What decides: high mortality in paediatric acute renal failure?

Forty paediatric cases of A.R.F. (Acute Renal Failure) of various aetiology were included in the study. 60% of patients were less than 4 years of age with male predominance. 80% cases reported to us very late with oligoanuria of more than 24 hours (2-7 days). Diarrhoea, vomiting and fever were other dominant symptoms. Maximum cases were severely anaemic (87.5%) with mean Hb 7.73 +/- 1.9 gm%. 40% cases were of underweight while only one case (2.5%) was of over weight, inspite of volume excess in 40% cases. All 24 cases, who were estimated for serum albumin, found to have marked hypoalbuminemia. Mortality was found to be as high as 65% inspite of effective peritoneal dialysis in all cases. High mortality seems to be due to profound anuria of many days (because of marked delay in reaching the hospital), fever and malnutrition besides other factors as aetiology.     

Retroviral gene transfer is inhibited by chondroitin sulfate proteoglycans/glycosaminoglycans in malignant pleural effusions

Gene therapy may be an important adjuvant for treating cancer in the pleural space. The initial results of retroviral gene transfer to cancer cells in malignant pleural effusions revealed that transduction was markedly inhibited, and studies to characterize the inhibitory factor(s) were performed. The inhibition was contained within the soluble, rather than cellular, components of the effusions and was demonstrated with amphotropic, gibbon ape leukemia virus, and vesicular stomatitis virus-glycoprotein pseudotyped retroviral vectors. After excluding complement proteins, a series of studies identified chondroitin sulfates (CSs) as the inhibitory substances. First, treatment of the effusions with mammalian hyaluronidase or chondroitinases, but not Streptomyces hyaluronidase, abolished the inhibitory activity. Second, addition of exogenous CS glycosaminoglycans mimicked the inhibition observed with pleural effusions. Third, immunoassays and biochemical analyses of malignant pleural effusion specimens revealed CS in relevant concentrations within pleural fluid. Fourth, proteoglycans/glycosaminoglycans isolated from the effusions inhibited retroviral gene transfer. Analyses of the mechanism of inhibition indicate that the chondroitin sulfates interact with vector in solution rather than at the target cell surface. These results suggest that drainage of the malignant pleural effusion, and perhaps enzymatic pretreatment of the pleural cavity, will be necessary for efficient retroviral vector mediated gene delivery to pleural metastases.     

Urological emergencies

Every general practitioner has to deal with urologic emergencies. The most frequent illnesses are urinary retention, acute scrotum, priapism, macrohematuria, nephritic colic, obstructive pyelonephritis and pyonephrosis. Whereas urinary retention, as well as acute ureteric stone colic must generally be treated by the practitioner, the urologist must often be consulted in case of an acute scrotum or for priapism. Testicular torsion is one situation, where surgical treatment needs to be performed within 6 hours. Of utmost importance is his timely assistance with the obstructive pyelonephritis and pyonephrosis. These are initially often not recognized, especially because the first ultrasound examination of the intrarenal pyelone may not show a dilatation of the collecting system despite obstruction. If the adequate treatment with drainage and antibiotics is applied too late, this can result in serious and potentially lethal consequences.     

Ethical dilemmas in the delivery room

The novel uracil analog, 6-chloro-5-(2-propenyl)uracil (TI90), inhibited the growth of myeloid leukemia cells and induced morphologic and functional differentiation of the cells. Although TI90 was a weak inducer of differentiation, it greatly enhanced the growth inhibition and differentiation of the leukemia cells previously induced by 1alpha,25-dihydroxyvitamin D3 (VD3) or all-trans retinoic acid (ATRA). TI90 cooperated with VD3 much more effectively than with ATRA in inhibiting cell growth and inducing differentiation. It also decreased the effective concentration of VD3 to the 10(-10) M level. On the other hand, there was no significant synergy between VD3 and the other uracil analogs. TI90 did not affect VD3 metabolism or the number and affinity of VD3 receptors (VDR) in HL-60 cells. Signals from VD3 are predominantly mediated by VDR and the ligand-activated binding of VDR to vitamin D-responsive element (VDRE) as a heterodimer with the retinoid X receptor (RXR). According to the results of a gel shift assay, TI90 enhanced the intensity of the retarded band with synthetic VDRE oligomer in the presence of VD3, suggesting that TI90 increases the number of phosphorylated receptors by inhibiting phosphatase activity, and also stimulates the formation of a functional complex of VDR with RXR.     

