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Biomedical subjects

G L Jones

Publications and source records attributed to G L Jones.

At least 73 records · Page 4Linked to original sources
PubMed1990

Variable linking region immunogenicity using malarial peptide carrier protein conjugates of defined composition.

Thirty-five overlapping peptides from both conserved and variable parts of the N-terminal region of a malarial merozoite surface antigen (MSA2) were synthesised using solid phase chemistry. All peptides were synthesised with an added N-terminal cysteine and purified by reverse-phase HPLC to facilitate coupling to a carrier protein diphtheria toxoid (DT) using the hetero-bifunctional reagent maleimidocaproloxysuccinimide (MCS). Mice were immunised with these peptide-DT conjugates using Freund's complete adjuvant (FCA). The immune response of these mice was tested against peptide hapten, carrier protein (DT) and the linking region itself, using enzyme-linked immunoassay (ELISA). Although there was great variation in the immune response to each part of the immunogen construct, no significant correlation could be seen between each set of responses.

Amino Acid Sequence↗
PubMed1990

Effect of thromboxane antagonists on ozone-induced airway responses in dogs.

Airway hyperresponsiveness after inhaled ozone in dogs may occur as a result of thromboxane release in the airway. In this study, two thromboxane receptor antagonists, L-655,240 and L-670,596, were used in doses that inhibit the response to an inhaled thromboxane mimetic, U-46619, to determine further the role of thromboxane in ozone-induced airway hyperresponsiveness. Dogs were studied on 2 days separated by 1 wk. On each day, the dogs inhaled ozone (3 ppm) for 30 min. On one randomly assigned day, 10 dogs received an infusion of L-655,240 (5 mg.kg-1.h-1) and 5 dogs received an infusion of L-670,596 (1 mg.kg-1.h-1); on the other day dogs received a control infusion. Airway responses to doubling doses of acetylcholine were measured before and after inhalation of ozone and were expressed as the concentration of acetylcholine giving a rise in resistance of 5 cmH2O.l-1.s from baseline (acetylcholine provocation concentration). The development of airway hyperresponsiveness after ozone was not inhibited by the thromboxane antagonists. The mean log difference in the acetylcholine provocative concentration before and after ozone on the L-655,240 treatment day was 0.62 +/- 0.12 (SE) and on the control day was 0.71 +/- 0.12 (P = 0.48); on the L-670,596 treatment day the mean log difference was 0.68 +/- 0.15 (SE) and on the control day it was 0.75 +/- 0.19 (P = 0.45). These results do not support an important role for thromboxane in causing ozone-induced airway hyperresponsiveness.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

The use of maleimidocaproyloxysuccinimide to prepare malarial peptide carrier immunogens. Immunogenicity of the linking region.

Malarial peptides synthesized with an added N terminal cysteine were conjugated to purified diphtheria toxoid (DT) protein using the bifunctional reagent maleimidocaproyloxysuccinimide (MCS). The molar ratio of peptide to carrier was determined by subtractive sulphydryl titration and confirmed by sodium dodecyl sulphate (SDS) electrophoresis. For enzyme-linked immunoabsorbent (ELISA) analysis of sera from animals immunized with the DT conjugates, peptides were conjugated to bovine serum albumin (BSA) using MCS as well as a glutaraldehyde based coupling procedure. Western blotting analysis shows that both DT and BSA adducts were recognized by monoclonal antibodies (Mabs) directed against the peptide epitopes in the native sequences. Animals immunized with the DT-peptide conjugates produced antibodies to the coupling reagent (MCS) as well as diphtheria toxoid and peptide specific antibodies. This MCS specificity could be largely abolished by pre-incubation of sera with a soluble MCS homologue, a thiosuccinimidocaproylamide (TSC).

Amino Acid Sequence↗
PubMed1988

Airway smooth muscle responsiveness from dogs with airway hyperresponsiveness after O3 inhalation.

Airway hyperresponsiveness occurs after inhalation of O3 in dogs. The purpose of this study was to examine the responsiveness of trachealis smooth muscle in vitro to electrical field stimulation, exogenous acetylcholine, and potassium chloride from dogs with airway hyperresponsiveness after inhaled O3 in vivo and to compare this with the responsiveness of trachealis muscle from control dogs. In addition, excitatory junction potentials were measured with the use of single and double sucrose gap techniques in both groups of dogs to determine whether inhaled O3 affects the release of acetylcholine from parasympathetic nerves in trachealis muscle. Airway hyperresponsiveness developed in all dogs after inhaled O3 (3 ppm for 30 min). The acetylcholine provocative concentration decreased from 4.11 mg/ml before O3 inhalation to 0.66 mg/ml after O3 (P less than 0.0001). The acetylcholine provocative concentration increased slightly after control inhalation of dry room air. Airway smooth muscle showed increased responses to both electrical field stimulation and exogenous acetylcholine but not to potassium chloride in preparations from dogs with airway hyperresponsiveness in vivo. The increased response to electrical field stimulation was not associated with a change in excitatory junctional potentials. These results suggest that a postjunctional alteration in trachealis muscle function occurs after inhaled O3 in dogs, which may account for airway hyperresponsiveness after O3 in vivo.

