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.     

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.     

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.     

Miniature Ag−AgCl electrode for voltage clamping of theAmbystoma collecting duct

Summary We have developed a miniature silver-silver chloride electrode. The outer diameter of the electrodes averaged 22 m and the input resistance 8.8 k. Since the core of the electrode is a glass fiber, the problem of the extreme malleability of a small diameter silver fiber is circumvented. The properties of the electrode permit us to insert it into short (600 m) fragments of the amphibian collecting duct while they are being perfusedin vitro. The passage of currents in the range of 0 to 6×10^–8 amperes allowed us to voltage clamp the nephron fragment between +20 and –20 mV. The current-voltage plots are linear over this range. Two lines of evidence suggest that the voltage clamp is homogeneous. First, the voltage measured at the perfusion end during a voltage-clamp experiment of the tubule is not significantly different from that measured at the collecting end. Secondly, the specific resistance of collecting ducts estimated from the core conductor analysis is 3.3±0.8×10⁴ cm, a value not significantly different from that computed from the current-voltage plots as determined with the Ag–AgCl electrode, 3.0±0.5×10⁴ cm. This method permits precise control of both the ionic and electrical gradients across fragments of the amphibian collecting duct.     

The effects of diet, lipolysis and limb ischaemia on the distribution of plasma tryptophan in the rat.

A non-linear relationship between the plasma non-esterified fatty acid concentration and the percentage of free plasma tryptophan was found in rats in different nutritional states, although non-esterified fatty acids are not the only factors determining the percentage of free tryptophan. This relationship was not seen in rats injured by limb ischaemia. The effect of drugs causing rapid increases in the plasma non-esterified fatty acid concentration was also studied. Isoprenaline decreased the total plasma tryptophan concentration. Dichloroisoprenaline caused a sustained increase in the plasma non-esterified fatty acid concentration which was accompanied by an increase in the concentration of free plasma tryptophan and followed by a fall in the concentration of total tryptophan. The loss of tryptophan from the plasma was attributed to an altered distribution of tryptophan in the extracellular space rather than to increased metabolism. This interpretation was supported by determinations of the irreversible disposal rate of plasma tryptophan which in uninjured rats was unaffected by the concentration of free plasma tryptophan. In the injured rats this rate was unaltered during limb ischaemia but was decreased after removal of the tourniquets; increased competition for tissue entry by other neutral amino acids and the fall in body temperature could be factors in this fall.     

Pseudomonas aeruginosa polysaccharide Psl supports airway microbial community development

Pseudomonas aeruginosa dominates the complex polymicrobial cystic fibrosis (CF) airway and is a leading cause of death in persons with CF. Oral streptococcal colonization has been associated with stable CF lung function. However, no studies have demonstrated how Streptococcus salivarius, the most abundant streptococcal species found in individuals with stable CF lung disease, potentially improves lung function or becomes incorporated into the CF airway biofilm. By utilizing a two-species biofilm model to probe interactions between S. salivarius and P. aeruginosa, we discovered that the P. aeruginosa exopolysaccharide Psl promoted S. salivarius biofilm formation. Further, we identified a S. salivarius maltose-binding protein (MalE) that is required for promotion of biofilm formation both in vitro and in a Drosophila melanogaster co-infection model. Finally, we demonstrate that promotion of dual biofilm formation with S. salivarius is common among environmental and clinical P. aeruginosa isolates. Overall, our data supports a model in which S. salivarius uses a sugar-binding protein to interact with P. aeruginosa exopolysaccharide, which may be a strategy by which S. salivarius establishes itself within the CF airway microbial community.Subject terms: Bacteriology, Biofilms, Microbiome, Clinical microbiology     

Relationship between estrone sulfate in plasma and litter size at farrowing for sows and gilts

A positive association (P < 0.01) was detected between estrone sulfate (ES) concentrations in maternal plasma at Day 30 of pregnancy and litter size at parturition in swine. This relationship was best described by a fifth order regression equation (R(2) = 0.5) which indicated that as ES increased from 1 to 7.5 ng/ml on Day 30, litter size increased from 0 (nonpregnant) to 18 piglets farrowed. Day of sampling (P < 0.02), month (P < 0.04) and parity (P < 0.08) were major sources of variation in the model. This indicated that effects of environmental factors such as heat stress, which influence conception rate and embryonic survival, are reflected in changes in maternal ES. Also, larger litter size associated with parous sows is reflected in increased ES in maternal plasma. We conclude that measurement of ES early in gestation may be useful in reproductive management to identify nonpregnant gilts and sows as well as those with small litters.     

