Estramustine and estrone analogs rapidly and reversibly inhibit deoxyribonucleic acid synthesis and alter morphology in cultured human glioblastoma cells

Estramustine is an estradiol-based agent that has been shown to accumulate in human glioma cells, resulting in a concentration-dependent alteration in cell size and shape within minutes and an inhibition of proliferation over 3 to 6 days. We evaluated human glioblastoma cultures with [3H]thymidine incorporation assays to determine estramustine's early effects on deoxyribonucleic acid synthesis in these tumors. Because estramustine shares a common structural motif with other antimicrotubule drugs, we synthesized four A-ring conjugates of estrone that contained a carbamate moiety but lacked nitrogen mustard. These analogs were examined by [3H]thymidine incorporation and compared with vinblastine. Greater than 70% inhibition of [3H]thymidine incorporation occurred within 1 hour of treatment with estramustine at 10(-5) mol/L, which increased to 80% inhibition at 4 hours. Ethyl carbamate JE208 was nearly as effective as estramustine in inhibiting deoxyribonucleic acid synthesis, and both were more effective than vinblastine. The inhibitory effects of estramustine and estrone analogs were reversible; vinblastine was not reversible. Although estramustine and JE208 induced similar antiproliferative and morphological changes in glioblastoma cells that persisted for at least 4 days, there was a modest recovery of morphology and thymidine incorporation with JE208 after prolonged treatment. The common findings with estramustine and JE208 suggest that these agents may have a similar mechanism of action and form the basis for the investigation of new agents that may rapidly and reversibly inhibit glioblastoma.     

Fast and Compact 16 by 16 Cellular Neural Network Implementation

The paper presents a Cellular Neural Network implementation based on a high gain sigmoid operation. The required simplifications to the original theory are described that allow the use of high gain. With this design black and white images can be processed. The basic building blocks in a cell are described. A 16×16 cells network has been designed and processed with 1.2 micron CMOS technology. Measurement results which show the operation of the network are presented.     

A model to assess the effectiveness of topical antipruritics

A model has been developed to determine the effectiveness of topical antipruritics. It utilizes controlled, experimentally induced itch and has demonstrated the effectiveness of the direct action on cutaneous receptor sites of a topical anesthetic, benzocaine, in a topical antipruritic formulation, and has been used to differentiate between two effective topical antipruritics. Three studies are presented: The first study examined the reliability of the experimentally induced itch. Several indices of reliability were computed from the data of this first study. Cronbach's alpha was 0.92. Winer's theta also was 0.92. Simple test-retest reliability, computed at intervals of 29 min, 1 day, and 6-7 days, resulted in Pearson correlations of 0.84, 0.73, and 0.60, respectively. In the second study, the model differentiated statistically between the itch relief resulting from the topical application of a formulation with 6% benzocaine and the same formulation without benzocaine. The third study examined 2 known topical antipruritics: one containing 6% benzocaine and the other 1% hydrocortisone. Both topical antipruritics were found to relieve itch; however, the benzocaine antipruritic produced statistically significantly greater itch relief in more subjects than the hydrocortisone antipruritic at both 1 and 30 min after application. These results demonstrate that OTC antipruritics can be differentiated for effectiveness.     

Relaxed stability and performance conditions for Takagi-Sugeno fuzzy systems with knowledge on membership function overlap.

This correspondence presents a relaxation of some earlier linear matrix inequality (LMI) conditions, which allow setting up less conservative stability or performance conditions for Takagi-Sugeno fuzzy models. Unlike the previous literature, this correspondence takes into account the knowledge of the membership functions' shape by considering bounds on them and their cross products (interpreted as an overlap measure), introducing auxiliary LMI variables. Numerical examples illustrate the achieved improvements.     

Adult onset Krabbe''s leukodystrophy

Benign mesenchymal tumours of the bladder are rare, accounting for only 1-5% of bladder neoplasms. We describe what appears to be the first reported case of massive bleeding from a leiomyoma of the urinary bladder causing tamponade requiring emergency surgery.     

Elements of the art of practice in mental health

This study examined links between impaired nitric oxide production in the sciatic endoneurium, nerve blood flow, and polyol pathway flux, to test the hypothesis that reduced nerve blood flow might be compromised by competition for NADPH between aldose reductase and nitric oxide synthase. Sciatic nerves of streptozotocin-diabetic rats showed reduced laser Doppler flux (by 51% or 63%; both p<0.05)-indicative of reduced nerve blood flow-and reduced motor nerve conduction velocity (17% in two experiments; p<0.05). Acute interruption of nitric oxide production in the sciatic nerves of control rats, via endoneurial injection of N omega-nitro-D-arginine methyl ester (L-NAME), caused a local reduction (of 64%; p<0.001) in nerve Doppler flux. This was reversed by either L-arginine or sodium nitroprusside. The response to L-NAME was greatly reduced in diabetic rats (only 22% reduction; p<0.01), though both L-arginine and SNP caused marked increases in flux. Chronic inhibition of aldose reductase in diabetic rats (with either sorbinil or imirestat at a range of doses) had little effect on resting sciatic nerve Doppler flux, though both inhibitors normalized conduction velocity. Both aldose reductase inhibitors reduced sorbitol pathway intermediates in a dose-related manner. These findings do not support the proposition that aldose reductase inhibitors normalise conduction velocity by mechanisms dependent upon either normalization of endoneurial nitric oxide or nerve blood flow. Instead, a mechanism based upon more direct effects on axon or Schwann cell function is favoured.     

Effect of surfactant replacement therapy on the outcome of premature infants with respiratory distress syndrome

Lung surfactant replacement has been tested clinically in recent years. In this study the outcome of 31 premature infants with moderate to severe neonatal respiratory distress syndrome (RDS) treated with surfactant was compared to that of 74 prematures with RDS treated conventionally by positive pressure ventilation and supportive care. The groups were well matched for gestational age, birthweight, sex, and Apgar scores at 1 and 5 min. Surfactant treatment resulted in a significant decrease in mortality--from 36.6% in the untreated group to 12.9% in the surfactant-treated group (P < 0.04). This improvement in survival was seen also in prematures with a birthweight < 1,000 g; in the untreated group mortality was 57.6% compared to 23.5% in the treated group (P < 0.05). The incidence of pneumothorax was lower in the treated group--42% vs. 13% (P < 0.01). Surfactant treatment resulted in a trend of more survivors without bronchopulmonary dysplasia or intraventricular hemorrhage, even though surfactant therapy did not change the incidence of either.     

A Universal Method of Scientific Inquiry

A paradigm of scientific discovery is defined within a first-order logical framework. Within this paradigm, the concept of successful scientific inquiry is formalized and investigated. Among other results, it is shown that a simple method of scientific inquiry is universal in the sense that it leads to success on every problem for which success is in principle possible.