Structure of nitric oxide synthase oxygenase dimer with pterin and substrate

Crystal structures of the murine cytokine-inducible nitric oxide synthase oxygenase dimer with active-center water molecules, the substrate L-arginine (L-Arg), or product analog thiocitrulline reveal how dimerization, cofactor tetrahydrobiopterin, and L-Arg binding complete the catalytic center for synthesis of the essential biological signal and cytotoxin nitric oxide. Pterin binding refolds the central interface region, recruits new structural elements, creates a 30 angstrom deep active-center channel, and causes a 35 degrees helical tilt to expose a heme edge and the adjacent residue tryptophan-366 for likely reductase domain interactions and caveolin inhibition. Heme propionate interactions with pterin and L-Arg suggest that pterin has electronic influences on heme-bound oxygen. L-Arginine binds to glutamic acid-371 and stacks with heme in an otherwise hydrophobic pocket to aid activation of heme-bound oxygen by direct proton donation and thereby differentiate the two chemical steps of nitric oxide synthesis.     

Central GABAA and GABAB receptor modulation of basal and stress-induced plasma interleukin-6 levels in mice

The development of control strategies for loiasis is of crucial importance in endemic areas and depends heavily on the accurate identification of occult-infected individuals. A polymerase chain reaction (PCR) and nested polymerase chain reaction (nested PCR) were developed and based on sequences of the repeat 3 region (15r3) of the gene encoding a Loa loa 15-kD protein. The assays was performed on 20 blood samples from occult-infected subjects and 30 from field-collected amicrofilaremic individuals. The size of the initial PCR product was 396 basepairs (bp). When this initial amplification using primers 15r3(1) and 15r3(2) was carried out for 30 cycles, the PCR products from three of the 20 occult-infected and five of the 30 amicrofilaremic individuals were visualized after electrophoresis by staining the gel with ethidium bromide. Subsequent Southern blotting and hybridization with the specific probe revealed hybridization in 19 of 20 occult-infected and 23 of 30 amicrofilaremic samples but only after two days of exposure of the blot to the x-ray film. When the nested PCR was carried out (product size = 366 bp, primers 15r3(3) and 15r3(4)), 19 of 20 occult-infected and 23 of 30 amicrofilaremic samples that were positive by Southern hybridization of the initial PCR products were strongly positive by staining with ethidium bromide. Qualitative Southern blotting of the nested PCR products using the same probe previously described confirmed the ethidium bromide staining results after a very short exposure time of 4 hr. These results demonstrate that the nested PCR amplification product is specific and that its sensitivity in detecting occult loiasis is 95%. This approach has significant promise for the screening of large human populations for active loiasis without the requirement for blotting and hybridization of the PCR products.     

Central NO is involved in the antinociceptive action of intracisternal antidepressants in freely moving rats

The present study was performed to examine the central effects of antidepressants on nociceptive jaw opening reflex after intracisternal injection. we also investigated the mechanisms of central antinociceptive action of intracisternal antidepressants. We recorded the jaw opening reflex in freely moving rats and chose to administer antidepressants intracisternally in order to eliminate the effects of anesthetic agents on the pain assessment and evaluate the importance of the spinal site of action of antidepressants. After intracisternal injection of 15 microg imipramine, digastric electromyogram (dEMG) was decreased to 76+/-6% of the control. Intracisternal administration of 30 microg desipramine, nortriptyline or imipramine suppressed dEMG remarkably to 48+/-2, 27+/-8, or 25+/-5% of the control, respectively. The suppression of dEMG was maintained for 50 min. L-NG-Nitroarginine methyl ester (NAME) blocked the suppression of dEMG from 32+/-2 to 81+/-5% of the control. These results indicate that antidepressants produce antinociception through central mechanisms in the orofacial area. The central NO pathway seems to be involved in the antinociception of intracisternal antidepressants at supraspinal sites.