Mechanisms of protection induced by attenuated simian immunodeficiency virus. IV. Protection against challenge with virus grown in autologous simian cells

Attenuated simian immunodeficiency virus (SIV) induces potent protection against infection with wild-type virus, but the mechanism of this immunity remains obscure. Allogeneic antibodies, which arise within animals as a result of SIV infection, might protect against challenge with exogenous SIV grown in allogeneic cells. To test this hypothesis, eight macaques were infected with attenuated SIV and subsequently challenged with wild-type SIV grown in autologous cells or heterologous cells. The results clearly demonstrated that animals infected with attenuated SIV are protected against wild-type SIV grown in autologous or heterologous cells. Thus, the hypothesis that live attenuated SIV protects by the induction of allogeneic antibodies is not tenable.     

Genetic basis of attenuation of the Sabin oral poliovirus vaccines

Four cases of synovial sarcoma with extensive calcification and osteoid and bone formation are reported. Ages ranged from 21 to 38 years. Two tumors were located in the foot and two in the thigh. Because of a well-circumscribed, densely calcified soft tissue mass, radiologically three patients were thought to have a benign lesion. The fourth patient was thought to have a paraosteal osteosarcoma because of an accompanying bone defect. Tumor size varied from 4.0 to 9.0 cm. Histologically, three tumors were biphasic and one predominantly monophasic. All showed amorphous calcifications with extensive ossification sometimes in a ribbon-like pattern of osteoid, simulating osteosarcoma. The extensive bone formation with abundant osteoid deposition may lead to a misdiagnosis of osteosarcoma. It is important to recognize this variant of synovial sarcoma with ossification and bone formation and distinguish it from extraskeletal osteosarcoma because of the difference in clinical behavior and course. Although the most important point in the recognition of this variant of synovial sarcoma is its biphasic pattern, this may not be apparent in a small tissue sample. Points that aid in the diagnosis include the uniform nuclear appearance of both the epithelial and the spindle cells versus the pleomorphism of osteosarcoma and in some cases the presence of amorphous concretions in sheets and small calcospherites within spaces surrounded by flat or conspicuous epithelial cells. These cells are immunoreactive for cytokeratin and epithelial membrane antigen.     

(R)-5-fluoro-5,6-dihydrouracil: kinetics of oxidation by dihydropyrimidine dehydrogenase and hydrolysis by dihydropyrimidine aminohydrolase

The biologically active isomer of 5-fluoro-5,6-dihydrouracil [(R)-5-fluoro-5,6-dihydrouracil, R-FUH2] was synthesized to study the kinetics of its enzymatic oxidation and hydrolysis by homogeneous dihydropyrimidine dehydrogenase (DPDase) and dihydropyrimidine aminohydrolase (DPHase), respectively. DPDase catalyzed the slow oxidation of R-FUH2 at pH 8 and 37 degrees with a Km of 210 microM and a kcat of 0.026 sec-1 at a saturating concentration of NADP+. The catalytic efficiency (kcat/Km) of DPDase for R-FUH2 was 1/14th of that for 5,6-dihydrouracil (UH2). In the opposite direction, DPDase catalyzed the reduction of 5-fluorouracil (FU) with a Km of 0.70 microM and a kcat of 3 sec-1 at a saturating concentration of NADPH. Thus, DPDase catalyzed the reduction of FU 30,000-fold more efficiently than the oxidation of R-FUH2. In contrast to the slow oxidation of R-FUH2 by DPDase, R-FUH2 was hydrolyzed very efficiently by DPHase with a Km of 130 microM and a kcat of 126 sec-1. The catalytic efficiency of DPHase for the hydrolysis of R-FUH2 was approximately twice that for the hydrolysis of UH2. Because R-FUH2 is hydrolysis of R-FUH2 was approximately twice that for the hydrolysis of UH2. Because R-FUH2 is hydrolyzed considerably more efficiently than it is oxidized and because the activity of DPHase was 250- to 500-fold greater than that of DPDase in bovine and rat liver, the hydrolytic pathway should predominate in vivo.     

Polyarteritis nodosa and the antiphospholipid syndrome

We describe a case of classical polyarteritis nodosa (PAN) with visceral aneurysms presenting with renal infarction and hypertension. The female patient also had all the laboratory features of the antiphospholipid syndrome (APS) and 2 months into her illness developed a large iliofemoral thrombosis. She responded well to immunosuppressive therapy and anti-coagulation. Repeat arteriogram showed regression of the visceral aneurysms. The link between PAN and APS, and the therapeutic dilemma posed by this association, are discussed.     

Sulfamethazine water medication pharmacokinetics and contamination in a commercial pig production unit

Sulfamethazine is often used to treat disease in the swine industry. Sulfamethazine is available as water or feed medication and historically (over the past 40 years) has been associated with residue violations in both the United States and Europe. Despite sulfamethazine's approval for use as a water medication, little research on the pharmacokinetics of the water formulation is available. Therefore, a pilot study was performed to determine the plasma levels of an approved sulfamethazine water medication. Plasma levels in pigs treated with an oral bolus (250 mg/kg), which is equivalent to the total drug consumed within a 24-h period, achieved therapeutic concentrations (50 microg/ml). Noncompartmental-based pharmacokinetic model parameters for clearance, half-life, and volume of distribution were consistent with previously published values in swine. However, the above treatment resulted in exposure of pen mates to sulfamethazine at levels currently above tolerance (0.1 ppm). Using a physiologically based pharmacokinetic model, the treatment dose simulation was compared with observed plasma levels of treated pigs. Flexibility of the physiologically based pharmacokinetic model also allowed simulation of control-pig plasma levels to estimate contamination exposure. A simulated exposure to 0.15 mg/kg twice within approximately 8 h resulted in detectable levels of sulfamethazine in the control pigs. After initial exposure, a much lower dose of 0.059 mg/kg maintained the contamination levels above tolerance for at least 3 days. These results are of concern for producers and veterinarians, because in commercial farms, the entire barn is often treated,and environmental contamination could result in residues of an unknown duration.