Die rheumatoide Arthritis (RA) ist eine chronische, progressive und systemische Autoimmunerkrankung, in deren Zentrum das dauerhaft entzündete Synovialgewebe der Gelenke steht. Aufgrund vielfältiger Knochen- und Knorpel-destruierender Prozesse kommt es zu irreversiblen Funktionalitätsverlusten der betroffenen Gelenke. Eine tragende Rolle bei der Ausprägung der klinischen Manifestationen wird dabei der exzessiven Synthese des proinflammatorischen Cytokins IL-1 zugesprochen. Dessen Aktivität kann durch kompetitive Blockade des IL-1 Rezeptors Typ I mit dem natürlich vorkommenden, antiinflammatorischen IL-1 Rezeptorantagonisten (IL-1Ra) inhibiert werden. Der Cytokin-blockierende Therapieansatz mit Anakinra, einem rekombinant hergestellten IL-1Ra, konnte die pharmakologischen Behandlungsmöglichkeiten der RA seit 2001 wesentlich erweitern. Gleichwohl erfordern die geringen Halbwertszeiten von IL-1Ra regelmäßige subkutane Injektionen, um hinreichende therapeutische Wirkstoffspiegel im Patienten aufrecht zu erhalten. Vor diesem Hintergrund bieten somatische Gentherapiekonzepte eine vielversprechende Alternative zu den konventionellen Behandlungsstrategien bei der RA-Therapie. Ein IL-1Ra-Gentransfer ins Gelenk soll die persistierende, lokale, endogene Synthese des therapeutischen IL-1Ra-Proteins ermöglichen und lässt in dieser Hinsicht eine nachhaltige Verbesserung der klinischen Symptomatik erwarten. In dieser Arbeit wurden dafür gentherapeutische Foamyvirus-Adenovirus-Hybridvektoren (FAD) zur Expression des IL-1Ra entwickelt und die Funktionalität der Konstrukte evaluiert. Die Vektoren sollten die effizienten adenoviralen Transduktionsmechanismen mit dem Potential der foamyviralen somatischen Integration für einen direkten in vivo Gentransfer kombinieren. Das System besteht aus einem adenoviralen Hochkapazitätsvektor vom Serotyp 5, der eine selbstinaktivierende PFV-Vektorkassette unter Kontrolle des Reversen Tetracyclin Transaktivator Systems (Tet-On) enthält. In FAD-transduzierten Zellen wurde die funktionelle Induzierbarkeit der PFV-Vektorexpression nachgewiesen und die Kinetik der PFV-Partikelfreisetzung charakterisiert. Nach Induktion der PFV-Vektorkassette konnte in FAD-transduzierten Zellen ein langfristig-stabiler IL-1Ra-Gentransfer gezeigt werden. Ferner konnten protektive Effekte eines FAD-vermittelten IL-1Ra-Gentransfers im Zellkulturmodell nachgewiesen werden. Tierexperimentelle Untersuchungen zeigten eine erfolgreiche Transduktion von Synovialzellen nach intraartikulärer Applikation von FAD-Vektoren. Das Tetracyclin-regulierbare Hybridvektorsystem zur Expression des IL-1Ra, das in der vorliegenden Arbeit geschaffen wurde, könnte zukünftig die Basis für ein effektives Werkzeug zum intraartikulären Gentransfer in der klinischen Praxis bieten. / Rheumatoid arthritis (RA) is a chronic, progressive and systemic autoimmune disease, characterized by invasive synovial hyperplasia. Several inflammatory cartilage- and bone- destroying processes lead to an irreversible loss of joint functionality. The excessive synthesis of the pro-inflammatory cytokine IL-1 has been implicated as a primary mediator of pathology in RA. The activity of IL-1 is initiated upon binding to the IL-1 receptor type I and can be inhibited by the naturally occurring anti-inflammatory IL-1 receptor antagonist (IL1-Ra) protein. The cytokine-blocking therapeutic approach with anakinra, a recombinant form of IL-1Ra, has significantly improved the pharmacological treatment of RA since 2001. Nevertheless, due to the short half-life of IL-1Ra, repeated subcutaneous injections are required to maintain therapeutic concentrations in the patient. Thus, somatic gene therapy may offer a promising alternative to conventional therapeutic strategies for treating RA. Following gene delivery of IL-1Ra, it may be expected that a sustained improvement of clinical symptoms is achievable due to the endogenous cellular synthesis and local secretion of the therapeutic IL-1Ra protein. In this work, foamy virus-adenovirus hybrid vectors (FAD) were developed for the expression of IL-1Ra and the functionality of the constructs was evaluated. The hybrids combine the high transduction efficiency of adenovirus vectors with the integrative potential provided by prototype foamy virus (PFV) vectors, for direct in vivo gene transfer. In the system, a complete expression cassette for self-inactivating PFV vectors, which is under the control of the tetracycline-dependent regulatory system (Tet-On), was inserted into the backbone of a serotype 5-based high-capacity adenoviral vector. In FAD-transduced cells, the induction of the PFV vector cassette was demonstrated and the release of secondary infectious PFV vectors was characterized. After the induction of the PFV vector cassette in FAD-transduced cells, a stable long-term IL1-Ra expression was shown. Furthermore, the anti-inflammatory potential of the FAD-mediated IL-1Ra gene transfer was successfully evaluated in a cell culture model. Animal studies indicated successful transduction of cells in the synovium after intra-articular application of FAD-vectors. The tetracycline-inducible hybrid vector system for the expression of IL-1Ra, which was created in the present work, may provide the future basis for an effective tool for intra-articular gene transfer in clinical settings.

