GSK-3 inhibition by an orally active small molecule increases bone mass in rats

Glycogen synthase kinase 3β (GSK-3β) actions are central in the canonical Wnt pathway, important in many biological processes and a potential drug target for treating several diseases. It is appreciated that a balanced Wnt canonical signaling is crucial for the maintenance of normal bone mass. In this study we investigated the effects of a potent orally active GSK-3 inhibitor, AZD2858, on bone mass in rats. Treatment (1 μM) of human osteoblast cells with AZD2858 in vitro increased β-catenin levels after a short period of time. In rats, oral AZD2858 treatment caused a dose-dependent increase in trabecular bone mass compared to control after a two-week treatment with a maximum effect at a dose of 20 mg/kg once daily (total BMC: 172% of control; p<0.001). A small but significant effect was also seen at cortical sites (total BMC: 111% of control; p<0.001). Biomechanical testing demonstrated an increase in both vertebral compression strength at a dose of 20 mg/kg once daily (Load at failure: 370% of control, p<0.001) and diaphyseal strength of femora subjected to a three point bending test (Load at failure: 115% of control; p<0.01). Furthermore, histomorphometry showed a dramatic increase in bone formation indices, and serum markers of both bone formation (Osteocalcin, 146% of control; p<0.001) and resorption (CTX, 189% of control; p<0.001) were elevated. Our conclusion is that a GSK-3 inhibitor drug may prove effective as an anabolic strategy in the treatment of diseases characterized by low bone mass, since AZD2858 has extensive bone building effects at predominantly trabecular sites.     

The use of Zenker's solution in linear craniectomy for craniosynostosis: Technical modification and reappraisal

Summary Regrowth of bone after craniectomy for craniosynostosis is still a problem, despite the advent of newer and extensive surgical techniques. A clinical study on 25 consecutive patients was undertaken to determine whether a modification of previous routines could retain the advantages of a tissue fixative, Zenker's solution, while eliminating the drawback of convulsive activity. After brief coagulation, Zenker's solution was sparingly applied to the durai surface for maximally one minute followed by copious irrigation of the surgical field. The results were satisfactory and postoperative complications unrelated to the fixative. The present procedure seems safe, effective, and easy to use.     

Ultraviolet B irradiation inhibits the induction of photoallergy to systemically administered quinidine in the mouse.

In albino mice photosensitized to quinidine, 100 mg/kg by intraperitoneal injection, pretreatment of the induction area with ultraviolet B (UVB) on 3 consecutive days was shown to significantly reduce the inflammatory response when the mice were challenged at a distant site 1 week later. Mice controlled for phototoxicity did not react. The inhibition was dose-dependent within the UVB dose range tested (0.05-1.0 J/cm2 x 3), being almost complete with the highest doses. Inhibition, although somewhat less pronounced, was also seen when an area on the back, distant from the induction site, was preirradiated following a similar protocol. The reduced response at elicitation persisted when the time to challenge was increased up to 4 weeks. At 5 weeks, a second attempt to photosensitize the previously inhibited animals failed, suggesting that a state of tolerance had been acquired. The timing of the UV exposure in relation to the photoactive chemical is critically important in determining whether an exposure promotes or inhibits photoallergic sensitization.     

Liver injury following administration of 8-methoxypsoralen during PUVA therapy.

A case of liver injury caused by 8-methoxypsoralen given orally during PUVA therapy is presented. The reaction, manifested by elevated serum alanine-aminotransferase and serum aspartate-aminotransferase, was provoked on three consecutive occasions, on the last one with 8-MOP only. The liver injury seems to be of the hepatocellular and nonpredictable type.     

Antinuclear antibodies during Puva therapy.

During PUVA therapy 7 patients out of 34 with severe psoriasis developed circulating antinuclear antibodies (ANA) (21%). Before treatment only 3 patients of 50 (6%) considered for PUVA had detectable ANA. The ANA titres were usually low. Antibodies against native DNA as studied with the Crithidia luciliae test, were not found, and blood and urinary screening for collagenosis was negative. All 7 patients responded well to the PUVA treatment. The significance of these findings remains to be determined.