In the studies this thesis is based upon, microarrays were applied to profilemRNA populations in biological samples to gain insights into transcriptionalpatterns and their relation to inflammatory disease.Rheumatoid arthritis (RA) is a chronic inflammatory disease, which leads todegradation of cartilage and bone. RA is characterized by synovial inflammationwith varying levels of tissue heterogeneity. This was confirmed by microarrayanalyses of multiple biopsies from the joints of 13 patients, which showed interindividualvariation in transcript populations to be higher than intra‐individualvariationTherapeutic antibodies targeting TNF‐α have revolutionized treatment of RA,although some patients do not respond well. Identification of non‐responders isimportant, not only because anti‐TNF treatment elevates the risk of infections,but also because of the cost of treatment. A proof‐of‐concept study to investigatetranscriptional effects of anti‐TNF treatment demonstrated that differencesbetween response groups could be identified and that these differences revealedbiological themes related to inflammatory disease.A subsequent study was therefore initiated with a larger cohort of 62 patients toinvestigate gene expression patterns in the synovium prior to anti‐TNFtreatment. Here, the heterogeneity was even more pronounced, thetranscriptional patterns were confounded by the presence of synovial aggregatesand only a weak therapy‐correlated signature was detected. The presence oflymphocyte aggregates was found to correlate to response to therapy, which isconsistent with previous findings indicating a higher level of inflammation ingood responding patients.Periodontitis is an inflammatory disease with many similarities to RA. Both areincurable chronic auto‐immune diseases, characterized by tissue destructionwith common genetic associations. Individuals with RA are at higher risk ofaccumulating significant periodontal problems than the general population. PGE2(prostaglandin E2) is known to stimulate inflammation and bone resorption inperiodontitis. In further studies, microarrays were applied in a time seriesdesign on human gingival fibroblats to explore the signal transduction pathwayscontrolling TNF‐α induced PGE2 synthesis in order to identify novel therapeutictargets. The JNK and NF‐kb pathways were identified as being differentiallyaffected by TNF‐a treatment. The transcriptional patterns were further verifiedusing antibodies against phosphorylated JNK/NF‐kb molecules and specificinhibitors of the JNK and NF‐kb signaling cascades. / QC 20100820

Darbo tikslas: Įvertinti sergančiųjų reumatoidiniu artritu plaštakos ir riešo funkciją ir su ja susijusius veiklos sutrikimus bei jos korekcijos galimybes, taikant ergoterapiją. Darbo uždaviniai: 1. Įvertinti ligonių, sergančių reumatoidiniu artritu, plaštakos ir riešo funkciją. 2. Nustatyti sergančiųjų reumatoidiniu artritu savarankiškos veiklos sutrikimus. 3. Įvertinti sergančiųjų reumatoidiniu artritu ergoterapijos efektyvumą. 4. Nustatyti veiksnius įtakojančius ergoterapijos efektyvumą ir jų prognostinę vertę. / Aim of study: To evaluate the hand and wrist function and related dysfunction in rheumatoid arthritis patients, and the possibilities for its restoration by means of occupational therapy. Objectives of the study: 1. To evaluate the hand and wrist function in rheumatoid arthritis patients. 2. To evaluate the functional limitations of self-dependence in rheumatoid arthritis patients. 3. To evaluate the effectiveness of occupational therapy in the rheumatoid arthritis patients. 4. To identify factors which have an impact on the effectiveness of the occupational therapy, and to estimate their forecast value.