Background: Juvenile idiopathic arthritis (JIA) refers to a group of auto-immune conditions involving joint inflammation that first appears before the age of 16. In the United States, about 294,000 children are affected. Although JIA can be widely attributed to genetic factors, the consensus is that environmental factors also play a role. Attempts to assess the role of environmental factors, though scarce, have focused on the role of infections, smoking exposure, and breastfeeding. Hygiene hypothesis, which suggests that adaptive immunological response improves with higher frequencies of pathogen exposure in early childhood, has been used to try to explain the risk of JIA. Common markers of microbe exposure in early life include sibling number, pet number, and maternal parity. Some prior studies conducted outside the U.S. suggests that increasing sibling number is protective against the risk of JIA. This study aimed to evaluate prior findings, using data from the U.S. Methods: The study used data from the 2017 Centers for Disease Control and Prevention National Survey for Child Health. The survey used a sample size of 21599 children to estimate the number of children in the U.S. Descriptive statistics was carried out, and logistic regression was used to determine the association between family number and the odds of developing JIA, while adjusting for sociodemographic variables. Family number was used as a proxy for sibling number. SAS v 9.4 was used for analysis. Results: Complete data on all the variables of interest were available for 17618 children, of which 67 had JIA. Although there was a marginal association between sibling number and JIA in the unadjusted model (OR [95% CI] 0.983-1.602) (P=0.068), in the adjusted model, there was no significant association between JIA and sibling number ([OR 95% CI] 0.8985-1.447) (P=0.29). There was a significant association between JIA and age, low birth weight, highest education level in the family, while sex had a marginal association. Conclusion: There was no association between family size and the development of JIA in this study. While some prior results have supported the observed significant effect of low birth weight, the disparity in results between this study and the Australian study could be due to the use of family number instead of sibling number. Further studies should assess the association of sibling number and developing JIA in the U.S.

Young women with mobility limiting disorders face many challenges as they move through adolescence into young adulthood. In addition to the challenges of this developmental period, they must consider their disability as they manage their lives. Competent decision making is a foundational skill for self-management and for transition in adulthood. It is also a protective factor for resilience.There is little research on decision making in adolescents with disabilities. Therefore, the purpose of this qualitative study was to explore the decision making experiences of female adolescents and young women with mobility limiting disorders. Theoretical underpinnings for the study included Resilience Theory and Phenomenology. Phenomenological methodology guided data collection and analysis. Study participants included six young women between the ages of 16 and 25 who met established inclusion criteria. Participants were interviewed using an interview schedule. Transcripts of the audiotaped interviews were analyzed for themes. An individual profile of decision making in self-management for each participant was developed from analysis of interviews. A composite depiction of the phenomenon of decision making in self-management was developed from analysis of the participant profiles. The following conclusions were drawn from the composite depiction. Decision making in self-management is a dynamic, developmental process that encompasses choices across many dimensions of life activities. Parents' attitudes and expectations can have significant influence on the development of decision making in young women with mobility limiting disorders. Having or taking the opportunity to make decisions may contribute to the development of decisional competence and independence. Barriers, such as social stereotypes and lack of community resources, influence decision making. The ability of the study participants to "see past the disability" creates a broader vision of opportunities for decision making to achieve their goals.The results of this research should be useful to nurses and other health professionals as they collaborate with adolescents with disabilities and their families in fostering and supporting competent decision making in self-management. Future research is recommended on decision making in specific dimensions of self-management such as socialization and, using quantitative and qualitative methods to compare this phenomenon in adolescents with and without disabilities and between genders.

