Dual mechanisms of regulation of type I iodothyronine 5''-deiodinase in the rat kidney, liver, and thyroid gland. Implications for the treatment of hyperthyroidism with radiographic contrast agents.

Alterations in thyroid hormone status and the administration of radiographic contrast agents can markedly influence iodothyronine metabolism and, in particular, the activity of type I 5'-deiodinase (5'DI). In the present studies, the mechanisms responsible for these effects have been reassessed. As previously reported, the addition of iopanoic acid (IOP) to broken cell preparations resulted in a competitive pattern of 5'DI inhibition. However, the in vivo administration to rats of IOP or 3,3',5'-triiodothyronine (rT3) resulted in a noncompetitive pattern of inhibition of 5'DI in the liver, kidney, and thyroid gland, whereby marked decreases in maximal enzyme velocity (V max) were noted, with no change in the value of the Michaelis-Menten constant. In rats rendered hyperthyroid by the injection of 3,5,3'-triiodothyronine (T3), 5'DI activity was significantly increased in the liver and the kidney. The administration of IOP to these thyrotoxic animals resulted in a rapid loss of enzyme activity characterized by an approximate 80% decrease in 5'DI V max values in both tissues. Furthermore, this inhibitory effect persisted for longer than 60 h after a single IOP injection. IOP administration also decreased 5'DI V max levels in the thyroid gland by 52%. In other experiments, treatment of intact Reuber FAO hepatoma cells with IOP or rT3 induced a rapid decrease in 5'DI V max levels. In cells treated with cycloheximide, these agents enhanced the rate of disappearance of enzyme activity by greater than 12-fold, indicating a predominant effect on accelerating the rate of enzyme inactivation and/or degradation. These studies demonstrate that iodothyronines and other iodinated compounds have complex regulatory effects on 5'DI that entail alterations in the rates of both enzyme activation and inactivation. The previously accepted concept that rT3 and IOP impair thyroxine (T4) to T3 conversion in vivo by acting as competitive inhibitors is an oversimplification. Rather, the clinically beneficial effects of administering these agents to patients with hyperthyroidism may result primarily from the rapid and prolonged inactivation of 5'DI which occurs in the thyroid gland and peripheral tissues.     

Clinical pharmacokinetics of Neoral in pediatric recipients of primary liver transplants

Pediatric liver transplant recipients constitute a population characterized by a particularly unpredictable and poor bioavailability of cyclosporin (CyA). Even though several adult studies show that the new oral formulation of CyA, Neoral (NEO), produces better bioavailability and blood level predictability, few data describe its pharmacokinetics in children. We performed a complete analysis of the pharmacokinetics of NEO in ten small children after primary liver transplantation. Three pharmacokinetic profiles were set up with data obtained from tests taken during i. v. administration of CyA, after the first oral NEO dose, and after the last NEO dose before discharge from the hospital. The mean half-lives obtained were 8.1, 7.7, and 6.9 h, respectively, and the bioavailabilities were 22 % and 21 % for the first and last NEO doses. A large interpatient variability was observed. This was due, in part, to episodes of diarrhea that interfered with the pharmacokinetic evaluation and, in part, to the variability of post-transplant hepatic function. There was a good correlation between CyA trough levels and their related AUCs for both NEO profiles (r = 0.93 and r = 0.74, respectively). We conclude that, even though the pediatric OLT population remains more unpredictable than that of adults, NEO has a relatively rapid half-life and a remarkably improved bioavailability. Received: 29 November 1996 Received after revision: 10 April 1997 Accepted: 15 May 1997     

Das Zytokinnetzwerk

Cytokines are extracellular mediators which co-ordinate the immune system and which are essential for several differentiation processes e.g.hematopoiesis.Cytokines bind to specific receptors on the surface of target cells thereby initiating an intracellular signalling cascade leading to cytokine- and cell-specific reactions.The cytokine network is characterised by diverse regulation mechanisms and by the close interaction of different cytokine systems.Interaction and regulation takes place at the level of cytokines, its receptors and at the level of intracellular signal transduction molecules.The resulting network allows the co-ordinated response of different cell types and tissues to environmental changes.A detailed knowledge of this “language of the immunsystem” may reveal many new therapeutical strategies for the treatment of inflammation, autoimmune disease or neoplasia.     

