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Objective: The purpose of the present investigation was to analyze the effets of zidovudine on the postimplantation embryo and fetus.Methods: Pregnant Sprague-Dawley rats were given various doses (10 mg/kg, 30 mg/kg, 150 mg/kg) of zidovudine or saline by an endotracheal tube during the period of embryogenesis (days 6–8, 9–11, 6–11 postconception). The animals were sacrificed on days 18–19 of pregnancy, and their fetuses were removed by hysterotomy. Autopsies under low (15×) and high (40×) power light microscopy were performed on all fetuses.Results: There was no statistically significant difference among the groups with respect to maternal weight gain. There were more pregnancy resorptions in the group receiving high-dose zidovudine (150 mg/kg/day) throughout embryogenesis than in the control group (P = 0.001, respectively). Four major structural anomalies were noted among the 689 fetuses examined, but zidovudine was not associated with an increased frequency of congenital anomalies in rats when it was administered in doses similar to, 3-, and 15-fold higher than the regimen recommended for adult humans. The drug, however, was embryocidal in the high-dose group (P = 0.002).Conclusions: These findings are consistent with previous studies of preimplantation mouse embryos that demonstrated an embryocidal effect on preimplantation conceptuses. In summary, post-implantation embryonic zidovudine exposure was associated with significantly increased pregnancy losses (resorptions and intrauterine deaths).

Objective:The transfer of abacavir, a new nucleoside inhibitor, and amprenavir, a new protease inhibitor, used for the treatment of human immunodeficiency virus, has been studied in theex vivohuman placental model.Methods:Theex vivohuman placental model used C14antipyrine to determine the transport fraction and clearance index of these compounds at both the peak and trough serum concentrations. The clearance index accumulation and tissue concentrations were determined for each drug by high pressure liquid chromatography.Results:The clearance index of abacavir was 0.47 ± 0.19 and 0.50 ± 0.07 at peak and trough concentrations, respectively. The clearance index of amprenavir was 0.38 ± 0.09 and 0.14 ± 0.08 at peak and trough concentrations, respectively. There was no unusual accumulation of either drug in the media or tissue when the perfusion system was closed.Conclusion:Abacavir is the first nueleoside compound studied in the perfusion system with a high clearance index. The transfer of the protease inhibitor amprenavir had a clearance index 2.75 times greater than the clearance index of ritonavir at peak concentration determined in a previous study. At trough concentration the clearance index was much less than at the peak concentration. A similar result was found with ritonavir.

The MHC class I-related receptor, neonatal Fc receptor (FcRn), plays a central role in regulating the transport andin vivopersistence of immunoglobulin G (IgG). IgG–FcRn interactions can be targeted for engineering to modulate thein vivolongevity and transport of an antibody, and this has implications for the successful application of therapeutic IgGs. Although mice are widely used to preclinically test antibodies, human and mouse FcRn have significant differences in binding specificity. Here we show that an engineered human IgG1 has disparate properties in murine and human systems. The mutant shows improved transport relative to wild-type human IgG1 in assays of human FcRn function but has shortin vivopersistence and competitively inhibits FcRn activity in mice. These studies indicate potential limitations of using mice as preclinical models for the analysis of engineered antibodies. Alternative assays are proposed that serve as indicators of the properties of IgGs in humans.

Background. The incidence of unilateral twin ectopic pregnancy is a rare condition. Several factors increase the risk of ectopic pregnancy, the most important of which is pelvic inflammatory disease, followed by operative trauma, congenital anomalies, tumors, and adhesions resulting in anatomically distorted fallopian tubes. We present a case of a woman with a history of four confirmed sexually transmitted infections (STIs) including Chlamydia trachomatis, Neisseria gonorrhoeae, herpes simplex virus 2, and Treponema pallidum. The case illustrates the potential impact of sexually transmitted infections (STIs) on the risk of a twin ectopic pregnancy. Case. A 24-year-old primigravida, presented with an unknown last menstrual period, lower abdominal pain, watery vaginal discharge, and vaginal spotting. During this hospitalization, serumβ-HCG testing was 263 mIU/mL and transvaginal ultrasonographic examination suggested a nonviable unilateral twin ectopic pregnancy. At exploratory laparotomy, a 10 cm mass involving the right fallopian tube and ovary was excised. Pathological evaluation of the specimen identified a monochorionic, diamnionic twin ectopic pregnancy within the fallopian tube. Conclusions Patients with a history of multiple (STIs) are known to be at risk for the development of chronic pelvic infection and postinflammatory scarring. The resulting distortion of the normal tubal anatomy leads to an increased risk of an uncommon presentation of ectopic pregnancy.

