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Biomedical subjects

R J Pierce

Publications and source records attributed to R J Pierce.

At least 19 recordsLinked to original sources
PubMed1999

Vaccine potential of a recombinant glutathione S-transferase cloned from Schistosoma haematobium in primates experimentally infected with an homologous challenge.

Patas monkeys were twice immunized with a Schistosoma haematobium-derived recombinant glutathione S-transferase (Sh28GST) then challenged with an homologous calibrated challenge. BCG and Freund's Complete Adjuvant (FCA) were used as adjuvants in two distinct protocols. Specific IgG and IgA antibody responses were intense and homogeneous in the animals receiving Sh28GST in the presence of FCA, whereas BCG could only induce moderate and heterogeneous antibody titres. No significant effect on worm burdens was evidenced 36 weeks post-infection in either group of Sh28GST-immunized animals compared to their matched controls receiving an irrelevant protein. Although not significant, 50% reductions in the numbers of eggs located in all tissues (FCA group) and in the urogenital system (BCG group) were noted. Moreover, the total number of excreted eggs was dramatically diminished by 60% and 77% in the BCG and FCA groups, respectively. These reductions reached 75% and 80% in the urines of vaccinated monkeys. Bladder pathology was also reduced in the animals displaying the lowest urinary egg excretions. There was no clear positive or negative correlate between antibody responses and individual levels of protection. Taken as a whole, our results show that Sh28GST was capable of significantly reducing S. haematobium worm fecundity in experimentally infected primates. Although FCA induced higher levels of protection, the efficacy of BCG as an adjuvant appeared sufficient to justify consideration of the future application of this new formulation as a vaccine against human urogenital schistosomosis.

Animals↗
PubMed1999

Upper airway function and dysfunction in respiration.

1. The upper airway not only provides a passage for air to be breathed in and out of the lungs, but it also heats, humidifies and filters the air and is involved in cough, swallowing and speech. 2. The complex muscle structure of the upper airway that produces speech and swallowing in humans also modulates respiratory airflow throughout the respiratory cycle, but is vulnerable to functional problems that may compromise respiration. 3. Even in normals, there is some collapse of the upper airway and increased upper airway resistance during sleep. 4. A substantial proportion of people suffer from obstructive sleep apnoea, in which the collapse of the upper airway is so great that respiration is compromised to the extent that arousal from sleep is required to restore adequate ventilation; the resulting disturbed sleep and hypoxia produce daytime sleepiness and neuropsychological and cardiorespiratory morbidity. 5. Functional abnormalities of the larynx can also occur, including prolonged inspiratory laryngeal dysfunction, brief upper airway dysfunction and expiratory laryngeal dysfunction or factitious asthma.

Humans↗
PubMed1998

Alterations in cytochrome-c oxidase expression between praziquantel-resistant and susceptible strains of Schistosoma mansoni.

The genetic differences between praziquantel-resistant (R) and susceptible (S) strains of Schistosoma mansoni (Fallon & Doenhoff, 1994) were explored using RAPD and by cloning differentially expressed mRNAs by subtractive PCR. No differences between the 2 strains were detectable by RAPD using 41 different primers indicating that no major genomic rearrangements were present. Subtractive PCR generated a number of fragments, 1 of which was shown to correspond to an over-expressed mRNA in the R strain and to encode a fragment of the subunit 1 of cytochrome-c oxidase (SCOX1). In the absence of a complete sequence for this gene, we used EST sequences to compile a consensus sequence for the 904 bp at the 3' end that enabled us to choose primers for semi-quantitative RT-PCR. This technique showed that SCOX1 was indeed over-expressed about 5 to 10-fold in the R strain whereas the genes encoding the 28 kDa glutathione S-transferase, glutathione peroxidase, NADH dehydrogenase subunit 5 and the ATP-binding cassette family protein SMDR2 were not. In contrast, cytochrome-c oxidase enzyme activity was 4-fold lower in the R strain than in the S strain.

Amino Acid Sequence↗
PubMed1998

The prevalence of obstructive sleep apnea in hypertensives.

This study was designed to measure the prevalence of obstructive sleep apnea in untreated and treated hypertensive patients by comparing them with normotensive subjects, taking into account the possible confounding variables body mass index, age, sex, and alcohol consumption. Subjects with no known sleep disorders were recruited, had full polysomnography, and had their blood pressure assessed with a 24-h ambulatory monitor. Subjects with a mean 24-h blood pressure greater than 140/90, and receiving no treatment for, or with no history of, hypertension were classified as untreated hypertensives; those receiving antihypertension medication were classified as treated hypertensives; those with a mean 24-h blood pressure less than 140/90 and no history of hypertension were classified as normotensives. Thirty-eight percent of the 34 untreated and 38% of the 34 treated hypertensives, and 4% of the 25 normotensives had apnea-hypopnea indexes greater than 5. Logistic regression analysis showed that body mass index (p = 0.001), age (p = 0.07), sex (p = 0.07), treated hypertension (p = 0.05), and untreated hypertension (p = 0.06) were associated with the presence of sleep apnea, but that alcohol consumption (p = 0.82) was not. It is concluded that there is a relationship between sleep apnea and hypertension that, although partially explained by the confounding variables body mass index, age, and sex, persists when these are allowed for.

