Biomedical subjects
Publications and source records attributed to J Hilliard.
Ellagic acid was found to inhibit E. coli DNA gyrase supercoiling with approximately the same potency as nalidixic acid. Tricyclic analogs of ellagic acid, which vary in the number and position of the hydroxy groups as well as their replacement with halogens, have been synthesized. The biological activity of these analogs is discussed.
Several viral and nonviral methods have introduced functional genes into the lungs. An alternative strategy, receptor-mediated gene transfer, exploits the ability of receptors on the surface of cells to bind and internalize DNA complexes and could potentially be used to deliver genes to specific cells in the lung. The gene encoding human alpha1-antitrypsin (A1AT) was delivered to macrophages in vitro and in vivo by targeting the mannose receptor with mannose-terminal molecular conjugates. The human A1AT transcript was detected 2 d after transfection of macrophages in culture, but transgene expression was transient. Human A1AT protein was secreted into the culture medium, and Western blot hybridization revealed the mature human antiprotease. In addition, Sprague-Dawley rats underwent intravenous injections of increasing doses of plasmid DNA (0.2 mg, 1.0 mg, and 2.0 mg) complexed to the molecular conjugate. Four days after transfection, human A1AT mRNA was found in lungs from six of the 13 rats (46%) that received the higher doses of plasmid. Transgene expression was limited to cells in perivascular and alveolar regions, which conformed to the distribution of pulmonary macrophages. Human A1AT was measured in the epithelial lining fluid of rats treated with transfection complexes. Animals that received 1.0 mg of plasmid had human A1AT levels of 7.4 +/- 3.4 pM, which was significantly different from nontransfected and mock-transfected controls. Thus the mannose receptor permitted direct delivery of genes to pulmonary macrophages, though transgene expression was detected in the lung only at low levels.
Herpes B virus (BV) is a common cause of recurring mucocutaneous infections in monkeys of the genus Macaca. Like its human counterpart, herpes simplex virus (HSV), BV establishes lifelong latency and can be reactivated from infected monkeys symptomatically or asymptomatically. Incidental infection of humans handling BV-shedding monkeys can result in fatal meningoencephalitis. To determine whether humans exposed to infected monkeys can acquire asymptomatic BV infections, 480 subjects were evaluated in a controlled seroprevalence study. Sera from 321 primate handlers, including many with repeated injuries inflicted by Macaca monkeys, and 159 people never exposed to monkeys were tested in blinded fashion by both competition ELISA and Western blot to determine the prevalence of BV and HSV seropositivity. Although 293 persons proved positive for HSV antibodies, no primate handlers or control subjects showed BV-specific antibody responses. There is no serologic evidence that BV causes asymptomatic infections in humans.
Increased use of monkeys in biomedical research has led to an intensified awareness of potential dangers posed by zoonotic infections. Zoonoses have an impact not only upon human health and safety but also upon continued availability of nonhuman primate resources for the biomedical community. Neurotropic herpesviruses indigenous to primates are significant owing to their potential for causing severe or fatal infections when transmitted between human and nonhuman primates or between different species of monkeys. Although the macaque herpesvirus (B virus) is known to many investigators, other simian herpesviruses have remained relatively obscure in spite of reports of disease-causing potential. In this review we summarize what is known about the natural history and pathogenic potential of simian alpha-herpesviruses. Recent research into the molecular biology of this group of viruses is also reviewed, and recent advances toward development of diagnostic tests based on these data are discussed.
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The in vitro activity of saperconazole against selected isolates of dermatophytes and its in vivo efficacy in a guinea pig dermatophytic infection model using Trichophyton mentagrophytes were evaluated. Susceptibility testing was determined with an agar dilution method in three media: yeast nitrogen base agar (YNBA), brain heart infusion agar (BHIA) and Sabouraud dextrose agar (SDA). An inoculum of 1 x 10(5) CFU of T. mentagrophytes spores was placed onto the surface of these agars. Incubation was at 32 degrees C for 72 h. The MIC of saperconazole against all isolates was less than 1 microgram/ml, whereas the MIC ranged from 0.1 to > 128 micrograms/ml for fluconazole. The MIC range of saperconazole against Trichophyton species was < or = 0.002 to 0.25 micrograms/ml; against Microsporum species it was < 0.001 to 0.1 microgram/ml; and against Epidemophyton species was < or = 0.002 to 0.25 micrograms/ml. These data showed that saperconazole was the most active compound tested against these selected dermatophytes. The activities of saperconazole against T. mentagrophytes, T. rubrum and M. canis were not affected by the medium. The MICs against these organisms were < or = 0.008 micrograms/ml in SDA, YNBA or BHIA. There were 2- to 4-fold decreases in activity for fluconazole at the same conditions. In vivo, topical treatment with saperconazole at concentrations of 0.125% and 0.25% resulted in 50% and 75% microbiological cure rates, respectively, in the guinea pig topically infected with T. mentagrophytes.
