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Biomedical subjects

J B Johnson

Publications and source records attributed to J B Johnson.

At least 19 recordsLinked to original sources
PubMed2001

Flavonolignan and flavone inhibitors of a Staphylococcus aureus multidrug resistance pump: structure-activity relationships.

Although some progress has been reported on structure-activity relationships (SARs) for inhibitors of mammalian P-glycoprotein MDR efflux pumps, there is almost nothing in the literature regarding SARs for inhibitors of any bacterial efflux pump. Indeed, only a few of these have been described. Our discovery of a potent naturally occurring flavonolignan inhibitor of the NorA MDR pump of Staphylococcus aureus provided a structural foundation upon which SARs could be assessed via synthetic analogues. Several flavonolignans were prepared which proved to have greater potency than the natural isolate, 5'-methoxyhydnocarpin-D, while others showed decreased potency. Surprisingly, some simple alkylated flavones also were quite active MDR pump inhibitors. Variability of activity among the compounds tested was sufficient so that at least some SARs could be postulated and compared with those known for P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Adaptive life-history evolution in the livebearing fish Brachyrhaphis rhabdophora: genetic basis for parallel divergence in age and size at maturity and a test of predator-induced plasticity.

I document a genetic basis for parallel evolution of life-history phenotypes in the livebearing fish Brachyrhaphis rhabdophora from northwestern Costa Rica. In previous work, I showed that populations of B. rhabdophora that co-occur with predators attain maturity at smaller sizes than populations that live in predator-free environments. I also demonstrated that this pattern of phenotypic divergence in life histories was independently repeated in at least five isolated drainages. However, life-history phenotypes measured from wild-caught fish could be attributed to environmental effects rather than to genetic differences among populations. In the present study, I reared male fish from four populations (two that co-occur with predators and two from predator-free environments) under four sets of environmental conditions. The pattern of phenotypic divergence in maturation size documented in the field between populations collected from different predation environments persisted after two generations in the laboratory. I also found a genetic basis for differences between populations in the age at which males attain maturity and in growth rates. By rearing fish in four different common environments, I tested for phenotypic plasticity in male life-history traits in response to nonlethal exposure to predators. There was a significant delay in the onset of sexual maturity in fish exposed to predators relative to those in the control, but no differences among treatments in size at maturity or growth rates. These results, coupled with previous work on B. rhabdophora, demonstrate a repeated pattern of parallel evolutionary divergence among genetically isolated populations that is strongly associated with predation.

Adaptation, Physiological↗
PubMed2000

Sulfur mustard-induced skin burns in weanling swine evaluated clinically and histopathologically.

Histopathological indicators and clinical observations were used to evaluate wound severity, depth and degree of healing on days 2 and 8 for full-skin-thickness sulfur-mustard (HD)-induced burns in weanling swine. Six female weanling swine were exposed for 2 h to 400 microl of HD at each of six dose sites on the hairless abdominal skin. Biopsy samples (8 mm) were taken from the periphery and from the center of the wound on day 2, and the wound was excised on day 8. Histopathological indicators evaluated were epidermal necrosis, follicular necrosis, dermal necrosis, vascular necrosis, depth of injury, ulceration (loss of epidermis), granulation tissue response, neovascularization, re-epithelialization (hyperplasia) and completeness of healing. Wounds were more severe from anterior to posterior. Histopathological assessment of epidermal ulceration and necrosis of epidermis, dermis, basal epithelium, adnexal structures and subcutaneous tissue were useful indicators of wound development on day 2. Granulation tissue response (observed as early as day 8) and re-epithelialization were good indicators of wound healing. Clinical evaluations were performed on day 2 prior to and after debriding, and on study day 8. Clinical observations on study day 2 were for wound size and for exudation, erythema, edema, necrosis and eschar. Clinical observations on study day 8 were for the previous parameters and for re-epithelialization, granulation and infection. Wound size and severity increased from anterior to posterior position. Size, exudation and edema were useful indicators of wound development. These histological and clinical observation parameters will be used in future experiments to compare various treatments for HD-induced burns.

Animals↗
PubMed2000

Phylogenetic divergence in leatherside chub (Gila copei) inferred from mitochondrial cytochrome b sequences.