En Amérique du Nord, Mycoplasma bovis est le plus pathogène des mycoplasmes retrouvés chez les bovins. Les principales maladies qu’on lui associe (maladies respiratoires, mammites, arthrites septiques et otites moyennes et/ou internes) constituent un défi à l’industrie laitière à cause de la difficulté à les traiter et à les prévenir par une vaccination. L’objectif principal de ce projet était d’étudier l’excrétion nasale et la réponse sérologique à M. bovis chez les génisses de remplacement, entre la naissance et 7 mois d’âge, dans 4 troupeaux laitiers au Québec. Quatre-vingt-trois paires mère/génisse provenant de 4 cohortes de bovins laitiers étaient prélevées mensuellement (génisses : 0 à 7 mois ; mères : 0, 1 et 5 mois après vêlage). Écouvillons nasaux et échantillons de lait étaient analysés par culture bactériologique et par immunofluorescence indirecte. Les anticorps circulants étaient détectés par le test ELISA. À la naissance, la prévalence sérologique des génisses était supérieure à celle des mères (P = 0,01). La transmission de M. bovis aux génisses par le lait et par l’excrétion nasale des mères était faible. L’âge moyen (jour) d’une génisse à sa 1ère excrétion nasale et sa 1ère séroconversion à M. bovis était loin de la période néonatale: 77,5 ± 11,2 (n = 22) et 96,8 ± 7,4 (n = 36) respectivement. Conclusion, les vaches adultes n’ont constitué qu’une voie mineure de transmission de M. bovis aux génisses, la principale voie de transmission était fort probablement le contact direct ou indirect avec d’autres génisses excrétrices nasales de M. bovis. / In North America, Mycoplasma bovis is the most pathogenic mycoplasma found in cattle. The main diseases associated with it (respiratory disease, mastitis, septic arthritis and otitis median and/or internal) are a challenge to the dairy industry because of the difficulty to treat them and to prevent them by vaccination. The principal objective of this project was to study nasal shedding and serological response to M. bovis in replacement heifers, between birth and 7 months of age, in four dairy herds in Quebec. Eighty three pairs cow/heifer in 4 cohorts of dairy cattle were sampled monthly (heifers: 0 to 7 months; cows: 0, 1 and 5 months after calving). Nasal swabs and milk samples were analyzed by bacteriological culture and by indirect immunofluorescence. Circulating antibodies were detected by ELISA test. At birth, the serologic prevalence of heifers was significantly higher than the serologic prevalence of cows (P = 0,01). Transmission of M. bovis to heifers in milk and nasal shedding from cows was low. The average age (days) of a heifer for first nasal shedding and first seroconversion to M. bovis was far from the neonatal period: 77,5 ± 11,2 days (n = 22) and 96,8 ± 7,4 days (n = 36) respectively. Conclusion, cows were only a minor route of transmission of M. bovis to heifers, the main route of transmission was most likely the direct or indirect contact with other heifers shedding M. bovis in their upper respiratory tract.

Genetic as well as environmental factors are believed to be of importance in the etiology of rheumatoid arthritis (RA). There are a number of previous studies of genetic markers in RA, but so far no genetic linkage and only a few associations have been found. Of the associations only one (with the HLA antigen DR4) appears to be well documented. In most previous association studies the patients have not been divided according to sex and family history of RA. In this investigation the HLA antigens A, B and DR and five serum protein systems (Bf, C3, Pi, Hp and Tf) were studied in patients with erosive rheumatoid arthritis (RA), from northern Sweden. Special attention was paid to variations in the strength of associations accord­ing to sex and family history of polyarthritis. The following results were found:  The frequency of the HLA antigen B27 was significantly increased in the North-Swedish population (16.6%) and among patients with a family history of polyarthritis (42.6%). In agree­ment with previous investigations a significantly increased frequency of the DR4 antigen was found in the RA patients.  In the properdin factor B (Bf) system the S phenotype was found to be significantly in­creased in male patients and in patients with a family history of polyarthritis, more severe form of RA and high titres of rheumatoid factor.  No significant differences with respect to phenotype or gene frequencies were found in the C3 complement system. Thus, the association between RA and C3 found in previous investiga­tions was not confirmed.  A significant increase of rare alpha-1-antitrypsin (Pi) types (MS, MZ, MF and SZ) was found among RA patients. However, the increase concerned mainly Z heterozygotes and was more strongly pronounced among male patients.  In the haptoglobin system a significant increase of the Hp^ gene and the Hp2-2 type was found among patients with a family history of polyarthritis, more pronounced among males.  A significant increase of the transferrin gene and of the 2 type was found among male RA patients, more pronounced among patients with a family history of polyarthritis. In 6 out of 8 gene loci studied significant associations were found, which is in agreement with a multifactorial etiology of RA. The results were largely in agreement with the hypothesis that associations would be expected to be stronger in males and in patients with a family history of polyarthritis. A notable finding was the high frequency of first degree relatives (around 40%) with symmetric peripheral polyarthritis of which more than 70% had a diagnosis of RA verified by hospital records. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1985, härtill 6 uppsatser.</p> / digitalisering@umu

