In vitro and in vivo characterization of A-940894: a potent histamine H4 receptor antagonist with anti-inflammatory properties

Background and purpose:

The histamine H₄ receptor is widely expressed in cells of immune origin and has been shown to play a role in a variety of inflammatory processes mediated by histamine. In this report, we describe the in vitro and in vivo anti-inflammatory properties of a potent histamine H₄ receptor antagonist, A-940894 (4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine).

Experimental approach:

We have analysed the pharmacological profile of A-940894 at mouse native, rat recombinant and human recombinant and native, histamine H₄ receptors by radioligand binding, calcium mobilization, mast cell shape change, eosinophil chemotaxis assays and in the mouse model of zymosan-induced peritonitis.

Key results:

A-940894 potently binds to both human and rat histamine H₄ receptors and exhibits considerably lower affinity for the human histamine H₁, H₂ or H₃ receptors. It potently blocked histamine-evoked calcium mobilization in the fluorometric imaging plate reader assays and inhibited histamine-induced shape change of mouse bone marrow-derived mast cells and chemotaxis of human eosinophils in vitro. In a mouse mast cell-dependent model of zymosan-induced peritonitis, A-940894 significantly blocked neutrophil influx and reduced intraperitoneal prostaglandin D₂ levels. Finally, A-940894 has good pharmacokinetic properties, including half-life and oral bioavailability in rats and mice.

Conclusions and Implications:

These data suggest that A-940894 is a potent and selective histamine H₄ receptor antagonist with pharmacokinetic properties suitable for long-term in vivo testing and could serve as a useful tool for the further characterization of histamine H₄ receptor pharmacology.     

Pancreaticoduodenectomy in children: optimising outcome of uncommon paediatric procedures

Contemporary surgical practice is increasingly dominated by subspecialisation in response to improved outcome from high volume centres, though uncertainties persist for uncommon paediatric procedures. Three paediatric pancreaticoduodenectomies performed at Our Lady's Children's Hospital, Dublin, over a period of 9 years were evaluated to substantiate their continuing performance by paediatric rather than adult pancreatic surgeons. With ages ranging from 18 months to 8 years old, the mean operating time was 263 minutes, while the average hospital stay was 12 days. There was no perioperative mortality, although complication rate was 100%. Re-operation was required in 33%. The long term outcome of this small paediatric cohort was comparable to adult series despite the low patient accrual, underscoring the advantages of a multidisciplinary approach afforded by tertiary paediatric institutions for intricate yet infrequent operations in children.     

Falls,injuries from falls,health related quality of life and mortality in older adults with vision and hearing impairment-Is there a gender difference?

Background

Vision and hearing decline with age. Loss of these senses is associated with increased risk of falls, injuries from falls, mortality and decreased health-related quality of life (HRQOL). Our objective was to determine if there are gender differences in the associations between visual and hearing impairment and these outcomes.

Methods

2340 men and 3014 women aged 76–81 years from the Health in Men Study and the Australian Longitudinal Study on Women's Health were followed for an average of 6.36 years. Dependent variables were self-reported vision and hearing impairment. Outcome variables were falls, injuries from falls, physical and mental components of HRQOL (SF-36 PCS and MCS) and all-cause mortality.

Results

Vision impairment was more common in women and hearing impairment was more common in men. Vision impairment was associated with increased falls risk (odds ratio (OR) = 1.77, 95% CI = 1.35–2.32 in men; OR = 1.82, 95% CI = 1.44–2.30 in women), injuries from falls (OR = 1.69, 95% CI = 1.23–2.34 in men, OR = 1.79, 95% CI = 1.38–2.33 in women), and mortality (hazard ratio (HR) = 1.44; 95% CI = 1.17–1.77 in men; HR = 1.50, 95% CI = 1.24–1.82 in women) and declines in SF-36 PCS and MCS. Hearing impairment was associated with increased falls risk (OR = 1.38, 95% CI = 1.08–1.78 in men; OR = 1.45, 95% CI = 1.08–1.93 in women) and declines in SF-36 PCS and MCS. Overall there were no gender differences in the association between vision and hearing impairment and the outcomes.

Conclusion

In men and women aged 76–81 years, there were no gender differences in the association between self-reported vision and hearing impairment and the outcomes of falls, mortality and HRQOL.     

Endodontic treatment of an immature maxillary lateral incisor with type II dens invaginatus in an orthodontic patient: A case report

This paper presents a case report of an immature maxillary lateral incisor with type II dens invaginatus, with a periapical lesion. The tooth was treated with MTA apical barrier followed by root filling with thermoplasticised GP and restoration with resin composite. Three-year radiographic follow-up showed healing of the apical lesion and normal clinical parameters.