Evidence that the Receptor for Soluble CD14:LPS Complexes may not be the Putative Signal-Transducing Molecule Associated with Membrane-Bound CD14

Membrane-bound CD14 acts as a receptor for lipopolysaccharide (LPS) on monocytes/macrophages and neutrophils. Studies have suggested that the activation of monocytes/macrophages by the binding of LPS to membrane-bound CD14 may require the association of a signal-transducing molecule with membrane-bound CD14. The observation that non-CD14 expressing cells, such as endothelial cells, can nevertheless be activated by a complex of LPS and a soluble form of CD14 (sCD14) suggests that the receptor for this complex may be identical to the signal transducing molecule associated with membrane-bound CD14. The studies described show that two CD14-specific MoAb are able to block the LPS-induced activation of endothelial cells but do not affect the response of monocytes to LPS. This suggests that the interaction of the sCD14:LPS complex with endothelial cells is distinct from the interaction of membrane-bound CD14 with its putative signal-transducing molecule.     

Atrioventricular Node Ablation for Optimization of Pacemaker Treatment in Hypertrophic Obstructive Cardiomyopathy

Dual chamber pacing is a new indication for the treatment of drug resistant hypertrophic obstructive cardiontyopathy (HOCM) in patients with normal atrioventricular (AV) conduction. In sinus rhythm, the efficacy of the treatment is mainly related to the ability to bypass the normal AV conduction system in order to obtain a complete and permanent right ventricular (RV) capture. This is achieved by programming short AV delays. On the other hand, patients with HOCM frequently have co-existing left ventricular diastolic dysfunction, and the atrial contribution to left ventricular filling is critical. The lack of improvement, rarely encountered, is probably due to incomplete RV capture andlor to the deleterious effect of short AV delay. Instrumental AV node prolongation may he indicated in this situation. This procedure should be undertaken when previous drug-induced AV prolongation has failed. In theory, AV node modulation (i.e., creating a I ± AV block) seems ideal. However, this technique remains difficult, with disappointing chronic results. Most authors hence perform "conventional" AV node ablation. Particular attention is taken in order to perform a proximal node ablation, resulting in a complete AV block with narrow QRS escape rhythm. The reported incidence of AV node prolongation ranges from 7.5%-37.5%. The efficacy of the procedure on symptoms is explained by improved left ventricular filling and/or a further reduction in the systolic gradient evoked by complete RV capture. Another indication for AV node ablation in HOCM is the occurrence of atrial fibrillation, in order to restore adequate and permanent RV capture .     

Dose-Related Effects of the Hepatocarcinogen, Wy-14,643, on Peroxisomes and Cell Replication

Dose-Related Effects of the Hepatocarcinogen, Wy-14,643, onPeroxisomes and Cell Replication. WADA, N., MARSMAN, D. S.,AND POPP, J. A. (1992). Fundam. Appl. Toxicol. 18, 149–154. The dose and time dependency of peroxisome proliferation andhepatocyte replication was evaluated in the liver of rats fedthe peroxisome proliferator and hepatocarcinogen, Wy-14,643.Male F344 rats were fed NIH07 diet blended with Wy-14,643 at0, 5, 10, 50, 100, or 1000 ppm for 1, 3, 6, or 13 weeks. Hepatomegalywas induced by Wy-14,643 at all doses and at all time points.Peroxisome proliferation was present in rats fed 5 ppm Wy-14,643as early as 1 week, as determined by the peroxisome-specificNAD⁺ reduction of palmitoyl CoA (PCO) and the peroxisome-associatedactivity of carnitine acetyltransferase (CAT) (5-and 11-foldover control, respectively). The elevations of PCO and CAT weredose-dependent from 5 to 50 ppm and then plateaued from 50 to1000 ppm throughout the treatment period. Hepatocellular replication,evaluated by nuclear histoautoradiography ([³H]thymidine labeling,6-day infusion), was increased in all Wy-14,643 dose groupsafter 1 week of treatment (5 ppm, 4-fold; 10 ppm, 5-fold; 50ppm, 13-fold; 100 ppm, 12-fold; and 1000 ppm, 13-fold over controls).However, in 5 and 10 ppm groups this cell replication returnedto control levels by 3 weeks. In contrast, 50, 100, and 1000ppm groups had sustained increases in cell replication up to13 weeks (13 weeks: 6-, 7-, and 9-fold over controls, respectively).We have demonstrated that Wy-14,643 can induce peroxisome proliferationat 5 ppm, a dose 200 times lower than the dose shown to be highlyhepatocarcinogenic in rats (100% incidence by 60 weeks). Incontrast, 50 ppm was identified as the minimal dose which inducedsustained cell replication in rat liver. These data show thatperoxisome proliferation can be dissected from sustained cellreplication for correlating either peroxisome induction or cellreplication with tumor formation. These results provide importantinformation that can be used to design carcinogenicity experimentsto test if peroxisome proliferation and/or chronic enhancementof cell replication predictive risk factors for hepatocarcinogenieity.     

Interaction of glucagon with artificial lipid bilayer membranes

The enhancement of fluorescence emission from the tryptophan residue of glucagon, the quenching of that emission with acrylamide and with 5-doxyl and 16-doxyl stearic acid, circular dichroism spectra, the release of 6-carboxytluorescein, and polarized infrared attenuated total reflection (IR-ATR) spectra were used to study the interaction of glucagon with intact lipid vesicles and flat bilayers. Dimyristoylphosphatidylcholine bound the peptide only below the main transition temperature, thus confirming earlier results of Epand et al. (1977). However, the peptide is also bound by vesicles of unsaturated lipids above their transition temperature, suggesting an influence of lipid area on the binding process. Circular dichroism showed that binding to such vesicles also increases the helix content of glucagon. The IR-ATR study and a comparison with dynorphin-A-(I-13)-tridecapeptide revealed profound differences in orientation of the two peptides. The dichroic ratios and the derived order parameters indicated an isotropic orientation of the helical segments of glucagon, but did not exclude a principal orientation of the molecules lying flat on the nienibrane surface. In contrast, the axis of the dynorphin helix is clearly oriented normal to the interface. The two peptides also differ in their rates of 6-carboxyfluorescein release, suggesting a deeper penetration of the primary amphiphilic helix of dynorphin A-(I-13) than of the secondary amphiphilic helix of glucagon.