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Biomedical subjects

E M Johnson

Publications and source records attributed to E M Johnson.

At least 289 records · Page 16Linked to original sources
PubMed1986

In-vitro effect of itraconazole, ketoconazole and amphotericin B on the phagocytic and candidacidal function of human neutrophils.

Neither itraconazole nor ketoconazole had significant effects on the phagocytosis or killing of Candida albicans blastospores by human neutrophil polymorphonuclear (PMN) leucocytes, whether following simultaneous addition of drug with the blastospores, prior treatment of the PMN cells with drug, or prior treatment of the blastospores with drug. Following simultaneous addition, amphotericin B caused significant impairment of phagocytosis in tests with PMN cells from one of two donors, but had no effect on subsequent killing of ingested blastospores. Prior treatment of PMN cells or blastospores with amphotericin B had no effect on phagocytosis or killing. In tests in which blastospores of an azole-sensitive and an azole-resistant strain of C. albicans were added to PMN cells, fewer than 25% of ingested blastospores of either strain had initiated germ tube formation after 6 h. Addition of ketoconazole had no effect on the proportion of ingested blastospores of either strain which germinated. Ketoconazole had no effect on germ tube elongation of ingested blastospores of the azole-resistant strain, but caused marked inhibition of germ tube elongation of ingested blastospores of the azole-sensitive strain. After 24 h, the azole-resistant strain had produced abundant mycelium and few phagocytic cells remained intact. With the azole-sensitive strain, PMN cells were still evident at 24 h, with ingested germ-tube-forming blastospores, most of which were dead.

Amphotericin B↗
PubMed1986

Perspectives on reproductive and developmental toxicity.

Human reproduction and development is a cycle of interdependent events. Virtually all of its phases have been shown to be the primary target of one or more non-mutagenic exogenous agents. Such agents interfere with certain of the countless epigenetic or ontogenic events essential for normal completion of the cycle. Mutagens disrupt this cycle at some points, but the overwhelming majority of reproductive and developmental toxins are not mutagenic. As in all aspects of toxicology, the reproductive and developmental effects of chemicals are determined by the intrinsic nature of the chemical, the quantity of the chemical exposure, the duration of exposure and the stage of the cycle at which it occurs. Signs of reproductive toxicity range from reduced fertility to spontaneous abortion. Adverse effects on the conceptus are categorized as functional deficits, developmental retardation, structural abnormality and death. One or more of these is anticipated to occur as a result of excess exposure to most chemicals. Although the degree of hazard and risk potential can be calculated in each instance, chemicals differ markedly in their ability to interfere with reproduction (Amann, 1982) and/or development (Johnson, 1984). Standardized methods for reproductive and developmental toxicity safety evaluation are available for detecting adverse effects upon any aspect of reproduction and development. Data currently available establish that these state-of-the-art tests conducted in laboratory animals are often highly predictive of the type of adverse effect a particular chemical will have in humans, as well as the exposure level at which it will occur. By adding a modest safety factor to the no-observed-effect-level of well-executed animal studies, safe human exposure levels can be established. Responsibility for determining the intrinsic hazard potential and the risk estimate of exposure rests with manufacturers and major users of occupational and other environmental chemicals. As public awareness of reproductive and developmental hazards has increased in recent years, it has come to be understood that some chemicals have a predilection for causing reproductive impairment and/or disrupting development in the absence of other toxicity. Such substances must be identified to establish safe exposure levels and to determine the types of effects to be expected, should excessive human exposure occur. The setting of safe exposure levels is necessary both from the standpoints of ensuring public safety and avoiding product liability.

Animals↗
PubMed1986

Azole resistance in Candida albicans.

An isolate of Candida albicans from a patient with chronic mucocutaneous candidosis who relapsed during ketoconazole treatment was compared with a number of other azole-sensitive and azole-resistant isolates by tests in vitro and in three animal models of vaginal or disseminated infection. In-vitro tests indicated that the isolate was cross-resistant to all imidazole and triazole antifungals tested. In the animal models, treatment with miconazole, ketoconazole, itraconazole or fluconazole failed to influence the infection.

Adult↗
PubMed1986

Effect of a uniform partial denervation of the periphery on the peripheral and central vibrissal system in guinea pigs.

