Metabolism of 2-fluoro-4-iodoaniline in earthworm Eisenia veneta using (19)F-NMR spectroscopy, HPLC-MS, and HPLC-ICPMS ((127)I)

A combination of (19)F-NMR spectroscopy, HPLC-MS/MS, HPLC-MS with constant neutral loss scanning of 127, and HPLC-ICPMS with iodine detection has enabled the profiling, quantification, and limited characterization of the metabolites produced in the earthworm Eisenia veneta, following exposure to 2-fluoro-4-iodoaniline. Mass spectrometric analysis of the worm tissue and coelomic fluid afforded the identification of two Phase II metabolites, N-glutamyl and N-glucoside conjugates, indicating the importance of these pathways in the detoxification of xenobiotics for earthworms. Several further metabolites were observed and quantified by (19)F-NMR spectroscopy and HPLC-(127)I-ICPMS, although these were of low abundance and their structures were not unequivocally identified. The parent compound and the glutamyl conjugate were found to be the major xenobiotic components of both the coelomic fluid and the worm tissue, representing approximately 23 and approximately 35%, respectively, of the dose that was recovered from the earthworm tissue extract.     

A novel polymorphism in the factor XIII B-subunit (His95Arg): relationship to subunit dissociation and venous thrombosis

BACKGROUND: Factor (F)XIII B-subunit, which plays a carrier role for zymogen FXIIIA, is highly polymorphic, but the molecular basis for these polymorphisms and their relationship to disease remains unknown. OBJECTIVES: To screen the FXIIIB gene coding region for common variation and analyze possible functional effects. METHODS AND RESULTS: We examined the FXIIIB gene by PCR-SSCP and identified three common single nucleotide polymorphisms: A8259G, C29470T and A30899G. A8259G results in substitution of His95Arg in the second Sushi domain. An FXIII tetramer ELISA was developed to analyze B-subunit dissociation from A-subunit (leading to access to the catalytic site of FXIII). Increased subunit dissociation, 0.51 vs. 0.45 (fraction of total tetramer), was found in plasma from subjects possessing the Arg-allele. However, when the variants were purified to homogeneity and binding was analyzed by steady-state kinetics, no difference was observed. The relationship between His95Arg and venous thrombosis was investigated in 214 patients and 291 controls from Leeds. His/Arg + Arg/Arg genotypes were more frequent in patients than controls (22.4% vs. 15.1%). His95Arg was also investigated in the Leiden Thrombophilia Study, in which a similar difference was observed for 471 patients vs. 472 controls (18.5% vs. 14.0%), for a pooled odds ratio (OR) of 1.5 (CI95 1.1-2.0). CONCLUSIONS: We have identified three FXIIIB polymorphisms, one of which codes for substitution of His95Arg. The Arg95 variant associates with a moderately increased risk for venous thrombosis, and with increased dissociation of the FXIII subunits in plasma, although in vitro steady-state binding between purified subunits was not affected.     

Preputial calculus: a case report

A preputial calculus developed postoperatively in a child with epispadias. Analysis of the pathophysiological development of this lesion and a review of the literature are presented. The inert subpreputial space may become calculogenic in the presence of phimosis and urinary stasis.     

Concerning Kuru plaques alias 'cactus', 'stellate', 'hairy' or 'asteroid' bodies

Klatzo, Gadusek and Zigas described nodular swellings of dendrites of Purkinje cells in their study of the neuropathology of Kuru as 'the presence of remarkable plaque-like structures' ( Laboratory Invest 1959; 8 : 799). Henceforth these structures were named 'Kuru plaques' and were considered to be specific or nearly specific for Kuru. However, this is not quite the case. Such plaques or bodies had been described and profusely illustrated in animal and human neurological diseases by Cajal (1907, 1911, 1926), Nageotte and Leon-Kindberg (1908, 1910), Hechst (1929), Von Santha (1930), Norman (1940), Hunter and Russell (1954) and Fowler and Robertson (also in 1959), among others. They were variously named as cactus, stellate, asteroid or hairy bodies. In 1963, Friede referred to these bodies and axonal torpedoes as 'nonspecific injury responses'. This presentation is a review of the literature concerning these bodies. Their history illustrates Raymond Garcin's observation: 'Tout àétéécrit mais pas tout àété lu' (everything has been written but not everything has been read).     

