahaishapporehu oli laadultaan tyydyttävää etikkahapon pitoisuuden osalta. Rehussa tapahtui epätyypillistä etanolikäymistä hiivojen toimesta, jonka johdosta rehussa muodostui suuri määrä kaasua säilönnän aikana. Muurahaishapporehu ei kuitenkaan lämmennyt aerobisen stabiilisuuden mittauksen aikana, johtuen todennäköisesti suuresta etikkahapon määrästä ja toisaalta pienestä sokerin määrästä. Maitohappobakteerisäilöntäaineilla saatiin käymislaadultaan parempaa säilörehua verrattuna painorehuun, lukuun ottamatta maitohappobakteeri-entsyymirehua. Entsyymilisäyksestä ei todennäköisesti ollut hyötyä rehun säilöntälaadun kannalta. Raaka-aineen suuren sokeripitoisuuden johdosta säilörehussa oli koko säilönnän ajan tarpeeksi sokeria maitohappobakteerien käytettäväksi ja sokeri toimi siten substraattina haitallisille mikrobeille tuottaen suuren etikkahappopitoisuuden. Maitohappobakteeri-entsyymiseoksella tehty rehu oli etikkahappopitoisuuden perusteella heikkolaatuista. Lactobacillus plantarumin molemmilla annostustasoilla (1x10? ja 1x10? pmy/g rehua) saatiin laadultaan hyvää rehua. Suuri sokeripitoisuus molemmissa rehuissa johtui todennäköisesti raaka-aineen tavallista suuremmasta sokerin määrästä. Molempien rehujen maitohappo-etikkahappo-suhde oli melko korkea, viitaten homofermentatiiviseen maitohappokäymiseen. Lactobacillus buchneri –lisäyksellä rehu oli säilönnälliseltä laadultaan hyvää. Heterofermentatiivisen ympin lisäys nosti tyypillisesti rehun pH:ta sekä pienensi maitohappoetikkahappo-suhdelukua verrattuna homofermentatiiviseen ymppiin. L. buchneri –lisäys paransi hieman säilörehun aerobista stabiilisuutta verrattuna homofermentatiivisella maitohappobakteerilla säilöttyyn rehuun, mutta tulos ei ollut tilastollisesti merkitsevä.

Genetic polymorphisms and laboratory variables as predictors of blood pressure response to antihypertensive drugs

Hypertension is one of the major risk factors for cardiovascular morbidity. The advantages of antihypertensive therapy have been clearly demonstrated, but only about 30% of hypertensive patients have their blood pressure (BP) controlled by such treatment. One of the reasons for this poor BP control may lie in the difficulty in predicting BP response to antihypertensive treatment. The average BP reduction achieved is similar for each drug in the main classes of antihypertensive agents, but there is a marked individual variation in BP responses to any given drug. The purpose of the present study was to examine BP response to four different antihypertensive monotherapies with regard to demographic characteristics, laboratory test results and common genetic polymorphisms. The subjects of the present study are participants in the pharmacogenetic GENRES Study. A total of 208 subjects completed the whole study protocol including four drug treatment periods of four weeks, separated by four-week placebo periods. The study drugs were amlodipine, bisoprolol, hydrochlorothiazide and losartan. Both office (OBP) and 24-hour ambulatory blood pressure (ABP) measurements were carried out. BP response to study drugs were related to basic clinical characteristics, pretreatment laboratory test results and common polymorphisms in genes coding for components of the renin-angiotensin system, alpha-adducin (ADD1), beta1-adrenergic receptor (ADRB1) and beta2-adrenergic receptor (ADRB2). Age was positively correlated with BP responses to amlodipine and with OBP and systolic ABP responses to hydrochlorothiazide, while body mass index was negatively correlated with ABP responses to amlodipine. Of the laboratory test results, plasma renin activity (PRA) correlated positively with BP responses to losartan, with ABP responses to bisoprolol, and negatively with ABP responses to hydrochlorothiazide. Uniquely to this study, it was found that serum total calcium level was negatively correlated with BP responses to amlodipine, whilst serum total cholesterol level was negatively correlated with ABP responses to amlodipine. There were no significant associations of angiotensin II type I receptor 1166A/C, angiotensin converting enzyme I/D, angiotensinogen Met235Thr, ADD1 Gly460Trp, ADRB1 Ser49Gly and Gly389Arg and ADRB2 Arg16Gly and Gln27Glu polymorphisms with BP responses to the study drugs. In conclusion, this study confirmed the relationship between pretreatment PRA levels and response to three classes of antihypertensive drugs. This study is the first to note a significant inverse relation between serum calcium level and responsiveness to a calcium channel blocker. However, this study could not replicate the observations that common polymorphisms in angiotensin II type I receptor, angiotensin converting enzyme, angiotensinogen, ADD1, ADRB1, or ADRB2 genes can predict BP response to antihypertensive drugs.