Decreased blood perfusion in canine tibial diaphysis after filling with acrylic bone cement compared with inert bone wax

Sixteen dogs had one tibia filled with acrylic PMMA bone cement and the opposite, control tibia filled with inert bone wax. After 1, 4, and 12 weeks, the blood perfusion in diaphyses was measured with Sc-46 labeled microspheres. The blood flow rates increased from 1 to 4 weeks and dropped to about the 1-week level after 12 weeks on both sides, with the acrylic side lower than the control side. On both sides, Disulphine Blue staining of the bones showed severe endosteal avascularity after 1 and 4 weeks and massive periosteal apposition after 4 and 12 weeks. The initial increase in blood flow is considered due to periosteal apposition, and the differences in blood flow rates are attributed to avascularity caused by the polymerization heat and toxicity of the acrylic cement.     

Buchbesprechungen

Ohne Zusammenfassung     

Sexual risk behavior in women with cervical human papillomavirus infection

In a study of 972 women, sexual characteristics of 66 women with a cervical human papillomavirus infection (CHPI) were compared to the remaining study population. Among a number of sexual variables that were significantly correlated with CHPI were number of lifetime sexual partners, short partnerships, many recent partners, infidelity, casual travel sex, sexual début abroad, oral and anal sex, and sexual abuse. In multifactorial analyses four variables remained significantly correlated with CHPI, i.e., number of lifetime sexual partners, casual travel sex, sexual début abroad, and infidelity. It is concluded that CHPI shows most of the epidemiological characteristics of a sexually transmitted disease.     

Effects of nail rigidity on fracture healing

The present study was undertaken to assess the effects of the rigidity of nails on the healing of fractures as evaluated by mechanical strength and rate of bone mineralisation. Ten rats supplied biomechanical data at the start of the experiment and another 100 rats were randomly assigned to 5 groups. In 20 rats no intervention was performed, and they served as a reference group of normal values. Thus, 80 rats underwent a standardised partial osteotomy in the left femur diaphysis prior to manual fracture, reaming and intramedullary nailing. One group received rigid steel nails (group 1) and another, cannulated steel nails (group 2). Group 3 received semi-rigid titanium nails and group 4, soft polyethylene nails. Ten rats in each group were evaluated at 6 and 12 weeks after fracture, and radiographs and callus diameter measurements were performed. Dual-energy X-ray absorptiometry (DEXA) of the bones was performed, and the degree of mineralisation in the callus segment, distal diaphysis and total femur was calculated by the scanner. Subsequently, the bones were tested mechanically by a three-point bending test in a Mini Bionix (MTS) testing system. Radiographs revealed clearly visible fractures at 6 weeks in the intervention groups. At 12 weeks there were no signs of bridging callus in group 4, while the other groups presented scarcely visible osteotomies. The callus area in group 4 was significantly larger at both 6 and 12 weeks than in groups 1–3. In these groups there was a significant decrease in callus area between 6 and 12 weeks. Both maximum bending load, bending rigidity and fracture energy increased significantly in groups 1–3 between 6 and 12 weeks, while bending load and fracture energy increased in group 4. At 6 weeks no significant differences were detected between groups 1–3 in mechanical strength. Group 4 had a significantly reduced maximum bending load and fracture energy at 6 and 12 weeks as well as bending rigidity at 12 weeks. At 12 weeks group 3 had a significantly increased maximum bending load and fracture energy compared with groups 1 and 2. Bone mineral count (BMC) in the callus region in group 4 was significantly reduced at both 6 and 12 weeks. BMC in the callus showed no significant differences between groups 1–3, either at 6 or at 12 weeks. BMC in the distal diaphysis was significantly reduced in groups 1 and 4 compared with group 2 at 12 weeks. Bone mineral density (BMD) in the callus region revealed no significant differences between groups 1–3 at 6 weeks, while at 12 weeks BMD was higher in group 3 than in group 1. BMD in the callus region and total femur in group 4 was significantly reduced at 6 weeks. This study demonstrates that diaphyseal fractures treated with titanium nails with a bending rigidity similar to the intact femur have a higher maximum bending load and fracture energy at 12 weeks than both rigidly or softly nailed fractures. BMD in the callus region was also highest after titanium nailing at 12 weeks. BMD in the distal diaphysis and total femur indicates that the degree of stiffness of the nails have little influence on total bone mineralisation at 12 weeks.