Crystallization in the nephron

Recent experimental studies on the crystallization of calcium salts at different nephron levels support the theory that the initial formation of calcium concrements starts with an intratubular crystallization of calcium phosphate (CaP) and calcium oxalate (CaOx). CaP seems to be the initial crystallization product in pure CaP and mixed calcium phosphate–calcium oxalate (CaPCaOx) concrements, with the formation of CaP crystals at a nephron level above the collecting duct. Urinary macromolecules and cellular degradation products most probably promote this process. During the passage through the collecting duct, CaP might partly or completely dissolve at the lower pH encountered there. This might result in an increased concentration of calcium and hence an increased supersaturation with CaOx, which in turn can bring about a heterogeneous nucleation of CaOx on or around preformed CaP crystals or crystal aggregates. The final result will be mixed CaOxCaP or pure CaOx concrements. Pure CaOx concrements might also be the result of an initial CaOx crystallization at nephron levels above or in the collecting duct under conditions with a high urinary excretion of oxalate. Whether intratubular crystallization of calcium salts results in the formation of small harmless crystals excreted with urine or calcium stones appears to be determined by a complex process, involving kinetic factors that influence crystal growth and crystal aggregation and crystal retention. Received: 24 December 1998 / Accepted: 11 March 1999     

Enzymic control of irreversible binding of metabolically activated benzo(a)pyrene in perfused rat liver by monooxygenase activity

Addition of [³H]-benzo(a)pyrene to the perfusion medium of isolated rat livers results in irreversible binding of radioactivity to DNA, RNA and protein. Binding to DNA accounted for about 0.1% of the total radioactivity which was bound in livers from animals treated with oil or saline and was increased by a factor of 3–5 after pretreatment of the animals with -naphthoflavone or with phenobarbital. When the inhibitiors of monooygenase activity, -naphthoflavone or metyrapone, were present in the perfusion medium, irreversible binding was reduced in livers from both -naphthoflavone- and phenobarbital-pretreated animals, irrespective of the inhibitor used.In livers from animals treated with oil or saline protein and a RNA fraction containing tightly associated protein were able to bind [³H]-benzo(a)pyrene metabolites to about the same extent but after induction by pretreatment with -naphthoflavone binding to the RNA fraction was enhanced to a much higher extent than binding to the protein fraction. Pretreatment with phenobarbital did not result in an increased irreversible binding to RNA and protein.A considerable amount of 15–25% of the total radioactivity added to the perfusion medium was excreted into the bile after treatment of the animals with the tested inducers of monooxygenase activity compared to an excretion of 3% in animals treated with oil or saline.The results indicate that nucleic acid and protein adduct formation in the liver is controlled by the action of the cytochrome P-450-dependent monooxygenases.In part subject of the doctoral thesis of Erik Klaus, Fachbereich Biologie, University of Mainz     

大分子为载体的抗体偶联药物研究进展

抗体偶联药物与肿瘤相关靶点结合有特异性,对肿瘤细胞有选择性杀伤作用,临床上已开始用于治疗肿瘤.综述了抗体与抗癌药物偶联物的偶联方式和药物释放的靶向机制,以及采用大分子聚合物做载体(如葡聚糖、人血清白蛋白、聚N-2羟丙甲基丙烯酰胺)的抗体偶联药物的研究现状.     

Quantification issues of in vivo 1H NMR spectroscopy of the rat brain investigated at 16.4 T

The accuracy and precision of the quantification of metabolite concentrations in in vivo ¹H NMR spectroscopy are affected by linewidth and signal‐to‐noise ratio (SNR). To study the effect of both factors in in vivo ¹H NMR spectra acquired at ultrahigh field, a reference spectrum was generated by summing nine in vivo ¹H NMR spectra obtained in rat brain with a STEAM sequence at 16.4 T. By progressive deterioration of linewidth and SNR, 6400 single spectra were generated. In an accuracy study, the variation in the mean concentrations of five metabolites was mainly dependent on SNR, whereas 11 metabolites were predominantly susceptible to the linewidth. However, the standard deviations of the concentrations obtained were dependent almost exclusively on the SNR. An insignificant correlation was found between most of the heavily overlapping metabolite peaks, indicating independent and reliable quantification. Two different approaches for the consideration of macromolecular signals were evaluated. The use of prior knowledge derived by parameterization of a metabolite‐nulled spectrum demonstrated improved fitting quality, with reduced Cramér–Rao lower bounds, compared to the calculation of a regularized spline baseline. Copyright © 2012 John Wiley & Sons, Ltd.     

