The use of radioactive 7α, 17α-dimethyl-19-nortestosterone (mibolerone) in the assay of androgen receptors

Tritiated 7α, 17α-dimethyl-19-nortestosterone (DMNT; mibolerone), a synthetic androgen stable to metabolic conversion in the rat ventral prostate, is an excellent radioactive ligand for the quantitation and characterization of androgen receptors in prostate, liver, and cultured cells. DMNT is more receptor-selective than 17α-methyl-17β-hydroxy-estra-4,9,11-trien-3-one (R1881); DMNT interacts with glucocorticoid and progestin receptors much less strongly than R1881. Unlike 5α-dihydrotestosterone, DMNT does not bind tightly to testosterone-estradiol binding globulin of human serum. The hydroxylapatite-filter assay we employed can clearly distinguish between DMNT binding to androgen receptors of rat ventral prostate and interaction of DMNT with androgen binding protein of epididymides. The prostate cytosol (³H)DMNT-receptor complex sediments in two forms (4 and 8 S) in a low salt medium. In 0.4 M KCl, both the prostate cytosol and nuclear (³H)DMNT-receptor complexes migrated as 3–4 S components. The formation of both the cytosol and nuclear DMNT-receptor complexes is inhibited by antiandrogens and 17β-estradiol.     

Dose-response curve and time-course of effect of vecuronium in male and female patients

To determine the differences between men and women in the dose-response curve and the time-course of effect of vecuronium, we studied 60 adult patients (30 male and 30 female), ASA I, age 18-51 yr, undergoing elective plastic surgery. Anaesthesia was maintained with nitrous oxide 60% in oxygen; thiopentone and incremental doses of fentanyl were given as required. Neuromuscular function was assessed mechanomyographically using the train-of-four (TOF) stimulation at the wrist every 12 s. The percentage depression of T1 was used as the study variable. The dose- response relationship of vecuronium was determined by a cumulative dose- response technique. The dose-response curve in men was shifted in a parallel fashion to the right, indicating a decrease in the sensitivity to vecuronium-induced neuromuscular block, compared with women. The ED50, ED90 and ED95 of vecuronium were 23.9 (4.7), 45.4 (11.2) and 55.7 (14.3) micrograms kg-1 in men and 18.4 (3.7), 33.5 (7.8) and 39.8 (9.6) micrograms kg-1 in women respectively. There were statistically significant differences in these values between the two groups (P < 0.01 in each instance). After a total dose of vecuronium 80 micrograms kg-1, neuromuscular block was significantly longer in women than in men. The duration of peak effect, clinical duration, and the total duration were 18.7 (7.1), 26.6 (8.8) and 50.6 (16.0) min respectively in men and 26.0 (7.2), 37.1 (11.2) and 65.9 (20.7) min in women. They differed significantly between men and women (P < 0.005 in each case).      

Quantitative structure-activity relationships and dipole moments of anticonvulsants and CNS depressants.

The anticonvulsant and CNS-depressant activities of 16 commercially available antiepileptics were subjected to regression analysis. For the maximal electroshock seizure test and pentylenetetrazol seizure threshold test, good correlations were obtained only after diazepam, clonazepam, and carbamazepam were deleted; for the median toxic dose (rotorod ataxia), all 16 compounds can be included in one single equation using log MW, log P, and dipole moment (mu) terms. For the anticonvulsant activities of 7-substituted 1,4-benzodiazepinones, a parabolic equation of pi combined with the Hammett sigma constant gave fair correlations for most derivatives examined in three different tests. Based upon the correlations obtained, further molecular modifications are suggested. The dipole moments of seven clinically used antiepileptic drugs were measured in 1,4-dioxane for the first time.     

Does the number of cells in the cornea decrease with age? A biochemical study.

We used biochemical techniques to investigate whether the cornea becomes more acellular with age. Guinea pigs of different body weights (age) were killed. From each cornea, a central full-thickness button (4 mm in diameter) was punched out. The DNA content of the corneal buttons was determined. Using spleen cells, the DNA content per diploid cell of guinea pig was also estimated. It was found that as the body weights of the animals increased, the amount of DNA per corneal disc decreased. This indicated that as the animal grows older the total cellular content of the cornea is reduced.     

