Moderately increased plasma concentrations of C-reactive protein are associated with an increased risk of cardiovascular disease. C-reactive protein, its relation to a low degree of inflammatory activation and its association with activation of the endothelium have not been systematically investigated in Type I (insulin-dependent) diabetes mellitus. C-reactive protein concentrations were measured in 40 non-smoking patients with Type I diabetes without symptoms of macrovascular disease and in healthy control subjects, and in a second group of Type I diabetic patients (n = 60) with normo- (n = 20), micro- (n = 20) or macroalbuminuria (n = 20). Differences in glycosylation of alpha1-acid glycoprotein were assayed by crossed affinity immunoelectrophoresis. Activation of the endothelium was measured with plasma concentrations of endothelial cell markers. The median plasma concentration of C-reactive protein was higher in Type I diabetic patients compared with healthy control subjects [1.20 (0.06-21.64) vs. 0.51 (0.04-9.44) mg/l; p<0.02]. The Type I diabetic subjects had a significantly increased relative amount of fucosylated alpha1-acid glycoprotein (79+/-12% vs. 69+/-14% in the healthy control subjects; p<0.005), indicating a chronic hepatic inflammatory response. In the Type I diabetic group, log(C-reactive protein) correlated significantly with von Willebrand factor (r = 0.439, p<0.005) and vascular cell adhesion molecule-1 (r = 0.384, p<0.02), but not with sE-selectin (r = 0.008, p = 0.96). In the second group of Type I diabetic patients, increased urinary albumin excretion was associated with a significant increase of von Willebrand factor (p<0.0005) and C-reactive protein (p = 0.003), which were strongly correlated (r = 0.53, p<0.0005). Plasma concentrations of C-reactive protein were higher in Type I diabetic patients without (clinical) macroangiopathy than in control subjects, probably due to a chronic hepatic inflammatory response. The correlation of C-reactive protein with markers of endothelial dysfunction suggests a relation between activation of the endothelium and chronic inflammation.

It has been shown that proinflammatory and antiinflammatory cytokines correlate with disease activity in multiple sclerosis (MS). To establish whether such correlations depend on the disease stage, we assessed in a longitudinal fashion the expression of interleukin (IL)‐12 (p40 and p35), tumor necrosis factor‐α, interferon‐γ, and IL‐10 mRNA by competitive polymerase chain reaction in unstimulated peripheral blood mononuclear cells of relapsing–remitting (RR) and secondary progressive (SP) MS patients, in relation to monthly clinical and magnetic resonance imaging monitoring. MS patients had increased levels of IL‐12p40 and decreased levels of IL‐10 mRNA compared with controls; this difference was most pronounced in SP patients. Both RR and SP patients had increased levels of IL‐12p40 mRNA compared with controls during the development of active lesions. Moreover, in RR MS an increase was found before relapse. IL‐12p35 mRNA was decreased in both groups, and in relation to disease activity it showed a pattern different from IL‐12p40 mRNA. In RR MS, IL‐10 mRNA was low 4 weeks before magnetic resonance imaging activity and 6 weeks before relapse; a significant increase to normal levels was noted when active lesions became apparent. In contrast, SP patients showed low IL‐10 mRNA levels constitutively, suggesting that IL‐10 plays an important role in the control of disease progression. Ann Neurol 1999;45:695–703

The recently defined ligand for the Mpl receptor, thrombopoietin (TPO), has been found to be the principal regulatory cytokine of megakaryocytopoiesis. Furthermore, it has been hypothesized that direct interaction between stroma or stromaderived extracellular matrix (ECM) and human progenitor cells (HPC) may modulate megakaryocytopoiesis. For that purpose, we studied megakaryocytic development of HPC, obtained from patients with hematological malignancies in complete remission or solid tumors without bone marrow involvement, under the influence of megakaryocyte growth and development factor (MGDF, a pegylated, truncated molecule related to the endogenous Mpl ligand). The megakaryocytic development of HPC cultured in contact with a stromal layer (contact cultures) was compared with cultures in which HPC were grown separated from a stromal layer by a microporous membrane (noncontact cultures). A significantly lower number of megakaryocytes (CD41-and CD61-positive cells) was obtained from contact cultures compared to non-contact cultures. Furthermore, the expression of CD42b was higher in non-contact cultures, as compared to contact cultures, indicating an increase in megakaryocyte maturation in non-contact cultures. In contrast, no difference in clonogenic capacity was observed (CFU-GM, BFU-E, CFU-Mk). The possibility that direct contact between HPC and stroma induces the production of a soluble inhibitory cytokine as an explanation for the diminished megakaryocytic development in contact cultures, was excluded by performing transwell experiments in which HPC were cultured in direct contact and in a transwell simultaneously. The percentage of megakaryocytes raised from HPC present in the transwell did not decrease, irrespective of the presence of HPC simultaneous below the transwell in direct contact with stroma. It is concluded that both megakaryocytic development out of HPC and megakaryocytic differentiation is reduced in contact cultures, as compared to non-contact cultures. This is due to modulation by adhesive interactions with stroma, stromaderived ECM or cytokines bound to the membrane of stromal cells, rather than resulting from the production of diffusible cytokines by stromal cells.

In previous studies bryostatin has been shown to cause dosedependent stimulatory or inhibitory effects on colony formation in acute myeloid leukemias. In this study we investigated the inhibitory effect of high dose bryostatin-1 (bryo-1) on normal human bone marrow mononuclear cells (BMNC) colonyforming capacity. Preculturing BMNC for 24 h with 250 nM bryo-1 reduced colony formation by 66 ± 11% whereas this treatment did not reduce clonogenic capacity of highly purified CD34

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