Compensatory renal growth: Interactions of nephrectomy serum and urine antisera leading to a new theory of renal growth regulation

Summary Compensatory renal growth is mediated by a substance(s) found in the serum and in urine called renotropin. The interaction of nephrectomy serum and urine antisera upon compensatory renal growth was investigated by administering rat uninephrectomy serum and sham serum and urine to rabbits. The rabbit antisera was given intravenously to uninephrectomy and sham operated rats and kidney weight/body weight ratios were calculated. Antisera against sham serum and urine induced kidney growth as well as antisera aginst uninephrectomy serum and urine given to sham animals. These results suggest the presence of a circulating antigenic inhibitor to kidney growth and suggest that renotropin is made up of a inhibitory as well as a stimulatory substance.     

Hypertension in the elderly: a study of a combination of atenolol and nifedipine

The antihypertensive effects and tolerability of a once-daily, fixed combination of atenolol 50 mg and nifedipine retard 20 mg ('Nif-Ten') were monitored in a 12-month open study in 30 elderly hypertensive patients, whose blood pressure was inadequately controlled after four weeks treatment with atenolol 50 mg once daily. Sitting (and standing) blood pressure and heart rate one to four hours after dosing were recorded at entry (191/95 mmHg) and at the end of the run-in period (186/93 mmHg). After one month's therapy with the fixed combination the mean sitting blood pressure fell to 169/89 mm Hg and was maintained at this level for the entire 12-month period of observation. During the study four patients complained of side effects on fixed combination therapy with one patient withdrawn due to flushes and hot sweats. One other patient suffered flushes and hot sweats and two patients complained of mild dizziness. There were no demonstrable effects of fixed combination therapy upon the biochemical parameters measured. We conclude that the fixed combination of atenolol plus nifedipine retard was well tolerated over a 12-month period in the group of elderly hypertensive patients studied. The combination appears to exert a greater antihypertensive effect than the beta-blocker monotherapy with no evidence of tachyphylaxis, although these findings require confirmation in a controlled trial.     

Biological and immunological characterization of ATG and ALG

Antithymocyte globulin (ATG) and antilymphocyte globulin (ALG) are effective therapies in aplastic anemia; their mechanism of action is undefined. We assayed multiple properties of ATG and ALG to address the biological and immunological bases for differences between ATG and ALG and lot variation. In addition, we studied a lot reported to be inactive in an American clinical trial; however in retrospect, this lot appeared to be active in patients treated in Europe. Immunoprecipitation of thymocyte and lymphocyte membrane proteins with ATG and ALG showed between 14 and 18 major bands on SDS-PAGE, but the patterns for ATG and ALG were not identical. The ability of ATG and ALG to block binding of labeled monoclonal antibodies was assessed using flow cytometry and a radioimmunoassay. In general, there was more lot variation among ALGs than ATGs; however, all ALG lots were more potent blockers of binding of anti-HLA-DR and anti-Leu 1 antibodies than was ATG. Both ALG and ATG effectively blocked binding of anti-Leu 2a, anti- Leu 3a, anti-Leu 4, anti-Leu 5b, and anti-IL 2 receptor abs; neither blocked binding of anti-Leu 7. All preparations were capable of inducing T-cell blastogenesis, although there was considerable lot variation. All lots lysed 60% to 75% T cells in a rabbit complement- mediated cytotoxicity assay, with most having a plateau of activity at 5 to 10 ug/mL. Two lots of ALG, including the lot reported to be clinically inactive, showed less toxicity at suboptimal concentrations and did not plateau even at 80 ug/mL. In total, these results indicate important differences between ATG and ALG in general, more lot variation among ALGs than ATGs and only differences in cytotoxicity between an "inactive" lot of ALG and most, but not all, other active ATG and ALG preparations.