Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma.

This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase inhibitor (IC50 values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150× against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy of compound 7f in the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma.

SAR and evaluation of novel 5H-benzo[c][1,8]naphthyridin-6-one analogs as Aurora kinase inhibitors.

Several potent Aurora kinase inhibitors derived from 5H-benzo[c][1,8]naphthyridin-6-one scaffold were identified. A crystal structure of Aurora kinase A in complex with an initial hit revealed a binding mode of the inhibitor within the ATP binding site and provided insight for structure-guided compound optimization. Subsequent SAR campaign provided a potent and selective pan Aurora inhibitor, which demonstrated potent target modulation and antiproliferative effects in the pancreatic cell line, MIAPaCa-2. Furthermore, this compound inhibited phosphorylation of histone H3 (pHH3) in mouse bone morrow upon oral administration, which is consistent with inhibition of Aurora kinase B activity.

Anterior shoulder forces in professional and Little League pitchers.

BACKGROUND: The developing musculoskeletal system of a youth pitcher is substantially different from that of the adult professional pitcher, predisposing the younger players to a different set of injuries. METHODS: High-speed videography of 39 professional and 13 youth pitchers were obtained. High-speed motion analysis was performed to calculate average anterior forces and arm positions at maximal force generation. RESULTS: Professional players generated an average of 33.8+/-14.4 N/kg maximal anterior force, corresponding to 151.9+/-17.0 degrees of external rotation. Youth pitchers generated 16.2+/-3.8 N/kg of anterior forces, corresponding to 118.0+/-23.4 degrees of external rotation. The degree of coronal abduction and horizontal abduction between the 2 groups were not significantly different-92.4+/-9.0 degrees in professionals versus 91.7+/-7.9 degrees in the youth and 11.1+/-11.1 degrees of horizontal abduction in professionals versus 7.8+/-14.1 degrees in the younger throwers. Professional pitchers exerted higher internal rotation torque at 19.4+/-4.1 Nm/kg versus 5.6+/-1.0 Nm/kg in youth, and compressive forces were found to be 121.7+/-21.7 N/kg in professional pitchers compared with 47.5+/-7.6 N/kg in the youth pitchers. CONCLUSIONS: Youth pitchers experience significant anterior shoulder forces and internal rotation torques, although these are lower than professional pitchers. CLINICAL RELEVANCE: Overhead throwing as a youth can lead to shoulder injuries and can predispose the shoulder to more significant injuries as an adult pitcher.

When should I do rural general practice? A qualitative study of job/life satisfaction of male rural GPs of differing ages in New Zealand.

AIMS: There is a shortage of rural general practitioners in New Zealand (NZ), and many are approaching retirement. This qualitative study was undertaken to investigate the perceived advantages and disadvantages of rural general practice at various stages of family life of male NZ-trained GPs. METHODS: Semi-structured interviews were conducted with 12 male NZ-trained rural GPs from the Waikato and Northland regions during December 2006. Major themes relating to rural general practice as a career were identified and analysed with respect to the family life cycle: no children yet, pre-school children, high school children, or 'empty nest'. RESULTS: Trends in the frequency of themes, and changes in the sentiments within each theme across different stages of family life were noted. CONCLUSION: Based on the frequency of themes and sentiments, a conceptual picture of the influences of stages of a male rural GP's family life on the GP are discussed.