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Biomedical subjects

C N Johnson

Publications and source records attributed to C N Johnson.

At least 19 recordsLinked to original sources
PubMed2007

Bryophyte dispersal by flying foxes: a novel discovery.

This research provides the first evidence of dispersal of bryophytes and associated microorganisms through ingestion by a highly mobile vertebrate vector, the spectacled flying fox (Pteropus conspicillatus). Bryophyte fragments were found in faeces collected at four P. conspicillatus' camps in the Wet Tropics bioregion, northeastern Australia. These fragments were viable when grown in culture; live invertebrates and other organisms were also present. Our study has significantly increased understanding of the role of flying foxes as dispersal vectors in tropical forests.

Animals↗
PubMed2006

Adaptation of the WHO guideline for residual DNA in parenteral vaccines produced on continuous cell lines to a limit for oral vaccines.

Although there is a WHO guidance for a limit on residual DNA for parenterally administered vaccines produced on continuous cell lines, there is no corresponding guidance for oral vaccines. To help determine an oral limit, we performed a study of Vero cell DNA uptake in rats, in which the relative uptake and persistence of Vero cell DNA administered orally was compared to its uptake when delivered intramuscularly (IM). The results of this study allowed the generation of an empirically derived IM versus oral factor (10(6)) representing the relative inefficiency of DNA uptake by oral administration. This factor was then applied to the WHO recommended parenteral limit of 10 ng/dose to determine a corresponding upper limit on the level of residual Vero cell DNA for an oral vaccine of 10 mg. As a conservative approach, this empirically determined limit was reduced 100-fold to 100 microg. Thus, the results of this animal study, together with additional evidence in the literature, support a residual DNA safety limit of 100 microg per dose for an oral vaccine produced on a continuous cell line.

Administration, Oral↗
PubMed2003

Vancomycin-resistant enterococci: 15 years and counting.

We review the history of vancomycin-resistant enterococci (VRE) and propose a causal model illustrating the roles of exposure to VRE reservoirs, patient characteristics, antimicrobial exposure, and prevalence of VRE in the progression from potential VRE reservoirs to active disease in hospitalized patients. Differences in VRE colonization and VRE infection are discussed with respect to hospital surveillance methodology and implications for interventions. We further document clonal transmission of VRE in a large, urban, teaching hospital and demonstrate VRE susceptibility to a wide array of antimicrobial agents. This model can guide the identification of mutable factors that are focal points for intervention.

Carrier State↗
PubMed2002

Determinants of loss of mammal species during the Late Quaternary 'megafauna' extinctions: life history and ecology, but not body size.

Extinctions of megafauna species during the Late Quaternary dramatically reduced the global diversity of mammals. There is intense debate over the causes of these extinctions, especially regarding the extent to which humans were involved. Most previous analyses of this question have focused on chronologies of extinction and on the archaeological evidence for human-megafauna interaction. Here, I take an alternative approach: comparison of the biological traits of extinct species with those of survivors. I use this to demonstrate two general features of the selectivity of Late Quaternary mammal extinctions in Australia, Eurasia, the Americas and Madagascar. First, large size was not directly related to risk of extinction; rather, species with slow reproductive rates were at high risk regardless of their body size. This finding rejects the 'blitzkrieg' model of overkill, in which extinctions were completed during brief intervals of selective hunting of large-bodied prey. Second, species that survived despite having low reproductive rates typically occurred in closed habitats and many were arboreal or nocturnal. Such traits would have reduced their exposure to direct interaction with people. Therefore, although this analysis rejects blitzkrieg as a general scenario for the mammal megafauna extinctions, it is consistent with extinctions being due to interaction with human populations.

Animals↗
PubMed2001

Adjustment of offspring sex ratios in relation to the availability of resources for philopatric offspring in the common brushtail possum.

The local-resource-competition hypothesis predicts that where philopatric offspring compete for resources with their mothers, offspring sex ratios will be biased in favour of the dispersing sex. This should produce variation in sex ratios between populations in relation to differences in the availability of resources for philopatric offspring. However, previous tests of local resource competition in mammals have used indirect measures of resource availability and have focused on sex-ratio variation between species or individuals rather than between local populations. Here, we show that the availability of den sites predicts the offspring sex ratio in populations of the common brushtail possum. Female possums defend access to dens, and daughters, but not sons, occupy dens within their mother's range. However, the abundances of possums in our study areas were determined principally by food availability. Consequently, in food-rich areas with a high population density, the per-capita availability of dens was low, and the cost of having a daughter should have been high. This cost was positively correlated with male bias in the sex ratio at birth. Low per capita availability of dens was correlated with male bias in the sex ratio at birth.

Animals↗
PubMed2001

A regioselective cycloaddition route to isoxazoleboronic esters.

Alkynylboronates participate in 1,3-dipolar cycloaddition reactions with nitrile oxides to provide isoxazoleboronic esters with excellent levels of regiocontrol; additionally, these potentially valuable synthetic intermediates have been shown to participate efficiently in Suzuki coupling reactions.