Rheumatoid arthritis (RA) is an autoimmune disease, which affects 0.5–1.0 % of adults. The aim of this thesis is to study accumulation and localization of endogenous porphyrins by means of spectroscopy and microscopy in experimental rheumatoid arthritis model and postoperative samples of patients after application of 5-aminolevulinic acid or its methyl ester. The spectroscopic measurements of endogenous porphyrins were performed in synoviocytes, chondrons and cartilage explants of patients with RA or osteoarthritis (OA) and in rabbit antigen induced arthritis model. The localization of endogenous porphyrins in synovium and cartilage tissues of rabbit knee joints was determined based on fluorescence spectroscopy, fluorescence intensity and lifetime microscopy, and histology imaging results. Studies showed that selective sensitization of inflamed synovium in the in vitro model may be achieved using ALA and ALA-Me, while in the in vivo model only using ALA-Me. The photosensitizer protoporphyrin IX induced by these precursors is accumulated in the cells of synovium and cartilage tissues. The results presented in this dissertation can be used anticipating to apply the sensitization with endogenous porphyrins for diagnostic and therapeutic purposes in the case of rheumatoid arthritis. / Reumatoidinis artritas (RA) yra autoimuninė liga, kuria pasaulyje serga 0,5-1 % suaugusių žmonių. Disertacijos tikslas – spektroskopiniais ir mikroskopiniais metodais ištirti endogeninių porfirinų susikaupimą ir pasiskirstymą eksperimentinio reumatoidinio artrito modelyje ir pacientų pooperacinėje medžiagoje po 5-aminolevulininės rūgšties (ALA) ar jos metilo esterio (ALA-Me) panaudojimo. Atlikti endogeninių porfirinų fluorescencinės spektroskopijos tyrimai RA ir osteoartritu sergančių (OA) pacientų sinoviocituose, chondronuose ir kremzlės bandiniuose bei triušių antigenu indukuotame artrito modelyje. Endogeninių porfirinų lokalizacija triušių kelio sąnario kremzlės ir sinovijos audiniuose nustatyta remiantis fluorescencinės spektroskopijos, fluorescencijos intensyvumo ir gyvavimo trukmių mikroskopijos bei histologinių vaizdų analizės rezultatais. Tyrimais nustatyta, kad selektyviai sensibilizuoti uždegiminę sinoviją modelyje in vitro galima naudojant ALA bei ALA-Me, o modelyje in vivo tik ALA-Me. Šių pirmtakų indukuotas fotosensibilizatorius protoporfirinas IX yra susikaupęs sinovijos ir kremzlės audinių ląstelėse. Disertaciniame darbe pristatomų tyrimų rezultatai gali būti panaudoti norint ateityje endogeniniais porfirinais pagrįstą sensibilizaciją pritaikyti diagnostikos ir terapijos tikslais reumatoidinio artrito atveju.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease associated with high levels of tumour necrosis factor-alpha (TNF-a) in synovial fluid and synovial tissue (Saxne et al., 1989). Thalidomide is a proven inhibitor of the biological synthesis of TNF-a (Sampaio et al., 1991) and is believed to rely on this action for its suppression of the wasting of tissue which accompanies RA. Oral administration of thalidomide has proven to be effective in RA, but unacceptable side effects are easily provoked (Gutierrez-Rodriguez, 1984). Administration of thalidomide via the dermal route can down-regulate TNF-a production in and around the affected joint, and this without raising the systemic blood level to a problematical level. Based on thalidomide's physicochemical properties, it is unlikely that it can be delivered percutaneously at a dose required for RA. Therefore, we have embraced the idea of using N-alkyl analogues of thalidomide. The most important feature that an analogue of this compound might contribute is decreased crystallinity and increased lipophilicity. Ordinarily both these parameters should favour percutaneous delivery. The current study was primarily aimed at exploring the feasibility of percutaneous delivery of thalidomide and subsequently, three of its odd chain IV-alkyl analogues (methyl, propyl and pentyl) via physicochemical characterization and assessment of their innate abilities to diffuse through skin as an initial step towards developing a topical dosage form for the best compound. The biological activities, more specifically their potential to inhibit the production of TNF-a was determined for thalidomide and its N-alkyl analogues. In order to achieve the objectives, the study was undertaken by synthesizing and determining the physicochemical parameters of thalidomide and its N-alkyl analogues. A high level of crystallinity is expressed in the form of a high melting point and heat of fusion. This limits solubility itself, and thus also sets a limit on mass transfer across the skin. Generally, the greater a drug's innate tendency to dissolve, the more likely it is that the drug can be delivered at an appropriate rate across the skin (Ostrenga et al., 1971). Therefore, the melting points and heats of fusion were determined by differential scanning calorimetry. Aqueous solubility and the partition coefficient (relative solubility) are major determinants of a drug's dissolution, distribution and availability. N-octanollwater partition coefficients were determined at pH 6.4. Solubilities in water, a series of n-alcohols and mixed solvents were obtained, as well as the solubility parameters of the compounds in study. Secondly, in vitro permeation studies were performed from these solvents and vehicles using vertical Franz diffusion cells with human epidermal membranes. Thirdly, tumour necrosis factor-alpha (TNF-a) inhibition activities were assessed for thalidomide and its N-alkyl analogues. By adding a methyl group to the thalidomide structure, the melting point drops by over 100°C and, in this particular instance upon increasing the alkyl chain length to five -CH2- units the melting points decrease linearly. Heats of fusion decreased dramatically upon thalidomide's alkylation as well. Methylation of the thalidomide molecule enhanced the aqueous solubility 6-fold, but as the alkyl chain length is further extended from methyl to pentyl, the aqueous solubility decreased exponentially. The destabilization of the crystalline structure with increasing alkyl chain length led to an increase in lipophilicity and consequently an increase in solubility in nonpolar media. Log partition coefficients increased linearly with increasing alkyl chain length. Solubilities in a series of n-alcohols, methanol through dodecanol, were found to be in the order of pentyl > propyl > methyl > thalidomide. The N-alkyl analogues have more favourable physicochemical properties than thalidomide to be delivered percutaneously. The in vitro skin permeation data proved that the analogues can be delivered far easier than thalidomide itself. N-methyl thalidomide showed the highest steady-state flux through human skin from water, n-alcohols and combination vehicles. Thalidomide and its N-alkyl analogues were all active as TNF-a inhibitors. Finally, active as a TNF-a inhibitor, N-methyl thalidomide is the most promising candidate to be delivered percutaneously for treatment of rheumatoid arthritis, of those studied. / Thesis (PhD (Pharmaceutics))--PU for CHE, 1999.

