Pro-Secretory Activity and Pharmacology in Rabbits of an Aminophenyl-1,3,5-Triazine CFTR Activator for Dry Eye Disorders.

PurposePharmacological activation of ocular surface cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels is a potential pro-secretory approach to treat dry eye disorders. We previously reported the discovery of aminophenyl-1,3,5-triazines, one of which, N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine (herein called CFTRact-K267), fully activated human wildtype CFTR with EC50 ∼ 30 nM and increased tear volume for 8 hours in mice. Here, functional and pharmacological studies of CFTRact-K267 were done in adult New Zealand white rabbits.MethodsCFTR chloride conductance was measured in vivo by ocular surface potential differences and in ex vivo conjunctiva by short-circuit current. Tear volume was measured by the Schirmer tear test II and CFTRact-K267 pharmacokinetics and tissue distribution by liquid chromatography/mass spectrometry. Toxicity profile was studied for 28 days with twice-daily topical administration.ResultsElectrophysiological measurements in vivo and in ex vivo conjunctiva demonstrated CFTR activation by CFTRact-K267. A single topical dose of 3 nmol CFTRact-K267 increased tear production by >5 mm for 9 hours by the Schirmer tear test, with predicted therapeutic concentrations maintained in tear fluid. No tachyphylaxis was seen following 28-day twice-daily administration, and changes were not observed in corneal surface integrity or thickness, intraocular pressure, or ocular histology. At day 28, CFTRact-K267 was concentrated in the cornea and conjunctiva and was not detectable in blood or peripheral organs.ConclusionsThese studies support the development of CFTRact-K267 as a pro-secretory therapy for dry eye disorders

Open Roads and Overflowing Jails: Addressing High Rates of Rural Pretrial Incarceration

The axiom that a person is considered innocent of a criminal act until he or shehas been proven guilty is a bedrock principle of the American criminal justicesystem. Yet in many jurisdictions, it appears to have been forgotten. The pretrialpopulation of defendants has significantly increased—particularly in rural areasof the country. Jails in smaller jurisdictions are responsible for an outsized shareof jail population growth. Indeed, from 1970 to 2014, jail populations grew byalmost sevenfold in small counties but only threefold in large counties.This paper explores why this growth may have occurred and makes numerousrecommendations to reduce pretrial populations, particularly in rural America.The first place to start is by reducing the number of offenses carrying the potentia

Smartphone Applications and Website Software Available for Pre-Operative Virtual Rhinoplasty Planning

Background: There are emerging virtual simulation technologies that allow facial plastic surgeons to accurately and objectively show patients how they may appear following rhinoplasty surgery. There is no collective understanding of which virtual rhinoplasty preoperative planning software exist and their associated features. Aim: This article will synthesise information on smartphone and web-based resources for virtual rhinoplasty planning to provide facial plastic surgeons with an up-to-date understanding of the available technologies. Methods: This was a cross-sectional website and smartphone application software review. The Apple App Store and the Google Play were searched for smartphone applications and the Google search engine was searched for website software. Results: Five websites and six smartphone applications met inclusion criteria. Software features included self-directed simulation, in-app purchases, multiple languages, three-dimensional facial rendering and patient-specific perioperative planning. Conclusion: Many smartphone and website based software exist for surgeons to plan their patients’ rhinoplasties. Further data is needed to understand how facial plastic surgeons and patients perceive this software

Chronic intestinal inflammation: Inflammatory bowel disease and colitis-associated colon cancer

The inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the intestine. The prevalence in the United States is greater than 200 cases per 100,000, with the total number of IBD patients between 1 and 1.5 million. CD may affect all parts of the gastrointestinal tract, from mouth to anus, but most commonly involves the distal part of the small intestine or ileum, and colon. UC results in colonic inflammation that can affect the rectum only, or can progress proximally to involve part of or the entire colon. Clinical symptoms include diarrhea, abdominal pain, gastrointestinal bleeding, and weight loss. A serious long-term complication of chronic inflammation is the development of colorectal cancer. A genetic basis for IBD had long been recognized based on the increased familial risk. However, significant discordance for CD in twins, and a much less robust phenotypic concordance for UC, suggested additional factors play a role in disease pathogenesis, including environmental factors. In the past several years, progress in understanding the molecular basis of IBD has accelerated, beginning with the generation of animal models of colitis and progressing to the identification of specific genetic markers from candidate gene, gene linkage, and genome-wide association analyses. Genetic studies have also resulted in the recognition of the importance of environmental factors, particularly the crucial role of the gut microbiota in CD and UC. Altered immune responses to the normal intestinal flora are key factors in IBD pathogenesis. In this research topic, the genetic basis of IBD, the genetic and cellular alterations associated with colitis-associated colon cancer, and the emerging role of the intestinal microbiota and other environmental factors will be reviewed

Glauber dynamics for the quantum Ising model in a transverse field on a regular tree

Motivated by a recent use of Glauber dynamics for Monte-Carlo simulations of path integral representation of quantum spin models [Krzakala, Rosso, Semerjian, and Zamponi, Phys. Rev. B (2008)], we analyse a natural Glauber dynamics for the quantum Ising model with a transverse field on a finite graph $G$. We establish strict monotonicity properties of the equilibrium distribution and we extend (and improve) the censoring inequality of Peres and Winkler to the quantum setting. Then we consider the case when $G$ is a regular $b$-ary tree and prove the same fast mixing results established in [Martinelli, Sinclair, and Weitz, Comm. Math. Phys. (2004)] for the classical Ising model. Our main tool is an inductive relation between conditional marginals (known as the "cavity equation") together with sharp bounds on the operator norm of the derivative at the stable fixed point. It is here that the main difference between the quantum and the classical case appear, as the cavity equation is formulated here in an infinite dimensional vector space, whereas in the classical case marginals belong to a one-dimensional space