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Biomedical subjects

A M Clark

Publications and source records attributed to A M Clark.

At least 19 recordsLinked to original sources
PubMed1992

Copyrine alkaloids: synthesis, spectroscopic characterization, and antimycotic/antimycobacterial activity of A- and B-ring-functionalized sampangines.

Several A- and B-ring-substituted sampangines were synthesized and evaluated for antifungal and antimycobacterial activity against AIDS-related opportunistic infection pathogens. Electrophilic halogenation provided a channel for structural elaboration of the sampangine B-ring at position 4, while the synthesis of A-ring 3-substituted sampangines and benzo[4,5]sampangine (24) were achieved from the corresponding functionalized cleistopholines. Two-dimensional NMR spectroscopy was used to rigorously characterize the A- and B-ring substituent patterns. Structure-activity relationship studies revealed the activity of the sampangines was enhanced by the presence of a substituent at position 3 or by a 4,5-benzo group.

AIDS-Related Opportunistic Infections↗
PubMed1992

Epidermis-specific gene expression in Pachyphytum.

Transcripts of exclusively epidermis-specific expression were obtained by differential screening of a cDNA library prepared from isolated epidermis tissue of a succulent plant, Pachyphytum. Six transcripts were selected and characterized by RNA gel blot hybridization. Five cDNAs represented abundant mRNAs found exclusively in the epidermis. In situ hybridizations with three of these transcripts further substantiated their epidermal location. While two transcripts were present in all cells of the epidermis, one transcript was enriched in subsidiary cells of the stomatal complexes. All of the transcripts were highly expressed in the protoderm of the shoot apical meristem. DNA sequence determination indicated that the mRNAs identified represent novel sequences, encoding yet unknown plant functions. These transcripts, their control elements, and their encoded functions should help to advance our understanding of epidermal cell determination and differentiation.

Amino Acid Sequence↗
PubMed1992

The metabolism of muzigadial by microorganisms.

1. A total of 114 microorganisms were evaluated for their ability to metabolize the antifungal drimane sesquiterpene, muzigadial. 2. Cryptococcus neoformans was found to convert muzigadial to one major metabolite, identified as a hemiacetal. 3. Streptomyces platensis produced three metabolites: the hemiacetal, its corresponding lactone, and the epoxide of the hemiacetal. 4. Streptomyces spectabilis produced the hemiacetal as well as the epoxy hemiacetal. 5. The proposed structures of all of the metabolites were based on comparisons of the spectroscopic data (1H- and 13C-n.m.r. spectra and mass spectra) between the metabolites and the parent compound. 6. Antimicrobial evaluation of the microbial metabolites indicate that metabolism decreases antifungal activity.

Antifungal Agents↗
PubMed1991

Comparative acute nephrotoxicity of salicylic acid, 2,3-dihydroxybenzoic acid, and 2,5-dihydroxybenzoic acid in young and middle aged Fischer 344 rats.

Experimental evidence suggests that the oxidative metabolites 2,3- and 2,5-dihydroxybenzoic acid (DIOH) may be responsible for the nephrotoxicity of salicylic acid (SAL). In the present study, enzymuria in conjunction with glucose (GLU) and protein (PRO) excretion were used as endpoints to compare the relative nephrotoxicity of SAL with 2,3- and 2,5-DIOH. In addition, the effect of age on enzymuria and GLU and PRO excretion following treatment with SAL or 2,3- and 2,5-DIOH was investigated because the elderly are at greater risk for SAL-induced nephrotoxicity. Three and 12-month male Fischer 344 rats were administered either no treatment, vehicle, SAL, 2,3-DIOH, or 2,5-DIOH at 500 mg/kg p.o. in 5 ml/kg corn oil/DMSO (5:1). Effects of these treatments on functional integrity of renal tissue was assessed from 0--72 h after dosing by measurement of urinary creatinine, GLU, and PRO, as well as excretion of proximal and distal tubular renal enzymes. Enzymes measured as indicators of proximal tubular damage were N-acetyl-beta-glucosaminidase (NAG), gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), and alkaline phosphatase (AP), while urinary lactate dehydrogenase (LD) and aspartate aminotransferase (AST) were measured as indicators of distal tubular damage. In comparison to 3-month vehicle-treated rats, 2,3- and 2,5-DIOH caused a significant increase between 0-8 h in excretion of urinary GLU and activities of AST, NAG, and LD, with peak effects occurring between 4-8 h. Toxic effects of either metabolite were not evident beyond 24 h, and toxicity of 2,5-DIOH was significantly greater in comparison to 2,3-DIOH. SAL treatment resulted in similar effects on enzymuria as well as GLU and PRO excretion, but peak effects did not occur until 16-24 h, and often persisted until 72 h after dosing. Maximal enzymuria in response to SAL treatment was significantly greater in 12- vs. 3-month rats for AST, NAG, and LD. In response to 2,3-DIOH treatment, the maximal response was significantly greater in 12- vs. 3-month rats for LD and AST, and for NAG in response to 2,5-DIOH treatment. The results of this study suggest that both 2,3- and 2,5-DIOH are nephrotoxic metabolites of SAL, but implicate 2,5-DIOH as the more potent nephrotoxic metabolite. The relative lack of an age effect for 2,3- and 2,5-DIOH vs. SAL supports the hypothesis [2] that age-related differences in biotransformation of SAL, and not increased tissue sensitivity to 2,3- or 2,5-DIOH, contribute to the age-related increase in susceptibility to SAL-induced nephrotoxicity.

