Synthesis of neoglycoconjugates and oligosaccharides with potential anti-Helicobacter pylori activity

The significance of carbohydrate-protein interactions in many biological phenomena is now widely acknowledged and carbohydrate based pharmaceuticals are under intensive development. The interactions between monomeric carbohydrate ligands and their receptors are usually of low affinity. To overcome this limitation natural carbohydrate ligands are often organized as multivalent structures. Therefore, artificial carbohydrate pharmaceuticals should be constructed on the same concept, as multivalent carbohydrates or glycoclusters. Infections of specific host tissues by bacteria, viruses, and fungi are among the unfavorable disease processes for which suitably designed carbohydrate inhibitors represent worthy targets. The bacterium Helicobacter pylori colonizes more than half of all people worldwide, causing gastritis, gastric ulcer, and conferring a greater risk of stomach cancer. The present medication therapy for H. pylori includes the use of antibiotics, which is associated with increasing incidence of bacterial resistance to traditional antibiotics. Therefore, the need for an alternative treatment method is urgent. In this study, four novel synthesis procedures of multivalent glycoconjugates were created. Three different scaffolds representing linear (chondroitin oligomer), cyclic (γ-cyclodextrin), and globular (dendrimer) molecules were used. Multivalent conjugates were produced using the human milk type oligosaccharides LNDFH I (Lewis-b hexasaccharide), LNnT (Galβ1-4GlcNAcβ1-3Galβ1-4Glc), and GlcNAcβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4Glc all representing analogues of the tissue binding epitopes for H. pylori. The first synthetic method included the reductive amination of scaffold molecules modified to express primary amine groups, and in the case of dendrimer direct amination to scaffold molecule presenting 64 primary amine groups. The second method described a direct procedure for amidation of glycosylamine modified oligosaccharides to scaffold molecules presenting carboxyl groups. The final two methods that were created both included an oxime-linkage on linkers of different length. All the new synthetic procedures synthesized had the advantage of using unmodified reducing sugars as starting material making it easy to synthesize glycoconjugates of different specificity. In addition, the binding activity of an array of neoglycolipids to H. pylori was studied. Consequently, two new neolacto-based structures, Glcβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4Glcβ1-Cer and GlcAβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4Glcβ1-Cer, with binding activity toward H. pylori were discovered. Interestingly, N-methyl and N-ethyl amide modification of the GlcAβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4Glcβ1-Cer glucuronic acid residue resulted in more effective H. pylori binding epitopes than the parent molecule.

On the Rademacher maximal function

Tools known as maximal functions are frequently used in harmonic analysis when studying local behaviour of functions. Typically they measure the suprema of local averages of non-negative functions. It is essential that the size (more precisely, the L^p-norm) of the maximal function is comparable to the size of the original function. When dealing with families of operators between Banach spaces we are often forced to replace the uniform bound with the larger R-bound. Hence such a replacement is also needed in the maximal function for functions taking values in spaces of operators. More specifically, the suprema of norms of local averages (i.e. their uniform bound in the operator norm) has to be replaced by their R-bound. This procedure gives us the Rademacher maximal function, which was introduced by Hytönen, McIntosh and Portal in order to prove a certain vector-valued Carleson's embedding theorem. They noticed that the sizes of an operator-valued function and its Rademacher maximal function are comparable for many common range spaces, but not for all. Certain requirements on the type and cotype of the spaces involved are necessary for this comparability, henceforth referred to as the “RMF-property”. It was shown, that other objects and parameters appearing in the definition, such as the domain of functions and the exponent p of the norm, make no difference to this. After a short introduction to randomized norms and geometry in Banach spaces we study the Rademacher maximal function on Euclidean spaces. The requirements on the type and cotype are considered, providing examples of spaces without RMF. L^p-spaces are shown to have RMF not only for p greater or equal to 2 (when it is trivial) but also for 1 < p < 2. A dyadic version of Carleson's embedding theorem is proven for scalar- and operator-valued functions. As the analysis with dyadic cubes can be generalized to filtrations on sigma-finite measure spaces, we consider the Rademacher maximal function in this case as well. It turns out that the RMF-property is independent of the filtration and the underlying measure space and that it is enough to consider very simple ones known as Haar filtrations. Scalar- and operator-valued analogues of Carleson's embedding theorem are also provided. With the RMF-property proven independent of the underlying measure space, we can use probabilistic notions and formulate it for martingales. Following a similar result for UMD-spaces, a weak type inequality is shown to be (necessary and) sufficient for the RMF-property. The RMF-property is also studied using concave functions giving yet another proof of its independence from various parameters.

