Conservative Management of Penile and Urethral Lichen Sclerosus: A Systematic Review.

PURPOSE: We evaluate the efficacy and safety profiles of currently available conservative management options for penile and urethral lichen sclerosus. MATERIALS AND METHODS: A systematic review of existing literature on lichen sclerosus was conducted utilizing the PubMed, Embase, and Web of Science databases. References were assessed for relevance to nonsurgical management of male genital lichen sclerosus by title and abstract by 3 independent reviewers, then reviewed in full and in duplicate by 5 independent reviewers. RESULTS: Seventeen studies describing conservative management of histologically confirmed penile and urethral lichen sclerosus in male patients were included in the final review. We present available evidence supporting the use of 4 major treatment modalities represented in the existing literature: topical corticosteroids, tacrolimus, platelet-rich plasma, and CO2 laser. We also briefly discuss the limited studies on the use of oral acitretin and polydeoxyribonucleotide injections. Outcomes assessed include symptoms, clinical appearance, quality of life, sexual satisfaction, adverse effects, and long-term efficacy of treatment. CONCLUSIONS: Topical corticosteroids remain the mainstay of conservative management of penile and urethral lichen sclerosus, with current literature supporting the use of other therapies such as tacrolimus and platelet-rich plasma as alternatives or adjuvant treatments when escalation of treatment is necessary. Future research should further explore the efficacy and safety of newer therapies through additional controlled clinical trials in the targeted population.

A new model to analyze the temperature effect on the microalgae performance at large scale raceway reactors.

In this study a simplified temperature model for raceway reactors is developed, allowing to determine the temperature of the microalgae culture as a function of reactor design and environmental conditions. The model considers the major phenomena taking place in raceway reactors, especially heat absorption by radiation and heat losses by evaporation among others. The characteristic parameters of the model have been calibrated using genetic algorithms, next being validated with a long set of more than 50 days covering different weather conditions. It is worth to highlight the use of the developed model as a tool to analyze the influence of the temperature on the performance of microalgae cultures at large scale. As example, the annual variation of the performance of up to five different microalgae strains has been determined by computing the temperature index, thus the normalized value of performance of whatever microalgae at the real temperature with respect to that achievable at optimal temperature can be established. Results confirm that only strains tolerant to wide ranges of temperature can be efficiently produced all the year around in large scale outdoor raceway reactors without additional temperature control systems.

Mechanism-Based Rational Discovery and In Vitro Evaluation of Novel Microtubule Stabilizing Agents with Non-Taxol-Competitive Activity.

Microtubules (MT) are cytoskeletal polymers of αß-tubulin dimers that play a critical role in many cellular functions. Diverse antimitotic drugs bind to MT and disrupt their dynamics acting as MT stabilizing or destabilizing agents. The occurrence of undesired side effects and drug resistance encourages the search for novel MT binding agents with chemically diverse structures and different interaction profiles compared to known active compounds. This work reports the rational discovery of seven novel MT stabilizers using a combination of molecular modeling methods and in vitro experimental assays. Virtual screening, similarity filtering, and molecular mechanics generalized Born surface area (MM/GBSA) binding free energy refinement were employed to select seven potential candidates with high predicted affinity toward the non-taxoid site for MT stabilizers on ß-tubulin. MD simulations of 150 ns on reduced MT models suggest that candidate compounds strengthen the longitudinal interactions between tubulin dimers across protofilaments, which is a primary molecular mechanism of action for known MT stabilizers. In vitro MT polymerization assays confirmed that all candidates promote MT assembly at concentrations of >50 mM and exhibit noncompetitive MT polymerization profiles when cotreating with Taxol. Preliminary HeLa cell viability assays revealed a moderate cytotoxic effect for the compounds under study at 100 µM concentration. These results support the validity of our rational discovery strategy and the use of molecular modeling methods to pursue the search and optimization of new MT targeting agents.

Polyamidoamine-based nanovector for the efficient delivery of methotrexate to U87 glioma cells.

The purpose of this study was to design a polyamidoamine (PAMAM)-based nanovector for the efficient delivery of methotrexate to U87 glioma cells. To this end, 0-100% acetylated PAMAM dendrimers of the fourth generation were synthesized and evaluated using drug encapsulation measurements, molecular dynamics simulations, neurotoxicity assays and neuronal internalization experiments. The best system was tested as a nanovector for methotrexate delivery to U87 glioma cells. The authors found that 25% acetylated PAMAM dendrimers of the fourth-generation combine low intrinsic toxicity, large drug complexation capacity and efficient internalization into hippocampal neurons. Nanovector complexation enhances the cytotoxic response of methotrexate against U87 glioma cells compared with free drug solutions. In conclusion, 25% acetylated PAMAM dendrimers of the fourth-generation increase drug uptake by glioma cells and thereby act as efficient nanovectors for methotrexate delivery.

Large Intracellular Domain-Dependent Effects of Positive Allosteric Modulators on Glycine Receptors.

Glycine receptors (GlyRs) are members of the pentameric ligand-gated ionic channel family (pLGICs) and mediate fast inhibitory neurotransmission in the brain stem and spinal cord. The function of GlyRs can be modulated by positive allosteric modulators (PAMs). So far, it is largely accepted that both the extracellular (ECD) and transmembrane (TMD) domains constitute the primary target for many of these PAMs. On the other hand, the contribution of the intracellular domain (ICD) to the PAM effects on GlyRs remains poorly understood. To gain insight about the role of the ICD in the pharmacology of GlyRs, we examined the contribution of each domain using a chimeric receptor. Two chimeras were generated, one consisting of the ECD of the prokaryotic homologue Gloeobacter violaceus ligand-gated ion channel (GLIC) fused to the TMD of the human α1GlyR lacking the ICD (Lily) and a second with the ICD (Lily-ICD). The sensitivity to PAMs of both chimeric receptors was studied using electrophysiological techniques. The Lily receptor showed a significant decrease in the sensitivity to four recognized PAMs. Remarkably, the incorporation of the ICD into the Lily background was sufficient to restore the wild-type α1GlyR sensitivity to these PAMs. Based on these data, we can suggest that the ICD is necessary to form a pLGIC having full sensitivity to positive allosteric modulators.

Enhancement of the male effect on reproductive performance in female Mediterranean goats with long day and/or melatonin treatment.

The aim of this study was to determine whether the male effect on reproductive performance in female Mediterranean goats could be enhanced if used in combination with long day and/or melatonin treatments. Thirty-two does were exposed to long days (16 h of light/day) for 95 days. At the end of this period, 16 received one melatonin implant (group LD-M) and 16 did not (group LD). Simultaneously, 16 does under natural photoperiod were implanted with melatonin (group M) or given no treatment (group C, n=16). On April 14th, after 49 days of isolation from males, all does were exposed to bucks fitted with marking harnesses. Oestrous activity, as detected by visual observation, was recorded daily. Transrectal ultrasonography was used to record ovulation, and ovarian activity confirmed by determining plasma progesterone concentration. Oestrous activity, ovulation and fertility were greater in all treatment groups compared with group C (P<0.05), but no differences in ovulation rate or litter size were observed (P>0.05). Productivity (mean number of kids per female) of the LD-M and M groups was significantly greater than in group C (1.50 ± 0.01 and 1.37 ± 0.01 vs. 0.69 ± 0.01 kids, respectively) (P<0.05). Combining melatonin treatment with natural or artificial long days adds to the impact of the male effect.