Acetylglucosaminidase↗
PubMed1991

Use of microorganisms for the study of drug metabolism: an update.

The use of microorganisms as tools in the study of drug metabolism appears to be gaining popularity. The selected examples cited here provide additional evidence of the utility of these systems as alternative in vitro models for studying drug metabolism in humans. However, as was noted earlier, this model, nor any other in vitro model system could ever replace animals in biomedical research. However, it is apparent from the numerous examples cited here and in the previous review of this area that microorganisms are a reliable, reproducible alternative to small animals as predictive models in drug metabolism studies. The continuing development of techniques that reduce the use of animals in research is encouraged and this procedure appears to be gaining more widespread acceptance for such use.

Animals↗
PubMed1991

Synthesis and the biological evaluation of the structural units of drummondin C.

Drummondin C (1) is an antibiotic isolated from a bioassay-directed fractionation of Hypericum drummondii (Grev. & Hook.)T.&G. It showed significant activity against the Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis and the acid-fast bacterium Mycobacterium smegmatis. Two structural units of drummondin C, the 8-acetyl-5,7-dihydroxy-2,2-dimethylchromene (6) and 5-acetyl-3-methyl-filicinic acid (9), were synthesized to determine the relative importance of the two substructure portions to the antibiotic activity of the compound. The low antimicrobial activity of 6 and 9 demonstrates the necessity of both units for the antibiotic activity of drummondin C.

Anti-Bacterial Agents↗
PubMed1991

Nonoxynol-9: differential antibacterial activity and enhancement of bacterial adherence to vaginal epithelial cells.

The antibacterial activity and adherence-enhancing effects of nonoxynol-9 were evaluated against vaginal and uropathogenic bacteria. Nonoxynol-9 was markedly less active against the 43 uropathogenic bacterial and yeast strains tested (MIC90, greater than 32%) than against the 26 Gardnerella vaginalis strains (MIC90, less than or equal to 0.015%) and the 53 Lactobacillus strains (MIC90, 8%) tested. Hydrogen peroxide-producing strains of Lactobacillus were more susceptible to nonoxynol-9 (MIC90, 4%) than nonproducers (MIC90, 16%). Two Escherichia coli strains that expressed type 1 fimbriae and three vaginal strains of lactobacilli adhered in significantly higher numbers to vaginal epithelial cells preincubated with 5% nonoxynol-9 than to control cells preincubated with PBS. Spermicides may provide a selective advantage in colonizing the vagina with nonoxynol-9-resistant uropathogens such as E. coli, perhaps via a reduction in vaginal lactobacilli (especially hydrogen peroxide-producing strains) and through enhancement of adherence of E. coli to epithelial cells.

Bacteria↗
PubMed1991

Attitudes of donors and recipients to gamete donation.

An anonymous questionnaire was circulated at two gamete donation clinics to survey the attitudes of donor insemination patients (n = 71; 89% response rate), sperm donors (n = 52; 85% response rate) and ovum donors (n = 5; 63% response rate) to the release of medical records with non-identifying information, or with identifying information of the donor involved. The majority of established sperm donors agreed to the release of medical records with or without identifying information. In the subset of potential sperm donors 85% would not enter a sperm donation programme unless anonymity was maintained, but 60% would agree to the release of non-identifying medical records. Sixty per cent of recipients of donated spermatozoa would agree to the release of medical records with identifying information of the donor, but 85% stated that they would not tell their children of their genetic origin. There is a significant difference between the attitudes of potential sperm donor recruits to these questions and those of established donors and recipients of donated spermatozoa. In conclusion, the results of this survey show that although established sperm donors would continue to donate spermatozoa if their status of anonymity was withdrawn, recruitment of new donors would be significantly reduced. This would be to the detriment of gamete donation programmes and to the subfertile couples who request this form of treatment.

