The ethics of randomised controlled trials from the perspectives of patients, the public, and healthcare professionals.
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Attitude of Health Personnel↗
Biomedical subjects
S J Edwards
Publications and source records attributed to S J Edwards.
Informed consent for clinical trials: in search of the "best" method.
OBJECTIVE: To review the literature on comparisons between different methods of obtaining informed consent for clinical trials. DESIGN: Eight hundred and twelve articles were traced, in the process of conducting a systematic review of the ethics of clinical trials, by searching a number of sources: bibliographic databases (Medline, Psychlit and BIDS science and social science indices), hand searches, personal contacts, an original collection and a systematic follow-up of reference lists. Fourteen research reports were found which provided comparative data on different methods of obtaining informed consent. Eleven of these used a randomised design. Studies were classified according to three outcome measures (anxiety, consent rate and understanding). RESULTS: The results of the various studies suggest that giving people more information and more time to reflect tends to be associated with a lower consent rate. There seems to be an optimal level of information about side-effects such that patients are not overburdened by detail, while grasping the most important risks. More information in general is associated with greater awareness of the research nature of the trial, voluntariness of participation, right to withdraw and (available) alternative treatments. This result does not, however, extend to explanations of the concept of randomisation on which the literature is contradictory--sometimes more information is associated with increased understanding of the concept and sometimes it is not. Although divulging less information seems to be associated with less anxiety, there is evidence of an interaction with knowledge--high levels of knowledge are significantly associated with less anxiety, irrespective of consent method. The more that patients know before they are invited to participate in a trial, the better equipped they are to cope with the informed consent procedure. CONCLUSION: There is some evidence to suggest that there is an optimal amount of information which enhances patient understanding and which might, in turn, reduce anxiety. However. the studies were not altogether conclusive. More work needs to be carried out, especially on public understanding of science and on how different ways of explaining scientific concepts affect that understanding.
Clinical Trials as Topic↗
Ethical issues in the design and conduct of randomised controlled trials.
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Attitude↗
Why "underpowered" trials are not necessarily unethical.
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Clinical Trials as Topic↗
Impaired vision for binocular tasks after unilateral optic nerve regeneration in the frog Litoria moorei.
Behavioural responses to objects in the binocular field were examined in frogs with one regenerate and one intact optic nerve. Data were compared to those for normal controls and for frogs with vision via one intact optic nerve. During prey acquisition, frogs with regenerated optic nerves underestimated the distance to the prey on their first strike; as a consequence, the regenerate series made several attempts to achieve a successful prey capture. By contrast, normal frogs and those using only one eye struck accurately at the prey and usually captured it on the first attempt. However, frogs using only one eye struck from a closer distance than either the regenerate or normal series. Frogs with regenerated optic nerves also made more errors than either of the other series when leaping through a set of closely spaced horizontally aligned rods. Our results show that prey capture and the negotiation of horizontally aligned rods is impaired in animals using one regenerated and one intact optic nerve as compared to both normal frogs and those using only one eye. We suggest that the poor visual performance for frogs with one regenerated and one intact optic nerve for tasks presented in the binocular field is related to the integration of a degraded and a normal image within the visual centres.
Animals↗
Identification of the complete coding sequence and genomic organization of the Treacher Collins syndrome gene.
Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. Recently, the demonstration of a series of 10 mutations within a partial-length cDNA clone have indicated that the TCS gene (TCOF1) has been positionally cloned. Although it has been shown that the gene is expressed in a wide variety of fetal and adult tissues, database sequence comparisons have failed to provide significant information on the function of the gene. In the current investigation, a combination of cDNA library screening and rapid amplification of cDNA ends has permitted the isolation of the complete coding sequence of TCOF1, which is encoded by 26 exons and predicts a low complexity, serine/alanine-rich protein of approximately 144 kD. The use of a variety of bioinformatics tools has resulted in the identification of repeated units within the gene, each of which maps onto an individual exon. The predicted protein Treacle contains numerous potential phosphorylaiton sites, a number of which map to similar positions within the repeated units, and shows weak but significant homology to the nucleolar phosphoproteins. Although the precise function of Treacle remains unknown, these observations suggest that phosphorylation may be important for its role in early embryonic development and that it may play a role in nucleolar-cytoplasmic shuttling. The information presented in this study will allow continued mutation analysis in families with a history of TCS and should facilitate continued experimentation to shed further light on the function of the gene/protein during development of the craniofacial complex.
