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Biomedical subjects

J F Young

Publications and source records attributed to J F Young.

16 recordsLinked to original sources
PubMed1992

Induction of protective class I MHC-restricted CTL in mice by a recombinant influenza vaccine in aluminium hydroxide adjuvant.

Induction of class I MHC-restricted cytotoxic T lymphocyte (CTL) responses by soluble proteins or peptides requires complex adjuvants or carrier systems which are not licensed for use with human vaccines. The data presented in this report show that vaccination with a highly purified recombinant influenza protein antigen in aluminium hydroxide adjuvant, the only adjuvant currently licensed for clinical use, elicited class I restricted CTL and protection from lethal challenge with H1N1 and H2N2 viruses. The antigen (D protein, SK&F 106160) is produced by expression of H1N1 influenza virus-derived cDNA (strain A/PR/8/34) in Escherichia coli, and is composed of the first 81 N-terminal amino acids (aa) of the non-structural protein 1 (NS1) fused via a nine nucleotide non-viral linker sequence to the 157 C-terminal aa of the haemagglutinin 2 subunit (HA2). Previous work by Kuwano et al demonstrated that in vitro stimulation of spleen cells from influenza virus-primed mice, with a partially purified preparation of the D protein, selected for CD8+ CTL clones which facilitated lung clearance of H1N1 and H2N2 viruses. In the current study, these results were extended by studying the responses of mice actively immunized with highly purified D protein in the presence or absence of adjuvants. Vaccination of CB6F1 (H-2dxb) mice with D protein in aluminum hydroxide or Freund's complete adjuvant generated H1N1 cross-reactive, H-2d-restricted, CD8+ CTL directed against an immunodominant HA2 epitope (aa 189-199). D protein without adjuvant did not elicit CTL, regardless of the route of injection. However, long-lived (greater than 6 months) splenic memory CTL were elicited by boosting mice intraperitoneally (i.p.) with the D protein in the absence of adjuvant. In mice injected subcutaneously with D protein in aluminium hydroxide at weeks 0 and 3, survival was increased relative to controls up to 16 weeks beyond the second vaccination, after which time additional boosting was required for protection. Studies in H-2b and H-2k mice vaccinated with the D protein showed that induction of CD4+ T-cell or antibody responses, in the absence of CD8+ CTL, did not correlate with protection. Passive transfer of immune sera from CB6F1 mice was also not protective. This prototype H1N1 recombinant subunit vaccine in aluminium adjuvant should directly address the feasibility of achieving a protective cell-mediated immune response in human influenza.

Adjuvants, Immunologic↗
PubMed1992

Prenatal dexamethasone exposure in rats: effects of dose, age at exposure, and drug-induced hypophagia on malformations and fetal organ weights.

Glucocorticoids cause stunting and cleft palate in rodents. The aim of this study is to identify fetal organs and developmental periods sensitive to stunting induced by maternal exposure to dexamethasone (DEX). DEX (0.2 or 0.4 mg/kg) or saline was given sc to pregnant CD albino rats on Gestation Days (GD) 9-14 or 14-19. On GD 20 dams were euthanized. Fetuses were weighed and examined for cleft palate. Eight fetuses/litter were randomly selected, and weights were obtained. Fetal skeletons were examined for abnormalities, and long bone measurements were taken. A dose-related decrease in maternal and fetal body weights occurred at both exposure periods. Developmental stage-specific malformations were noted in the high-dose group on GD 9-14 (cleft palate) and on GD 14-19 (wavy ribs). A dose-response in stunting occurred in all organs except cerebellum in at least one exposure period. Across both exposure periods the brain, heart, testes, and long bones were relatively resistant to DEX. Sensitive organs included thymus, spleen, adrenals, lungs, liver, and kidneys. DEX substantially reduced maternal food intake and increased water intake in some dams. Pair-feeding experiments suggested that the hypophagic effect of DEX was not responsible for the noted malformations and had little impact on growth stunting. The present findings have identified fetal organs, skeletal regions, and developmental periods sensitive to DEX exposure.

Abnormalities, Drug-Induced↗
PubMed1992

Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites.