Journal Article↗
PubMed2001

Synthesis of novel quinone boronic ester derivatives via a highly regioselective Cr-mediated benzannulation reaction and their application in Pd-catalyzed coupling processes.

This paper describes the synthesis and reactivity of a novel class of quinone boronic esters. These compounds are prepared utilizing a highly regioselective Dötz annulation of Fischer carbene complexes with alkynylboronates. All substrates studied to date provided a single regioisomeric arylboronic ester product; the origin of this selectivity is discussed in the context of steric and electronic effects. Additionally, these compounds have been found to undergo Pd-catalyzed coupling reactions with a range of aryl and allyl halides and provides a strategy for the selective and predictable preparation of highly substituted quinones and hydroquinones. Finally, the propensity of this technique to prepare highly functionalized aromatic compounds in an expeditious fashion is demonstrated in the total synthesis of dimeric carbazole (+/-)-bis-N-dimethylbismurrayaquinone-A 33.

Journal Article↗
PubMed2001

Design and synthesis of novel 2,3-dihydro-1H-isoindoles with high affinity and selectivity for the dopamine D3 receptor.

Starting from the tetrahydroisoquinoline SB-277011 1, a novel series of 5-substituted-2,3-dihydro-1H-isoindoles has been designed. Subsequent optimisation resulted in identification of 19, which has high affinity for the dopamine D3 receptor (pKi 8.3) and > or = 100-fold selectivity over other aminergic receptors. In rat studies 19 was brain penetrant with an excellent pharmacokinetic profile (oral bioavailability 77%, t1/2 5.2h).

Animals↗
PubMed2001

In vitro activity of ABT-773, telithromycin and eight other antimicrobials against erythromycin-resistant Streptococcus pneumoniae respiratory isolates of children.

The activity of the ketolide ABT-773 against 180 erythromycin-resistant Streptococcus pneumoniae obtained from children was compared with telithromycin, azithromycin, clarithromyin, roxithromycin, clindamycin, penicillin, levofloxacin and gatifloxacin. Ketolide MICs were all < or =1 mg/l, with ABT-773 being the most potent of all drugs tested. MIC(90)s for macrolides and azithromycin in mefE+ isolates were 16-32 compared with >128 mg/l for ermB+ isolates. ABT-773 and telithromycin MIC(90)s for mefE+ isolates were 0.125 and 0.5, compared with 0.032 and 0.016 mg/l for ermB+ isolates and 0.5 and 1 mg/l, respectively, for isolates containing both genes. Clindamycin was active against mefE+ but not ermB+ isolates. 155 isolates were resistant to penicillin. All fluoroquinolone MICs were < 1 mg/l. Further studies of ketolides for treatment of paediatric S. pneumoniae infections are warranted.

Anti-Bacterial Agents↗
PubMed2000

Experimental analyses of sexual and natural selection on short tails in a polygynous warbler.

We believe that no experimental study has yet tested Darwin's idea that, as well as generating trait elaboration, intersexual selection might sometimes drive sex-biased trait reduction. Here we present the results of two experiments exploring the negative relationship between tail length and reproductive success in male golden-headed cisticolas (Cisticola exilis). In the first experiment, artificially shortening a male's tail produced a dramatic increase in his reproductive success, measured as either the number of females nesting or number of chicks Hedged on his territory. A second experiment, in which manipulated birds were flown through a maze, revealed that short tails also impose costs by reducing aerodynamic performance during slow-speed foraging flight. Because tail shortening yields reproductive benefits and viability costs, we conclude it has evolved via sexual selection. Disentangling exactly how short tails enhance male reproductive success is more difficult. Male-male competition appears partly responsible: aerodynamic theory predicts that tail reduction enhances high-speed flight and, in line with this, shortened-tail males spent more time engaged in high-speed aerial chases of rivals and defended higher-quality territories. However, shortened-tail males had higher reproductive success independent of territory quality and spent more time in aerial displays which may be directed at females. This suggests that tail shortening is also favoured via female choice based on male phenotype.

Animals↗
PubMed2000

Design and synthesis of trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011): A potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and CNS penetration in the rat.

A selective dopamine D(3) receptor antagonist offers the potential for an effective antipsychotic therapy, free of the serious side effects of currently available drugs. Using clearance and brain penetration studies as a screen, a series of 1,2,3, 4-tetrahydroisoquinolines, exemplified by 13, was identified with high D(3) affinity and selectivity against the D(2) receptor. Following examination of molecular models, the flexible butyl linker present in 13 was replaced by a more conformationally constrained cyclohexylethyl linker, leading to compounds with improved oral bioavailability and selectivity over other receptors. Subsequent optimization of this new series to improve the cytochrome P450 inhibitory profile and CNS penetration gave trans-N-[4-[2-(6-cyano-1, 2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarbo xamide (24, SB-277011). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and brain penetration in the rat and represents an excellent new chemical tool for the investigation of the role of the dopamine D(3) receptor in the CNS.