In some rodents, somatotopically organized architectonic patterns corresponding precisely to the arrangement of the vibrissae on the face are found in each of the central stations of the trigeminal (V) pathway. Two lines of evidence indicate that these architectonic patterns reflect the level of peripheral innervation. First, in normal mice, the sizes of the individual units within the cortical representation are proportional to the number of fibers supplying the corresponding vibrissal follicles. Second, complete surgical denervation of groups of vibrissae can severely attenuate the sizes of and alter the patterns of their central representations. However, previous studies in this system do not distinguish the effects of the absolute and the relative levels of peripheral innervation on central representations. To address this question, we have studied guinea pigs in which all vibrissae are partially deafferentated before birth by fetal exposure to antibodies against NGF. This approach reduces the absolute level of peripheral innervation in a graded way, and does so uniformly, without changing the pattern of vibrissal innervation. In the most severely affected animals, only 18% of the normal number of V ganglion neurons survive. The effect of this loss on the V system was assessed by comparing the peripheral and central components of the vibrissal system in normal and NGF-deprived animals. Peripheral fibers from the V ganglion neurons, including those to the vibrissae, are less reduced in number (50%) than expected. The number of peripheral fiber fascicles is also decreased. In contrast, neither the patterns nor the areas of the central representations in medulla and cortex differ from those of normal animals. We conclude that 18% of the normal number of V ganglion cells is sufficient to establish normal central architectonic patterns and the size of the central vibrissal representations is independent of the absolute magnitude of peripheral innervation. These observations are of relevance to understanding the role of NGF on the morphogenesis of central somatosensory pathways, the effects of "mismatches" between peripheral innervation, and the development of projections to central targets in the mammalian brain, and provide new data for understanding competitive interactions in the developing central and peripheral trigeminal system.

Animals↗
PubMed1985

Protection from guanethidine-induced neuronal destruction by nerve growth factor: effect of NGF on immune function.

The chronic administration of guanethidine causes an immune-mediated destruction of sympathetic neurons in rats. Destruction can be prevented by various immunosuppressive agents, including gamma-irradiation and cyclophosphamide, as well as by administration with nerve growth factor (NGF). Experiments were conducted to determine whether: (1) NGF prevented accumulation of guanethidine within sympathetic neurons; and (2) NGF caused an inhibition of immune function by either blocking proliferation of immune-competent cells or by blocking effector function even in the presence of antigen and activated immune cells. NGF did not prevent accumulation of guanethidine within sympathetic ganglia in vivo, a necessary prerequisite for neuronal destruction, nor was it inhibitory on immune function using several assay systems. NGF, purified by either conventional methods or additionally by HPLC ("ultrapure'), did not inhibit either proliferation of cloned cytotoxic T lymphocytes (CTL) to antigen (class I major histocompatibility antigens) or lysis of target cells bearing the appropriate antigens. In addition, NGF did not exhibit growth stimulating effects in this assay system (i.e. it could not substitute for T cell growth factor). NGF also did not cause an inhibition of either murine or rat allogeneic mixed lymphocyte responses measured by lysis of appropriate target cells or proliferation, respectively. Finally, NGF did not inhibit, but rather appeared to stimulate the antibody response to sheep red blood cells generated in vivo in young rats. Thus NGF does not appear to prevent the immune-mediated neural destruction induced by guanethidine by acting as an immunosuppressive agent, but rather acts by some other mechanism such as preventing expression or recognition of antigen(s) on the sympathetic neuron.

Animals↗
PubMed1985

Ventral rhizotomy enhances regeneration of uninjured sensory neurons.

Uninjured sensory neurons show metabolic and morphologic changes, as well as enhanced regeneration, when exposed to adjacent degenerating ventral root fibers. The release of a neurotrophic factor from the degenerating nerve fibers may be responsible for 'priming' the uninjured neuron and thereby enhancing its response to injury.

Animals↗
PubMed1985

Effect of capsaicin upon fluoride sensitive acid phosphatases in selected ganglia and spinal cord and upon neuronal size and number in dorsal root ganglion.

A quantitative method for the analytical separation of the fluoride sensitive acid phosphatases of rat spinal cord and peripheral nervous tissues into tartrate-sensitive and tartrate-resistant forms (TSAP and TRAP, respectively) is described. Evidence supporting the use of L-(+)-tartrate rather than fluoride as an inhibitor is presented. The method is used for the quantitative description of the consequences of neonatal capsaicin treatment, and the results appear to justify the attribution of the TRAP activity to the capsaicin sensitive neurons. In the first experiment, rats were killed at weekly intervals after neonatal capsaicin treatment. In controls, both TRAP and TSAP activities in dorsal root ganglia (DRG) increased during the second postnatal week and remained constant thereafter. At all ages (1-4 weeks) TRAP activity was reduced 50-60% in capsaicin-treated DRG. Reduction of TSAP activity was much less. In a second experiment, rats were treated neonatally with capsaicin or vehicle (control) and allowed to grow to adulthood (4 months). TRAP activity was found to be decreased 38% in the dorsal half of the lumbar spinal cord (L3-L5), decreased 33% in nodose ganglion, and unchanged in superior cervical ganglion of the capsaicin treated animals. TSAP activity was unchanged in dorsal spinal cord and superior cervical ganglion and decreased 33% in nodose ganglion. The number of neurons in C8 DRG was found to be reduced 28% in capsaicin treated animals. The loss appeared to be among the small neurons. The number of large neurons was actually increased in ganglia from capsaicin-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Phosphatase↗
PubMed1985

Candidosis of the genital tract in non-pregnant women.

