The clinical development of a 5 alpha-reductase inhibitor, finasteride.

Finasteride, a 4-aza steroid compound, is an orally active inhibitor of the 5 alpha-reductase enzyme. 5 alpha-Reductase is necessary for the metabolism of testosterone (T) to dihydrotestosterone (DHT) and is found in high levels only in certain tissues such as the prostate. Finasteride has been shown to markedly suppress serum DHT levels in man without lowering testosterone levels. In patients with benign prostate hyperplasia (BPH), finasteride was found to decrease prostate volume by a mean of 28% over a period of 6 months, without causing clinically significant adverse effects. DHT appears to be the primary androgen for prostatic growth. Selective inhibition of 5 alpha-reductase by finasteride may provide a novel approach to BPH therapy by reducing prostate size without affecting T-dependent processes such as fertility, muscle strength, and libido. The clinical development of finasteride for the treatment of benign prostate hyperplasia is reviewed.     

Dual-Label Radioisotope Method for Simultaneously Measuring Bacterial Production and Metabolism in Natural Waters

Bacterial production and amino acid metabolism in aquatic systems can be estimated by simultaneous incubation of water samples with both tritiated methyl-thymidine and ¹⁴C-labeled amino acids. This dual-label method not only saves time, labor, and materials, but also allows determination of these two parameters in the same microbial subcommunity. Both organic carbon incorporation and respiration can be estimated. The results obtained with the dual-label technique are not significantly different from single-radiolabel methods over a wide range of bacterial activity. The method is particularly suitable for large-scale field programs and has been used successfully with eutrophic estuarine samples as well as with oligotrophic oceanic water. In the mesohaline portion of Chesapeake Bay, thymidine incorporation ranged seasonally from 2 to 635 pmol liter⁻¹ h⁻¹ and amino acid turnover rates ranged from 0.01 to 28.4% h⁻¹. Comparison of thymidine incorporation with amino acid turnover measurements made at a deep, midbay station in 1985 suggested a close coupling between bacterial production and amino acid metabolism during most of the year. However, production-specific amino acid turnover rates increased dramatically in deep bay waters during the spring phytoplankton bloom, indicating transient decoupling of bacterial production from metabolism. Ecological features such as this are readily detectable with the dual-label method.     

Regulation of proliferation and differentiation of respiratory tract epithelial cells by TGFβ

In this paper we examined the effects of transforming growth factor β (TGFβ) on the proliferation and differentiation of rabbit tracheal epithelial cells in primary culture. Treatment of these cells with TGFβ inhibits cell proliferation in a time- and dose-dependent manner; concentrations as low as 1 pM are able to inhibit cell growth. Concomitantly, TGFβ causes cells to accumulate in the G0/G1 phase of the cell cycle and a sharp reduction in the ability of the cells to form colonies after subculture at clonal density. These results indicate that TGFβ induces terminal cell division in these cells. The inhibition of cell growth is accompanied by changes in cell morphology and a stimulation of the formation of cross-linked envelopes. TGFβ enhances the levels of transglutaminase activity and cholesterol sulfate, two markers of squamous differentiation. Our results indicate that TGFβ induces terminal squamous cell differentiation in rabbit tracheal epithelial cells. Retinoic acid (RA) does not affect the commitment to terminal cell division induced by TGFβ, but inhibits the expression of the squamous phenotype. Growth of normal human bronchial epithelial cells was affected by TGFβ in a way similar to that of rabbit tracheal epithelial cells. Several carcinoma cell lines tested were quite resistant to TGFβ, whereas growth of one carcinoma cell line was stimulated by TGFβ. These results indicate that a modified response to TGFβ could be one mechanism involved in the aberrant growth control of malignant cells.     

Screening for Chlamydial Infections in Women Attending Family Planning Clinics—Evaluation of Presumptive Indicators for Therapy

Chlamydia trachomatis was recovered from the cervices of 9.8 percent (268/2,729) of women attending seven family planning clinics. The infection rate varied from 5.5 percent to 22.5 percent in different clinics. Chlamydial infection could be associated with younger age, nulliparity, being black and use of oral contraceptives. Most (70 percent) of the chlamydial infections were inapparent and presumptive indicators for antichlamydial therapy that are useful for symptomatic women will not make a major impact on this reservoir. It is concluded that chlamydial cultures are needed to deal with the high prevalence of these infections.     

Billingen (Lower Arenig/Lower Ordovician) acritarchs from the East European Platform and their palaeobiogeographic significance

Billingen (Lower Arenig/Lower Ordovician) sediments of the St. Petersburg region, northwest Russia and the Leba area, northern Poland of the East European Craton yield acritarch assemblages, which are largely homogenous though displaying minor compositional differences that probably reflect a gradient from inner to outer shelf environments. Comparison with coeval acritarch microflora from the Yangtze Platform, South China, shows an overall similarity between Baltoscandian and South Chinese phytoplankton. The widespread uniformity in the fossil microphytoplankton may be related to the extensive global 'evae' sea-level transgression, which characterized the Billingen time. This suggests that during the Tremadoc through early Arenig times, acritarch assemblages displayed essentially an undifferentiated cold-water and oceanic character along the whole margin of Perigondwana in the South, as well as on the South Chinese and Baltic platforms, at middle latitudes (Mediterranean oceanic Realm). Despite this overall similarity, however, some typical taxa of the high-latitude Mediterranean Province (Arbusculidium, Coryphidium and Striatotheca) occur in South China, but are absent in Baltica. This discrepancy is explained as caused by differences in climatic and physiographic conditions that prevailed at the two palaeocontinents at this time. The inferred pattern of oceanic circulation during the Lower Ordovician is consistent with the palynological evidence of a prevailing warmer climate in Baltica than in South China, although the two palaeocontinents occupied the same palaeolatitudinal position.     

Steady-state kinetics of the overall oxidative phosphorylation reaction in heart mitochondria. Determination of the coupling relationships between the respiratory reactions and miscellaneous observations concerning rate-limiting steps

The linear sequence of steps involved in the oxidation of extramitochondrial succinate by O₂ in bovine heart mitochondria was examined by a steady-state kinetic method to determine whether or not freely diffusible intermediates occur between the various inhibitor-sensitive steps. The kinetic method is based on the facts (1) that if two inhibitor-sensitive steps within a sequence are linked by a freely diffusible intermediate, inhibition of one will make the other less rate limiting in the overall reaction and thus will increase the amount of inhibitor of the other step required for half-maximal inhibition of the overall reaction, and (2) that if the two steps are not linked in this manner, inhibition of one will make the other more rate limiting and thus will decrease the amount of inhibitor of the other required for half-maximal inhibition. These two types of coupling relationships between steps were designated as sequential and fixed, respectively. The results indicate the existence of freely diffusible intermediates (sequential coupling relationships) between the succinate transport and succinate dehydrogenase reactions, between the succinate dehydrogenase and cytochromebc ₁ reactions, and between the cytochromesbc ₁ andaa ₃ reactions. Uncoupling respiration from phosphorylation results in the coupling relationship between thebc ₁ andaa ₃ reactions becoming partially fixed. This change is accompanied by marked decreases in the degrees to which thebc ₁ andaa ₃ reactions limit the overall reaction and appears to account for the large uncoupler-induced releases of inhibition at the levels of thebc ₁ andaa ₃ reactions observed previously by others. It is suggested that cytochromec is the freely diffusible intermediate between thebc ₁ andaa ₃ reactions and that the uncoupler-induced changes occur as a result of formation of functional and highly efficient supercomplexes between cytochromec and the cytochromesbc ₁ andaa ₃ complexes.