Enzootic hepatitis A infection in cynomolgus monkeys (Macaca fascicularis).

During a toxicology study in cynomolgus (long-tailed or crab-eating) monkeys (Macaca fascicularis), a randomly distributed incidence of significantly increased hepatic enzyme activity was observed. Premedication hepatic enzyme activity in all monkeys of this study was normal, but increased alanine aminotransferase (ALT) activity was found in 4 of the 24 animals 2 weeks after initiation of the study and in 10 of 24 at 4 weeks. A drug-related effect was considered unlikely initially because the increases were not doserelated, and a 3-year review of 655 cynomolgus monkeys revealed a 15-20% incidence of increased hepatic enzyme activity. Good correlation was subsequently established between increased hepatic enzyme activity, active hepatitis A virus (HAV) infection, and histomorphologic confirmation of hepatitis (chronic periportal inflammation). Follow-up viral serodiagnostic screening of resident macaques revealed an overall incidence of anti-HAV IgG in 80% (155/193) of cynomolgus and in 70% (14/20) of rhesus monkeys. Serial screening demonstrated that several initially negative monkeys became seropositive for anti-HAV IgG, and a few acquired active infection (anti-HAV IgM). Among newly acquired cynomolgus monkeys, 2.5% (2/80) had an acute HAV infection, and 35% (28/80) eventually tested positive for anti-HAV IgG while quarantined in the primate facility. The characterization of an enzootic HAV infection in incoming monkeys posed a significant risk for the primate colony and handlers. Rigorous sanitation, isolation, and quarantine procedures, including personnel training and additional protective clothing for personnel working in the primate colony, reduced tho potential for transmission and arrested the outbreak. Experimenters should be cautious in ascribing toxicity to a test article based solely on increased hepatic enzyme activity associated with chronic periportal inflammation.

Tissue response in dogs to dense hydroxylapatite implantation in the femur.

Six and eight years after the implantation of both granular and solid ceramic hydroxylapatite forms in the femurs of beagle dogs, histologic examination demonstrated that the implants were totally encased in dense mature bone. The endosteal and periosteal surfaces appeared normal, and no resorption of the solid implants was observed. However, at six years, a few granules located at the periosteal surface showed interdigitation of connective tissue stalks, with large multinucleated cells at the interface with the implant. This phenomenon may represent some limited resorptive activity on the surfaces of these few isolated granules. Initially, radiographs showed exaggerated degrees of bone deposition on the endosteal surface under the solid implants (discs), as opposed to a less pronounced endosteal response to the implants of particulate material. In some cases, particularly with the disc implants, cracks were found in the ceramic material six years after implantation. These cracks, on staining, were found to be filled with amorphous material, suggesting an osseous matrix. The results of these long-term studies indicate that such hydroxylapatite implants in bone are highly biocompatible. Bone deposition and maturation on the implant surface resulted in a homogeneous bone/implant interface in which the host tissues appeared to respond to the implant as if it were normal bone.

Histologic observation of soft tissue responses to implanted, multifaceted particles and discs of hydroxylapatite.

The effects on soft tissue of short- and long-term implants of ceramic hydroxylapatite (durapatite) are reported. In rats, after one week and one, six, and 12 months of subcutaneous implantation of hydroxylapatite in multifaceted particle and disc form, neither particles nor discs had resulted in any microscopically remarkable inflammation. In beagle dogs, after subcutaneous implantation of hydroxylapatite as multifaceted particles and as discs for seven and 24 days, nine months, and two and six years, no implant migration was observed. Encapsulation of particles and discs of increasing thickness was seen throughout the six years of observation. Except for a few isolated macrophages seen within the connective tissue stroma at seven and 24 days, no evidence of inflammation was found. In tissue sections taken at six months from beagle dogs in which multifaceted particles had been placed subperiosteally beneath the gingiva, dense connective tissue was observed adjacent to and surrounding the individual particles. These results show that hydroxylapatite implanted subcutaneously in rats and dogs produces little or no inflammatory response and is compatible with tissue irrespective of the shape of the implant.