Age Distribution↗
PubMed1997

Clinical spirometry.

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Forced Expiratory Volume↗
PubMed1997

Intranasal priming with recombinant Bordetella pertussis for the induction of a systemic immune response against a heterologous antigen.

One of the current goals in vaccine development is the noninvasive administration of protective antigens via mucosal surfaces. In this context, the gut-associated lymphoid tissues have already been extensively explored. Vaccination via the nasal route has only recently been the focus of intensive investigation, and no live vector specifically designed for the respiratory mucosa is yet available. In this study we show that intranasal administration of the recombinant Bordetella pertussis BPGR60, producing the Schistosoma mansoni 28-kDa glutathione S-transferase (Sm28GST) protective antigen fused to filamentous hemagglutinin, induces priming in mice for the production of serum antibodies. In addition to significant levels of anti-Sm28GST immunoglobulin A (IgA) antibodies, high levels of anti-Sm28GST serum antibodies were obtained after intranasal boost with the purified antigen or infection with S. mansoni following intranasal priming with BPGR60. These antibodies were of the IgG1, IgG2a, and IgG2b isotypes, suggesting a mixed immune response. No priming was observed in animals that had received nonrecombinant B. pertussis or purified Sm28GST, indicating specific priming by BPGR60. This priming was also evident in immune protection against S. mansoni challenge. Significant protection against worm burden and egg output was obtained in mice primed with BPGR60 and intranasally boosted with purified Sm28GST. A lower but still significant degree of protection against egg output was also obtained in mice infected with a single dose of BPGR60. These results indicate that intranasal administration of recombinant B. pertussis can prime for serum antibody responses against a foreign antigen and for heterologous protection.

Administration, Intranasal↗
PubMed1997

Expression of a Schistosoma mansoni 28-kilodalton glutathione S-transferase in the livers of transgenic mice and its effect on parasite infection.

Schistosomiasis is a debilitating tropical disease for which an effective vaccine is needed. A 28-kDa glutathione S-transferase from Schistosoma mansoni (Sm28GST) has been shown to induce protective immunity. Sm28GST possesses significant sequence identity to mammalian GST isoforms. In order to study self-reactivity in mice immunized with Sm28GST and the concomitant phenomena of immune tolerance and epitope suppression, as well as their consequences for the protective immunity induced by this vaccination, we developed transgenic (Tg) mice that express Sm28GST under the control of a part of the mouse transferrin gene promoter. A study of (P28)Tg mice showed that the expression of Sm28GST was strictly localized in pericentrolobular hepatocytes. No histological change, inflammatory infiltrates, or modification of seric L-aspartate: 2-oxoglutarate aminotransferase concentration was observed over an 18-month period, despite a cross-reactivity between Sm28GST and a mouse molecule of 30 kDa. The immunoglobulin G anti-Sm28GST response of (P28)Tg mice immunized with recombinant Sm28GST was lower (P < 0.001) than that observed in non-(P28)Tg littermates and inversely proportional of Sm28GST liver expression. The response of non-(P28)Tg mouse spleen cells to Sm28GST stimulation was greater (P < 0.01) than that observed with (P28)Tg mouse spleen cells. (P28)Tg mice infected with 40 S. mansoni furcocercariae harbored more worms (P < 0.05) than did non-(P28)Tg control mice. The increase in the level of infection in (P28)Tg mice was reflected in concomitant increases in the numbers of adult worms and schistosome eggs found in livers and intestines after whole-body perfusion at 56 days postinfection, but no relative increase in the fertility of individual female worms was observed. The results obtained argue for the involvement of Sm28GST in reducing levels of infection and support the view that this enzyme has a central role in the maintenance of parasite viability, at least during its migration through host tissues.

Animals↗
PubMed1997

Comparison of oral bambuterol and terbutaline in elderly patients with chronic reversible airflow obstruction.

