Darbo problema – vis dar lieka neaiškus PRR efektyvumas ir jos sąsajos su amžiumi, lytimi, išsilavinimu, IŠL forma, subjektyvia savijauta, subjektyviu sveikatos vertinimu bei organizmo raumenų įtampa, sergantiems IŠL. Todėl šio tyrimo tikslas - nustatyti progresuojančios raumenų relaksacijos taikymo efektyvumą AKS reguliavimui, atsižvelgiant į lytį, amžių, ligos formą, subjektyvų sveikatos vertinimą, išsilavinimą, raumenų įtampą ir subjektyvią savijautos įtampą, sergantiems IŠL, stacionarinės reabilitacijos etape. Tyrime buvo pakviesti dalyvauti 204 Abromiškių reabilitacinės ligoninės, kardiologinio skyriaus pacientai, tačiau į 1 užsiėmimą atėjo 53 (48,18 %) vyrai ir 40 (42,55 %) moterų, į 2 – 20 (18,18 %) vyrų ir 14 (14,89 %) moterų, į 3 – 15 (13,63 %) vyrų ir 12 (12,76 %) moterų ir į 4 – 12 (10,9 %) vyrų ir 8 (8,51 %) moterys. Tiriamieji dalyvavo 4 vienos valandos užsiėmimuose, kurie vyko 4 kartus per savaitę. Siekiant įvertinti PRR efektyvumą AKS mažinimui ir efektyvumo sąsajas su prieš tai išvardintais faktoriais, tiriamiesiems buvo pateikiamos anketos, vedami relaksaciniai užsiėmimai. Kiekvieno užsiėmimo pradžioje ir pabaigoje buvo matuojamas AKS ir duodamas užpildyti manekenas (raumenų įtampai įvertinti) bei subjektyvios savijautos skalė. Tyrimo rezultatai parodė, kad po relaksacijos AKS statistiškai reikšmingi sumažėjimai buvo tik vyrų tarpe, taip pat tarp jaunesnių pacientų, žmonėms sergantiems lengvesne IŠL forma, pacientams su aukštuoju išsilavinimu ir blogesniu... [toliau žr. visą tekstą] / It is still unclear if effectiveness of PMR is related with age, gender, education, IHD form, subjective health status, subjective tension and muscle tension for ischemic heart disease patients. So the aim of this survey is to analize how effectiveness of progressive muscle relaxation in blood pressure regulation is related with these factors for ischemic heart disease in-patients at their rehabilitation period. 204 patients from Abromiškės rehabilitation hospital, cardiac department were invited to participate in relaxation groups, but in the first group participated only 53 (48,18%) men and 40 (42,55%) women, in the second - 20 (18,18%) men and 14 (14,89%) women, in the third - 15 (13,63%) men and 12 (12,76%) women and in fourth - 12 (10,9%) men and 8 (8,51%) women. Participants attended in four hourly relaxation groups which were four times per week. With the purpose to evaluate PMR effectiveness for blood pressure regulation and its’ relation with factors, participants were given questionnaires also relaxation groups were provided. At the beginning and at the end of each session blood pressure was measured also muscle tension was evaluated with the given model and 10 score scale was given for subjective feeling evaluation. The results of this study showed that the statistically significant reductions of blood pressure were only for men also for younger patients and patients with higher education, for patients with easier IHD form and for patients with worse... [to full text]

No description available.

Le système immunitaire protège un organisme du développement de pathogènes et participe activement au maintien de la tolérance immunitaire. Les cellules dendritiques (DC) sont des cellules spécialisées dans l’équilibre pro et anti-inflammatoire de la réponse immunitaire. Les DC jouent un rôle important dans de nombreux contextes pathologiques notamment la transplantation d’organes, en oncologie et dans les pathologies inflammatoires. Elles sont modulables grâce à divers facteurs, intrinsèques et extrinsèques. Parce qu’elles sont capables d’induire une réponse tolérogène, ces cellules représentent des cibles intéressantes pour moduler la réponse immunitaire dans le contexte de la transplantation d’organes et des pathologies inflammatoires. Certains agents pathogènes utilisent des mécanismes d’échappement au système immunitaire en favorisant l’induction d’une tolérance immunitaire. Cette modulation est réalisée par le ciblage des récepteurs de reconnaissance des pathogènes (PRR) sur la présence des DC, induisant la synthèse d’une cytokine antiinflammatoire IL-10, un des inducteurs de la tolérance immunitaire. Notre stratégie a été de construire un anticorps bispécifique ciblant deux PRR différents à partir d’une banque d’anticorps anti-PRR. Notre travail montre que cet anticorps bispécifique est capable d’orienter les DC vers d’un profil tolérogène. Cet anticorps bispécifique induit un phénotype de DC semi-mature avec un profil de sécrétion pro-tolérogène avec de l’IL-10 et peu de cytokines inflammatoires. Le profil de tolérance immunitaire induite par ces cellules reste à explorer. Nos travaux ouvrent de perspectives intéressantes sur l’association des PRR en vue d’obtenir la modulation des cellules de l’immunité. / The immune system protects an organism from the development of pathogens and actively participates in maintaining immune tolerance. Dendritic cells (DC) are specialized cells in the balance and anti-inflammatory immune response. DC play an important role in many pathological contexts, including organ transplantation, oncology and inflammatory diseases. Various factors, both intrinsic and extrinsic, can modulate. Because they are capable to inducing a tolerogenic response, these cells represent interesting targets for the immune response in the context of organ transplantation and in inflammatory pathologies. Some pathogens use mechanisms of escape to the immune system by promoting the induction of immune tolerance. This modulation is achieved by targeting the pathogen recognition receptors (PRRs) present on the surface of DC, inducing the synthesis of an anti-inflammatory cytokine IL-10, one of the main inducers of immune tolerance. Our strategy was to construct a bispecific antibody targeting two different PPRs from an anti-PRR antibody library. Our work shows that this bispecific antibody is able to direct the DC to a pro-tolerogenic profile. This bispecific antibody induces a semi-mature DC phenotype with a secretion profile of pro-tolerogenic cytokines such as IL-10 and few inflammatory cytokines. The immune tolerance profile of these DC remains to be explored. Our work opens interesting perspectives on the association of PRRs in order to obtain the modulation of the cells of the immunity.