Acetylcholine↗
PubMed1988

Release of epithelium-derived relaxing factor after ozone inhalation in dogs.

Airway epithelium has been reported to release epithelium-derived relaxing factor (EpDRF), which inhibits contraction of airway smooth muscle. This study tested the hypothesis that airway hyperresponsiveness after inhalation of ozone in dogs results from an inability to produce EpDRF. Two groups of five dogs each were studied; one group inhaled ozone, the other dry room air. Ozone-treated dogs developed airway hyperresponsiveness, whereas the control group did not. The acetylcholine provocative concentration decreased from 4.17 (%SE 1.35) to 0.56 mg/ml (%SE 1.24) (P = 0.0006) in the ozone-treated dogs and was 18.76 (%SE 2.04) and 29.77 mg/ml (%SE 2.07) in the air-treated dogs (P = 0.47). In vitro the presence of airway epithelium reduced the constrictor responses to acetylcholine, histamine, serotonin, and KCl in trachealis strips from the control dogs. This effect of epithelium was still present in trachealis strips from dogs with airway hyperresponsiveness. These results demonstrate that EpDRF is released from canine tracheal epithelium, that this function is not impaired in dogs with airway hyperresponsiveness after inhaled ozone, and that loss of EpDRF is not responsible for the development of airway hyperresponsiveness after inhaled ozone in dogs.

Acetylcholine↗
PubMed1987

Trace metals in the hair of habitants of the Ok Tedi region, Papua New Guinea.

It has long been known that mining activity can markedly change the level and distribution of certain heavy metals in the adjacent environment. This pollution can be quite widespread and long lasting and often has deleterious effects on the health of local populations. In the present study scalp hair was used as the biopsy material because of its ease of collection and long history of use in this connection. Hair was collected from all the local villages in the vicinity of the mine site, as well as from Papua New Guinean nationals from other provinces, and European expatriates who were employed by the mining company and who were resident in the area. Hair from local people showed a remarkably high iron content by comparison with previously studied populations. The extreme variations in hair iron levels were reflected in the differential distribution of levels according to location, age and sex. Hair cadmium was also high in the population studied. Hair copper, lead, zinc and mercury all appeared to be within 'normal' limits by comparison with other general populations. These results are discussed in the context of the environmental and social impact of the mining operations on the local people.

Journal Article↗
PubMed1987

Role of the parasympathetic nervous system in airway hyperresponsiveness after ozone inhalation.

Airway hyperresponsiveness develops in dogs after ozone inhalation. This study examined the role of the parasympathetic nervous system in ozone-induced airway hyperresponsiveness in dogs. Dose-response curves to acetylcholine (n = 8) and histamine (n = 4) were measured before and after exposure to ozone (3 ppm for 30 min). The provocative concentration of each agonist was measured on two randomly assigned days separated by at least 1 wk. On one day a control experiment was performed, and on the other day the dogs were pretreated with the ganglionic blocker hexamethonium bromide in doses that block ganglionic transmission. The acetylcholine provocative concentration decreased on the control day from 5.5 mg/ml (%SE 1.8) before ozone to 0.5 mg/ml (%SE 2.0) after ozone (P less than 0.0001). After pretreatment with hexamethonium the acetylcholine provocative concentration decreased from 9.0 mg/ml (%SE 1.8) before ozone to 1.0 mg/ml (%SE 2.0) after ozone (P = 0.002). The results were similar when histamine was used as the agonist. Therefore, ganglionic blockade does not prevent airway hyperresponsiveness after ozone inhalation, and a parasympathetic reflex mechanism is not responsible for airway hyperresponsiveness after ozone inhalation in dogs.

Acetylcholine↗
PubMed1987

Tachyphylaxis to inhaled histamine in asthmatic subjects.