We examined intra-specific phylogenetic relationships in leatherside chub, Gila copei. The complete mitochondrial (mt) cytochrome b gene (1140 bp) was sequenced for 30 individuals from 10 populations that span the geographical distribution of this species. Traditional phylogenetic analyses revealed two deeply divergent and evolutionarily distinct mtDNA clades that are geographically separated in northern and southern drainage basins. Interpopulation sequence variation between clades ranged from 7.7 to 8.1%. The northern clade was genetically more similar and phylogenetically more closely related to the selected out-group Lepidomeda m. mollispinus than to the southern clade, suggesting that the taxonomy of this species may require revision. Sequence variation among populations within clades ranged from 0 to 0.3% in the north and from 0 to 0.7% in the south. Statistical parsimony was used to construct phylogenetic networks of haplotypes within clades. Nested clade analysis revealed that geographical fragmentation has played an important role in genetic structuring within northern and southern clades.

Animals↗
PubMed1996

Ligand binding to heme proteins. VI. Interconversion of taxonomic substates in carbonmonoxymyoglobin.

The kinetic properties of the three taxonomic A substates of sperm whale carbonmonoxy myoglobin in 75% glycerol/buffer are studied by flash photolysis with monitoring in the infrared stretch bands of bound CO at nu(A0) approximately 1967 cm-1, nu(A1) approximately 1947 cm-1, and nu(A3) approximately 1929 cm-1 between 60 and 300 K. Below 160 K the photodissociated CO rebinds from the heme pocket, no interconversion among the A substates is observed, and rebinding in each A substate is nonexponential in time and described by a different temperature-independent distribution of enthalpy barriers with a different preexponential. Measurements in the electronic bands, e.g., the Soret, contain contributions of all three A substates and can, therefore, be only approximately modeled with a single enthalpy distribution and a single preexponential. The bond formation step at the heme is fastest for the A0 substate, intermediate for the A1 substate, and slowest for A3. Rebinding between 200 and 300 K displays several processes, including geminate rebinding, rebinding after ligand escape to the solvent, and interconversion among the A substates. Different kinetics are measured in each of the A bands for times shorter than the characteristic time of fluctuations among the A substates. At longer times, fluctuational averaging yields the same kinetics in all three A substates. The interconversion rates between A1 and A3 are determined from the time when the scaled kinetic traces of the two substates merge. Fluctuations between A1 and A3 are much faster than those between A0 and either A1 or A3, so A1 and A3 appear as one kinetic species in the exchange with A0. The maximum-entropy method is used to extract the distribution of rate coefficients for the interconversion process A0 <--> A1 + A3 from the flash photolysis data. The temperature dependencies of the A substate interconversion processes are fitted with a non-Arrhenius expression similar to that used to describe relaxation processes in glasses. At 300 K the interconversion time for A0 <--> A1 + A3 is 10 microseconds, and extrapolation yields approximately 1 ns for A1 <--> A3. The pronounced kinetic differences imply different structural rearrangements. Crystallographic data support this conclusion: They show that formation of the A0 substate involves a major change of the protein structure; the distal histidine rotates about the C(alpha)-C(beta) bond, and its imidazole sidechain swings out of the heme pocket into the solvent, whereas it remains in the heme pocket in the A1 <--> A3 interconversion. The fast A1 <--> A3 exchange is inconsistent with structural models that involve differences in the protonation between A1 and A3.

Animals↗
PubMed1996

Obagi's modified trichloroacetic acid (TCA)-controlled variable-depth peel: a study of clinical signs correlating with histological findings.

Currently, no documentation correlates histological changes with clinical signs of depth of the trichloroacetic acid peel. Obagi identified clinical signs of depth of injury following topical trichloroacetic acid application, employing prepeel conditioning and a method for slowing trichloroacetic acid action. A three-part study of 20 patients was undertaken to determine whether Obagi's visual and palpatory signs of depth correlated histologically with depth of peel. Also analyzed were physiological mechanisms associated with these signs. Patients were pretreated and biopsy specimens were harvested before and after modified trichloroacetic acid peeling. The results largely confirmed the validity of Obagi's observations regarding the method of trichloroacetic acid peel described. These clinical signs are verified by histology and correlated with some findings by electron microscopy. Differentiation of papillary from upper reticular dermal penetration is particularly useful. Physiological explanations for the phenomena observed are proposed. The specificity and safety of peels may be improved with these criteria.