Microneurovascular free muscle transfer with cross-over nerve grafts in facial reanimation

Microneurovascular free muscle transfer with cross-over nerve grafts in facial reanimation Loss of facial symmetry and mimetic function as seen in facial paralysis has an enormous impact on the psychosocial conditions of the patients. Patients with severe long-term facial paralysis are often reanimated with a two-stage procedure combining cross-facial nerve grafting, and 6 to 8 months later with microneurovascular (MNV) muscle transfer. In this thesis, we recorded the long-term results of MNV surgery in facial paralysis and observed the possible contributing factors to final functional and aesthetic outcome after this procedure. Twenty-seven out of forty patients operated on were interviewed, and the functional outcome was graded. Magnetic resonance imaging (MRI) of MNV muscle flaps was done, and nerve graft samples (n=37) were obtained in second stage of the operation and muscle biopsies (n=18) were taken during secondary operations.. The structure of MNV muscles and nerve grafts was evaluated using histological and immunohistochemical methods ( Ki-67, anti-myosin fast, S-100, NF-200, CD-31, p75NGFR, VEGF, Flt-1, Flk-1). Statistical analysis was performed. In our studies, we found that almost two-thirds of the patients achieved good result in facial reanimation. The longer the follow-up time after muscle transfer the weaker was the muscle function. A majority of the patients (78%) defined their quality of life improved after surgery. In MRI study, the free MNV flaps were significantly smaller than originally. A correlation was found between good functional outcome and normal muscle structure in MRI. In muscle biopsies, the mean muscle fiber diameter was diminished to 40% compared to control values. Proliferative activity of satellite cells was seen in 60% of the samples and it tended to decline with an increase of follow-up time. All samples showed intramuscular innervation. Severe muscle atrophy correlated with prolonged intraoperative ischaemia. The good long-term functional outcome correlated with dominance of fast fibers in muscle grafts. In nerve grafts, the mean number of viable axons amounted to 38% of that in control samples. The grafted nerves characterized by fibrosis and regenerated axons were thinner than in control samples although they were well vascularized. A longer time between cross facial nerve grafting and biopsy sampling correlated with a higher number of viable axons. P75Nerve Growth Factor Receptor (p75NGFR) was expressed in every nerve graft sample. The expression of p75NGFR was lower in older than in younger patients. A high expression of p75NGFR was often seen with better function of the transplanted muscle. In grafted nerve Vascular Endothelial Growth Factor (VEGF) and its receptors were expressed in nervous tissue. In conclusion, most of the patients achieved good result in facial reanimation and were satisfied with the functional outcome. The mimic function was poorer in patients with longer follow-up time. MRI can be used to evaluate the structure of the microneurovascular muscle flaps. Regeneration of the muscle flaps was still going on many years after the transplantation and reinnervation was seen in all muscle samples. Grafted nerves were characterized by fibrosis and fewer, thinner axons compared to control nerves although they were well vascularized. P75NGFR and VEGF were expressed in human nerve grafts with higher intensity than in control nerves which is described for the first time.

Outcomes of ruptured abdominal aortic aneurysm

Ruptured abdominal aortic aneurysm (RAAA) is a life-threatening event, and without operative treatment the patient will die. The overall mortality can be as high as 80-90%; thus repair of RAAA should be attempted whenever feasible. The quality of life (QoL) has become an increasingly important outcome measure in vascular surgery. Aim of the study was to evaluate outcomes of RAAA and to find out predictors of mortality. In Helsinki and Uusimaa district 626 patients were identified to have RAAA in 1996-2004. Altogether 352 of them were admitted to Helsinki University Central Hospital (HUCH). Based on Finnvasc Registry, 836 RAAA patients underwent repair of RAAA in 1991-1999. The 30-day operative mortality, hospital and population-based mortality were assessed, and the effect of regional centralisation and improving in-hospital quality on the outcome of RAAA. QoL was evaluated by a RAND-36 questionnaire of survivors of RAAA. Quality-adjusted life years (QALYs), which measure length and QoL, were calculated using the EQ-5D index and estimation of life expectancy. The predictors of outcome after RAAA were assessed at admission and 48 hours after repair of RAAA. The 30-day operative mortality rate was 38% in HUCH and 44% nationwide, whereas the hospital mortality was 45% in HUCH. Population-based mortality was 69% in 1996-2004 and 56% in 2003-2004. After organisational changes were undertaken, the mortality decreased significantly at all levels. Among the survivors, the QoL was almost equal when compared with norms of age- and sex-matched controls; only physical functioning was slightly impaired. Successful repair of RAAA gave a mean of 4.1 (0-30.9) QALYs for all RAAA patients, although non-survivors were included. The preoperative Glasgow Aneurysm Score was an independent predictor of 30-day operative mortality after RAAA, and it also predicted the outcome at 48- hours for initial survivors of repair of RAAA. A high Glasgow Aneurysm Score and high age were associated with low numbers of QALYs to be achieved. Organ dysfunction measured by the Sequential Organ Failure Assessment (SOFA) score at 48 hours after repair of RAAA was the strongest predictor of death. In conclusion surgery of RAAA is a life-saving and cost-effective procedure. The centralisation of vascular emergencies improved the outcome of RAAA patients. The survivors had a good QoL after RAAA. Predictive models can be used on individual level only to provide supplementary information for clinical decision-making due to their moderate discriminatory value. These results support an active operation policy, as there is no reliable measure to predict the outcome after RAAA.

