A reaction route graph analysis of the electrochemical hydrogen oxidation and evolution reactions

The reaction route (RR) graph approach recently developed by us for complex, non-linear kinetic mechanisms is applied to the hydrogen oxidation and evolution reactions. A corresponding RR graph is constructed and translated into an equivalent electrical circuit network by associating each elementary step with a characteristic resistance for the steady-state case and considering the overall reaction as a power source. It is further shown that the steady-state kinetics of the reaction can be investigated employing the conventional methods of the electrical network theory. Using a set of rate constants for the hydrogen evolution reaction (her) in alkaline solutions from the literature, the dominant RRs are identified and simplified mechanisms and kinetics derived.     

Differential Effects of Immunosuppressive Drugs on T-Cell Motility

The best-characterized mechanism of the action of immunosuppressive drugs is to prevent T-cell clonal expansion, thus containing the magnitude of the ensuing immune response. As T-cell recruitment to the inflammatory site is another key step in the development of T-cell-mediated inflammation, we analyzed and compared the effects of two commonly used immunosuppressants, cyclosporin A (CsA) and the rapamycin-related compound SDZ-RAD, on the motility of human CD4+ T cells. We show that CsA, but not SDZ-RAD, inhibits T-cell transendothelial migration in vitro. CsA selectively impaired chemokine-induced T-cell chemotaxis while integrin-mediated migration was unaffected. The inhibition of T-cell chemotaxis correlated with reduced AKT/PKB but not ERK activation following exposure to the chemokine CXCL-12/SDF-1. In addition, CsA, but not SDZ-RAD, prevents some T-cell receptor-mediated effects on T-cell motility. Finally, we show that CsA, but not SDZ-RAD inhibits tissue infiltration by T cells in vivo. Our data suggest a prominent antiinflammatory role for CsA in T-cell-mediated tissue damage, by inhibiting T-cell trafficking into tissues in addition to containing clonal expansion.     

Ultrastructural study of micro-blood vessels in human brain tumors and peritumoral tissue

Summary Ultrastructural and tracer studies have demonstrated that vasogenic edema, a serious complication of brain tumor is the result of increased permeability of tumor vessels. However, not much information is available on the alterations in the vessels in the peritumoral areas. Therefore, we studied the ultrastructural changes in the tumor micro-blood vessels (MBVs) in 20 cases of glioma and compared these with the changes in the peritumoral MBVs in 10 of these cases.The tumor MBVs showed remarkable structural changes, viz, increase in pinocytotic vesicles, large vacuoles and microvilli in the endothelial cells, varying degrees of endothelial attenuation and fenestration, an occasional partially or completely opened-up junction and some pale and edematous endothelial cells, which can adequately explain their increased permeability.The peritumoral MBVs also showed evidence of increased permeability in the form of increased pinocytotic vesicles, large vacuoles and microvilli associated with pale and edematous cytoplasm of some endothelial cells. Thickened multilayered basement membrane, absence of ensheathment of capillary basement membrane by astrocytic cell processes and widened perivascular space were observed in both tumoral and peritumoral MBVs.An interesting observation was that in the peritumoral MBVs, the pinocytotic vesicles were most conspicuously seen on the abluminal side of the endothelial cells often fused with the abluminal plasma membrane. Although a static study like this cannot indicate any definite direction of movement of fluid, we feel that the occurrence of reverse pinocytosis is a distinct possibility in the peritumoral MBVs and that it may be an important means of resorption of edema fluid.     

Osteoclastic inhibition: an action of nitric oxide not mediated by cyclic GMP.

The osteoclast is unique in its ability to resorb bone, and excessive osteoclastic activity has been implicated in osteoporosis, Paget disease of bone, rheumatoid arthritis, and the growth of metastases in bone. The activity of this cell is controlled by the main circulating inhibitor, calcitonin, in association with locally produced modulators. We show that nitric oxide (NO) may be an important member of the latter group. NO is produced by the vascular endothelium and nervous system and is involved in both neurotransmission and the regulation of blood pressure. However, our results show that the autocoid is also a potent inhibitor of osteoclast function. NO (30 microM) produced a decrease to approximately 50% of the original osteoclast spread area. Similar effects were also produced by 3-morpholinosydnonimine or sodium nitroprusside, reagents that spontaneously release NO. These shape changes were associated with a reduction of bone resorption after a 24-hr incubation of isolated osteoclasts on devitalized bone slices. NO is thought to act by stimulating guanylate cyclase, with a consequent increase in cyclic GMP, but a different mode of action is likely in the osteoclast since dibutyryl or 8-bromo cyclic GMP have no effect. It should be noted that calcitonin can produce similar changes in shape and activity but is associated with an increase in osteoclast intracellular calcium and cessation of membrane movement; neither of these is produced by NO, suggesting that its mode of action is different. The abundance of NO-producing endothelial cells in bone marrow and their proximity to osteoclasts suggests that marrow endothelial cells may play a physiological role in the regulation of osteoclastic activity.