The bronchoconstriction induced by repeated histamine inhalation tests was studied in eight mild stable asthmatic subjects to determine whether histamine tachyphylaxis occurs in asthmatics. We also studied the specificity of histamine tachyphylaxis by examining for tachyphylaxis in response to inhaled acetylcholine in these subjects. We subsequently investigated whether indomethacin pretreatment inhibited histamine tachyphylaxis. Tachyphylaxis in response to inhaled histamine occurred in all subjects. The mean histamine provocative concentration causing a 20% fall in the forced expiratory volume in 1 s (PC20) increased from 3.04 +/- 1.9 (%SD), to 4.88 +/- 1.9, and to 6.53 +/- 2.2 mg/ml (P less than 0.0005) with successive inhalation tests. Tachyphylaxis was still present at 3 h (P less than 0.01), but not in all subjects at 6 h (P greater than 0.05). Tachyphylaxis, however, did not occur in response to inhaled acetylcholine. In addition, indomethacin pretreatment prevented histamine tachyphylaxis. Thus this study demonstrates that there is a histamine-specific mechanism that can partially protect the airways against repeated bronchoconstriction caused by histamine. This effect may occur through the release of inhibitory prostaglandins in the airway after histamine stimulation. Also when histamine inhalation tests are repeated on the same day, the tests should be separated by greater than 6 h to avoid tachyphylaxis.

Acetylcholine↗
PubMed1986

Alpha-thalassemia in Papua New Guinea.

A study of the distribution of alpha-thalassemia in Papua New Guinea (PNG) was carried out by DNA analysis. A total of 664 DNA samples were screened for alpha-thalassemia 2 and alpha-thalassemia 1 caused respectively by either deletion of one or both of the duplicated alpha-globin genes. alpha-Thalassemia 2 was detected in high frequencies in coastal and lowland regions where malaria has been holo- to hyperendemic but in low frequencies in non-malarious highland regions. The highest frequency was observed in the north coast of PNG. The distribution of alpha-thalassemia 2 seems to be in accordance with other conditions such as ovalocytosis and G6PD deficiency which are also prevalent in this population, suggesting that they may interact in protection against malaria. However, it appears to be negatively correlated with beta-thalassemia and alpha-thalassemia 1, the latter being extremely rare in this population. Analysis of the types and subtypes of the single alpha-globin gene deletion revealed a predominance of the -alpha 4.2 type in general, except in some regions in the south where the -alpha 3.7 type is prevalent. The -alpha 3.7 I subtype is the common form of the -alpha 3.7 deletion in the PNG mainland. The -alpha 3.7 III subtype, previously reported to be unique in Melanesians and Polynesians, was detected in an offshore island of PNG. However, this subtype is very rare in Melanesians from the PNG mainland.

Chromosome Deletion↗
PubMed1986

The effect of indomethacin on exercise-induced bronchoconstriction and refractoriness after exercise.

Exercise causes bronchoconstriction in asthmatic subjects, which is usually followed by a refractory period during which exercise of the same intensity will cause less bronchoconstriction. This study examined the role of contractile prostaglandins in the initial bronchoconstriction after exercise and the role of inhibitory prostaglandins in the refractoriness after exercise. Subjects were pretreated with indomethacin, 50 mg twice daily, on 1 occasion or placebo on 2 occasions for 3 days. This was followed by 2 exercise challenges on a bicycle ergometer at least 30 min apart. Indomethacin did not alter the initial bronchoconstriction after exercise. The maximal fall in FEV1 after the first exercise challenge after placebo was 0.67 +/- 0.17 L and 0.68 +/- 0.17 L, and after indomethacin it was 0.67 +/- 0.12 L. Indomethacin, however, did prevent refractoriness after exercise. The maximal fall in FEV1 after the second exercise challenge after placebo was 0.31 +/- 0.06 L and 0.36 +/- 0.12 L, and after indomethacin it was 0.64 +/- 0.12 L. These results indicate that indomethacin pretreatment does not alter bronchoconstriction after exercise, and they also indicate that indomethacin pretreatment prevents refractoriness after exercise in asthmatic subjects.

Adult↗
PubMed1986

A potent and selective inhibitor of cyclic AMP phosphodiesterase with potential cardiotonic and antithrombotic properties.

Some biochemical and pharmacological properties of a novel, potent inhibitor of cyclic AMP phosphodiesterase, N-cyclohexyl-N-methyl-4-(7-oxy-1,2,3,5-tetrahydroimidazo[2,1-b] quinazolin-2-one) butyramide (RS-82856), were investigated. RS-82856 selectively inhibits the high affinity form of cyclic AMP phosphodiesterase (type IV) isolated from human platelets (Ki = 0.5 nM) with only weak effects on both the nonspecific and cyclic GMP-sensitive phosphodiesterases. The inhibitor reduces both maximum velocity and substrate affinity of the type IV enzyme. This mixed pattern of partial competitive and noncompetitive inhibition was also obtained with one of the two high affinity forms of phosphodiesterase found in dog heart (Ki = 0.75 nM). Of several human and dog tissues examined, RS-82856 exhibits marked selectively for the platelet high affinity enzyme. It also has significant inhibitory effects on cardiac membrane-bound phosphodiesterase. RS-82856 inhibits the aggregation of human platelets in response to adenosine 5'-diphosphate (IC50 = 0.11 microM) in vitro and is active ex vivo for at least 2 hr following oral administration (10 mg/kg) to rhesus monkeys. Administration of RS-82856 to instrumented, anesthetized dogs by either intravenous or intraduodenal routes increases cardiac contractile force and reduces afterload. These data suggest that RS-82856 may be useful as an agent to increase cardiac output in the treatment of congestive heart failure.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

