Stress- and growth-related gene expression are independent of chemical-induced prostaglandin E(2) synthesis in renal epithelial cells

Cellular stress can initiate prostaglandin (PG) biosynthesis which, through changes in gene expression, can modulate cellular functions, including cell growth. PGA(2), a metabolite of PGE(2), induces the expression of stress response genes, including gadd153 and hsp70, in HeLa cells and human diploid fibroblasts. PGs, gadd153, and hsp70 expression are also influenced by the cellular redox status. Polyphenolic glutathione conjugates retain the ability to redox cycle, with the concomitant generation of reactive oxygen species. One such conjugate, 2,3,5-tris(glutathion-S-yl)hydroquinone (TGHQ), is a potent nephrotoxic and nephrocarcinogenic metabolite of the nephrocarcinogen, hydroquinone. We therefore investigated the effects of TGHQ on PGE(2) synthesis and gene expression in a renal proximal tubular epithelial cell line (LLC-PK(1)). TGHQ (200 microM, 2 h) increases PGE(2) synthesis (2-3-fold) in LLC-PK(1) cells with only minor (5%) reductions in cell viability. This response is toxicant-specific, since another proximal tubular toxicant, S-(1, 2-dichlorovinyl)-L-cysteine (DCVC), stimulates PGE(2) synthesis only after massive (68%) reductions in cell viability. Consistent with the ability of TGHQ to generate an oxidative stress, both deferoxamine mesylate and catalase protect LLC-PK(1) cells from TGHQ-mediated cytotoxicity. Only catalase, however, completely blocks TGHQ-mediated PGE(2) synthesis, implying a major role for hydrogen peroxide in this response. TGHQ induces the early (60 min) expression of gadd153 and hsp70. However, while inhibition of cyclooxygenase with aspirin prevents TGHQ-induced PGE(2) synthesis, it does not affect TGHQ-mediated induction of gadd153 or hsp70 expression. In contrast, a stable PGE(2) analogue, 11-deoxy-16, 16-dimethyl-PGE(2) (DDM-PGE(2)), which protects LLC-PK(1) cells against TGHQ-mediated cytotoxicity, modestly elevates the levels of gadd153 and hsp70 expression. In addition, catalase and, to a lesser extent, deferoxamine mesylate block TGHQ-induced gene expression. Therefore, although TGHQ-induced generation of reactive oxygen species is required for PGE(2) synthesis and stress gene expression, acute TGHQ-mediated increases in gadd153 and hsp70 mRNA levels are independent of PGE(2) synthesis.     

Adrenocortical carcinoma with Ectopic LH production

This report concerns a 3 1/4-year-old boy, in whom a left-sided adrenocortical adenocarcinoma of predominantly androgenic potency caused isosexual precocious development with enlargement of the testicles and, probably, predominantly testicular testosterone secretion. It was possible to identify an increase in LH production as the cause of this phenomenon; the seat of origin was the tumor. Ectopic LH production was proved upon extraction of the tumor and by the decline of gonadotropic activity after its removal.     

Effects of the 5-HT3 antagonist cilansetron vs placebo on phasic sigmoid colonic motility in healthy man: a double-blind crossover trial

AIMS: 5-hydroxytryptamine3 receptor antagonists act antiemetically and slow colonic transit. This study evaluated effects of the high-affinity 5-HT3 antagonist, cilansetron, on fasting, meal-and anticholinesterase-stimulated phasic contractile activity of the human sigmoid colon as well as on bowel habits and stool consistency. METHODS: Five female and seven male healthy volunteers received, during three 7 day periods separated by 7 day wash-out periods, 4 mg cilansetron, 8 mg cilansetron or placebo three times daily orally under random, double-blind, crossover conditions. On day 8 of each treatment period, motility 20-40 cm from the anal verge was recorded using five pressure sensors spaced at 5 cm intervals. After a basal 30 min, subjects swallowed a further dose of the scheduled treatment; 60 min later, blood was taken for the determination of plasma cilansetron levels. Thereafter, subjects ingested a 4200 kJ meal and 250 ml sweetened mallow tea (166 kJ); 90 min after meal onset, 1 mg neostigmine was administered intramuscularly and motility recording was continued for 60 min RESULTS: Phasic contractile activity and intraluminal base-line pressure increased postprandially and more so after neostigmine. With cilansetron, the area under the pressure curve as the primary outcome variable and the number of contractions were significantly greater than with placebo (P = 0.005), amplitude and duration of contractions and base-line pressure were not affected. The effects of the two cilansetron dosages did not differ. With cilansetron, stool tended to become firmer. No adverse effects were observed. Plasma levels were highest with 8 mg cilansetron. CONCLUSIONS: Cilansetron slightly augments meal-stimulated and markedly neostigmine-stimulated phasic motility of the sigmoid colon. When administered over 7 days, it tends to increase stool consistency and is well tolerated.     

