Mutations in the SCN9A gene leading to deficiency of its protein product, Na(v)1.7, cause congenital indifference to pain (CIP). CIP is characterized by the absence of the ability to sense pain associated with noxious stimuli. In contrast, the opposite phenotype to CIP, inherited erythromelalgia (IEM), is a disorder of spontaneous pain caused by missense mutations resulting in gain-of-function in Na(v)1.7 that promote neuronal hyperexcitability. The primary aim of this study was to demonstrate that Na(v)1.7 antagonism could alleviate the pain of IEM, thereby demonstrating the utility of this opposite phenotype model as a tool for rapid proof-of-concept for novel analgesics. An exploratory, randomized, double-blind, 2-period crossover study was conducted in 4 SCN9A mutation-proven IEM patients. In each treatment period (2days), separated by a 2-day washout period, patients were orally administered XEN402 (400mg twice daily) or matching placebo. In 3 patients, pain was induced by heat or exercise during each treatment arm. A fourth patient, in constant severe pain, required no induction. Patient-reported outcomes of pain intensity and/or relief were recorded, and the time taken to induce pain was measured. The ability to induce pain in IEM patients was significantly attenuated by XEN402 compared with placebo. XEN402 increased the time to maximal pain induction and significantly reduced the amount of pain (42% less) after induction (P=.014). This pilot study showed that XEN402 blocks Na(v)1.7-mediated pain associated with IEM, thereby demonstrating target engagement in humans and underscoring the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of-concept.
The indentation deformation and cracking responses of ion-exchanged glasses were measured using quasi-static and dynamic loading cycles. Two glass types were compared, a normal glass that deforms to a large extent by a shearing mechanism and a damage-resistant glass that comparatively deforms with less shear and more densification. The quasi-static indentation cracking threshold for median/radial cracks for the ion-exchanged normal glass was determined to be 7 kgf, while the ionexchanged damage-resistant glass required loads exceeding 30 kgf. The increased cracking threshold of the damage-resistant glass composition is attributed to the deformation mechanism, i.e., deformation with greater densification/less shear results in less subsurface damage and less residual stress. Both glass types were also subjected to dynamic indentation where the contact event time was more than 10,000 times shorter than the quasi-static condition. Under dynamic loading conditions, the cracking thresholds of the ion-exchanged normal and damage-resistant glasses increased to greater than 50 kgf and greater than 150 kgf, respectively. The stress-induced optical retardation was compared for quasi-static and dynamic indents made at sub-cracking threshold loads for both glasses. For indents made at the same sub-cracking threshold load in the normal glass, optical retardation mapping indicates less residual stress surrounding dynamic indents when compared to quasi-static indents. This suggests a rate dependence on the deformation mechanism in normal glasses with higher rates promoting densification in favor of shear. However, for damage-resistant glass, the stress-induced optical retardation is the same for indents made at both quasi-static and dynamic indentation rates.
A cover glass that is capable of having a deep ion exchange compression layer enables one to tailor the glass to the intended device application. Key to this effort is having a glass mechanics framework that includes resistance to visible and strength‐limiting contact damage as well as maintaining sufficient strength to survive localized glass flexing during contact events.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.