Prostaglandins and the developing kidney

Prostaglandins PGE2, PGD2, PGI2, and PGF2 alpha, as well as thromboxanes and leukotrienes, are synthesized by the fetal and neonatal kidney. The major prostaglandin, PGE2, PGD2, and PGI2, increase RBF, free water clearance, urine flow, and natriuresis. Alterations in the synthetic and catabolic activity of renal prostaglandins with advancing gestational and postnatal age occur along with concomitant alterations in RBF, GFR, and water and electrolyte excretion, suggesting that the prostaglandins play an important role in renal functional development. Indomethacin treatment may affect both fetal and neonatal renal function. Long-term maternal indomethacin treatment may decrease fetal urine output enough to alter amniotic fluid volume. Neonatal indomethacin therapy may cause transient dose-related renal dysfunction characterized by a decrease in urine output, but this renal dysfunction also depends in part on dosage, timing of therapy, and the cardiovascular and renal status of the infant prior to treatment. New areas of research interest include urinary prostaglandins as a marker for development of essential hypertension, and the possible interaction between antenatal steroids and renal function in the newborn.     

Utilization of an abbreviated diabetes impact management scale to assess change in subjective disability during a trial of pulsatile insulin delivery demonstrates benefit

A prospective interventional study of pulsatile intravenous insulin infusion therapy has demonstrated reduction of left ventricular mass and blunting of progression of diabetic nephropathy. We anticipated that improvements in objective parameters would be associated with similar improvement measurable by the self-administered Diabetes Impact Management Scale (DIMS). The DIMS was administered at baseline and 12 months for 19 participants randomized to receive either standard insulin treatment of 3 to 4 injections of insulin daily or insulin treatment plus an additional day per week of 3 intravenous pulses over an 8-hour period. For standard vs pulsed intravenous insulin therapy, mean baseline scores were similar for the 12 total questions as well as the groups of 7 questions with emotional content and 5 with physical (neurologic) content. Mean study group scores at 1 year and changes over 1 year were not significantly different for the 7 questions with emotional content (P = .3143, .7574). Score results for the 5 questions related to neurologic status at 1 year and changes over 1 year were significantly different between patients with standard and with pulsed insulin therapy (P = .0144, 0.0004). Pulsatile intravenous insulin, when added to standard multiple-dose insulin therapy, was demonstrated to improve subjective perception of neurologic disability on repeated use of an abbreviated form of the DIMS.     

Immunosuppression-related fibroproliferative polyps: a substantial subset of acquired pediatric mucocutaneous polyps.

A distinct group of fibroproliferative polyps of the tongue arising in immunosuppressed children and often associated with chromosomal breakpoints at chromosomes 9p34 or 22q11 was recently described. Based on this finding, we reviewed fibroepithelial polyps arising in nonlingual sites in the pediatric population to investigate a possible relationship with immunosuppression. We identified 8 fibroepithelial polyps arising in 6 immunosuppressed patients (4 males and 2 females, median age 17 years) in a wide range of mucocutaneous sites. Histologic features were identical to the common fibroepithelial polyp, or skin tag, with a variably collagenous fibrovascular core covered by unremarkable squamous epithelium. No viral cytopathic changes were identified in any case. Although cytogenetic studies were not performed on any of the biopsy material, 1 patient had a constitutional deletion of chromosome 22q11. We suggest that there may be a relationship between these polyps and the previously described tongue lesions and that immunosuppression may be an important factor in their pathogenesis.     

Effectiveness of dental office instrument sterilization procedures.

To evaluate instrument sterilization procedures in Minnesota, biological indicators were used to monitor 406 sterilizers in 381 dental offices. Findings suggest a general improvement in instrument performance over that of a decade ago, but sterilization failure rates are still too high. Sterilizer operator errors are a major cause of sterilization failures. BIs are useful in monitoring sterilization performance only when sterilization procedures are performed consistently and competently by well-trained staff using adequately maintained equipment.     

