Jeanne W. George

Age-related differences in erythropoietic response to recombinant human erythropoietin: comparison in adult and infant rhesus monkeys.

ABSRACT: Human recombinant erythropoietin (r-HuEPO) was given i.v. to rhesus monkeys to compare its safety, erythropoietic effects, and pharmacokinetics in healthy adult and infant animals. Eighteen adult and 18 infant (9- to 15-d-old) monkeys were divided into three groups each of six animals. One group was given 250 U/kg twice weekly, another was given 100 U/kg twice weekly, and a control group was given the drug vehicle for 6 wk. All animals were healthy throughout this period, and for 10 wk after that. Administration of r-HuEPO at these dosages did not produce any changes in leukocytes, platelets, urea nitrogen, bilirubin, creatinine, alkaline phosphatase, alanine amino transferase, γ-glutamyl transferase, and blood pressure in either age group. At 6 wk, both adult treatment groups had statistically significant increases in Hb concentration. The same dosages that produced these increases in Hb concentration in adults produced no changes in Hb concentration in infant monkeys. Despite active erythropoiesis, as determined by reticulocytosis and increased total body Hb, Hb concentration decreased similarly in the infant treatment and control groups. Pharmacokinetic profiles were obtained at 5 wk of dosing. One h after administration, both doses of r-HuEPO produced significantly lower serum r-HuEPO concentration in the infant monkeys compared with the adults. These differences appeared to be due to a larger volume of distribution of r-HuEPO in the infant monkeys. The t½ of r-HuEPO in circulation was the same in both age groups.

Detection of feline immunodeficiency virus infection in bone marrow of cats

Natural or experimental feline immunodeficiency virus (FIV) infection in cats is often associated with hematologic abnormalities which are similar to those observed in human immunodeficiency virus (HIV) infected patients. To determine if cells in bone marrow are infected with FIV and whether severity of hematopoietic disorder is correlated with the level of viral infection, bone marrow tissues from ten experimentally and two naturally FIV infected cats were examined by in situ hybridization for presence of FIV RNA. Seven of the 12 FIV infected cats were also naturally or experimentally coinfected with feline leukemia virus (FeLV). FIV RNA was detected mainly in megakaryocytes and unidentified mononuclear cells in the bone marrow of cats that were sick and had marrow hypercellularity and immaturity. These included all cats in the acute phase of FIV infection and two of seven long term FIV infected cats. One long term FIV infected cat with lymphosarcoma was also positive for FIV RNA in bone marrow cells. The other four long term FIV infected cats were relatively healthy, with normal bone marrow morphology, and were negative for FIV infected cells. Bone marrow from three non-infected and two cats infected with FeLV alone were also negative for FIV RNA by in situ hybridization. We concluded that megakaryocytes and mononuclear cells were targets of the viral infection and that the presence of FIV RNA in cells of the bone marrow correlated with marrow hypercellularity and immaturity, and severity of illness.

Effect of chronic feline immunodeficiency virus infection on experimental feline calicivirus-induced disease

Acute feline calicivirus (FCV) infection caused a more severe disease in chronically feline immunodeficiency virus (FIV) infected than in non-FIV infected cats. FIV infected cats shed significantly higher amounts of FCV through their saliva after FCV challenge than the non-FIV infected cats. However, there was no difference in the duration of FCV shedding. None of the cats exposed to FCV developed chronic FCV carriage. Both groups of cats mounted similar titers of neutralizing antibodies to FCV. Although FIV infected cats started out with significantly lower total lymphocyte and neutrophil numbers than the non-FIV infected cats, the transient lymphopenia and neutrophilia attributable to the FCV infection was of similar intensity in both groups of animals. There was no evidence that the underlying FIV-related disease or viremia was influenced by acute FCV infection. Acute FCV infection did not significantly alter the CD4+/CD8+ T lymphocyte ratio in FIV infected compared to non-FIV infected cats. The ongoing humoral IgG response to FIV was not affected by the FCV infection. There was no significant change in the proportion of FIV infected peripheral blood mononuclear cells during 8 subsequent weeks after FCV challenge as determined by polymerase chain reaction.