Attitude↗
PubMed1991

Use of a urine enzyme immunoassay as a diagnostic tool for Chlamydia trachomatis urethritis in men.

We collected first-voided urine specimens from 659 males attending a sexually transmitted disease clinic and performed both enzyme immunoassay (EIA) for detection of chlamydial antigen and leukocyte esterase testing on these urine samples. The overall prevalence of chlamydial urethritis in the study population as determined by culture of urethral swabs was 11%. However, 46% of all men in the study had no symptoms of urethritis. Compared with urethral cultures for chlamydiae, the urine EIA had a sensitivity of 42% and a specificity of 99%. The sensitivity of the EIA strongly correlated with the amount of antigen present in culture as assessed by numbers of inclusion-forming units. The sensitivity of the leukocyte esterase test compared with that of chlamydia culture was 88%. We conclude that in this population of men, which included many patients without symptoms of urethritis, the urine EIA was a relatively insensitive means of screening for chlamydial infection.

Adolescent↗
PubMed1991

Effects of exogenous porcine growth hormone (pGH) on growth, carcass traits, reproductive characteristics, and meat sensory attributes of young boars.

Two studies were conducted to examine the possible reduction in odors in fat and loin samples from boars treated with porcine growth hormone (pGH). In Exp. 1, boars were treated with either 0 (control: C), 3.5, or 7 mg of pGH daily from 72 to 119 kg BW. Treatment with pGH improved feed efficiency (P less than .05) but did not affect ADG, concentrations of testosterone in plasma, or aroma of cooked meat (all P greater than .05). Boars treated with pGH had less average backfat depth and marbling (both P less than .05) than C boars. Tenderness of the meat was reduced (P less than .05) by pGH treatment compared with control boars and contemporary barrows. Fat odors of pGH-treated boars were intermediate to those of barrows and control boars. In Exp. 2, boars were treated with vehicle (C) beginning at 62 kg BW or with 5 mg of pGH from either 65 kg (L) or 77 kg (H) BW to 118 kg BW. Average daily gain was higher in Group H than in Group C; Group L was intermediate. Average fat depth was lower (P = .0005) in Groups H and L than in Group C. Treatment had no effect on loin eye area, muscle marbling, texture, firmness, or pH, but color scores of Groups L and H tended to be different from each other (P = .06), and Group H muscle had more free water than that of Groups C and L (P less than .05). Weights of reproductive organs were unaffected by treatment (both experiments: P greater than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1991

Effect of constant versus adjusted dose of exogenous porcine growth hormone (pGH) on growth and reproductive characteristics of gilts.

Growth, carcass traits, and selected reproductive characteristics were evaluated in prepubertal gilts treated with either a constant mass of pGH or a mass of pGH adjusted periodically for changes in BW. Gilts (64 kg, n = 24) were given 24 daily injections of either vehicle (C; control) or one of two doses of pGH: 70 micrograms/kg of BW, with dose adjusted every 5th d for changes in BW (A; adjusted), or 70 micrograms/kg of initial BW (U; unadjusted). Gilts were slaughtered on d 25. Gilts treated with pGH had higher ADG (P less than .002) and improved feed efficiency (kg of feed/kg of gain; P = .0003) compared with controls. Weights of adrenal glands, liver, heart, and kidney were higher (all P less than .01) for Groups A and U than for Group C gilts. Average backfat thickness was less (P less than .004) for A and U gilts than for C gilts and less for Group A than for Group U (P less than .02). Furthermore, growth and carcass traits were similar (P greater than .05) for Groups A and U, except for measurements of first rib backfat, last rib backfat, and average backfat depth (P less than .05). Culture of granulosa cells (GC) was employed to assess ovarian function. Addition of FSH to the culture media enhanced secretion of progesterone (P4) by cultured GC from all in vivo treatments compared with unsupplemented cultures of GC (P less than .05). Addition of LH to the culture media enhanced secretion of P4 by cultured GC from pGH-treated gilts only (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1991

Regulatory domains within the P0 promoter of human c-myc.