Acne Vulgaris↗
PubMed1993

Pharmacokinetic comparison of leucovorin and levoleucovorin.

The pharmacokinetic values of d,l-leucovorin and l-leucovorin were compared in eight healthy volunteers following oral administration of 25 mg d,l-leucovorin and 12.5 mg l-leucovorin. Serum levels of l-5-formyltetrahydrofolate, l-5-methyltetrahydrofolate, and total reduced folates were measured by an established microbiological method. Pharmacokinetic data for both preparations were consistent with those previously reported for d,l-leucovorin, with essentially complete first pass metabolism to l-5-methyltetrahydrofolate, the active metabolite. No differences were found between the two preparations in serum concentrations of active folate fractions, AUC, or Cmax, or in clearance and volume of distribution estimates. These data suggest that after administration of 25 mg of d,l-leucovorin, the d-diastereoisomer has no significant effect on the standard pharmacokinetic measurements of the active l-folates.

Adolescent↗
PubMed1993

Evaluation of cell culture propagated and in vivo propagated hemorrhagic enteritis vaccines in turkeys.

The immune response of turkeys to a liquid, was compared with a previously frozen, cell culture propagated hemorrhagic enteritis (HE) vaccine. The liquid cell culture propagated HE vaccine was able to induce 100% seroconversion in turkeys 4 weeks after being vaccinated at 3.5 weeks of age; however, the previously frozen cell culture propagated HE vaccine induced 80% seroconversion 4 weeks post vaccination (P < 0.05). The average seroconversion in turkey flocks administered the liquid cell culture propagated HE was 97% in comparison with 98.5% in flocks given the splenic vaccine (P > 0.05). The complete absence of HE antigens in spleens of birds 5 days after being challenged with the virulent HE virus (40,000 TCID50 per bird) at an age of 9.5 weeks, was used as a model for successful protection against HE disease. The HE antigens were absent from spleens of all challenged birds that were previously vaccinated by the liquid cell culture propagated HE vaccine or splenic vaccine.

Animals↗
PubMed1993

Bioequivalence of oral and injectable levoleucovorin and leucovorin.

The bioequivalence and bioavailability of oral and intravenous formulations of levoleucovorin and leucovorin were studied, and the absolute bioavailabilities of levoleucovorin and leucovorin tablet formulations were determined. Healthy male volunteers participated in two randomized, single-dose, four-way crossover studies. The treatment groups were as follows: A = five 2.5-mg levoleucovorin tablets, B = five 5-mg leucovorin tablets, C = one 12.5-mg levoleucovorin tablet, D = one 25-mg leucovorin tablet, in study 1; A = 15-mg levoleucovorin injection, B = two 7.5-mg levoleucovorin tablets, C = 30-mg leucovorin injection, D = two 15-mg leucovorin tablets, in study 2. Serum concentrations of N-5-methyltetrahydrofolate (the primary metabolite and circulating form of reduced folate after leucovorin administration) and total tetrahydrofolate were measured over 24 hours after dose administration. Pharmacokinetic values were calculated for N-5-methyltetrahydrofolate and total tetrahydrofolates; values were compared for A versus B, C versus D, A versus C, and B versus D in study 1 and A versus C and B versus D in study 2. Results from 35 men in study 1 and 33 in study 2 showed that 12.5-mg oral doses and 15-mg intravenous doses of levoleucovorin are bioequivalent to 25-mg oral doses and 30-mg intravenous doses of leucovorin, respectively. Equivalence was observed after oral and intravenous administration. The absolute bioavailability of levoleucovorin (74%) was not significantly different from that of leucovorin (65%).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

The effect of food on the absorption of methotrexate sodium tablets in healthy volunteers.