Climate change impacts on asphalt road pavement construction and maintenance: An economic life cycle assessment of adaptation measures in the State of Virginia,United States

Pavement design and management practices must be adapted in response to future climate change. While many studies have attempted to identify different methods to adapt pavements to future climate conditions, the potential economic impacts of the adaptations still remain largely unquantified. This study presents the results of a comprehensive life‐cycle cost analysis (LCCA) aimed at quantifying the potential economic impacts of a climate adaptation method, in which an upgraded asphalt binder (Performance Grade PG 76‐22) is used in the construction and maintenance of flexible pavement sections in lieu of the original binder (PG 70‐22) for improved resistance against high temperatures. For each of three major Virginia Department of Transportation (VDOT) districts with different climates, three case studies consisting of typical interstate, primary, and secondary pavement sections were considered. The LCCA accounted for the costs incurred during the mixture's production, maintenance, and use phases of the pavement life cycle by explicitly considering future climate projections, pavement life‐cycle performance, maintenance effects, and work zone user delays. The study concludes that pavements using the upgraded binder not only perform better over time but are also economically advantageous compared to those with the original binder under the conditions of the anticipated future climate conditions (2020–2039).     

Distribution of Competition Potential Between Native Ungulates and Free-Roaming Equids on Western Rangelands

Free-roaming equids (i.e., feral horses [Equus caballus] and burros [Equus asinus]) are widely distributed and locally abundant across the rangelands of the western United States. The 1971 Wild Free Roaming Horse and Burro Act (WFRHBA) gave the Bureau of Land Management (BLM) and United States Forest Service (USFS) the legal authority to manage these animals on designated public lands. To fulfill this responsibility, federal agencies established an Appropriate Management Level (AML), defined as the number of horses or burros that can be sustained on a given management unit under prevailing environmental conditions and land uses. Although the WFRHBA specifies that feral equids must be managed in ecological balance with other land uses, including conservation of native wildlife, population control measures such as gathers, contraception, and adoptions have failed to keep pace with intrinsic growth rates. Over 80% of federally managed herds currently exceed prescribed population levels, making the potential for competition between native ungulates and feral equids a growing concern among state wildlife agencies. Mule deer (Odocoileus hemionus), pronghorn (Antilocapra americana), elk (Cervus canadensis), and bighorn sheep (Ovis canadensis) are of ecological and economic value to the states where they occur, and all exhibit some degree of distributional, habitat, or dietary overlap with horses or burros. Notwithstanding the scale of the problem, to date there have been no range-wide assessments of competition potential among native and feral ungulates for space, forage, or water. To address this need, we compiled demographic, jurisdictional, and species occurrence data collected from 2010–2019 by federal and state agencies. We used these data to map the distributions of 4 native ungulate species across federal equid management units (FEMUS) in 10 western states (n = 174). We then made within-state rankings of the 50 units that were ≥2 times over AML and encompassed ≥3 native ungulates. Collectively, FEMUs covered approximately 225,000 km², representing 18% of all BLM and USFS lands in affected states. Each FEMU supported ≥1 native ungulate and 14% contained all 4. The degree of overlap between native and feral species varied by state, ranging from <1% for mule deer in Montana, to 40% for bighorn sheep in Nevada. Oregon had the largest proportion of units that supported all 4 native ungulates (58%), whereas Montana and New Mexico had the fewest equids, but all populations were over target densities. Despite the perception that the problem of equid abundance is limited to the Great Basin states, high intrinsic growth rates and social constraints on management practices suggest all affected states should monitor range conditions and native ungulate demography in areas where forage and water resources are limited and expanding equid populations are a concern. © 2021 The Wildlife Society.