Vaccinia virus (VACV) is the most intensively studied orthopoxvirus and acts as an excellent model to investigate host-pathogen interactions. VACV encodes about 200 proteins, many of which modulate the immune response. This study focusses on two of these: C16 and C4, that share 43.7 % amino acid identity. Given the sequence similarity, we explored whether C16 and C4 have any shared functions, whilst also searching for novel functions. To gain mechanistic insight, we sought to identify binding partners and determine the residues responsible. C16 has two reported functions. Firstly, it inhibits DNA-PK-mediated DNA sensing, and this study found that C4 can perform this function as well. Like C16, C4 associates with the Ku heterodimer to block its binding to DNA leading to reduced production of cytokines and chemokines. For both proteins, the function localised to the C termini and was abrogated by mutating three residues. Secondly, C16 induces a hypoxic response by binding to PHD2. This function was mapped to the N-terminal 156 residues and a full length C16 mutant (D70K,D82K) lost the ability to induce a hypoxic response. In contrast, C4 did not bind PHD2. C4 inhibits NF-κB signalling by an unknown mechanism. Reporter gene assays showed that C16 also suppresses NF-κB activity and, intriguingly, this was carried out by both the N and C termini. C16 acts at or downstream of p65 and the N terminus of C16 associated with p65 independently of PHD2-binding. Conversely, C4 acted upstream of p65, did not display an interaction with p65, and the function was restricted to its C-terminal region. Novel binding partners were identified by a screen utilising tandem mass tagging and mass spectrometry, and selected hits were validated. The C terminus of C16 associated with VACV protein K1, a known NF-κB inhibitor. Additionally, C16 bound to the transcriptional regulator ARID4B. C4 did not interact with these proteins, but the N-terminal region of C4 associated with filamins A and B. The functional consequences of these interactions remain to be determined. In vivo, C4 and C16 share some redundancy in that a double deletion virus exhibits an attenuated virulence phenotype that is not observed by single deletion viruses in the intradermal model of infection. However, non-redundant functions also contribute to virulence in that both single deletion viruses display attenuated virulence compared to a wild-type Western Reserve virus in the intranasal model of infection. Data presented also reveal that C4 inhibits the recruitment of immune cells to the site of infection, as was previously described for C16. Overall, this investigation highlights the complexity of host-pathogen interactions showing that VACV encodes two multifunctional proteins with both shared and unique functions. Moreover, their inhibition of DNA-PK emphasises the importance of this PRR as a DNA sensor in vivo.

No description available.

Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.

Increased possibilities during the last decades for early detection of prostate cancer have sparked research on preventable or treatable risk factors and on improvements in therapy. Treatments of the disease still entail significant side effects potentially affecting men during the rest of their lives. The studies of the present thesis concern different aspects of prostate cancer from etiological risk factors and factors influencing treatment to an improved methodology for the detection of treatment side effects. Papers I, II, both based in the population based cohort ULSAM (Uppsala Longitudinal Study of Adult Men), investigate possible risk factors of prostate cancer with options for intervention: selenium levels and the metabolic syndrome. The phenomenon of competing risk of death from other causes than prostate cancer and its impact on and importance for choice of statistical methods is also exemplified and discussed for the first time in prostate cancer research. -Smokers with low selenium status have an increased future risk of later development of prostate cancer. Influence of genetic variability appears plausible. -The metabolic syndrome and especially its increased waist circumference component are associated with later development of prostate cancer – taking competing risks of death from other causes into account. Papers III and IV using pharmacoepidemiological methods investigate aspects of drug utilisation in prostate cancer using nationwide and international databases. In Paper III factors influencing anti-androgen use in prostate cancer are investigated, both from a prescriber- and patient perspective.  The age and disease risk group of the patient, unsupported scientifically, influence both the prescribers’ choice of dose and the patients’ adherence to treatment. -Adherence, not previously investigated in male cancer patients, was considerably higher than reported for adjuvant breast cancer treatment. Subgroups of men suitable for intervention to increase adherence were identified. Paper IV, investigates the feasibility of improving an established method for screening large adverse drug reactions databases, the proportional reporting ratio (PRR), this by using restricted sub-databases according to treatment area (TA), introducing the concept of PRR-TA. -The PRR-TA method increases the signal-noise relationship of analyses; a finding highly relevant for possibly conserving manual resources in Pharmacovigilance work in a drug-authority setting.

