Longitudinal Outcomes of GastroIntestinal symptoms in Canada (LOGIC): key factors for an effective patient retention in observational studies.

BACKGROUND: Longitudinal Outcomes of GastroIntestinal symptoms in Canada (LOGIC) is an ongoing study on irritable bowel syndrome (IBS) treatment patterns and health outcomes in routine Canadian clinical practice. Advancements in understanding IBS, a chronic multifaceted GI disorder, may be possible through methodical observational studies. The objective of this paper is to describe site recruitment techniques and extensive subject follow-up methodology used to facilitate a high return rate of questionnaires from this population-based study of subjects with IBS. METHODS: Invitation letters along with protocol synopses and preliminary site assessment questionnaires were faxed to potential sites across Canada. There were 1,556 subjects enrolled in this study from general practitioner sites (GP) and specialist sites (SP) in Canada. Subjects were compensated for the return of questionnaires reporting symptoms, quality of life, productivity, healthcare and resource utilization at baseline, Month 1, 3, 6, 9, and 12. Upon the return of questionnaires, subjects received thank you cards which included a reminder of the next questionnaire's due date. If subject questionnaires were not received within 2 weeks after the due date, the subjects received a reminder letter in the mail. RESULTS: The methodology in the LOGIC study allowed for a high patient questionnaire return rate (89%) through extensive subject reminders and follow-up. Subject participation throughout the study was not found to be linked to study site size or type (GP or SP). CONCLUSION: Questionnaire based observational studies may benefit from focusing resources on increasing questionnaire return rates to effectively maintain data reliability and also reduce non-response bias.

Alterations in transcription factor binding at the IL-2 promoter region in anergized human CD4+ T lymphocytes.

BACKGROUND: The mechanisms responsible for the induction of clonal anergy are not well understood. We have utilized an in vitro model of human T cell anergy to explore the perturbations in cell signaling at the level of interleukin (IL)-2 gene transcription and to define the contribution of other cytokines to this effect. METHODS: An in vitro model of clonal anergy was established by using CD4+ T lymphocytes from healthy human donors. Cells were anergized by prestimulation with an anti-CD3 monoclonal antibody (mAb) followed by restimulation 72 hr later with anti-CD3 mAb with or without anti-CD28. RESULTS: CD4+ T cells, anergized with anti-CD3 monoclonal antibody (OKT3) prestimulation, displayed a marked reduction in proliferation (P=0.0036) and IL-2 production (P<0.0001). Co-incubation with IL-10 reduced cellular proliferation in OKT3/CD28 pretreated cells by 19% (P=NS) and reduced IL-2 production by 40% (P=0.0024). Anergized T cells demonstrated a reduced binding activity of the AP-1 complex to the IL-2 promoter. Supershift experiments and Western blots confirmed that the binding of c-Fos, JunB, and JunD, but not of FosB, was reduced in anergized cells. At the sis-inducible element (SIE)-binding region of the c-Fos promoter, Stat3 binding was reduced. CONCLUSIONS: T cell anergy, induced by prestimulation with OKT3, is characterized by reduced proliferation and a profound decrease in IL-2 production. Anergy can be prevented by co-incubation with anti-CD28 and partially re-established by IL-10. Anergy is accompanied by a reduction in AP-1 binding to the IL-2 promoter, with selective reduction in binding of c-Fos, JunB, and JunD. Defective binding for Stat3 at the c-Fos promoter suggests an involvement of the Jak-Stat pathway.

Influence of dialysis with polyamide vs haemophan haemodialysers on monokines and complement activation during a 4-month long-term study.

BACKGROUND: Contact between blood and dialysis membranes activates mononuclear cells and the complement system. The extent of activation is dependent on the dialyser material used and is considered an index of biocompatibility. Polyamide dialysers consist of a synthetic membrane that claims high standards of biocompatibility. Haemophan dialysers represent membranes made of modified cellulose that are now broadly used for treatment in Europe and are already considered to be more biocompatible than the cuprophane membranes that were used as reference in most previous studies. METHODS: In a cross-over treatment study short-term as well as long-term effects of a polyamide dialyser with respect to monokine induction and complement activation were compared to a haemophan dialyser. RESULTS: Neither haemophan nor polyamide dialysers induced relevant changes in plasma monokine levels. However, in vitro challenge of mononuclear cells with lipopolysaccharide (LPS) unmasked a significantly stronger preactivation for the secretion of proinflammatory monokines during haemophan than polyamide dialysis. Unlike other monokines the production of the regulatory monokine IL-10 was mainly influenced by individual factors and correlated with the patient's immune status rather than the dialyser type used. Enhanced preactivation of monocytes in haemophan compared to polyamide dialysis was paralleled by an increased complement activation. Cellular preactivation and formation of terminal complement complex remained constant over the 4-month treatment period. CONCLUSIONS: Haemophan and polyamide dialysers do not induce changes in plasma cytokine levels both during short-term and long-term use. However, they significantly differ in complement activation as well as preactivation of monocytes. Preactivated monocytes are prone to secrete high amounts of proinflammatory cytokines when exposed to a second stimulus like endotoxin. Secretion of the regulatory cytokine IL-10 is not influenced by the dialyser type.