Inhibition of Na+ channel currents in rat myoblasts by 4-aminopyridine

Our previous study revealed that 4-aminopyridine (4-AP), a specific blocker of A-type current, could also inhibit inward Na+ currents (I(Na)) with a state-independent mechanism in rat cerebellar granule cells. In the present study, we report an inhibitory effect of 4-AP on voltage-gated and tetrodotoxin (TTX)-sensitive I(Na) recorded from cultured rat myoblasts. 4-AP inhibited I(Na) amplitude in a dose-dependent manner between the concentrations of 0.5 and 10 mM without significant alteration in the activation or inactivation kinetics of the channel. By comparison to the 4-AP-induced inhibitory effect on cerebellum neurons, the inhibitory effect on myoblasts was enhanced through repetitive pulse and inflected by changing frequency. Specifically, the lower the frequency of pulse, the higher the inhibition observed, suggesting that block manner is inversely use-dependent. Moreover, experiments adding 4-AP to the intracellular solution indicate that the inhibitory effects are localized inside the cell. Additionally, 4-AP significantly modifies the properties of steady-state activation and inactivation kinetics of the channel. Our data suggest that the K+ channel blocker 4-AP inhibits both neuron and myoblast Na+ channels via different mechanisms. These findings may also provide information regarding 4-AP-induced pharmacological and toxicological effects in clinical use and experimental research.     

Apoptotic markers on lymphocytes and monocytes are unchanged during single hemodialysis sessions using either regenerated cellulose or polysulfone membranes

BACKGROUND: There is an increased rate of apoptosis of peripheral blood mononuclear cells (PBMCs) in patients undergoing hemodialysis (HD), but little is known about how different dialysis membranes may contribute to the process. We, therefore, studied the influence of two different dialysis membranes on apoptotic markers during HD. METHODS: 8 healthy controls and 8 patients on regular HD 3 times per week were enrolled in this cross-controlled study. Patients received HD using polysulfone and then regenerated cellulose dialysis membranes for one week each, sequentially. Serum was collected for C-reactive protein (CRP) detection; flow cytometry with dual antibody staining was used to measure the apoptotic markers Fas (CD95), FasL (CD 178) and TNF-R2 (CD120b) in T cells (CD3+), B cells (CD19+), and monocytes (CD14+) at 0, 15, 120 and 240 min after starting HD. We also measured total leukocyte numbers and differential white cell counts. RESULTS: Hemodialysis patients revealed lymphocytopenia, monocytopenia, higher CRP levels and higher Fas and TNF-R2 expression on lymphocytes and monocytes at baseline when compared with normal controls. Leukocyte numbers, including neutrophils, lymphocytes and monocytes, dropped significantly after 15 min of dialysis. There were no significant differences in Fas levels during hemodialysis on T and B lymphocytes or on monocytes. T lymphocyte FasL (CD 178) levels remained unchanged throughout the process. There was a significantly lower overall level of CD120b at 15 min of HD, whereas this marker was higher on monocytes after dialysis. There were no significant differences in the levels of apoptotic markers between the two membranes. CONCLUSION: Our results suggest that uremia itself contributes to PBMC apoptosis. The two different dialysis membranes used in this study did not influence apoptotic markers on PBMCs significantly, but increased TNF-R2 expression on monocytes during a single dialysis session.     

The ethics of using genetic engineering for sex selection

It is quite likely that parents will soon be able to use genetic engineering to select the sex of their child by directly manipulating the sex of an embryo. Some might think that this method would be a more ethical method of sex selection than present technologies such as preimplantation genetic diagnosis (PGD) because, unlike PGD, it does not need to create and destroy "wrong gendered" embryos. This paper argues that those who object to present technologies on the grounds that the embryo is a person are unlikely to be persuaded by this proposal, though for different reasons.