Stat6 activation is essential for interleukin-4 induction of P-selectin transcription in human umbilical vein endothelial cells.

Chronic upregulation of P-selectin expression on the surface of the endothelium has been observed in and likely contributes to a number of chronic inflammatory diseases, including atherosclerosis. Agonists of P-selectin expression fall into 2 categories: those that induce a very rapid, transient increase, lasting only hours, and those that induce prolonged upregulation lasting days. It is the latter group, which includes interleukin-4 (IL-4), that is likely to be a mediator of chronic P-selectin upregulation. The increase in P-selectin expression induced by IL-4 results from increased transcriptional activation of the P-selectin gene. The aim of this study was to deduce the postreceptor signaling pathway(s) giving rise to the prolonged increase in P-selectin expression induced by IL-4. We demonstrate the existence of 2 functional signal transducer and activator of transcription 6 (Stat6) binding sites on the P-selectin promoter and further demonstrate, by functional analysis of the P-selectin promoter, that binding of activated Stat6 to at least 1 site is essential for IL-4-induction of P-selectin transcription. Site 1 (nucleotide[nt] -142) bound Stat6 with a higher affinity than did site 2 (nt -229), and this difference was reflected functionally as constructs in which only site 1 was functional showed full IL-4 inducibility, whereas constructs in which only site 2 was functional showed only 40% of maximal IL-4 inducibility. IL-4 also induced prolonged activation of Stat6, which was contingent on the continuous presence of IL-4. The sustained activation of Stat6 induced by IL-4 is likely to be a key factor leading to the prolonged activation of the P-selectin promoter, thereby resulting in prolonged P-selectin upregulation.

Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial.

BACKGROUND: Cancer is most common in older age groups, but little information is available with regard to the impact of age on chemotherapy toxicity. This study was undertaken to determine if age is an independent risk factor for 5-fluorouracil (5-FU) toxicity. METHODS: Toxicity data from a prospective, randomized, multiinstitution trial of 5-FU-based treatment for advanced colorectal cancer were analyzed. Toxicity for each organ system was graded. Individual organ toxicity proportions were compared using chi-square analysis. A logistic regression was performed using age (younger than 70 years vs. 70 years or older), sex, treatment arm, performance status, and length of therapy as model parameters to predict severe toxicity. Toxicity in 331 patients was analyzed. RESULTS: Advanced age was significantly associated with the occurrence of any severe toxicity (58 vs. 36%, P < 0.001), leukopenia (24 vs. 10%, P < 0.005), diarrhea (24 vs. 14%, P = 0.01), vomiting (15 vs. 5%, P = 0.01), severe toxicity in more than 2 organ systems (10 vs. 3%, P = 0.02), and treatment mortality (9 vs. 2%, P = 0.01). By univariate analysis, age (P < 0.001) and sex (P < 0.0001) were independent predictors of severe toxicity. Twenty-two of 27 women age 70 years or older had severe toxicity. CONCLUSIONS: Age 70 years or older and sex are risk factors for severe toxicity from 5-FU-based chemotherapy. Advanced age does not contraindicate the use of this type of chemotherapy, but close monitoring for multiple organ toxicities and vigorous supportive care of those with toxicity are required. Dosing decisions in older patients are difficult and must integrate assessments of organ function, comorbidities, overall physical status, and goals of treatment, in an effort to ensure the best possible outcome for these patients.

Durable solutions for developing country refugees.

PIP: "Refugee problems demand durable solutions" is the opening statement of the Principles for Action in Developing Countries adopted by the 1984 Executive Committee of the UN High Commissioner for Refugees (UNHCR). In fact, in most refugee situations no such demand is made. Those same Principles weakened the demand for durable solutions by labelling 3rd country resettlement as the least desirable and most costly solution and by indicating that when voluntary repatriation is not immediately feasible, it is sufficient to provide only temporary settlement for the refugees. This article seeks to provide some background to recent changes in refugee problems that have impeded the attainment of durable solutions and to explore some of the difficulties and possibilities for durable solutions in developing countries in the 1980s (author's).^ieng

United States refugee and asylum policy: history and current approaches.

PIP: For most of the 4 decades since World War II, US refugee and asylum policy has been generous but ad hoc, discretionary, and highly variable favoring some refugee groups and discriminating against or ignoring others. This paper: 1) tries to clarify some of the terminology of the refugee field and explains the distinctions between asylum and resettlement, 2) provides some of the historical background that has brought the US to its present condition and chronicles the US overseas refugee admission policy, and 3) examines some asylum issues and other refugee issues. Asylum is far more difficult to control than refugee resettlement. As a result of what is perceived to be abuse of the asylum system, the US has joined the growing tendency of states to treat asylum-seekers as illegal migrants. The greatest problem with American asylum policy is its lack of fairness of application; many critics believe that foreign policy factors dominate asylum hearings rather than the individual merits of the case. The 3 classic solutions to this problem are resettlement, voluntary repatriation, and settlement in a country of 1st asylum. Only in the Indochinese refugee crisis has resettlement been widely used as a solution for 3rd World refugees. Nationalism and nation-building conflicts are at the root of many refugee movements; hosts are often no less nationalistic than source countries, thus many non-integrated refugees live in peril. Developed country political will and statesmanship are needed to revive resettlement as a durable solution. Resettlement may be difficult and costly, but the pluralistic western societies do offer an integrated new life.^ieng

Refugee research bibliography.

PIP: This is an unannotated, interdisciplinary bibliography on refugees, presented in alphabetical order by author and covering the period from the 1950s to the present.^ieng