We compared serum levels and tolerability of oral amoxicillin in 30 healthy adults who each received 2.0 g of amoxicillin and, 1 week later, 3.0 g of the same preparation. Serum levels of amoxicillin were determined at 1, 2, 4, and 6 hours following its ingestion. Mean serum levels of amoxicillin were significantly higher after 3.0-g doses than after 2.0-g doses. Levels in females were higher than in males; this was a reflection of differences in body weights. Food intake had no effect on serum levels. The 2.0-g doses resulted in adequate serum levels; 6 hours after dosing levels were still substantially higher than the MICs for oral streptococci. Three individuals (10%) experienced mild gastrointestinal side effects after they received the 3.0-g doses; no side effects were noted after the 2.0-g doses. We propose that to prevent bacterial endocarditis in adults who are at risk, a single 2.0-g dose of oral amoxicillin may be adequate prophylaxis for dental, oral, or upper respiratory tract procedures.

A simple, reproducible technique with potential taxonomic application was developed for the rapid detection of rhodanese activity in gram-negative and gram-positive bacteria. The method requires suspension of the growth from three colonies in a solution of lysozyme and ethylenediaminetetraacetic acid for 60 min. After cell lysis, the presence of rhodanese activity is determined colorimetrically by measuring the amount of thiocyanate formed from thiosulfate and potassium cyanide by use of ferric nitrate. By this technique, a survey of 411 bacterial strains revealed the presence of rhodanese in all test strains of Escherichia coli, Pseudomonas aeruginosa, Acinetobacter, Bordetella, Shigella, and Citrobacter. No activity was detected in Salmonella, Klebsiella, Enterobacter, Serratia, or Proteus species. Randomly selected strains which did not exhibit rhodanese activity were confirmed to be rhodanese-negative by assay of mechanically disrupted cells harvested from 500 ml of growth medium.

Cefoperazone and cefoxitin concentrations were determined in serum and pelvic tissue samples obtained at various intervals after a 2-g intramuscular dose. These levels were determined in 59 women scheduled for elective abdominal hysterectomy. Concentrations were measured by a new high-pressure liquid chromatography method which correlated with the microbiological assay. The mean times (+/- standard deviation) of specimen collection were 188.5 +/- 61 and 185.5 +/- 55 min for cefoperazone and cefoxitin, respectively. The mean serum levels (+/- standard deviation) were 60.8 +/- 18.0 and 14.6 +/- 8.6 micrograms/ml, respectively. For cefoperazone, the mean pelvic tissue concentration was 19.8 micrograms/g. The mean pelvic tissue concentration for cefoxitin was 7.8 micrograms/g. The ratio of tissue concentration to serum concentration varied from 0.220 to 0.469 for cefoperazone and from 0.176 to 1.031 for cefoxitin. Although the serum and tissue concentrations of cefoperazone were much higher than those of cefoxitin, a greater portion of cefoxitin remained in the tissue. The tissue levels of both cefoperazone and cefoxitin were above the minimum inhibitory concentration of most sensitive pathogens several hours after a single prophylactic dose of either antibiotic.

We studied the pharmacokinetics of intramuscular ceforanide in 46 infants, children, and adolescents, ranging in age from 1 month to 17 years. After the subjects were given 20-mg doses of ceforanide per kg, the mean peak plasma concentration was 56.3 microgram/ml (range, 27.0 to 95.0), the mean 8-h level was 5.9 microgram/ml (range, 1.5 to 13.5), and the mean 12-h level was 1.5 microgram/ml (range, 0.2 to 4.2). Ceforanide half-life varied with the ages of the patients: in 1- to 2-year-old children, in half-life was significantly shorter (1.5 h) than in younger or older children. Plasma concentrations at 8 and 12 h after a dose were lowest in 1- to 2-year-old children. There was no relationship between the area under the curve, the volume of distribution, or the body clearance of ceforanide to the ages of the patients. Within 6 h of administration of the drug, a mean of 77.5% of a dose was excreted in urine, and at the end of 12 h, virtually all (93.9%) of the administered dose was recovered in urine samples. The administration of ceforanide every 12 h did not result in drug accumulation. A dose of 20 mg of ceforanide per kg every 12 h is recommended for most pediatric patients. Dosage recommendations for 1- to 2 year-old children are presented.