Hepatitis delta virus (HDV) is the smallest known mammalian RNA virus, containing a genome of ~ 1700 nt. Replication of HDV is extremely dependent on the host transcription machinery. Previous studies indicated that RNA polymerase II (RNAPII) directly binds to and forms an active preinitiation complex on the right terminal stem-loop fragment (R199G) of HDV genomic RNA, and that the polypyrimidine tract-binding protein-associated splicing factor (PSF) directly binds to the same region. Further studies demonstrated that PSF also binds to the carboxyl-terminal domain (CTD) of RNAP II. In my thesis, co-immunoprecipitation assays were performed to show that PSF stimulates the interaction of RNAPII with R199G. Results of co-immunoprecipitation experiments also suggest that both the RNA recognition motif 2 (RRM2) and N-terminal proline-rich region (PRR) of PSF are required for the interaction between PSF and RNAPII, while the two RNA recognition motifs (RRM1 and RRM2) might be required for the interaction of PSF with R199G. Furthermore, in vitro run-off transcription assays suggest that PSF facilitates the HDV RNA transcription from the R199G template. Together, the above experiments suggest that PSF might act as a transcription factor for the RNAPII transcription of HDV RNA by linking the CTD of RNAPII and the HDV RNA promoter. My experiments provide a better understanding of the mechanism of HDV RNA-dependent transcription by RNAP II.

Hepatitis delta virus (HDV) is the smallest known mammalian RNA virus, containing a genome of ~ 1700 nt. Replication of HDV is extremely dependent on the host transcription machinery. Previous studies indicated that RNA polymerase II (RNAPII) directly binds to and forms an active preinitiation complex on the right terminal stem-loop fragment (R199G) of HDV genomic RNA, and that the polypyrimidine tract-binding protein-associated splicing factor (PSF) directly binds to the same region. Further studies demonstrated that PSF also binds to the carboxyl-terminal domain (CTD) of RNAP II. In my thesis, co-immunoprecipitation assays were performed to show that PSF stimulates the interaction of RNAPII with R199G. Results of co-immunoprecipitation experiments also suggest that both the RNA recognition motif 2 (RRM2) and N-terminal proline-rich region (PRR) of PSF are required for the interaction between PSF and RNAPII, while the two RNA recognition motifs (RRM1 and RRM2) might be required for the interaction of PSF with R199G. Furthermore, in vitro run-off transcription assays suggest that PSF facilitates the HDV RNA transcription from the R199G template. Together, the above experiments suggest that PSF might act as a transcription factor for the RNAPII transcription of HDV RNA by linking the CTD of RNAPII and the HDV RNA promoter. My experiments provide a better understanding of the mechanism of HDV RNA-dependent transcription by RNAP II.

O presente trabalho, através do estudo da trajetória dos membros da "geração de 1970", busca explicar como, contando com que recursos e em quais condições um grupo de políticos rio-grandenses logrou, ao final da década de 1920, ascender a posições de poder no Brasil. Definiu-se também os contornos do jogo político no Rio Grande do Sul e no Brasil em termos das práticas e dos recursos que os agentes que nele atuavam deveriam possuir para serem bem sucedidos. Desde os níveis paroquial, estadual e nacional, se pode verificar que este jogo era jogado enquanto uma disputa entre mediadores, que encarnavam posições alcançadas, a partir da liderança sobre parcelas da sociedade que tinham neles seus canais de relação com o mundo jurídico-político. / The present work, through the study of the "generation of 1907" member's trajectories, tries to explain how, counting with which resources and in what conditions agroup of rio-grandenses' politicians achieved, at the end of the 1920, to ascend to powerpositions in Brazil. We also defined the contours of the political game in Rio Grande doSul and Brazil in terms of the practices and resources that the agents that acted in it should possess to be succeed. From the parochial, regional and national levels, it was verified that this game was played as a dispute among mediators, that embodied positions reached through leadership on portions of the society that had in them its relationship channels with the juridical-political world.