Expression of P0 RNA in some Burkitt lymphoma cell lines varies independently of levels of RNA derived from P1 and P2. These data suggest the possibility that expression of P0 RNA may be capable of independent regulation. In order to investigate this possibility we have isolated putative regulatory domains flanking P0 RNA starts within the human c-myc gene and analysed both their ability to direct expression of control reporter genes and their ability to interact with specific transcription factors. Regulatory regions necessary for expression of P0 RNA have been located within 131 bp 5' of the first major P0 RNA start. DNAase 1 footprint analysis and gel retardation assays demonstrate binding of transcription factors Sp1, NF1 and CBP to this region. NF1 binds specifically to two consensus sequences. The more distal site overlaps with the binding site for CBP, and it is likely that concomitant binding of NF1 and CBP within the distal region of the P0 promoter is not possible. Previous work from our laboratory has described a negative regulatory domain within the 5' flanking region of c-myc. The P0 promoter resides within this domain and therefore may contain a negative regulator of c-myc gene expression.

Animals↗
PubMed1990

Carcinogenicity results for 114 laboratory animal studies used to assess the predictivity of four in vitro genetic toxicity assays for rodent carcinogenicity.

Carcinogenicity results are presented for 114 long-term rodent studies carried out by the National Toxicology Program. Tumor rates are given for each positive or equivocal effect observed in 67 studies judged to show carcinogenic effects and in the 17 studies that show equivocal effects. The liver was found to be the most common site of carcinogenicity for both mice and rats; other frequent target sites included the lung, kidney, hematopoietic system, forestomach, thyroid gland, and mammary gland. The evaluative approach used in reaching decisions regarding the carcinogenicity of chemicals is discussed. No rigid statistical decision rules were employed, and biological as well as statistical factors were considered in the overall evaluation of the data. These long-term studies were utilized in a comprehensive evaluation of the ability of four in vitro genetic toxicity tests to predict rodent carcinogenicity. Details concerning these procedures and the results of this investigation are given elsewhere [Zeiger E, Haseman JK, Shelby MD, Margolin BH, Tennant RW 1990: Environ Mol Mutagen 16 (Supp. 18):1-14]. Interestingly, those chemicals evaluated at relatively low doses in the rodent experiments (because of the underlying toxicity of the chemicals) were far more likely to be positive in each of the four genetic toxicity assays than were "less toxic" chemicals evaluated in higher doses in the rodent studies.

Animals↗
PubMed1990

Differential toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in C57BL/6J mice congenic at the Ah Locus.

The acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was examined in male C57BL/6J mice differing only at the Ah locus. Wild type mice (Ahb/b, "b/b") were treated once with 0, 50, 100, 200, 300, and 400 micrograms TCDD/kg po while congenic mice (Ahd/d, "d/d") received a single dose of 0, 400, 800, 1600, 2400, and 3200 micrograms TCDD/kg. Mice were checked daily, weighed twice a week, and those that survived, killed 35 days post-treatment. The LD50 values were 159 and 3351 micrograms/kg for b/b and d/d mice, respectively. Mean time to death was 22 days and was independent of dose and genotype. Decrease in body weight gain was noted in both strains 5 days after treatment and occurred at doses greater than or equal to 100 micrograms/kg in b/b mice and 1600 micrograms/kg in d/d mice. Dose-related increases in liver weight (both absolute and relative to body weight) and decreases in thymus, spleen, testes, and epididymal fat pad weights were observed at 8-24-fold higher doses in d/d than in b/b mice. A dose-related increase in segmented neutrophils was observed in both strains. Serum chemistry values indicated that 8-24X greater doses of TCDD were needed to elevate sorbitol dehydrogenase, alanine aminotransferase, and 5'-nucleotidase and to decrease total and esterified cholesterol in d/d than in b/b mice. Few effects were seen on total bile acids, serum triglycerides, glucose, or nonesterified cholesterol. In the liver, hepatocellular cytomegaly, fatty change, and bile duct hyperplasia occurred in both strains in a dose-related manner, as did thymic and splenic atrophy. Necrosis of germinal epithelium in the testes and edema in the stomach submucosa occurred at acutely toxic doses. These lesions also occurred at doses 8-24X greater in d/d than in b/b mice. Thus, the spectrum of toxicity is independent of the allele at the Ah locus, but the relative dose needed to bring about various acute responses is approximately 8-24X greater in congenic mice homozygous for the "d" allele than for the wild type animals carrying two copies of the "b" gene.

Animals↗
PubMed1990

The metabolism of CGP-291: the use of microorganisms as models of mammalian metabolism.

CGP-291 is an investigational antiprotozoal agent with unknown metabolism. Microbial systems were utilized, as a model of mammalian metabolism, to predict the oxidative metabolic pathway of this nitroimidazole. Large-scale fermentation of CGP-291 with Beauvaria bassiana produced two major metabolites, IV and V. Structures of both were elucidated by comparing spectral data of metabolites to that of the starting material. The presence of two minor monohydroxylated metabolites was verified using LC-MS.

Chromatography, Thin Layer↗