Although there was no significant difference in the rate of death between patients with shock who were treated with dopamine as the first-line vasopressor agent and those who were treated with norepinephrine, the use of dopamine was associated with a greater number of adverse events. (ClinicalTrials.gov number, NCT00314704.)

The production of tumor necrosis factor-␣ (TNF-␣) by lipopolysaccharide (LPS)-stimulated macrophages can be markedly inhibited by the two closely related cytokines, interleukin (IL)-4 and IL-13. To investigate the molecular mechanism of this inhibition, we analyzed the effect of the two cytokines on TNF-␣ production and TNF-␣ mRNA accumulation in the mouse macrophage cell lines RAW 264.7 and J774 stimulated by LPS. Whereas LPS-induced TNF-␣ production is strongly suppressed by both cytokines, TNF-␣ mRNA accumulation is not significantly affected, indicating that IL-4 and IL-13 induce a translational repression of TNF-␣ mRNA. Transfection of reporter gene constructs containing different regions of the TNF-␣ gene revealed that the inhibitory action of IL-4 and IL-13 is mediated by the UArich sequence present in the TNF-␣ mRNA 3-untranslated region. Tumor necrosis factor-␣ (TNF-␣)1 is a pleiotropic cytokine secreted by different cell types including macrophages, mastocytes, T and B lymphocytes, and natural killer cells in response to various stimuli (lipopolysaccharide (LPS), viruses, parasites, etc.) (1). A wide variety of cell types express TNF-␣ receptors, and the pleiotropism of TNF-␣ results from the complexity of the signal transduction pathways that are activated by its receptors. TNF-␣ is characterized by cytostatic and cytolytic effects on tumor cells of different origins (2), by antiviral properties (3), and by its important role in the activation of the immune system upon host invasion (4). TNF-␣ has also been identified as a major mediator of inflammatory processes, one of the most dramatic being Gram-negative endotoxic shock (1). Indeed, upon exposure to LPS or other agents simulating host invasion, macrophages produce large amounts of TNF-␣ that are released in the circulatory system. High levels of circulating TNF-␣ trigger a state of shock and tissue injury that carries an extremely high mortality rate (1).The expression of the TNF-␣ gene in mouse macrophages is regulated at the transcriptional (5, 6) and translational (1) levels. In resting macrophages, TNF-␣ synthesis is low because TNF-␣ gene transcription is weak and TNF-␣ mRNA translation is severely repressed. The translational repression is mediated by the UA-rich sequence present in the TNF-␣ mRNA 3Ј-untranslated region (1). Macrophage activation by LPS results in NF-B-dependent activation of TNF-␣ gene transcription, derepression of TNF-␣ mRNA translation, and secretion of TNF-␣ protein. TNF-␣ production by macrophages can be down-regulated by various agents including cytokines like IL-4 and IL-13 (7, 12). IL-4 and IL-13 are two closely related cytokines that are synthesized mainly by activated T lymphocytes (7,8). Both cytokines share many biological activities including the activation of B cell proliferation, IgE switching, and inhibition of inflammatory cytokine production (9 -11). TNF-␣ is one of the major inflammatory cytokines being repressed by IL-4 and IL-13. However, the molecular mechanism of this regulation has not been elucidate...

Guillain-Barré syndrome (GBS) is often triggered by a preceding bacterial or viral infection. Occasionally, it has been observed in association with acute hepatitis A, B and C, and three cases have been previously described in India in which GBS was associated with acute hepatitis E. A molecular mimicry mechanism is supposed to be involved in the pathogenesis of GBS triggered by infectious agents, although the nature of the shared epitopes has not been characterized in most instances, including that in the case of hepatotropic viruses. We report a case of GBS following acute hepatitis E in a European individual. The presence of antiganglioside GM2 antibodies in this patient suggested molecular mimicry involving ganglioside GM2 in the pathogenesis of GBS associated with hepatitis E.

The human c-myc proto-oncogene is transcribed from four alternative promoters (P0, P1, P2, and P3) giving rise to mRNAs having 5' leader sequences of various length. The c-myc P0 mRNA contains three open reading frames (ORFs), the last one encoding c-Myc1 and c-Myc2 proteins generated by alternative translation initiated at CUG and AUG codons. The middle ORF (MYCHEX1) and the 5' ORF (ORF1) code for proteins 188 and 114 amino acids in length, respectively. We and others previously identi®ed an internal ribosome entry site (IRES) in P0 and P2 c-myc mRNAs, promoting the cap-independent translation of c-Myc1 and c-Myc2. Here, we report the presence of a second IRES (named IRES1) promoting the cap-independent translation of MYCHEX1 in c-myc P0 mRNA. Using deletion analysis, we mapped an 80-nt region essential for IRES1 activity. c-myc P0 mRNA is thus the ®rst eukaryotic polycistronic mRNA described for which translation initiation of two dierent open reading frames (MY-CHEX1 and c-Myc1/c-Myc2) involves internal ribosome entry. Oncogene (2001) 20, 4270 ± 4280.

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