Isolation of Leishmania amastigote protein fractions which induced lymphocyte stimulation and remission of psoriasis

A first generation polyvalent vaccine (AS100¹) was manufactured with protein from several cultured leishmania species, which proved to be effective in the treatment of psoriasis. To determine the effective factor, a single blind trial with four monovalent second generation vaccines (AS100²) was done in 26 subjects, which also resulted in remission of psoriasis. AS100² vaccines were further purified, resulting in seven chromatography fractions (AS200) per species. In vitro testing of the fractions on blood lymphocytes resulted in subjects being categorized as low or high responders before treatment. Both responder groups had no statistical difference in clinical outcome after AS100¹ treatment. Subsequently, a single-blind trial in 55 subjects treated with AS200 fractions from Leishmania brasiliensis also induced remission of Psoriasis. Two HIV ± subjects with plaque psoriasis experienced remission after treatment with AS100¹. There are factors in leishmania species which induce remission of psoriasis by stimulating lymphocytes.     

Comparison of endothelin binding and calcium mobilization in C6-BU-1 rat glioma and N18TG2 mouse neuroblastoma cells.

We have previously reported that endothelin (RT) receptor activation increases intracellular calcium concentrations ([Ca2+]i) in NG108-15 cells, a hybrid of rat glioma C6-BU-1 and mouse neuroblastoma N18TG2 cells. This study was designed to further explore the origin of the ET receptor and [Ca2+]i mobilization in the parent cell lines hybridized to form the NG108-15 cells. [125I]ET-1 bound to a single class of high affinity sites in C6-BU-1 cells with a KD value of 108pM and Bmax of 12,400 sites/cell. ET-1, ET-2, ET-3 and big ET inhibited [125I]ET-1 binding to C6-BU-1 cells with KD values of 0.074, 0.167, 261 and 187 nM, respectively. All ETs produced a rapid increase in [Ca2+]i in C6-Bu-1 cells. EC50 values for ET-1, ET-2, ET-3 and big ET were 0.71, 1.14, 120 and 243 nM respectively. There was a significant correlation between the KD values obtained from competition binding experiments and the EC50 values from [Ca2+]i response curves in C6-BU-1 cells (r = 0.996, p less than 0.004). Ten nM ET-1 produced about 85% of the maximal [Ca2+]i increase in C6-BU-1 cells which was reduced by 96% in the absence of extracellular calcium. Furthermore, diltiazem (10 microM) and nifedipine (1 microM) failed to block ET-induced [Ca2+]i mobilization. None of the ETs elevated [Ca2+]i or displayed any specific [125I]ET-1 binding in N18TG2 cells. These data suggest that ET binds to a specific ET receptor in C6-BU-1 cells, and elevates [Ca2+]i through dihydropyridine-insensitive, receptor-mediated calcium influx. Further, the ability of ETs to elevate [Ca2+]i in NG108-15 hybrid cells is due to the ET receptor inherent to the C6-BU-1 glioma parent line.     

Endothelin stimulates 86Rb efflux in rat glioma C6-Bu-1 cells.

Endothelin-1 (ET) elevates intracellular calcium ([Ca2+]i) and increased [Ca2+]i has been associated with K+ efflux. Therefore, we investigated ET stimulation of K+ efflux in rat glioma C6-BU-1 cells. K+ efflux was measured by monitoring the release of 86Rb+ from cells pre-loaded with 86RbCl. ET stimulated 86Rb+ efflux with an EC50 of 5.9 nM. ET-stimulated 86Rb+ efflux was insensitive to Ca2+ channel blockade, however it was reduced by 68% in Ca(2+)-free buffer, suggesting a sizable dependence on an extracellular source of Ca2+ influx through non voltage-operated Ca2+ channels. ET-stimulated 45Ca2+ efflux slightly preceded 86Rb+ efflux, again suggesting the presence of Ca2+ dependent K+ channels. ET-stimulated 86Rb+ efflux was insensitive to glyburide suggesting that efflux is not through ATP-sensitive K+ channels. ET-stimulated 86Rb+ efflux was insensitive to pertussis toxin (PTX) pre-treatment. Pre-incubation with the protein kinase C (PKC) inhibitor, staurosporine, inhibited 86Rb+ efflux by 66%, suggesting the involvement of PKC activation in ET-mediated 86Rb+ efflux. In summary, in C6-BU-1 cells, ET stimulates Ca2+ dependent K+ efflux which is mediated in part by protein kinase C activation, but not a PTX sensitive G-protein, nor through an ATP-sensitive K+ channel. These data extend the intracellular mechanisms initiated by ET to include Ca2+ dependent K+ efflux in glial cells and further support a neuromodulatory role for ET.