Inspiratory muscle forces and endurance in maximum resistive loading.

The ability of the respiratory muscles to sustain ventilation against increasing inspiratory resistive loads was measured in 10 normal subjects. All subjects reached a maximum rating of perceived respiratory effort and at maximum resistance showed signs of respiratory failure (CO2 retention, O2 desaturation, and rib cage and abdominal paradox). The maximum resistance achieved varied widely (range 73-660 cmH2O X l-1 X s). The increase in O2 uptake (delta Vo2) associated with loading was linearly related to the integrated mouth pressure (IMP): delta Vo2 = 0.028 X IMP + 19 ml/min (r = 0.88, P less than 0.001). Maximum delta Vo2 was 142 ml/min +/- SD 68 ml/min. There were significant (P less than 0.05) relationships between the maximum voluntary inspiratory pressure against an occluded airway (MIP) and both maximum IMP (r = 0.80) and maximum delta Vo2 (r = 0.76). In five subjects, three imposed breathing patterns were used to examine the effect of different patterns of respiratory muscle force deployment. Increasing inspiratory duration (TI) from 1.5 to 3.0 and 6.0 s, at the same frequency of breathing (5.5 breaths/min) reduced peak inspiratory pressure and increased the maximum resistance tolerated (190, 269, and 366 cmH2O X l-1 X s, respectively) and maximum IMP (2043, 2473, and 2913 cmH2O X s X min-1, but the effect on maximum delta Vo2 was less consistent (166, 237, and 180 ml/min). The ventilatory endurance capacity and the maximum O2 uptake of the respiratory muscles are related to the strength of the inspiratory muscles, but are also modified through the pattern of force deployment.

Adult↗
PubMed1984

alpha,alpha-Diphenylsuccinimide: evaluation of anticonvulsant and hydrophobic properties.

The anticonvulsant potencies (ED50) of alpha,alpha-diphenylsuccinimide, phenytoin, and phenobarbital were evaluated in mice by a standard maximal electroshock technique. Potencies were expressed in terms of intraperitoneal dosage and blood and brain concentrations. Overt neurotoxicity (TD50) was assessed by the rotorod method. These data were compared with relative hydrophobicities for the above compounds and three others [carbamazepine, cyheptamide, and (diphenylacetyl)urea] taken from the literature. An approximate parabolic dependence of anticonvulsant potency on hydrophobicity was observed regardless of the means of expressing potency (intraperitoneal dosage, blood concentration, or brain concentration); approximate optimal hydrophobicities were in the range of 2.18-2.23 (log P). Calculated therapeutic indices (TD50/ED50) also displayed a parabolic dependence on hydrophobicity, while toxic potency (TD50) displayed a linear dependence (within the limited range of log P values studied). Implications of the parabolic dependence of anticonvulsant potency and linear dependence of toxic potency on hydrophobicity are discussed with respect to the possible mechanisms involved.

Animals↗
PubMed1984

Red cell membrane proteins in insulin-dependent diabetes: differential effects of treatment with calcium and various proteases.

Red cell ghosts prepared in the presence and absence of calcium from diabetics and age- and sex-matched controls, were subjected to proteolytic digestion with trypsin directly after extraction of the membranes and under conditions designed to maximize absorption of the protease to the membranes. Membranes were also directly digested with alpha-chymotrypsin and the V8 protease from S. aureus. The membrane protein profile was examined using sodium dodecyl sulfate (SDS) electrophoresis. In the untreated membranes, consistent apparent increases were seen in several minor bands in the area between bands 2 and 3 and in the area between the 4.1, 4.2 doublet and band 5. Calcium lysis caused major alterations in both diabetic and control membrane proteins. Trypsin hydrolysis proved most effective when the protease was preabsorbed to the membranes but whether preabsorbed or added directly prior to incubation, proteolysis was much less marked with the diabetic membranes. Only minor differences were seen in the alpha-chymotrypsin cleavage patterns and no differences at all were seen in the V8 protease cleavage patterns.

Adult↗