No abstract

Soluble gp130 (sgp130) is a soluble circulating receptor of IL-6 with "antagonistic" biologic activity. It is generated independently by either shedding of the extracellular domain of membrane gp130 or alternative mRNA splicing. This study was addressed to clarify the mechanisms underlying sgp130 synthesis and release in patients who undergo regular dialysis treatment (RDT) using dialytic membranes with different biocompatibility. Two groups of RDT patients were enrolled: 11 patients who were treated with cellulosic membranes (C) and 10 patients who were treated with synthetic membranes (S). Ten healthy subjects constituted the control group. Serum samples and peripheral blood mononuclear cells (PBMC) were harvested in all groups (before dialysis in RDT patients). PBMC were cultured for 24 h in the absence or presence of LPS. The serum levels of sgp130 were significantly higher in C group than in control and S patients (C, 603.1 ؎ 89.9; control, 396 ؎ 49.5; S, 423.4 ؎ 27.7 ng/ml; P < 0.01). PBMC from C patients, in the absence of any mitogenic stimulation, released a significantly greater amount of sgp130 as compared with S and control groups (C, 532.6 ؎ 161.2; S, 332.4 ؎ 148.6; control, 341.4 ؎ 125.4 pg/ml; P < 0.01). The sgp130 release was positively correlated with the release of both IL-6 (r ‫؍‬ 0.336, P < 0.05) and sIL-6R receptor (r ‫؍‬ 0.324, P < 0.05). A significantly higher gp130 gene expression was also observed in unstimulated PBMC from C patients when compared with control and S groups. It is interesting that the expression of the 85-bp exon characteristic of the alternative splicing mRNA for sgp130 was low in all groups. Finally, confocal microscopy analysis showed an increased expression of gp130 on cell surface in unstimulated PBMC from C patients as compared with control and S groups. Our results demonstrate that in patients on RDT with C membranes, the synthesis and release of sgp130 "antagonistic" receptor is significantly increased. This release is seemingly due to a shedding of membrane-bound gp130 receptor. The increased sgp130 release may partially counteract the inflammatory effects caused by IL-6.

Priming of the coagulation cascade during hemodialysis (HD) leads to the release of activated factor X (FXa). The binding of FXa to its specific receptors, effector protease receptor-1 (EPR-1) and protease-activated receptor-2 (PAR-2), may induce the activation of peripheral blood mononuclear cells (PBMC) and promote a chronic inflammatory state that is responsible for several HD-related morbidities. In the attempt to elucidate the mechanisms underlying the coagulation-associated inflammation in HD, 10 HD patients were randomized to be treated subsequently with a cellulose acetate membrane (CA) and Ethylen-vinyl-alcohol (EVAL), a synthetic membrane that has been shown to reduce FXa generation. At the end of each experimental period, surface FXa and thrombin receptors (EPR-1 and PAR-1, -2, and -4) and CCR2 (monocyte chemoattractant protein-1 receptor) gene expression in isolated PBMC were examined. the ability of dialytic membranes to activate proteintyrosine kinases and the stress-activated kinase JNK and to modulate the generation of terminal complement complex (TCC) was also investigated. EPR-1 and PAR-2 and -4 mRNA expression, barely detectable in normal PBMC, were significantly upregulated in HD patients, particularly in those who were treated with CA. A striking increase of tyrosine-phosphorylated proteins and JNK activation was observed at the end of HD only in CA-treated patients. Simultaneously, an increased gene expression for both splicing isoforms of CCR2, A and B, only in PBMC from CA-treated patients was demonstrated. The increased CCR-2 mRNA abundance was followed by a significant increase in its protein synthesis. The high expression of CCR2 was associated with an increased generation of plasma TCC and a significant drop in leukocyte and monocyte count. By contrast, EVAL treatment slightly lowered TCC generation and normalized leukocyte count. In vitro FXa induced CCR2 A and B expression and JNK activation in freshly isolated PBMC. FXa-induced CCR2 mRNA expression was completely abolished by JNK and tyrosine kinase inhibition. In conclusion, these data suggest that subclinical clotting activation may cause an increased CCR2 gene and protein expression on uremic PBMC, contributing to HD-related chronic microinflammation. The use of the less coagulation-activating membrane, EVAL, may reduce PBMC activation through the modulation of the stress-activated kinase JNK.

No abstract

ABSTRACT.The annular tendon is commonly named 'annulus of Zinn', from the German anatomist and botanist Johann Gottfried Zinn (1727-1759) who described this structure in his Descriptio anatomica oculi humani (Anatomical Description of the Human Eye, 1755). This structure, however, had been previously discovered not by Zinn, but by Antonio Maria Valsalva (1666-1723) some decades before the publication of Zinn, in his Dissertatio anatomica prima and Dissertatio anatomica altera (First and Second Anatomical Dissertations), inside Valsalva's Opera omnia published in 1740. We advance that this structure could be re-named such as 'annulus of Valsalva-Zinn' because Valsalva, even making a mistake in its functional interpretation, first described this anatomical structure. Likewise, Valsalva, with his discovery, advanced a revolutionary idea for that time on the usefulness of anatomy for clinic and pathology.