Interaction of acute feline herpesvirus-1 and chronic feline immunodeficiency virus infections in experimentally infected specific pathogen free cats.

Cats with or without chronic feline immunodeficiency virus (FIV) infection were exposed to feline herpesvirus, type 1 (FHV-1). FIV infected cats became sicker than non-FIV infected cats and required more supportive treatment. However, there were no differences in the length of their illness or in the levels and duration of FHV-1 shedding. FHV-1 infection caused a transient neutrophilia at Day 7 with a rapid return to preinfection levels. The neutrophilia coincided with a transient lymphopenia that was accompanied by a decline in both CD4+ and CD8+ T-lymphocytes. A brief decrease in the CD4+/CD8+ T-lymphocyte ratio occurred at Day 14 in both FIV infected and non-infected cats. This decrease was mainly the result of an absolute and transient increase in CD8+ T-lymphocytes. CD4+ and CD8+ T-lymphocyte numbers and CD4+/CD8+ T-lymphocyte ratios returned to baseline within 4-8 weeks in both FIV infected and non-infected cats. FIV infected cats produced less FHV-1 neutralizing antibodies during the first 3 weeks of infection than non-FIV infected animals. The IgM FHV-1 antibody response was depressed in FIV infected cats whereas the IgG antibody response was unaffected. FHV-1 infection evoked a comparable transient loss of lymphocyte blastogenic responses to concanavalin A and pokeweed mitogen in both FIV infected and non-infected cats. However, response to pokeweed mitogen took longer to return to normal in FIV infected animals. Lymphocytes from FIV infected cats had a greater and more sustained proliferative response to FHV-1 antigen than non-FIV infected cats. The ongoing IgG antibody response to FIV was not affected by FHV-1 infection.

Biliverdin reductase activity in cattle, sheep, rabbits and rats

1. Biliverdin reductase (BVR) activity was measured in post-microsomal supernatants of livers of cattle, sheep, rabbits and rats. BVR activities in bovine and ovine livers were 4.7 and 5.0%, respectively, of rat liver activity. 2. The finding of BVR activity in ruminants is in contrast to a previous report and may be due to the use of a different assay system. 3. Lapine liver had the lowest BVR activity of only 0.37% of rat liver activity. 4. Increasing the available heme by phenylhydrazine administration did not induce increased hepatic or splenic BVR activity in rabbits. 5. Maximal BVR activities were attained using NADPH as cofactor at pH 8.7 in sheep and rabbits and at pH 8.4 in cattle. 6. Differing concentrations of bovine or human albumins enhanced or inhibited BVR activity quite differently in the various species. 7. The finding of a very low, but measurable BVR activity in lapine liver and spleen may explain, in part, why rabbits, unlike rats, cattle and sheep, excrete primarily biliverdin (70%) into bile.

Bilirubin excretion and bile flow in fed and fasted Brazilian squirrel monkeys (Saimiri sciureus)

Fasted Brazilian squirrel monkeys (BrSMs) exhibited slightly higher serum bilirubin levels (0.30±0.05 mg/dl) than others in the fed state (0.13±0.01). The mean liver weight was 50% lower following a 22 h fast. The rate of bile flow was unaffected by fasting and averaged 13.8 μl/min/kg and 47.5 μl/min/100g liver in six BrSMs. No significant difference in mean bilirubin excretion/min was observed on a body weight basis following fasting. When the mean rate of bilirubin excretion was calculated as a function of liver weight, a two-fold higher rate was present in fasted monkeys, but only at the p=0.06 level of statistical significance. From data collected in this and earlier studies, it would appear that BrSMs represent the best animals studied to date to serve as experimental controls in comparative studies with Bovilian squirrel monkeys which exhibit a Gilbert-like syndrome.