The wide variations in urinary bladder and colo-rectal cancer incidence in humans have been attributed in part to metabolic factors associated with exposure to carcinogenic aromatic and heterocyclic amines. Cytochrome P-4501A2 (CYP1A2), which catalyses N-oxidation, and acetyltransferase (NAT2) which catalyses N- and O-acetylation, both appear to be polymorphically distributed in human populations; and slow and rapid NAT2 phenotypes have been implicated as risk factors for these cancers. Caffeine has also been shown to undergo 3-demethylation by CYP1A2, and it is further acetylated to 5-acetylamino-6-formylamino-3-methyluracil (AFMU) by the polymorphic NAT2. In this report, we describe a metabolic phenotyping procedure that can be used to determine concomitantly the hepatic CYP1A2 and NAT2 phenotypes. For the NAT2 phenotype, we confirm the valid use of the urinary molar ratio of AFMU/1-methylxanthine, even in alkaline urines. For the CYP1A2 phenotype, the urinary molar ratio of [1,7-dimethylxanthine + 1,7-dimethyluric acid]/caffeine, taken at 4-5 h after caffeine ingestion, was identified from pharmacokinetic analyses of 12 subjects as being better correlated (r = 0.73; p = 0.007) with the rate constant for caffeine 3-demethylation than other previously suggested ratios. This procedure was then used to determine the CYP1A2 phenotype in subjects from Arkansas (n = 101), Italy (n = 95), and China (n = 78). Statistical and probit analyses of nonsmokers indicated that the CYP1A2 activity was not normally distributed and appeared trimodal. This trimodality allowed arbitrary designation of slow, intermediate, and rapid phenotypes, which ranged from 12-13% slow, 51-67% intermediate, and 20-37% rapid, in the different populations. A reproducibility study of 13 subjects over a 5 day or 5 week period showed that, with one exception, intraindividual variability did not alter this CYP1A2 phenotypic classification. Induction of CYP1A2 by cigarette smoking was also confirmed by the increased caffeine metabolite ratios observed in the Arkansas and Italian smokers (blonde tobacco). However, Italian smokers of black tobacco and Chinese smokers did not appear to be induced. Furthermore, probit analyses of Arkansas and Italian blonde tobacco smokers could not discriminate between phenotypes, apparently as a consequence of enzyme induction.

Adult↗
PubMed1992

Malignant phyllodes tumor of the prostate. A case report with immunohistochemical and ultrastructural studies.

Phyllodes tumor of the prostate is a rare neoplasm with cellular or sarcomatoid stroma and hyperplastic glands. This lesion shares many histologic features with cystosarcoma phyllodes of the breast. Although a malignant variant of phyllodes tumor of the prostate has been described, the majority of cases have been clinically benign. We report an unusual case of phyllodes tumor of the prostate in which the stromal component underwent malignant degeneration, a finding not previously described (to our knowledge). Immunohistochemical and ultrastructural studies demonstrated smooth-muscle differentiation of the stromal cells.

Aged↗
PubMed1979

Evolution of human influenza A viruses in nature: sequential mutations in the genomes of new H1N1.

The genetic variation of the new pandemic H1N1 influenza A viruses isolated in 1977 was analyzed by two-dimensional oligonucleotide fingerprinting and RNA sequencing. Differences were observed in the fingerprints of the RNAs of these viruses, and analysis of the changes suggested that sequential mutations occurred in their genomes. Based on these data, a scheme is presented which proposes divergent evolution of strains from a common ancestry. Furthermore, it was found that mutations were not restricted to the genes coding for the hemagglutinin and the neuraminidase, but were scattered throughout the genome, suggesting that selective antibody pressure is not solely responsible for the emergence of genetic variants. Our data also strengthen the hypothesis that the new H1N1 influenza virus strains are derived from strains circulating in 1950.

Antigens, Viral↗
PubMed1979

Evolution of human influenza A viruses in nature: recombination contributes to genetic variation of H1N1 strains.

In June of 1977, a new influenza A pandemic was started by strains of the H1N1 serotype. Oligonucleotide fingerprint analysis of the RNA from viruses isolated during the early stage of this pandemic demonstrated that genetic variation among these 1977 strains could be attributed to sequential mutation [Young, J.F., Desselberger, U. & Palese, P. (1979) Cell, 18, 73-83]. Examination of more recent strains revealed that the H1N1 variants that were isolated in the winter of 1978-1979 differed considerably from the H1N1 viruses isolated the previous year. Oligonucleotide and peptide map analysis of the new prototype strain (A/Cal/10/78) suggested that it arose by recombination. It appears that only the HA, NA, M, and NS genes of this virus are derived from the earlier H1N1 viruses and that the P1, P2, P3, and NP genes most likely originate from an H3N2 parent. These data suggest that genetic variation in influenza virus strains of the same serotype is not restricted to mutation alone, but can also involve recombination (reassortment).