OBJECTIVE: To examine the effect of food on the absorption and bioavailability of low-dose orally administered methotrexate sodium tablets. METHODS: In this randomized, 2-way crossover study, a 7.5-mg dose of methotrexate (three 2.5-mg tablets) was administered to 12 healthy male volunteers after an overnight fast or within 10 minutes of consuming a high fat-content breakfast. Serum methotrexate concentrations over the next 24 hours were used to determine the area under the concentration-time curve (AUC), the maximum concentration, the time to maximum concentration (tmax), and the serum half-life for each phase. RESULTS: Food delayed the tmax by approximately 30 minutes, but the extent of absorption, as measured by the AUC, for both phases was similar. CONCLUSION: These results demonstrate that the bioavailability of low-dose orally administered methotrexate sodium tablets is not influenced by food.

Administration, Oral↗
PubMed1992

Stomatal patterning in Tradescantia: an evaluation of the cell lineage theory.

The cell lineage theory, which explains stomatal patterning in monocot leaves as a consequence of orderly divisions, was studied in Tradescantia. Data were collected to test the theory at three levels of organization: the individual stoma; stomata distributed in one dimension, in linear fashion along cell files; and stomata apportioned in two dimensions, across the length and breadth of the leaf. In an attempt to watch the patterning process through regeneration, stomata in all visible stages of development were laser ablated. The results showed that the formation of stomatal initials was highly regular, and measurements of stomatal frequency and spacing showed that pattern was determined near the basal meristem when the stomatal initials arose. Following the origin of initials, the pattern was not readjusted by division of epidermal cells. Stomatal initials were not committed when first present and a small percentage of them arrested. The arrested cells, unlike stomata, were consistently positioned in cell files midway between a developed pair of stomata. At the one-dimensional level of pattern, stomata in longitudinal files were separated by a variable number of epidermal cells and the frequency of these separations was not random. The sequential spacing of stomata also was not random, and stomata separated by single epidermal cells were grouped into more short and long series than expected by chance. The stomatal pattern across the width of the leaf resulted from cell files free of stomata which alternated with cell files containing stomata, but not with a recurring periodicity. Files lacking stomata were found only over longitudinal vascular bundles. Laser ablations of developing stomata did not disrupt the pattern in nearby cells or result in stomatal regeneration. We conclude that the cell lineage theory explains pattern as an individual stomatal initial arises from its immediate precursor and satisfactorily accounts for the minimum spacing of stomata in a cell file, i.e., stoma-epidermal cell-stoma. However, the theory does not explain the collective stomatal pattern along the cell files, at the one-dimensional level of patterning. Nor does the theory account for the for the two-dimensional distribution of stomata in which regions devoid of stomata alternate with regions enriched with stomata, but not in a highly regular nor haphazard manner. We suggest that the grouping of epidermal cells and stomata separated by single epidermal cells in cell files may result from cell lineages at a specific position in the cell cycle as they traverse the zone where stomatal initials form.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Division↗
PubMed1992

The determination and prevention of cytotoxic effects induced in human lymphocytes by the alkylating agent 2,2'-dichlorodiethyl sulfide (sulfur mustard, HD).

2,2'-Dichlorodiethyl sulfide (sulfur mustard, HD, 1,1'-thio-bis[2-chloroethane]) is a potent vesicant which can cause severe lesions to skin, lung, and eyes. There is no convenient in vitro or in vivo method(s) to objectively measure the damage induced by HD; therefore, a simple in vitro method was developed using human peripheral lymphocytes to study HD-induced cytotoxicity. The cytotoxicity of HD was measured using dye exclusion as an indicator of human lymphocyte viability. Exposure to HD resulted in both a time- and a concentration-dependent cytotoxic effect on human lymphocytes. Using this in vitro assay, the effectiveness of various therapeutics (niacin, niacinamide, and 3-aminobenzamide) in preventing HD-induced cytotoxicity was studied. Niacinamide and 3-aminobenzamide prevented the cytotoxic effects of HD for up to 2 days.

Benzamides↗
PubMed1992

Determination of rate distributions from kinetic experiments.

Rate processes in proteins are often not adequately described by simple exponential kinetics. Instead of modeling the kinetics in the time domain, it can be advantageous to perform a numerical inversion leading to a rate distribution function f(lambda). The features observed in f(lambda) (number, positions, and shapes of peaks) can then be interpreted. We discuss different numerical techniques for obtaining rate distribution functions, with special emphasis on the maximum entropy method. Examples are given for the application of these techniques to flash photolysis data of heme proteins.

Carbon Monoxide↗