Of 300 non-pregnant women seen in an STD clinic, 94 (31.3%) harboured C. albicans or C. glabrata in the genital tract; 84 of these women (89.4%) had at least one moderate or marked symptom or clinical sign. Of the 94 women with Candida, 50 had another genital infection; 38% of these 50 women had at least one moderate or marked symptom or clinical sign, compared with 75% of the 44 women with no other infection. This difference is significant. Of the 146 women taking oral contraceptives, 51 (34.9%) had Candida, compared with 43 (27.9%) of the 154 women who were not. The incidence of trichomoniasis, anaerobic vaginitis and non-specific genital infection was lower among women with Candida than among the others.

Candidiasis, Vulvovaginal↗
PubMed1985

A simple hidden line removal algorithm for serial section reconstruction.

A simple and efficient program for removing the hidden lines from the computer graphics display of a three-dimensional structure has been developed. The algorithm is optimized for serial section reconstruction, that is, for three-dimensional structures composed of a series of stacked planar outlines. Using the algorithm, an anatomist can generate a realistic static picture of a reasonably complex reconstruction in about 20 s on a small laboratory computer.

Anatomy↗
PubMed1985

Characterization of the binding properties and retrograde axonal transport of a monoclonal antibody directed against the rat nerve growth factor receptor.

We have demonstrated in vitro and in vivo the specific binding of a monoclonal antibody to the rat nerve growth factor (NGF) receptor. Previous work had shown that this antibody, designated 192-IgG, does not compete with NGF for binding to the NGF receptor of PC12 cells, but instead interacts with the receptor to increase NGF binding to PC12 cells (Chandler, C. E., L. M. Parsons, M. Hosang, and E. M. Shooter, 1984, J. Biol. Chem., 259:6882-6889). In the present study, a solid-phase separation assay verified the specific formation of a ternary complex of 192-IgG, the NGF receptor, and NGF: 125I-labeled 192-IgG precipitated from solution only when incubated with both solubilized NGF receptor and NGF covalently linked to a solid phase (Sepharose 4B). Filtration assays using plasma membrane preparations of various tissues showed strict correlation of 125I-192-IgG and 125I-labeled NGF binding; only membranes obtained from superior cervical ganglion bound significant amounts of the monoclonal antibody and NGF. Injection of 125I-192-IgG into the rat anterior eye chamber led to accumulation of intact antibody molecules in the ipsilateral superior cervical ganglion, indicating retrograde axonal transport of 125I-192-IgG from the neuronal termini, located at the iris, to the cell bodies situated in the ganglion. The time course and saturation characteristics of 125I-192-IgG retrograde transport were very similar to those previously reported for 125I-NGF transport, indicating that 192-IgG can be internalized and transported by the same mechanisms as is NGF. Consistent with results of the in vitro binding assays, 192-IgG and NGF failed to compete for retrograde transport and were actually co-transported. Retrograde axonal transport of 192-IgG appears to be species specific, since 125I-192-IgG was transported in the rat, but not in mice, gerbils, hamsters, or guinea pigs. These results establish monoclonal antibody 192-IgG as a specific probe for the rat NGF receptor in vitro and in vivo.

Animals↗
PubMed1985

Selective destruction of nerve growth factor receptor-bearing cells in vitro using a hybrid toxin composed of ricin A chain and a monoclonal antibody against the nerve growth factor receptor.