Antigens, Viral↗
PubMed1978

Osteomalacia and celiac disease: response to 25-hydroxyvitamin D.

In this 54 year old woman with celiac disease, osteomalacia developed while she was on a gluten-free diet which had caused regression of her steatorrhea. She was not responsive to large doses of parenterally administered dihydrotachysterol and calcium, but she was responsive to the oral administration of 25-hydroxyvitamin D3 (25-OHD3). The data suggest that 25-OHD3 is the treatment of choice for patients with vitamin D deficiency due to intestinal malabsorption.

Administration, Oral↗
PubMed1978

A pharmacokinetic study of pentachlorophenol poisoning and the effect of forced diuresis.

A pharmacokinetic study of an intentional pentachlorophenol ingestion by an elderly human has been undertaken. Information on the presence or absence of forced diuresis either continuously or for a short restricted period indicates that such treatment would materially reduce the body burden of pentachlorophenol. It is suggested that forced diuresis is the treatment of preference for such intoxication at this time.

Chlorophenols↗
PubMed1978

Comparative stability of physiological parameters during sustained anesthesia in rats.

Rats were anesthetized with pentobarbital, pentobarbital and atropine, inactin [5-ethyl-5-(1'-methyl-propyl)-2-thiobarbiturate], ether and inactin, or urethane. Cardiovascular and arterial acid-base parameters were monitored over a 3-hour period of anesthesia. Heart rate, arterial pressures, and pH progressively decreased with duration of pentobarbital anesthesia. Changes observed in rats anesthetized with the thiobarbiturate, inactin, were similar although generally less severe. Most subjects treated with the barbiturates were markedly hypercapnic. Urethane anesthesia was characterized by a higher and more stable heart rate and greater pulse pressure. Arterial carbon dioxide and bicarbonate levels in the urethane group were substantially lower at all sampling times than the values obtained in the barbiturate groups.

Acid-Base Equilibrium↗
PubMed1976

Trace analysis of 2,4,5-trichlorophenoxyacetic acid, its glycineamide, and their alkaline hydrolyzable conjugates in mouse blood, urine, and feces.

Chemical methods were developed for the trace analysis of the herbicide 2,4,5-trichlorophenoxyacetic acid, its glycineamide, and their alkaline hydrolyzable conjugates in mouse blood, urine, and feces. The salient elements of the methods are extraction of the free acids with benzene, methylation, cleanup on a silica gel column, and quantification via electron-capture GLC. Any unextracted conjugates remaining in the substrates are then subjected to alklaline hydrolysis, and the liberated 2,4,5-trichlorophenoxyacetic acid is assayed. Data are presented concerning recoveries of the compounds from the three spiked substrates. The utility of the procedures is illustrated by a preliminary pharmacolinetic study employing parallel electron-capture GLC and radioassays of the three substrates from mice injected with a single intravenous dose of 14C-2,4,5-trichlorophenoxyacetic acid. GLC characteristics and partition values of the the compounds and hydrolysis of the glycineamide under various conditions also are discussed.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMedDate not supplied

Utility of pharmacokinetics in designing toxicological protocols and improving interspecies extrapolation.

Key terms such as pharmacokinetics, pharmacodynamics, time course-concentration, and dosimetry and how they apply to predictive toxicology are defined and differentiated. The importance of utilizing pharmacokinetic techniques in teratology and developmental toxicology are discussed from the viewpoints that (1) agent's access to target tissue is modulated by the placenta, (2) interspecies sensitivities differ, (3) dose-response curves are steep, and (4) dosimetry information improves the validity of regulatory standards. We review the teratology literature where attempts were made to correlate embryonal/fetal exposure to teratogenic endpoints. The strengths and weaknesses of these papers are discussed as well as our suggested changes in their protocols, which would have improved interspecies extrapolation.

Age Factors↗