Three laboratories participated in studies of a hemagglutination treponemal test for syphilis (HATTS), using as antigen sonicated Treponema pallidum coupled to glutaraldehydestabilized turkey erythrocytes by the bis-diazotized benzidine procedure. A total of 1,056 cases of syphilis (373 untreated and 683 treated) was studied, with 93.7% overall agreement between the HATTS and the fluorescent treponemal antibody-absorbed (FTA-ABS) test. In addition, 1,805 nonsyphilitic sera, including 1,048 from presumably healthy subjects, 502 sera that were biologic false-positives, and 255 sera from patients with diseases other than syphilis, were studied. The HATTS was nonreactive for 99.4% of sera from presumably healthy subjects, 86.9% of biologic false-positive sera, and 84.7% of sera from patients with diseases other than syphilis, compared with FTA-ABS nonreactivity for 99.2% of presumably normal sera, 76.9% of false-positive sera, and 77.3% of sera from patients with other diseases. One laboratory also compared the HATTS with the microhemagglutination-Tre-ponema pallidum (MHA-TP) test. There was no statistically significant (P ≤ 0.01) difference in reactivities among the HATTS, MHA-TP, and FTA-ABS procedures for either 617 syphilitic or 966 nonsyphilitic sera. Studies of reproducibility showed no significant difference in performances of the HATTS by three laboratories, and the HATTS was significantly more reproducible than the MHA-TP test. It is concluded that the HATTS would be a suitable substitute for the MHA-TP or FTA-ABS test as a confirmatory test for the diagnosis of syphilis.

The base composition in moles percent guanine plus cytosine (%GC) of both nuclear and mitochondrial deoxyribonucleic acid (DNA) isolated from the yeastlike and mycelial phases of the dimorphic fungal pathogens Histoplasma capsulatum and Blastomyces dermatitidis was determined by techniques of thermal denaturation and CsCl buoyant density gradient equilibrium centrifugation. The mean observed values for GC content of nuclear DNA from H. capsulatum and B. dermatitidis were 47.3 and 48.2%, respectively. What is speculated to be mitochondrial DNA was found to be 34.0% for H. capsulatum and 34.3% for B. dermatitidis . Thermal denaturation curves for Blastomyces DNA indicated a bimodality in thermal denaturation profiles, thereby suggesting a significant mitochondrial DNA contamination. Mitochondrial DNA appeared to represent a smaller percentage of the total DNA prepared from Histoplasma , and was not observed consistently to affect%GC values as determined by thermal denaturation profiles. On the basis of the now known perfect stage of B. dermatitidis ( Ajellomyces dermatitidis ) as a member of the family Gymnoascaceae , the close approximation of%GC content of nuclear DNA of this fungal organism with that of H. capsulatum suggests possible phylogenetic relationship. It is suggested that the just reported, but as yet unclassified, perfect stage of H. capsulatum may be found to be phylogenetically a primitive form of the Gymnoascaceae .

The transfer of maternal gamma-globulin (IgG) provides the neonate with humoral immunity during early life. In humans, maternal IgG is transported across the placenta during the third trimester of pregnancy. The expression of the MHC class I-related receptor, FcRn, in the human placenta suggests that this Fc receptor might be involved in the delivery of maternal IgG, but direct evidence to support this is lacking. In the current study an ex vivo placental model has been used to analyze the maternofetal transfer of a recombinant, humanized (IgG1) antibody in which His435 has been mutated to alanine (H435A). In vitro binding studies using surface plasmon resonance indicate that the mutation ablates binding of the antibody to recombinant mouse and human FcRn. Relative to the wild-type antibody, the H435A mutant is deficient in transfer across the placenta. Significantly, the mutation does not affect binding to Fc gamma RIII, an FcR that has been suggested in earlier studies to mediate the transfer of maternal IgG. The analyses demonstrate that binding of an IgG to FcRn is a prerequisite for transport across the perfused placenta. FcRn therefore plays a central role in the maternofetal delivery of IgG and this has implications for the use of protein engineering to improve the properties of therapeutic antibodies.