Pleiotropic expression of heterologous cytokine/receptor genes in HTLV-1 associated diseases: candidate TRS for chimeric gene therapy.

DNA motifs that encode for specific transcriptional regulatory sequences (TRS) when engineered adjacent to the structural protein coding domain of a suicide enzyme can provide cell-lineage specific protein expression. The disparate up-regulation of several genes in adult T-cell leukemia (ATL) versus HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), seropositive carriers (SPC) and uninfected normals may reflect events at the molecular level related to leukemogenesis or to processes maintaining the heme-oncologic phenotype. Further, the genetic transduction of cytokine and receptor genes uniquely associated with ATL may provide targets for the development of leukemia-specific gene therapies aimed at exploiting differences in the production of certain growth factors and growth factor receptors. Comparisons of the transcriptional and translational levels of interleukin-2 receptor alpha chain (IL-2R alpha), transforming growth factor-beta 1 (TGF-beta 1) and intracellular adhesion molecule-1 (ICAM-1) in ATL, HAM/TSP, and SPC and in several control populations revealed selectively up-regulated expression in ATL. We evaluated the feasibility of using lymphoid-specific TRS to activate herpes simplex virus thymidine kinase (HSVtk) to achieve selective cytotoxicity in leukemias expressing terminal deoxynucleotidyl transferase (TdT). Selective and efficient leukemic cell killing was produced and suggests that similar chimeric gene constructs containing TRS elements for IL-2R alpha, TGF-beta 1, or ICAM-1 may prove useful in designing gene therapies to treat ATL.

Performance of domestic hens under progressive-ratio schedules of food delivery.

Domestic hens were exposed to progressive-ratio 2 and progressive-ratio 10 schedules of food delivery with different initial ratios (2, 10, 20, 30, and 40). Breaking points, defined as the largest ratios completed before responding ceased for 600 consecutive seconds, were recorded under all conditions. In general, breaking points were higher under the PR 10 schedule than under the PR 2 schedule, and the value of the initial ratio did not systematically affect the breaking point. The former finding suggests that relative satiation affected breaking points in the present study, but the latter finding suggests that the primary determinant was the 'price' of the reinforcer, defined in terms of the number of responses required to produce it. Breaking points were similar under conditions where initial ratios changed from session to session and under more conventional conditions, where initial ratios remained unchanged over several sessions.

Treatment of solar keratoses of the extremities with retinoic acid and 5-fluorouracil.

In contrast to solar keratoses of the face, twice daily application of 5% 5-fluorouracil cream was found to be incapable of destroying such lesions situated on the forearms and hands. Twice daily application of 0-1% retinoic acid was also ineffective. Combined use of these agents eradicated keratoses in all twenty subjects with numerous keratoses of the forearms; in only two was the treatment ineffective for keratoses of the hands.

Water ingestion does not improve 1-h cycling performance in moderate ambient temperatures.

Eight endurance-trained cyclists rode as far as possible in 1 h on a stationary cycle simulator in a moderate environment (20 degrees C, 60% relative humidity, 3 m.s-1 wind speed) while randomly receiving either no fluid (NF) or attempting to replace their approximate 1.71 sweat loss measured in a previous 1-h familiarisation performance ride at approximately 85% of peak oxygen uptake with artificially sweetened, coloured water (F). During F, the cyclists drank mean 1.49 (SEM 0.14) 1 of which mean 0.27 (SEM 0.08) 1 remained in the stomach at the end of exercise and mean 0.20 (SEM 0.05) 1 was urinated after the trial. Thus, only mean 1.02 (SEM 0.12) 1 of the ingested fluid was available to replace sweat losses during the 1-h performance ride. That fluid decreased the mean average heart rate from 166 (SEM 3) to 157 (SEM 5) beats.min-1 (P < 0.0001) and reduced the final mean serum [Na+] and osmolalities from 143 (SEM 0.6) to 139 (SEM 0.6) matom.l-1 (P < 0.005) and from 294 (SEM 1.7) to 290 (SEM 1.9) mosmol.l-1 (P = 0.05), respectively. Fluid ingestion did not significantly attenuate rises in plasma anti-diuretic hormone and angiotensin concentrations, or decrease the approximate-15% falls in estimated plasma volume in the F and NF trials. Nor did fluid ingestion significantly affect the approximate 1.71.h-1 sweat rates, the rises in rectal temperature (from 36.6 degrees to 38.3 degrees C) or the ratings of perceived exertion in the two trials.(ABSTRACT TRUNCATED AT 250 WORDS)