Mißbrauch von Antibiotika vermeiden

In einem aktuellen Editorial im NEW ENGLAND JOURNAL OF MEDICINE ruft F.A. Waldvogel zu einem Gro?krieg gegen den Mi?brauch von Antibiotika auf [42]. Hintergrund sind jüngste Berichte über das Auftreten von Resistenzen des Bacteriums Staphylococcus aureus gegenüber Vancomycin/Teicoplanin, die bisher als einziges effektives Therapeutikum auch bei multiresistenten (methicillin-resistenten) Staphylokokken galten. Staphylococcux aureus ist einer der bedeutendsten Keime, die nosokomiale Infektionen verursachen, und zugleich h?ufigste Ursache von Wundinfektionen in der Chirurgie.     

Biochemical and haematological variables in Gambian children with cerebral malaria

Biochemical and haematological measurements were made in Gambian children who satisfied the criteria for the diagnosis of cerebral malaria over a 3-year period. Biochemical and haematological values were available for 388 and 624 children, respectively. Biochemical signs of renal and hepatic dysfunction were found and these may have contributed in a cumulative way to the high mortality seen in the study children. Cerebral involvement in children with cerebral malaria is only one, though the most important, manifestation of a multi-organ disease.     

Patient positioning in prostate radiotherapy: is prone better than supine?

PURPOSE: To assess potential dose reductions to the rectum and to the bladder with three-dimensional conformal radiotherapy (3D-CRT) to the prostate in the prone as compared with the supine position; and to retrospectively evaluate treatment position reproducibility without immobilization devices. METHODS AND MATERIALS: Eighteen patients with localized prostate cancer underwent pelvic CT scans and 3D treatment planning in prone and supine positions. Dose-volume histograms (DVHs) were constructed for the clinical target volume, the rectum and the bladder for every patient in both treatment positions. "Comparative DVHs" (cDVHs) were defined for the rectum and for the bladder: cDVH was obtained by subtracting the organ volume receiving a given dose increment in the prone position from the corresponding value in the supine position. These values were then integrated over the entire dose range. The prescribed dose to the planning target volume (PTV) was 74 Gy using a 6-field technique. To evaluate reproducibility, portal films were subsequently reviewed in 12 patients treated prone and 10 contemporary patients treated supine (controls). No immobilization devices were used. Deviations in the anterio-posterior (X) and cranio-caudal (Y) axes were measured. Mean treatment position variation, total setup variation, systematic setup variation, and random setup variation were obtained. RESULTS: Prone position was associated with a higher dose to the rectum or to the bladder in 6 (33%) and 7 (39%) patients, respectively. A simultaneously higher dose to rectum and bladder was noted in 2 (11%) patients in prone and in 7 (39%) patients in supine. Rectal and bladder volumes were frequently larger in prone than in supine: mean prone/supine volume ratios were 1.21 (SD, 0.68) and 1.03 (SD, 1.32), respectively. In these cases cDVH analysis more often favored the prone position. Mean treatment position variation and total setup variation were similar for both prone and supine plans. A higher systematic setup variation was observed in prone positioning: 2.7 mm vs. 1.9 mm (X axis) and 4.1 mm vs. 2.2 mm (Y axis). The random variation was similar for both prone and supine: 4. 0 mm vs. 3.6 mm (X axis) and 3.7 mm vs. 3.6 mm (Y axis). CONCLUSIONS: Prone position 3D-CRT is frequently, but not always, associated with an apparent dose reduction to the rectum and/or to the bladder for prostate cancer patients. As suggested by the increased mean prone/supine rectal volume ratio, the advantage of prone positioning for the rectum may be artifactual, at least partly reflecting a position-dependent rectal air volume, which may significantly vary from treatment to treatment. In the absence of immobilization devices, daily setup reproducibility appears less accurate for the prone position, primarily due to systematic setup variations.