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The role of competition and cooperation in relation to the goal of health equity is examined in this paper. The authors explain why the win-lose mentality associated with avoidable competition is ethically questionable and less effective than cooperation in achieving positive outcomes, particularly as it relates to health and health equity. Competition, which differentiates winners from losers, often with the winner-takes-all reward system, inevitably leads to a few winners and many losers, resulting in social inequality, which, in turn, engenders and perpetuates health inequity.Competitive market-driven approaches to healthcare-brought about by capitalism, neo-liberalization, and globalization, based primarily on a competitive framework-are shown to have contributed to growing inequities with respect to the social determinants of health, and have undermined equal opportunity to access health care and achieve health equity. It is possible to redistribute income and wealth to reduce social inequality, but globalization poses increasing challenges to policy makers. John Stuart Mill provided a passionate, philosophical defense of cooperatives, followed by Karl Polanyi who offered an insightful critique of both state socialism and especially the self-regulating market, thereby opening up the cooperative way of shaping the future. We cite Hannah Arendt's "the banality of evil" to characterize the tragic concept of "ethical fading" witnessed in business and everyday life all over the world, often committed (without thinking and reflecting) by ordinary people under competitive pressures.To promote equity in health for all, we recommend the adoption of a radically new cooperation paradigm, applied whenever possible, to everything in our daily lives.

The mechanisms that regulate the strength and duration of CD8(+) cytotoxic T cell activity determine the effectiveness of an antitumor immune response. To better understand the antitumor effects of anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody treatment, we analyzed the effect of CTLA-4 signaling on CD8(+) T cells in vitro and in vivo. In vitro, cross-linking of CTLA-4 on purified CD8(+) T cells caused decreased proliferative responses to anti-CD3 stimulation and rapid loss of activation marker expression. In vivo, blockade of CTLA-4 by neutralizing anti-CTLA-4 mAb greatly enhanced the accumulation, activation, and cytotoxic activity of CD8(+) T cells induced by immunization with Ag on dendritic cells (DC). This enhanced response did not require the expression of MHC class II molecules on DC or the presence of CD4(+) T cells. These results demonstrate that CTLA-4 blockade is able to directly enhance the proliferation and activation of specific CD8(+) T cells, indicating its potential for tumor immunotherapy even in situations in which CD4(+) T cell help is limited or absent.

CTLA4 is currently viewed as a late-appearing T cell surface receptor which is able to inhibit the proliferation of activated T cells. We sought to identify how CTLA4 ligation exerts these anti-proliferative effects by studying its influence on the activities of the relevant nuclear transcription factors AP-1, NFAT and NF-kappaB. We found that cross-linking CTLA4 on activated T cells completely blocks AP-1 and NFAT transcription factor activity before any effects on T cell proliferation can be observed, with NF-kappaB activity affected to a lesser degree. The suppression of AP-1 and NFAT transcriptional activity correlates with reduced levels of AP-1 and NFAT DNA binding as early as 10 h after T cell activation, prior to detectable up-regulation of CTLA4 on the T cell surface. Additionally, inhibitory effects on T cell proliferation only occurred when CTLA4 molecules were ligated in proximity to signaling TCR complexes, and inhibition of transcription factor DNA binding and activity was observed in the absence of CD28 stimulation. CTLA4 can thus act early during T cell activation to reduce the activity of several key nuclear transcription factors important for continued T cell proliferation and differentiation.

Reactive oxygen species such as superoxide and hydrogen peroxide have been implicated as regulatory factors in the control of osteoclastic bone resorption. While superoxide radicals have been suggested to be the main bone resorbing species in organ culture and in vivo, hydrogen peroxide (H2O2) has recently been shown to activate isolated osteoclasts in vitro. In this study, we investigated the effects of hydrogen peroxide and superoxide on bone resorption in mouse calvarial organ cultures. Hydrogen peroxide stimulated bone resorption in a concentration-dependent manner in calvarial organ cultures with a maximal effect at 1 mumol/L (45Ca release; treated/control = 1.6 +/- 0.07; p < 0.001 from control). Bone resorption induced by H2O2 was significantly inhibited by catalase to 1.2 +/- 0.05; p < 0.02. In contrast, the combination of xanthine and xanthine oxidase, which generates superoxide anions, failed to stimulate bone resorption, except in the presence of superoxide dismutase (SOD), which resulted in a modest increase in bone resorption to a treated/control ratio of 1.2 +/- 0.05; p < 0.02. Analysis of calvarial bones which were exposed to H2O2 showed a significant increase in osteoclast numbers suggesting that H2O2 may be capable of stimulating osteoclast formation in addition to enhancing activity of mature osteoclasts. Our data are consistent with previous work, which has shown that H2O2 is a bone resorbing factor with effects on both osteoclast formation and in activity of mature osteoclasts. The experiments with SOD further suggest that the enhancement of bone resorption previously noted with superoxide generating systems may be due in part to generation of H2O2.

Measurements of rates of inosinate synthesis from radioactive hypoxanthine by human erythrocytes show a large degree of individual variation. Rates of inosinate synthesis also vary with the pH and phosphate concentration of the incubation medium. This may be due to changes in the rate of phosphoribosyl pyrophosphate synthesis, and the stimulatory effect of phosphate on this process seems to be more important than the inhibitory effect of 2,3-diphodphoglycerate. The rate of inosinate synthesis, and especially the extent of accumulation of inosine triphosphate, increase disproportionately with time of incubation up to at least 24 h. Storage of erythrocytes also tends to increase inosinate synthesis and inosine triphosphate accumulation.

Erythrocytes from 5% of a normal population accumulated relatively high amounts of radioactive inosine triphosphate (i.e., greater than 70 nmoles/10(10) cells in 2 hr) when they were incubated with [14C]hypoxanthine. The incidence of this characteristic in a mentally retarded population was 16%. Inosine triphosphate was synthesized from [14C]hypoxanthine, but not from [14C]adenine or [14C]guanine. The metabolism of [14C]adenine and [14C]guanine was the same in erythrocytes that accumulated "normal" and "high" amounts of inosine triphosphate. Inosine triphosphate did not accumulate in leukocytes.