Bambuterol, a carbamate prodrug of terbutaline, is the first once-daily oral beta 2-agonist. The effect/side effect ratio of bambuterol oral solution was compared with terbutaline mixture in elderly patients with chronic reversible obstructive airways disease. The study was of a double-blind, crossover, randomized design and consisted of a 4-7-day run-in period followed by four consecutive treatment periods each of 2 weeks. The treatments were bambuterol solution 20 mg nocte (B20), 10 mg nocte (B10), terbutaline mixture 3 mg t.i.d., (T), and placebo solution (P). Patients measured daily peak expiratory flow rate (PEFR), asthma symptoms, use of inhaled beta 2-agonist, and tremor. Of 84 patients, 66 completed all periods. Mean age was 67 years (60-90), basal FEV1 1.49 L, and reversibility of FEV1 30%. Ninety-four percent of the patients used inhaled/oral steroids in constant dosage. All treatments were significantly more effective than placebo. B20 resulted in higher morning PEFR than T (306 +/- 2.9 L/min vs. 297 +/- 2.9 L/min), while B10 gave equivalent results to T. No differences were seen in the use of inhaled beta 2-agonist. Less shortness of breath was experienced during the night with B20 and during the day with B10 compared with placebo. Both B20 and T produced more tremor than B10 and P. In elderly patients with chronic reversible airways obstruction once-daily bambuterol (10-20 mg) has a better effect/side effect ratio than 3 mg terbutaline thrice daily.

Administration, Oral↗
PubMed1996

Tissue localization and stage-specific expression of the phospholipid hydroperoxide glutathione peroxidase of Schistosoma mansoni.

The tissue localization and the stage-specific expression of the phospholipid hydroperoxide glutathione peroxidase of Schistosoma mansoni (SmPHGSHpx) have been determined. An antiserum raised against the C-terminal region of the predicted protein sequence was used for immunocytochemical investigations. The native protein is expressed only in female and egg vitelline cells and is practically absent from male worm tissue. Western blot data confirmed these results and showed the complete absence of SmPHGSHpx from cercariae. However, Northern blotting indicated the presence of the corresponding mRNA at all life-cycle stages investigated. The sequence determination of the 5' flanking region of the SmPHGSHpx gene revealed the presence of an extended TATA box (5'-TAAATA-3') at -32, a possible CAAT box at -75 and a putative monomeric estrogen response element 5'-GGTCAA-3' at position -486. In addition, direct and inverted repeat elements are present.

Amino Acid Sequence↗
PubMed1995

Is normobaric simulation of hypobaric hypoxia accurate in chronic airflow limitation?

Hypobaric hypoxemia is experienced by passengers during commercial aircraft flight. In order to assess the extent of hypoxemia and to test whether hypobaric hypoxia can be accurately estimated at sea level, the results of the normobaric hypoxia altitude simulation test (N-HAST) were compared with those of the hypobaric hypoxia altitude simulation test (H-HAST) in six normal control subjects and nine patients with chronic airflow limitation (CAL) at simulated cabin altitudes of 6,000 ft (1,829 m) and both at rest and during exercise at 8,000 ft (2,438 m). Serial arterial blood samples were drawn during the breathing of 15.1 and 16.3% inspired oxygen at sea level (N-HAST) at rest and during light exercise, and during the breathing of room air at simulated cabin altitudes (H-HAST) of 609 mm Hg (6,000 ft) and 565 mm Hg (8,000 ft) at rest and during light exercise. As measured with the H-HAST technique, the mean (+/- SD) PaO2 of the normal group fell from 96.2 +/- 6.2 mm Hg (sea level) to 70.1 +/- 6.0 mm Hg (6,000 ft), and to 61.7 +/- 1.6 mm Hg (8,000 ft at rest) and 54.8 +/- 7.1 mm Hg (8,000 ft during exercise) (p < 0.005 by analysis of variance [ANOVA]). In the CAL group, the mean (+/- SD) PaO2 fell from 75.8 +/- 8.2 mm Hg (sea level) to 57.0 +/- 6.3 mm Hg (6,000 ft), and 49.5 +/- 6.1 mm Hg (8,000 ft at rest), and 38.6 +/- 7.5 mm Hg (8,000 ft during exercise) (p < 0.005 by ANOVA).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Construction, expression, and immunogenicity of multiple tandem copies of the Schistosoma mansoni peptide 115-131 of the P28 glutathione S-transferase expressed as C-terminal fusions to tetanus toxin fragment C in a live aro-attenuated vaccine strain of Salmonella.

