"Knuckle Cracking": Can Blinded Observers Detect Changes with Physical Examination and Sonography?

Background: Voluntary knuckle cracking is a common habit, with a reported prevalence of 25% to 45%. Habitual knuckle cracking also is a frequent source of questions for physicians, and the largest study to date reported an association with functional hand impairments.

Questions/purposes: (1) When compared with subjects who are not habitual knuckle crackers, do habitual knuckle crackers have greater QuickDASH scores, swelling, weakness, joint laxity, or ROM? (2) In subjects who crack their knuckles, does cracking immediately increase ROM? (3) What are the characteristic sonographic findings in joints that crack?

Methods: A prospective, institutional review board-approved study was performed on 400 metacarpophalangeal joints (MPJs) in 40 asymptomatic adult subjects.

MR Imaging of the Triangular Fibrocartilage Complex.

MR imaging has emerged as the mainstay in imaging internal derangement of the soft tissues of the musculoskeletal system largely because of superior contrast resolution. The complex geometry and diminutive size of the triangular fibrocartilage complex (TFCC) and its constituent structures can make optimal imaging of the TFCC challenging; therefore, production of clinically useful images requires careful optimization of image acquisition parameters. This article provides a foundation for advanced TFCC imaging including factors to optimize magnetic resonance images, arthrography, detailed anatomy, and classification of injury.

Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors.

The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar substituents provided improvements in the compound's in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.

Highly selective c-Jun N-terminal kinase (JNK) 3 inhibitors with in vitro CNS-like pharmacokinetic properties II. Central core replacement.

In this Letter, we describe the evolution of selective JNK3 inhibitors from 1, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs. Strong SAR was found for substitution of the naphthalene ring, as well as for inhibitors adopting different central scaffolds. Significant potency gains were appreciated by inverting the polarity of the thione of the parent triazolothione 1, resulting in potent compounds with attractive pharmacokinetic profiles.

Highly selective c-Jun N-terminal kinase (JNK) 2 and 3 inhibitors with in vitro CNS-like pharmacokinetic properties prevent neurodegeneration.

In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38α and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases.

Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model.

In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days.