The physiological and biochemical basis of potency thresholds modeled using human estrogen receptor alpha: implications for identifying endocrine disruptors.

The endocrine system functions by interactions between ligands and receptors. Ligands exhibit potency for binding to and interacting with receptors. Potency is the product of affinity and efficacy. Potency and physiological concentration determine the ability of a ligand to produce physiological effects. The kinetic behavior of ligand-receptor interactions conforms to the laws of mass action. The laws of mass action define the relationship between the affinity of a ligand and the fraction of cognate receptors that it occupies at any physiological concentration. We previously identified the minimum ligand potency required to produce clinically observable estrogenic agonist effects via the human estrogen receptor-alpha (ERα). By examining data on botanical estrogens and dietary supplements, we demonstrated that ERα ligands with potency lower than one one-thousandth that of the primary endogenous hormone 17ß-estradiol (E2) do not produce clinically observable estrogenic effects. This allowed us to propose a Human-Relevant Potency Threshold (HRPT) for ERα ligands of 1 × 10-4 relative to E2. Here, we test the hypothesis that the HRPT for ERα arises from the receptor occupancy by the normal metabolic milieu of endogenous ERα ligands. The metabolic milieu comprises precursors to hormones, metabolites of hormones, and other normal products of metabolism. We have calculated fractional receptor occupancies for ERα ligands with potencies below and above the previously established HRPT when normal circulating levels of some endogenous ERα ligands and E2 were also present. Fractional receptor occupancy calculations showed that individual ERα ligands with potencies more than tenfold higher than the HRPT can compete for occupancy at ERα against individual components of the endogenous metabolic milieu and against mixtures of those components at concentrations found naturally in human blood. Ligands with potencies less than tenfold higher than the HRPT were unable to compete successfully for ERα. These results show that the HRPT for ERα agonism (10-4 relative to E2) proposed previously is quite conservative and should be considered strong evidence against the potential for disruption of the estrogenic pathway. For chemicals with potency 10-3 of E2, the potential for estrogenic endocrine disruption must be considered equivocal and subject to the presence of corroborative evidence. Most importantly, this work demonstrates that the endogenous metabolic milieu is responsible for the observed ERα agonist HRPT, that this HRPT applies also to ERα antagonists, and it provides a compelling mechanistic explanation for the HRPT that is grounded in basic principles of molecular kinetics using well characterized properties and concentrations of endogenous components of normal metabolism.

Advanced Solid Geopolymer Formulations for Refractory Applications.

Cement, as a construction material, has low thermal resistance, inherent fire resistance, and is incombustible up to a certain degree. However, the loss of its mechanical performance and spalling are its primary issues, and it thus cannot retain its performance in refractory applications. The present study explores the performance of geopolymer formulations that have excellent fire resistance properties for potential refractory applications. This study is unique, as it investigates advanced solid geopolymer formulations that need only water to activate and bind. Various solid geopolymer formulations with fly ash as a precursor; potassium hydroxide and potassium silicate as activators; and mullite and alumina as refractory aggregates were studied for their compressive strength at up to 1100 °C and compared with their two-part conventional liquid alkaline geopolymer counterparts. Advanced solid geopolymer formulations with mullite and alumina as refractory aggregates had mechanical strength values of 84 MPa and 64 MPa post-1100 °C exposure and were further exposed to ten thermal cycles of 1100 °C to study their fatigue resistance and post-exposure compressive strengths. The geopolymer sample with mullite as a refractory aggregate yielded 115.2 MPa compressive strength after the fourth cycle of exposure. This sample was also studied for its temperature distribution upon direct flame exposure. All the geopolymer formulations displayed a drop in compressive strength at 600 °C due to viscous sintering and then a rise in strength at 1100 °C due to phase transformation. X-ray diffraction studies revealed that the formation of crystalline phases such as leucite, sanidine, and annite were responsible for the superior strengths at 1100 °C for the alumina- and mullite-based geopolymer formulations.

A systematic review of the biomechanical properties of suture materials used in orthopaedics.

Background: Soft tissue injuries are frequently repaired using various suture material. The ideal suture should have the biomechanical properties of low displacement, high maximum load to failure, and high stiffness to avoid deformation. Since tendon healing occurs over a period of months, it is important for the surgeon to select the proper suture with certain biomechanical properties. Therefore, the purpose of this study is to qualitative summarize the published literature on biomechanical properties of different suture materials used in orthopaedic procedures. Methods: Following PRISMA guidelines, PubMed and Cochrane databases were queried for original articles containing "biomechanic(s)" and "suture" keywords. Following screening for inclusion and exclusion, final articles were reviewed for relevant data and collected for qualitative analysis. Data collected from each study included the tissue type repaired, suture material, and biomechanical properties, such as elongation, maximum load to failure, stiffness, and method of failure. Results: 17 articles met final inclusion criteria. Two studies found No.2 Fiberwire™ to have the lowest elongation and 4 studies found No. 2 Ultrabraid™ to have the greatest. 12 studies reported Maximum load to failure was highest in No. 2 Fiberwire™, No. 2 Ultrabraid™, and FiberTape™ while No. 2 Ethibond ™ had the lowest in 5 studies. 3 of the 5 studies that evaluated No. 2 Fiberwire™ found it to have the highest stiffness. No. 2 Ethibond™, No. 2 Orthocord™, and No. 2 PDS™ were reported as the least stiff sutures in 2 studies each. Conclusion: Fiberwire™, FiberTape™, and Ultrabraid™ demonstrated the highest load to failure while Ethibond™ consistently was the weakest. Fiberwire™ was found to have the lowest elongation while Ultrabraid™ had the highest. Fiberwire™ was also noted to be the stiffest while PDS, Ethibond™, and Orthocord™ were found to be the least stiff. Final treatment decisions on which suture to utilize to optimize repair integrity and healing are complex, and rarely solely dependent upon the biomechanical properties of the materials used. Level of evidence: Systematic Review, Level IV.

Mast cells in laser and surgical wounds / Mastócitos em feridas cirúrgicas e à laser

Precooling of tissues was investigated as a possible means of reducing thermal damage during CO² laser surgery of the oral mucosa. The changes in mast cells in scalpel, and in non-cooled and precooled (tissue temperature lowered to approximately l0ºC) CO² laser wounds were studied. Standard wounds five mm in length were created with the CO² laser or scalpel on the dorsum of the tongues of 32 Sprague-Dawley rats under general anesthesia with fentanyl/fluanisone and midazolam. Animals were killed with excess anesthetic immediately or six hours after surgery, their tongues were removed, trimmed, fixed in neutral formalin and processed to paraffin wax. Acid (pH 1.4) toluidine blue stained sections were used to count normal and degranulated mast cells in five fields (0.1mm²) located at defined positions immediately adjacent to the wound site. At both 0 and 6 hours normal mast cell numbers were significantly different between treament groups (P<0.045; ANOVA) with mean numbers highest in scalpel wounds and lowest in uncooled laser wounds. Similary, at 0 time, there were significant differences in degranulated mast cells between treatment groups (P=0.004; ANOVA) but highest numbers were detected in uncooled laser wounds and lowest in scalpel wounds. There were no significant differences in degranulated mast cell counts six hours although there was a similar distribution in numbers between groups. Total numbers of mast cells (normal + degranulated) did not differ between treatment groups. These results demonstrated that i) laser wounds are associated with greater levels of mast cell degranulation than scalpel wounds and ii) precooling of tissues prior to laser treatment decreases the level of mast cell degranulation. It is concluded that tissue damage in CO² laser surgery may be reduced by precooling of tissue