Genetic fusions have been constructed between the highly immunogenic but atoxic fragment C of tetanus toxin and a guest peptide, aa115-131, from the protective 28-kDa glutathione S-transferase Ag of Schistosoma mansoni. Fusions have been assembled to express one, two, four, and eight tandem copies of the peptide. The recombinant vectors have been electroporated into the nonvirulent aroA strain of Salmonella typhimurium SL3261. The fusion proteins are soluble and stably expressed in Salmonella as evaluated by Western blotting with fragment C and glutathione S-transferase antisera. Mice have been immunized i.v. with a single dose of the live recombinant salmonellae. The strains are stable in mice and elicit Ab responses directed against fragment C, as determined by enzyme-linked immunosorbent assays. Ab responses were also detected against the guest peptide. The Ab responses improved dramatically toward the aa115-131 peptide with increasing copy number, with the octameric "repitope" fusion displaying the greatest potency. This approach may represent a general strategy for eliciting immune responses against peptides in live bacterial vaccines.

Amino Acid Sequence↗
PubMed1994

Construction, expression, and immunogenicity of the Schistosoma mansoni P28 glutathione S-transferase as a genetic fusion to tetanus toxin fragment C in a live Aro attenuated vaccine strain of Salmonella.

A vector has been constructed to allow genetic fusions of guest antigens via a hinge domain to the C terminus of the highly immunogenic C fragment of tetanus toxin. A fusion has been constructed with the gene encoding the protective 28-kDa glutathione S-transferase (EC 2.5.1.18) from Schistosoma mansoni. The recombinant vector has been electroporated into the nonvirulent Salmonella typhimurium aroA live vaccine strain SL3261. The corresponding chimeric protein is stably expressed in a soluble form in Salmonella as evaluated by Western blotting with fragment C and glutathione S-transferase antisera. Mice immunized intravenously with a single dose of the live recombinant bacteria elicit antibodies to both fragment C and glutathione S-transferase as detected by enzyme-linked immunosorbent assays. Furthermore, all of the mice were solidly protected when challenged with lethal doses of either tetanus toxin or the virulent Salmonella typhimurium strain C5. Mice have also elicited antibodies to fragment C and glutathione S-transferase after oral immunization. It may be that a live trivalent vaccine against typhoid, tetanus, and schistosomiasis is feasible.

Animals↗
PubMed1994

Cloning and characterization of the gene encoding Schistosoma mansoni glutathione peroxidase.

Antioxidant enzymes are thought to play a crucial role in the survival of the parasite, Schistosoma mansoni, during its migration through the tissues of the definitive host. We recently cloned the cDNA encoding one such enzyme, glutathione peroxidase (Gpx). In order to elucidate the regulation of expression of this gene, we describe the cloning and characterization of a Gpx gene of S. mansoni. An initial screen of a lambda EMBL4 genomic library using the corresponding cDNA sequence as a probe yielded 14 positive clones, two of which have so far been analyzed in detail. The complete Gpx gene contains five introns, four of which, located at the 5' end, are extremely short (30-51 bp) and the last of which is approximately 6 kb long. We present the sequence of the gene including 73 bp at the 5' end, the complete sequence to 137 bp downstream from the penultimate exon, 164 bp upstream and 131 bp downstream from the last 3' exon. The potential mRNA cap site is situated 219 bp upstream from the ATG start codon. All intron/exon junctions correspond to the conventional eukaryotic splice signal. Analysis of the 5' flanking region revealed the presence of a potential TATA box at--26 bp from the cap site, but no CAAT-like element is present. Southern blot analysis showed a unique Gpx gene organisation in the S. mansoni genome.

Amino Acid Sequence↗
PubMed1994

Molecular characterization of two Schistosoma mansoni proteins sharing common motifs with the vif protein of HIV-1.

We have previously described a rat mAb directed against a peptide derived from the vif protein of HIV-1 that recognized two Schistosoma mansoni (Sm) antigens with a major band at 65 kDa. Epitope mapping of this mAb using overlapping hexapeptides derived from the vif peptide revealed that the motif recognized was PLPSVT. The screening of a Sm cDNA library led to the identification of two clones, Sm70 and Sm65. The two deduced protein sequences did not share any common structural features apart from the epitope recognized by the mAb (see below), and did not show significant identity to sequences present in the data bases. However, the N terminus of the deduced sequence of the Sm70 protein exhibits a consensus sequence known to be an ATP/GTP binding site. Furthermore, the C terminus of the deduced Sm65 protein sequence was found to contain a conserved hexapeptide with a consensus sequence LPETGE reported to be an important motif of the surface proteins of gram-positive cocci. Both proteins exhibit a peptide sequence (PLRSVT for Sm70 and PVGSVT for Sm65) similar to the epitope recognized by the mAb anti-vif. Western blotting experiments showed that the mAb anti-vif reacted with both proteins. However, only Sm65 was recognized by sera from HIV-1-seropositive individuals, whereas both proteins were recognized by S. mansoni-infected patients.

Amino Acid Sequence↗