Rheumatoid arthritis (RA) is a chronic, deteriorative disease, which leads to psychological distress. &lsquo / Conservation of Resources theory (COR)&rsquo / is a relatively recent stress model, developed by Hobfoll (1988, 1989). This resource-oriented theory is based on the assumption that psychological stress is a reaction to a threat of loss of resources, loss of resources and/or lack of resource gain after investment in resources. Religiousness, coping abilities, coping self-efficacy and social support are very important personal resources, which have been found to protect individuals against psychological distress. The aim of the present study was to examine the predictive values of socio-demographic and illness related variables, religiousness, perceived social support, ways of coping, resource loss and arthritis self efficacy for both psychological distress (anxiety and depression) and posttraumatic growth (PTG) of RA patient. In addition, the COR theory was tested for a chronic debilitating illness. Data were collected by administering eight scales to one hundred and seventeen RA patients in the Rheumatology and Physical Medicine and Rehabilitation Clinics of Ankara Numune Hospital. As a result of the regression analysis, it was found that being female, fatigue, resource loss, helplessness coping and perceived social support were significant predictors of anxiety. Impact of illness on daily activities, resource loss, problem solving coping and arthritis self-efficacy were significant predictors of depression. Gender, perceived severity of the illness, perceived social support and problem solving coping were significant predictors of PTG. Perceived social support was not related to depression and total psychological distress whereas it was related to anxiety and PTG. Religiousness was not related to psychological distress and PTG. The results of the study were discussed within the relevant literature, shortcomings of the current study, clinical implications and suggestions for future research were proposed.

No description available.

Thesis (Ph.D. in Biostatistics) -- University of Colorado Denver, 2008. / Typescript. Includes bibliographical references (leaves 53-56). Online version available via ProQuest Digital Dissertations.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2009. / Title from PDF title page (viewed on July 1, 2010). Includes bibliographical references.