Proefschrift Maastricht. / Samenvatting in het Nederlands. Ten dele eerder verschenen en nog te verschijnen art. Auteursnaam op rug en omslag: Michaël Vork. Met lit. opg. en een samenvatting in het Nederlands.

Proefschrift Rijksuniversiteit Limburg, Maastricht. / Met lit. opg. en een samenvatting in het Nederlands.

Proefschrift Universiteit Maastricht. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

With bibliogr., with a summary in Dutch. - Dissertation University of Nijmegen, 1989.

Th. 3e cycle--Biol. humaine et exp.--Paris 5, 1981. N°: 23.

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The work described in this thesis examines the renal excretion of nickel in humans and the Wistar Albino male rat. The renal clearance of nickel is characterized in two groups of electrolytic nickel-refinery workers. In the animal work, the mechanisms of nickel uptake in kidney tissue and its pathological consequences are investigated. Multi-void 24-h urine collections were obtained from 26 workers, as well as serum samples at the beginning and end of this sampling period. Nickel, ?[2]-microglobulin and creatinine concentrations were measured in both body fluids. In addition, specific gravity, protein and qualitative indices of kidney disfunction (by Dip Stick) were assessed in urine. Examination of the functional dependence in individuals of urinary nickel, creatinine and specific gravity on urine flow-rate indicates that specific gravity adjustment of spot-nickel voids is more appropriate than employing creatinine. The systematic strategy devised in this study to overcome concentration-dilution effects for nickel has wide application in biological monitoring. It is demonstrated that if the specific gravity values of spot urine voids in a group of 20 individuals are between 1.010 and 1.039, then the uncompensated uncertainty in specific-gravity adjusted urinary-nickel concentrations does not exceed +/- 10% (95% Confidence Level). Nickel clearance studies and the determination of nickel in serum ultrafiltrates indicated that 24 +/- 6% of serum nickel is available for renal filtration, of which 65% on average is reabsorbed in the human kidney. It is concluded for the nickel-refinery workers studied, that there was little evidence of kidney dysfunction. Studies with rat renal slices and isolated proximal tubules showed that the uptake of Ni[2+] and its histidine complexes is probably passive. Ni(His)[2] reduced the uptake of L-histidine and proline, but not of thymidine. The renal accumulation of nickel from nontoxic i.v. doses of [63]Ni(His)[2] (6 mug Ni kg[-1]) was followed by rapid subcellular clearance during the 24-h period after injection. Autoradiography of the nephron illustrated that only the S3 segment of the proximal tubule accumulated and retained nickel. There was no evidence of nephrotoxicity in the histopathological examination of these tissues. By contrast, high i.p. doses (3 and 6 mg Ni kg[-1] induced a decrease in Bowman's space and minor changes along the entire length of affected nephrons. Compartmentalization of nickel within subcellular fractions of the rat kidney is interpreted in terms of an "Equilibrium" model for metal- ion uptake under steady state conditions (i.e., at fixed pH, redox potential, intracellular and extracellular ligand concentrations). Effectively, nickel distribution is determined by thermodynamic parameters such as complex stability. The human and animal evidence support a passive mechanism of nickel reabsorption in the kidney. Simple pulmonary deposition and absorption considerations in man suggest that the dose of nickel acquired during an 8- h shift of work at a Threshold Limit Value (TLV) of 0.1 mg Ni m[-3] is roughly equivalent to the 6 mug Ni kg[-1] dose used in the rat study. Therefore, the absence of signs of significant nephrotoxicity in both the human and animal models appears to be consistent.

Abstract Dietary xylitol supplementation increases bone calcium and phosphorus concentrations in healthy rats, as well as protects against the decrease of bone minerals and bone density during experimental osteoporosis. This suggests that dietary xylitol might have a favorable effect on the prevention of osteoporosis. However, before any conclusions can be drawn about the usefulness of a compound, studies including structural evaluation and biomechanical testing of bones must first be performed. Thus, the aim of the present study was to clarify whether dietary xylitol affects bone resorption, bone structure, and bone biomechanics in healthy rats, and whether dietary xylitol offers some preventive effects against the increased bone resorption, decreased bone trabeculation, and weakened bone biomechanical properties during experimental osteoporosis. Dietary xylitol reduced bone resorption in 3-mo old healthy male rats, and protected significantly against the increase of bone resorption in 3-mo old ovariectomized rats, as measured by the urinary excretion of 3H following [3H]tetracycline-prelabeling. In addition, increased trabecular bone volume of proximal tibia in 4-mo old healthy male rats was detected after a 1-mo xylitol feeding period, and significant protection against the decrease of trabecular bone volume in 6-mo old ovariectomized rats was observed after a 3-mo xylitol feeding period. Furthermore, dietary xylitol increased the strength properties of long bones in 6-mo old healthy male rats after a 3-mo feeding period, without affecting the bone elastic properties as tested by three-point bending of tibia, torsion of femur, and loading of femoral neck. Accordingly, dietary xylitol protected significantly against the weakening of bone biomechanical properties in 6-mo old ovariectomized rats after a 3-mo feeding period. In conclusion, the above results strongly support the hypothesis that oral administration of xylitol protects effectively against the progression of experimental osteoporosis. Dietary xylitol was effective both in increasing bone mass in healthy rats, and in preventing bone loss in ovariectomized rats, suggesting a favorable effect of xylitol on both main targets in the prevention of osteoporosis. As dietary xylitol was effective also in protecting against the experimental osteoporosis-caused changes in bone structure and weakening of bone biomechanical properties, oral xylitol administration seems to provide interesting possibilities when searching for new physiological choices for the prevention of osteoporosis.

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