The effects of ofloxacin in Salmonella typhimurium infection in mice were compared with those of ciprofloxacin, ampicillin and chloramphenicol. Oral administration of ofloxacin at 10, 50 or 100 mg/kg once per day for seven days significantly (P less than 0.02) increased survival (20.1 days at 100 mg/kg) of infected mice relative to non-treated controls (4.1 days). In addition, after oral treatment with 100 mg/kg of each of the antibiotics, ofloxacin was significantly more effective than ampicillin (9.9 days), chloramphenicol (8.4 days) or ciprofloxacin (14.9 days) in prolonging the mean survival time of these mice. A comparison of oral potencies indicates that ofloxacin is five times more potent than ciprofloxacin (oral ED50 = 13.3 mg/kg vs ciprofloxacin = 69.9 mg/kg) and over eight times more potent than either of the other two antibiotics. When the number of bacteria from livers and spleens was quantitated, only ofloxacin (25 or 100 mg/kg,po) significantly (P less than 0.02) reduced the number of viable bacteria in both of these tissues in comparison with untreated controls, and, relative to the other antibiotics, ofloxacin (100 mg/kg) caused a significantly greater reduction. Single oral dosing of 20 mg/kg of either ofloxacin or ciprofloxacin showed that ofloxacin achieves approximately a four-fold higher peak serum or liver concentration than ciprofloxacin, which may contribute to its better efficacy in this infection model. These results taken together suggest that oral ofloxacin may be of value in treating systemic salmonella infections in humans.
B virus (Herpesvirus simiae) infections in macaque colonies are common. Herpetiform lesions as well as asymptomatic shedding of virus in bodily secretions from macaques pose a risk to animal handlers and laboratory workers. Fatal encephalitis in humans infected with B virus has occurred. Dermatologists may become involved in the initial evaluation of animal handlers exposed to this virus through bites or infectious secretions.
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Clinical isolates of herpes simplex virus (HSV) were identified as HSV type 1 or type 2 by sensitivity to (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), by differential replication in chick embryo cells versus guinea pig embryo cells, by restriction endonuclease analysis, and by a direct fluorescent antibody technique using monoclonal antibodies. More than 550 isolates were typed by two or three of the systems with complete agreements as to virus type between systems for each isolate. In appropriately equipped laboratories, any of the above typing systems can be used with complete confidence. However, the BVDU sensitivity assay, particularly when used in a continuous cell line as described, can be economically utilized in any virology laboratory.
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Hypoxia must be prevented in the newborn. It causes atelectasis, acidosis and pulmonary vasoconstriction, which leads to further hypoxia and, ultimately, brain damage. On the other hand, retrolental fibroplasia and bronchopulmonary dysplasia may result from too-vigorous use of oxygen therapy. Frequent blood gas measurements are required. Administered oxygen must be humidified and heated, and the oxygen concentration must be monitored with each delivery system. It is not enough to know the oxygen flow rate; an oxygen analyzer is essential.
The effect of synthetic luteinizing hormone-releasing hormone (LH-RH) on ovulation, implantation, and fetal survival rate was tested in pregnant rabbits. Single doses ranging from 2 to 900 mug, injected intravenously on the 3rd, 5th, or 6th postmating day, did not prevent implantation. Following the intravenous infusion of 20 to 200 mug of LH-RH on day 10 of pregnancy, the fetal survival rate was comparable to that of control rabbits laparotomized at the same stage of pregnancy. However, after repeated doses of 100 mug of LH-RH injected subcutaneously in a delaying vehicle either once or twice daily between the 8th and 13th days of gestation, multiple ovulations and severe luteolysis of original corpora lutea occurred, and fetal survival to term was highly variable. The results suggest that, depending on the dosage administered, LH-RH may either interrupt pregnancy by luteolysis or support fetal survival by stimulating luteotropic activity.
Levels of testosterone (T) and LH in the peripheral serum of male and female rabbits were measured and compared following coitus. Blood was collected by heart puncture from restrained, unanesthetized animals of both sexes. In male rabbits, basal serum T levels were highly variable, ranging from 131 to 12,149 pg/ml, and if low preceding coitus they tended to rise; whereas, if high, they usually dropped as they did in nonmated males subjected to repeated heart punctures. In contrast, basal serum LH levels in males were quite constant (mean +/- SE, 1993 +/- 152 pg/ml) and were not significantly altered after coitus unless blood T levels had been drastically lowered by two priming doses of estradiol benzoate. In intact does, on the other hand, copulation which resulted in ovulation induced an approximately 20-fold increase in serum LH concentration which was sustained for about 4 hr. Postcoital elevations in serum LH also occurred in estrogen-primed intact and estrogen-primed ovariectomized does. Under the conditions of our experiments, the parallel elevations in serum LH and T observed postcoitally in the female rabbit could not be demonstrated in the male.
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