Animals↗
PubMed2000

Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB-277011-A.

SB-277011-A (trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide), is a brain-penetrant, high-affinity, and selective dopamine D(3) receptor antagonist. Radioligand-binding experiments in Chinese hamster ovary (CHO) cells transfected with human dopamine D(3) or D(2 long) (hD(3), hD(2)) receptors showed SB-277011-A to have high affinity for the hD(3) receptor (pK(i) = 7.95) with 100-fold selectivity over the hD(2) receptor and over 66 other receptors, enzymes, and ion channels. Similar radioligand-binding data for SB-277011-A were obtained from CHO cells transfected with rat dopamine D(3) or D(2). In the microphysiometer functional assay, SB-277011-A antagonized quinpirole-induced increases in acidification in CHO cells overexpressing the hD(3) receptor (pK(b) = 8.3) and was 80-fold selective over hD(2) receptors. Central nervous system penetration studies showed that SB-277011-A readily entered the brain. In in vivo microdialysis studies, SB-277011-A (2. 8 mg/kg p.o.) reversed the quinelorane-induced reduction of dopamine efflux in the nucleus accumbens but not striatum, a regional selectivity consistent with the distribution of the dopamine D(3) receptor in rat brain. SB-277011-A (2-42.3 mg/kg p.o.) did not affect spontaneous locomotion, or stimulant-induced hyperlocomotion. SB-277011-A (4.1-42.2 mg/kg p.o.) did not reverse prepulse inhibition deficits in apomorphine- or quinpirole-treated rats, but did significantly reverse the prepulse inhibition deficit in isolation-reared rats at a dose of 3 mg/kg p.o. SB-277011-A (2.5-78. 8 mg/kg p.o.) was noncataleptogenic and did not raise plasma prolactin levels. Thus, dopamine D(3) receptor blockade produces few of the behavioral effects characteristic of nonselective dopamine receptor antagonists. The effect of SB-277011-A on isolation-induced prepulse inhibition deficit suggests that blockade of dopamine D(3) receptors may benefit the treatment of schizophrenia.

Animals↗
PubMed2000

Intravenous regional anesthesia: new approaches to an old technique.

The pace of modern surgical procedures demands a fast and effective regional anesthesia technique. Intravenous regional anesthesia (IVRA) is such a technique. Traditionally, IVRA has been limited by tourniquet pain, inability to provide postoperative analgesia, and lack of a bloodless field for microsurgical repairs. Current research indicates that these limitations can be significantly improved with alteration of the block solution or alteration of the exsanguination technique. Additions to the local anesthetic such as meperidine, ketorolac, and clonidine have been shown to increase tourniquet tolerance and significantly improve postoperative analgesia. Additionally, when a bloodless field is required for microvascular surgery or nerve repairs, a re-exsanguination technique can be used. Advances in IVRA have made this technique an excellent choice for cases involving the hand, forearm, foot, and lower leg cases that least 60 minutes or less.

Adjuvants, Anesthesia↗
PubMed1999

Heterocyclic analogues of 2-aminotetralins with high affinity and selectivity for the dopamine D3 receptor.

A novel series of 5,6,7,8-tetrahydroquinazolines, 4,5,6,7-tetrahydroindazoles and 4,5,6,7-tetrahydrobenzothiazoles has been prepared, having high affinity and selectivity for the dopamine D3 receptor. The 4-methoxy-5,6,7,8-tetrahydroquinazoline 6i and 2-amino-4,5,6,7-tetrahydrobenzothiazole 8 proved to be agonists with among the highest D3 receptor affinities and selectivities reported to date.

Heterocyclic Compounds↗
PubMed1999

Novel 1,2,3,4-tetrahydroisoquinolines with high affinity and selectivity for the dopamine D3 receptor.

Using clearance and brain penetration studies as a screen, tetrahydroisoquinoline 3 was identified as a lead having low clearance in rats (CLb 20 ml/min/kg). Introduction of a 7-CF3SO2O- substituent into the tetrahydroisoquinoline, followed by replacement of the biphenylamido group of 3 by a 3-indolylpropenamido group gave 31, having high D3 receptor affinity (pKi 8.4) and 150 fold selectivity over the D2 receptor.

Animals↗
PubMed1998

Fused aminotetralins: novel antagonists with high selectivity for the dopamine D3 receptor.

Starting from a series of 2-aminotetralins 1, a novel series of N-[4-(4-phenylbenzoylamino)butyl]-octahydrobenzoquinolines and hexahydrobenzoindoles with high potency and selectivity for the dopamine D3 receptor has been designed. The effect of ligand chirality on binding affinity has been established. Selected derivatives (e.g. 2o, 2p) show high functional selectivity and enhanced in vivo properties compared to 1.

Animals↗