Cigarette smoking has been a public health concern for many years, and the possible impact of smoking on surgical site infection (SSI) has been studied broadly. However, a gap in understanding has persisted concerning whether there is an association between smoking tobacco and the development of SSI among patients who undergo lower extremity surgery, specifically total knee arthroplasty (TKA). The purpose of this study was to examine the association between smoking and lower extremity SSI. Andersen's behavioral model (BM) was used to understand the risk factors relevant to the interaction between smoking and SSI. Application of the BM categories of predisposing, enabling, need, and behavioral habits facilitated the discussion of surgical outcomes. A quantitative, cross-sectional approach was used to analyze data from a legacy registry of an east coast hospital. The research question addressed whether there was a relationship of the smoking status of three groups (i.e., smokers, nonsmokers, and previous smokers) and the variables in the BM categories (predisposing variables of age, gender, and body mass index [BMI]; enabling variable of health care insurance coverage; and need variables of health diagnoses, diabetes, hypertension, deficiency anemia, rheumatoid arthritis [RA]) to postoperative SSI. Multiple logistic regression test was used and no statistical association was found between smoking status and SSI; however, RA had a significant association with SSI. Positive social change may occur through the dissemination of new knowledge to reduce the financial burden of the prevalence of SSI through behavioral changes and improvements to health wellness.

No description available.

Abstract not available

Includes bibliographical references (leaves 182-240). Explores alternate strategies that may alter inflammatory cytokine production, particularly tumour necrosis factor đ [tumor necrosis factor-alpha], and therefore provide a possible treatment for rheumatoid arthritis.

x, 156 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 1988

<p>The existence of immune self-tolerance allows the immune system to mount responses against infectious agents, but not against self-molecular constitutes. Although self-tolerance is a robust phenomenon, in some individuals as well as in experimental models, the self-tolerance breaks down and as a result, a self-destructive autoimmune disease emerges. The underlying mechanisms for the development of autoimmune diseases are not known, but genetic, environmental and immunological factors are suggested to be involved. In this thesis, we used murine mercury-induced autoimmunity to test this suggestion.</p><p>In susceptible mice mercuric chloride induces a systemic autoimmune disease characterized by increased serum levels of IgG1 and IgE, production of anti-nucleolar autoantibodies (ANolA) and formation of renal IgG deposits. In contrast, in resistant DBA/2 (H-2^d) mice, none of these characteristics develop after exposure to mercury. By crossing and backcrossing mercury-resistant DBA/2 mice to mercury susceptible strains, we found that the resistance was inherited as a dominant trait in F1 hybrids and that one gene or a cluster of genes located in the H-2 loci determined the resistance to ANolA production, whereas resistance to the other characteristics was found to be controlled by two or three non-H-2 genes.</p><p>We further put forward the “cryptic peptide hypothesis” to investigate whether mercury and another xenobiotic metal use similar pathway(s) to induce the H-2 linked production of ANolA. We found that while mercury stimulated ANolA synthesis in all H-2 susceptible (H-2^s, H-2^q and H-2^f) mouse strains, silver induced only ANolA responses in H-2^s and H-2^q mice, but not in H-2^fmice. Further studies showed that the resistance to silver-induced ANolA production in H-2^fmice was inherited as a dominant trait.</p><p>We next tested the proposition that mercury induces more adverse immunological effects in mouse strains, which are genetically prone to develop autoimmune diseases, using tight-skin 1 mice, an animal model for human Scleroderma. It was found that in this strain, mercury induced a strong immune activation with autoimmune characteristics, but did not accelerate the development of dermal fibrosis, a characteristic in Tsk/1 mice.</p><p>Finally we addressed the Th1/Th2 cross-regulation paradigm by examining if a Th1-type of response could interact with a Th2-type of response if simultaneous induced in susceptible mice. Our findings demonstrated that mercury-induced autoimmunity (Th2-type) and collagen-induced arthritis (CIA) (Th1-type) can interact in a synergistic, antagonistic or additive fashion, depending on at which stage of CIA mercury is administered.</p>

<p>An arthroscope is a diagnostic instrument for visualisation of the interior of a joint. By adding a laser to an arthroscope and feeding the images to a computer, one gets an method to measure the structure of the cartilage covering the joint. This gives an added diagnostic value. The laser will create laser speckles and this report covers the basic theories behind this. The anatomy of the joints, the properties of cartilage and the background on the disease arthritis are also covered, as well as the field of surface topography and image processing.</p><p>Experiments were performed on three different materials - metals of different definite surface roughness, polymerised collagen and bovine articular cartilage.</p><p>The conclusion is that the technique would work, providing that some obstacles could be overcome. The technique itself is very precise and detects nanometric differences in the surface structure, making it extremely interesting for research purposes, such as follow-ups on treatments and studies of arthritis and cartilage repair.</p>