A randomized prospective cross over study on the effects of medium cut-off membranes on T cellular and serologic immune phenotypes in hemodialysis.

Extended cut-off filtration by medium cut-off membranes (MCO) has been shown to be safe in maintenance hemodialysis (HD). The notion of using them for the control of chronic low-grade inflammation and positively influencing cellular immune aberrations seems tempting. We conducted an open label, multicenter, randomized, 90 day 2-phase cross over clinical trial (MCO- vs. high flux-HD). 46 patients underwent randomization of which 34 completed the study. Dialysate- or pre- and post-dialysis serum inflammatory mediators were assayed for each study visit. Ex vivo T cell activation was assessed from cryopreserved leucocytes by flow cytometry. Linear mixed models were used to compare treatment modalities, with difference in pre-dialysis serum MCP-1 levels after 3 months as the predefined primary endpoint. Filtration/dialysate concentrations of most mediators, including MCP-1 (mean ± SD: 10.5 ± 5.9 vs. 5.1 ± 3.8 pg/ml, P < 0.001) were significantly increased during MCO- versus high flux-HD. However, except for the largest mediator studied, i.e., YKL-40, this did not confer any advantages for single session elimination kinetics (post-HD mean ± SD: 360 ± 334 vs. 564 ± 422 pg/ml, P < 0.001). No sustained reduction of any of the studied mediators was found neither. Still, the long-term reduction of CD69+ (P = 0.01) and PD1+ (P = 0.02) activated CD4+ T cells was striking. Thus, MCO-HD does not induce reduction of a broad range of inflammatory mediators studied here. Long-term reduction over a 3-month period was not possible. Increased single session filtration, as evidenced by increased dialysate concentrations of inflammatory mediators during MCO-HD, might eventually be compensated for by compartment redistribution or increased production during dialysis session. Nevertheless, lasting effects on the T-cell phenotype were seen, which deserves further investigation.

Venlafaxine and mirtazapine treatment lowers serum concentrations of dehydroepiandrosterone-sulfate in depressed patients remitting during the course of treatment.

OBJECTIVES: The adrenal androgen dehydroepiandrosterone-sulfate (DHEA-S) seems to be involved in the pathophysiology of depression, although its precise role in the etiology and remission of depression remains unclear. In the present study we intended to examine possible differential effects of venlafaxine and mirtazapine in a randomised open trial with regard to DHEA-S serum concentrations in patients suffering from major depressive episode compared to healthy controls. METHODS: We assessed DHEA-S concentrations both at baseline and after a 4-week treatment period in 70 depressed patients (n=33 for venlafaxine and n=37 for mirtazapine) and 33 matched healthy controls. RESULTS: We describe the decrease of DHEA-S levels in depressive patients who remitted after treatment with both venlafaxine or mirtazapine. Patients without remission of depression did not show a significant decline in DHEA-S concentrations. CONCLUSIONS: Our results suggest an effect of treatment outcome upon DHEA-S concentrations rather than a direct drug effect. The change of plasma DHEA-S levels as a marker of treatment-response of depression warrant further investigation.

Binding analysis of 1alpha- and 17alpha-dihydrotestosterone derivatives to homodimeric sex hormone-binding globulin.

Binding studies of the interaction of immobilized 1alpha- and 17alpha-aminoalkyl derivatives of 5alpha-dihydrotestosterone (DHT) with purified N-deglycosylated homodimeric human sex hormone-binding globulin (SHBG) were performed using a surface plasmon resonance biosensor. These 1alpha- and 17alpha-derivatives with spacers of appropriate lengths between the amine function and the steroid ring skeleton enabled privileged, sterically undisturbed, interactions of either the 17- or 3-characteristic functional groups of DHT with SHBG. The association constants (K(a)1) for the binding of these immobilized DHT derivatives to the first binding site of SHBG, determined by SPR measurements, were 0.16 x 10(7) M(-1) for 17alpha-aminopropyl-17beta-hydroxy-5alpha-androstan-3-one (1), 1.64 x 10(7) M(-1) for 17alpha-aminocaproyl-17beta-hydroxy-5alpha-androstan-3-one (2), and 1.2 x 10(8) M(-1) for 1alpha-aminohexyl-17beta-hydroxy-5alpha-androstan-3-one (3). These values were compared with global K(a) data for the corresponding nonimmobilized DHT derivatives from equilibrium measurements using competitions with a tritiated testosterone tracer: the K(a) values were 1.25 x 10(7) M(-1) for 1, 1.50 x 10(7) M(-1) for 2, and 140 x 10(7) M(-1) for 3, confirming a remarkably high binding affinity of this latter compound for SHBG. A global fitting analysis of the biosensor data revealed that the interaction of the three immobilized steroids with SHBG was best described by a kinetic model assuming two structurally independent binding sites. This hypothesis of a bivalent binding model was also directly suggested by a dual fluorescent signal observed by the flow cytometry analysis of SHBG immobilized as a hybrid complex binding simultaneously two 1alpha-aminohexyl DHT ligands, one formed by 3, covalently coupled to phycoerythrin-labeled latex microspheres, and the other by the same DHT derivative, coupled to a fluorescein derivative (4).