A hybrid toxin composed of ricin A chain and a monoclonal antibody directed against the rat nerve growth factor (NGF) receptor (192-IgG) was prepared using the heterobifunctional cross-linking agent N-succinimidyl-3-(2-pyridyldithio)-propionate and purified by affinity chromatography. Characterization studies showed that the hybrid, 192-s-s-A, displaced bound 125I-labeled 192-IgG from rat superior cervical ganglion (SCG) membranes with an IC50 3-5 times lower than that of unconjugated 192-IgG. When incubated with cultured rat SCG neurons, 192-s-s-A inhibited protein synthesis in a concentration-dependent fashion. The effect of 192-s-s-A on these neurons was reversed by coincubation with an excess of 192-IgG. The IC50 of 192-s-s-A on protein synthesis in rat SCG neurons was 4 nM. Intact ricin and ricin A chain inhibited protein synthesis in these neurons with IC50 values of 5 pM and 500 nM, respectively. The 192-s-s-A hybrid had no effect on mouse SCG neurons or a human melanoma cell line known to have NGF receptors. This is consistent with the finding that 192-IgG recognizes only the rat NGF receptor. Also, 192-s-s-A did not inhibit protein synthesis in primary cultures of rat skeletal muscle or Vero cells, which do not have cell surface receptors for NGF. 192-s-s-A was able to inhibit protein synthesis in PC12 cells but the potency was 10-100 times less in these cells compared to rat SCG neurons. Ricin and A chain were also 10-100 times less potent in PC12 cells than neurons. Rat SCG neurons exposed to 192-s-s-A lost their refractile appearance under phase-contrast optics, showed granular degeneration of neurites, and died. Thus the decreased protein synthesis caused by the hybrid toxin correlated with the morphological destruction of the neurons. 192-s-s-A represents a potentially powerful tool by which to selectively destroy NGF receptor-bearing cells in vitro. The hybrid toxin may prove useful as an in vivo toxin.

Animals↗
PubMed1984

Role of nerve growth factor in the adult dorsal root ganglia neuron and its response to injury.

The response of dorsal root ganglia (DRG) neurons to NGF deprivation and to axotomy was examined in adult guinea pigs. The success of NGF deprivation by means of an autoimmune approach was monitored by the measurement of serum antibody titer levels against guinea pig NGF with the standard bioassay for NGF activity. That the antibody produced NGF deprivation was confirmed by histologic evidence of neuronal atrophy and apparent cell loss in sections of the superior cervical ganglia (SCG) and by marked decreases (65-80%) of SCG neurotransmitter-synthesizing enzyme activity levels. By using the autoimmune approach a new source of guinea pigs was found which consistently produced high titers of cross-reacting anti-NGF antibodies. Experiments were designed to examine the response of the sensory neuron to injury while chronically deprived of NGF. Total neuronal counts in the sixth lumbar DRG 98 days after sciatic nerve crush showed no difference between NGF-deprived and control ganglia. Measurement of the size spectrum of DRG neurons showed evidence of atrophy of the NGF-deprived neurons in both the uninjured and axotomized side compared to respective controls. The mean volume of uninjured sensory neurons measured in the NGF-deprived guinea pigs was decreased 27.7% (P less than .05) compared with that of control guinea pigs. The degree of regeneration 6 days following a nerve crush was the same in NGF-deprived sensory neurons and in controls when measured by the "pinch test" and by isotope-labeled axonal transport studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Developing dorsal root ganglion neurons require trophic support from their central processes: evidence for a role of retrogradely transported nerve growth factor from the central nervous system to the periphery.

Injury to the peripheral processes produces a profound cell loss (40-50%) in the dorsal root ganglion of newborn rats. Although division of central processes produces little or no cellular change in sensory ganglion of adult animals, no information has been available on the effect of dorsal root section in developing dorsal root ganglion. We show that 6 days after dorsal rhizotomy on newborn rats, there is a 50% decrease in neuronal number in L5 dorsal root ganglion. A combined central and peripheral lesion of the sensory process results in a greater decrease in neuronal number (70%). Both of these effects can be prevented by the concomitant treatment with nerve growth factor. We also demonstrate that 125I-Ia-labeled nerve growth factor is retrogradely transported with high selectivity from the spinal cord to the dorsal root ganglion via the dorsal roots. The results indicate that trophic support for developing sensory neurons is provided through the central processes. This is presumably due to the uptake and retrograde transport of a trophic factor by the terminals of the central processes. The data suggest that nerve growth factor may be the trophic factor.

Animals↗
PubMed1984

In-vitro resistance to imidazole antifungals in Candida albicans.

Three strains of Candida albicans from patients with chronic mucocutaneous candidosis (CMC) who relapsed during prolonged treatment with ketoconazole were compared with three other Can. albicans strains by means of an agar incorporation MIC method, a broth microdilution method for IC30 determination, and a hyphal elongation assessment method. The MICs of ketoconazole, tioconazole and miconazole were difficult to interpret, but were much higher for the three CMC strains if low inoculum concentrations and short incubation times were used. The IC30S of the three imidazoles were much higher for the CMC strains than for the others. The imidazoles all caused minimal inhibition of hyphal elongation by the three CMC strains at concentrations up to 50 mg/l. Concentrations of 0.5 mg/l caused marked inhibition of the other strains.

Antifungal Agents↗