Anti-TNF treatment in juvenile idiopathic arthritis and associated uveitis : Clinical perspectives on growth, uveitis, and drug survival

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of childhood chronic arthritides, associated with chronic uveitis in 20% of cases. For JIA patients responding inadequately to conventional disease-modifying anti-rheumatic drugs (DMARDs), biologic therapies, anti-tumor necrosis factor (anti-TNF) agents are available. In this retrospective multicenter study, 258 JIA-patients refractory to DMARDs and receiving biologic agents during 1999-2007 were included. Prior to initiation of anti-TNFs, growth velocity of 71 patients was delayed in 75% and normal in 25%. Those with delayed growth demonstrated a significant increase in growth velocity after initiation of anti-TNFs. Increase in growth rate was unrelated to pubertal growth spurt. No change was observed in skeletal maturation before and after anti-TNFs. The strongest predictor of change in growth velocity was growth rate prior to anti-TNFs. Change in inflammatory activity remained a significant predictor even after decrease in glucocorticoids was taken into account. In JIA-associated uveitis, impact of two first-line biologic agents, etanercept and infliximab, and second-line or third-line anti-TNF agent, adalimumab, was evaluated. In 108 refractory JIA patients receiving etanercept or infliximab, uveitis occurred in 45 (42%). Uveitis improved in 14 (31%), no change was observed in 14 (31%), and in 17 (38%) uveitis worsened. Uveitis improved more frequently (p=0.047) and frequency of annual uveitis flares was lower (p=0.015) in those on infliximab than in those on etanercept. In 20 patients taking adalimumab, 19 (95%) had previously failed etanercept and/or infliximab. In 7 patients (35%) uveitis improved, in one (5%) worsened, and in 12 (60%) no change occurred. Those with improved uveitis were younger and had shorter disease duration. Serious adverse events (AEs) or side-effects were not observed. Adalimumab was effective also in arthritis. Long-term drug survival (i.e. continuation rate on drug) with etanercept (n=105) vs. infliximab (n=104) was at 24 months 68% vs. 68%, and at 48 months 61% vs. 48% (p=0.194 in log-rank analysis). First-line anti-TNF agent was discontinued either due to inefficacy (etanercept 28% vs. infliximab 20%, p=0.445), AEs (7% vs. 22%, p=0.002), or inactive disease (10% vs. 16%, p=0.068). Females, patients with systemic JIA (sJIA), and those taking infliximab as the first therapy were at higher risk for treatment discontinuation. One-third switched to the second anti-TNF agent, which was discontinued less often than the first. In conclusion, in refractory JIA anti-TNFs induced enhanced growth velocity. Four-year treatment survival was comparable between etanercept and infliximab, and switching from first-line to second-line agent a reasonable therapeutic option. During anti-TNF treatment, one-third with JIA-associated anterior uveitis improved.

What should I think; How should I feel? : The balancing of personal experiences and social norms in the outgroup attitude formation of youth

The present study focused on the associations between the personal experiences of intergroup contact, perceived social norms and the outgroup attitudes of Finnish majority and Russian-speaking minority youth living in Finland. The theoretical background of the study was derived from Allport s (1954) theory of intergroup contact (i.e., the contact hypothesis), social psychological research on normative influences on outgroup attitudes (e.g., Rutland, 2004; Stangor and Leary, 2006) and developmental psychological research on the formation of explicit (deliberate) and implicit (automatically activated) outgroup attitudes in adolescence (e.g., Barrett, 2007; Killen, McGlothlin and Henning, 2008). The main objective of the study was to shed light on the role of perceived social norms in the formation of outgroup attitudes among adolescents. First, the study showed that perceived normative pressure to hold positive attitudes towards immigrants regulated the relationship between the explicit and implicit expression of outgroup attitudes among majority youth. Second, perceived social norms concerning outgroup attitudes (i.e., the perceived outgroup attitudes of parents and peers) affected the relationship between intergroup contact and explicit outgroup attitudes depending on gender and group status. Positive social norms seem to be especially important for majority boys, who need both pleasant contact experiences and normative support to develop outgroup attitudes that are as positive as girls attitudes. The role of social norms is accentuated also among minority youth, who, contrary to majority youth with their more powerful and independent status position, need to reflect upon their attitudes and experiences of negative intergroup encounters in relation to the experiences and attitudes of their ingroup members. Third, the results are indicative of the independent effects of social norms and intergroup anxiety on outgroup attitudes: the effect of perceived social norms on the outgroup attitudes of youth seems to be at least as strong as the effect of intergroup anxiety. Finally, it was shown that youth evaluate intergroup contact from the viewpoint of their ingroup and society as a whole, not just based on their own experiences. In conclusion, the outgroup attitudes of youth are formed in a close relationship with their social environment. On the basis of this study, the importance of perceived social norms for research on intergroup contact effects among youth cannot be overlooked. Positive normative influences have the potential to break the strong link between rare and/or negative personal contact experiences and negative outgroup attitudes, and norms also influence the relationship between implicit and explicit attitude expression.