The peritoneal microcirculation in peritoneal dialysis.

This paper deals with the peritoneal microcirculation and with peritoneal exchange occurring in peritoneal dialysis (PD). The capillary wall is a major barrier to solute and water exchange across the peritoneal membrane. There is a bimodal size-selectivity of solute transport between blood and the peritoneal cavity, through pores of radius approximately 40-50 A as well as through a very low number of large pores of radius approximately 250 A. Furthermore, during glucose-induced osmosis during PD, nearly 40% of the total osmotic water flow occurs through molecular water channels, termed "aquaporin-1." This causes an inequality between 1 - sigma and the sieving coefficient for small solutes, which is a key feature of the "three-pore model" of peritoneal transport. The peritoneal interstitium, coupled in series with the capillary walls, markedly modifies small-solute transport and makes large-solute transport asymmetric. Thus, although severely restricted in the blood-to-peritoneal direction, the absorption of large solutes from the peritoneal cavity occurs at a high clearance rate ( approximately 1 mL/min), largely independent of molecular radius. True absorption of macromolecules to the blood via lymphatics, however, seems to be occurring at a rate of approximately 0.2 mL/min. Several controversial issues regarding transcapillary and transperitoneal exchange mechanisms are discussed in this paper.     

Proton magnetic resonance spectroscopy with metabolite nulling reveals regional differences of macromolecules in normal human brain

PURPOSE: To quantify the macromolecular content in different anatomic brain regions and to evaluate an age dependency of the macromolecular concentrations. MATERIAL AND METHODS: A short echo time Stimulated Echo Acquisition Mode (STEAM) sequence was used without and with inversion recovery metabolite nulling in 8-12 healthy volunteers. Quantitation was achieved by an extended LCModel, and macromolecular resonances at 0.9, 1.4, 2.1, and 3.0 ppm were evaluated. RESULTS: In the cerebellum, the 1.4, 2.1, and 3.0 ppm resonances were highest compared to all other regions (P < 0.02); the 0.9 ppm resonance was significantly higher than that of pons (P < 0.01). In the motor cortex, the 0.9, 1.4, and 2.1 ppm resonances were higher than those of white matter and pons (P < 0.02). Pons and white matter did not differ significantly from each other. A significant correlation of the macromolecular concentrations with the age could not be found. CONCLUSION: There were higher macromolecular concentrations in the cerebellum and motor cortex than in pons or white matter. These were probably due to the higher portions of gray matter in these volumes of interest (VOIs) than in the other regions.     

Regulation by macromolecules of calcium oxalate crystal aggregation in stone formers

Based on the structure of kidney stones, it is likely that they form as aggregations of preformed crystals, mostly calcium oxalate monohydrate (COM). In this study, we examined the ability of a macromolecular mixture isolated from the urine of normal individuals and stone formers to inhibit aggregation of preformed COM seed crystals in a simple ionic solution using measurements of changes in the particle size distribution (PSD) of preformed COM crystal aggregates. We also examined the effect in this assay of a number of synthetic homopolymers, naturally occurring urine macromolecules, and binary mixtures thereof. The macromolecular mixtures from urine of normals and most stone formers reduced the degree of aggregation of the seed crystals, whereas 22% of stone former urine macromolecules either did not disaggregate or actually promoted further aggregation. Stone formers within one family shared this property, but a non-stone forming sibling did not. Polyanions, either synthetic or naturally occurring, induced disaggregation to an extent similar to that exhibited by normal urine macromolecules, while polycations had no effect on the PSD. However, mixing a polyanion, either poly-aspartate or osteopontin, with the polycation poly-arginine, changed their behavior from disaggregation to aggregation promotion. The disaggregating behavior of normal urinary macromolecules provides a defense against aggregation, but a minority of stone forming individuals lacks this defense, which may contribute to stone formation.