Kansalaisvaikuttamista? Habermasilaisen julkisuusteorian anti suomalaiselle ympäristöliikkeelle

Tässä pro gradu -tutkielmassa analysoidaan suomalaista ympäristöliikettä Jürgen Habermasin julkisuuden käsitteen näkökulmasta. Työn tutkimusongelmana on tarkastella julkisuutta ympäristövaikuttamisen keinona. Ponnahduslautana tutkimuksessa käytetään 2000-luvun Lapin metsien käyttöä koskevia kiistoja, joiden ratkomisyrityksiin moni Suomessa toimiva ympäristöjärjestö on osallistunut. Pitkään ratkaisemattomina olleet kiistat ovat johtaneet tilanteeseen, jossa on perusteltua kysyä, mikä ongelmien selvittämisessä on mennyt pieleen. Olisiko ennen kaikkea ammattimaiseen ja institutionalisoituneeseen vaikuttamiseen nojanneet ympäristöjärjestöt voineet toimia kiistojen yhteydessä jollakin vaihtoehtoisella tavalla? Vaihtoehdoksi esitetään Jürgen Habermasin tarjoamaa julkisuuden mallia, jonka on nähty olevan keskeinen modernin yhteiskunnan mahdollisuuksia ja rajoitteita arvioitaessa. Käsitys julkisuudesta sisältää ajatuksen kriittiseen keskusteluun pohjautuvasta, kaikille avoimesta kansalaisvaikuttamisesta. Näin muodostuneesta yleisestä mielipiteestä tulee poliittisen päätöksenteon ohjenuora. Julkisuuden ihanteen rinnalla Habermasin teoria sisältää kuvauksen julkisuuden rakennemuutoksesta – kriittisen julkisuuden alennustilasta myöhäiskapitalistisessa kulutusyhteiskunnassa. Tässä tutkimuksessa käytän näitä kahta teoreettista näkökulmaa arvioidessani nykyaikaista ympäristövaikuttamista. Keskeisin lähdeteos on Habermasin Julkisuuden rakennemuutos ja sen teoreettista perinnettä jatkaneet tutkimukset. Aineistoni koostuu kuudesta teemahaastattelusta, jotka toteutettiin keväällä 2009 Greenpeacessa, Suomen luonnonsuojeluliitossa ja WWF:ssä. Tutkimusmenetelmänä käytän teemoittelua. Sen tuloksena esiin nousevista teemoista keskeisin kertoo ympäristöjärjestöjen ammattimaistumisesta. Tulosteni mukaan ympäristövaikuttamista leimaa institutionalisoituneisuus ja hallinnollisuus, jolloin julkisuusperiaatteen toimintaedellytykset ovat heikentyneet. Julkisuuden käsitteelle löytyy kuitenkin myös varovaista tilausta suomalaisten ympäristöjärjestöjen keskuudessa.

Conflits de norms de justice distributive dans les fusions entre égaux Le cas de BioM.rieux-Pierre Fabre

Les strictes fusions entre égaux constituent un phénomène très rare. Pourtant, de nombreux dirigeants communiquent sur l’aspect égalitaire des fusions et acquisitions qu’ils conçoivent. Dans cet article, les auteurs expliquent pourquoi les dirigeants <> leurs F&A en <> ; montrent en quoi le postulat égalitaire initial accroît la probabilité de conflits entre deux normes de justice distributive pourtant compl.mentaires : l’égalité et l’équité ; et illustrent leurs propos avec un cas spectaculaire : la fusion égalitaire, puis la separation des entreprises BioMérieux et Pierre Fabre. Paradoxalement, la simple formulation en termes égalitaire des F&A favorise la diffusion de sentiments d’injustice distributive, qui nuit in fine à la performance de l’opération.