Amino Acid Sequence↗
The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon.
Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. The TCS locus has been mapped to human chromosome 5q31.3-32 and the mutated gene identified. In the current investigation, 25 previously undescribed mutations, which are spread throughout the gene, are presented. This brings the total reported to date to 35, which represents a detection rate of 60%. Of the mutations that have been reported to date, all but one result in the introduction of a premature-termination codon into the predicted protein, treacle. Moreover, the mutations are largely family specific, although a common 5 bp deletion in exon 24 (seven different families) and a recurrent splicing mutation in intron 3 (two different families) have been identified. This mutational spectrum supports the hypothesis that TCS results from haploinsufficiency.
Chromosomes, Human, Pair 5↗
Prenatal diagnosis in Treacher Collins syndrome using combined linkage analysis and ultrasound imaging.
Treacher Collins syndrome is an autosomal dominant disorder of facial development, the features of which include conductive hearing loss and cleft palate. In the current investigation, linkage analysis has been used to make first trimester diagnostic predictions in a pregnancy at high risk of producing an affected child. The results of this analysis predicted that the child would be affected. As predictions of the severity of the disease were not possible, the pregnancy was also assessed by ultrasound imaging. This confirmed the affected diagnosis and predicted that the child would be severely affected.
Chromosome Aberrations↗
Norepinephrine and serotonin vasoconstriction in rat hindlimb control different vascular flow routes.
The vasoconstrictors, norepinephrine at low dose ( < or = 0.1 microM; LDNE) and serotonin (5-HT), produce opposing metabolic effects in the constant-flow perfused rat hindlimb characterized by increased and decreased oxygen uptake, respectively. In the present study, the effects of each vasoconstrictor are compared in the red blood cell-free buffer-perfused hindlimb on postequilibration endogenous red blood cell efflux, vascular entrapment of fluorescein-labeled dextran (Fx), and vascular corrosion casting by use of 30-micron spheres of methyl methacrylate (MM). A marked transient washout of red blood cells occurred immediately in association with vasoconstriction induced by LDNE that was not apparent when a similar extent of vasoconstriction was induced by 5-HT. Fx perfusions indicated that LDNE recruited a new vascular space that was reaccessed by a second exposure to the vasoconstrictor. 5-HT closed off a previously perfused vascular space that was reaccessed when the vasoconstrictor was removed. Corrosion casting of the arterial tree with MM showed no increase in cast weight, but more vessels filled because of LDNE. Higher doses of NE (2.5 microM) or 5-HT caused a marked decrease in cast weight with fewer vessels filled. The data suggest that LDNE and 5-HT, in association with vasoconstriction at different sites, control different capillary flow routes in the hindlimb that in turn may influence metabolism by increasing or decreasing nutrient access, respectively.
Animals↗
Alpha-adrenergic stimulation of thermogenesis in a rat kangaroo (Marsupialia, Bettongia gaimardi).
The Tasmanian bettong (Bettongia gaimardi) is a small rat kangaroo without detectable brown adipose tissue (BAT). In view of our previous findings of norepinephrine-mediated increase in O2 consumption (Vo2) in the perfused hindlimb of this species, the present study examined the effect of alpha-adrenoceptors on the thermogenesis of conscious bettongs at rest by infusing adrenergic agents via an indwelling catheter in the tail vein. The resting Vo2 was 22.9 +/- 1.9 mmol.kg-1.h-1. Norepinephrine (10-80 micrograms.kg-1.min-1) stimulated Vo2 in a dose-dependent manner with the maximal increment of 46.7%. Naphazoline (an alpha 1,alpha 2-adrenergic agonist) and phenylephrine (an alpha 1-adrenergic agonist) also elicited increases in Vo2 with maximal values of 29.6 and 34.8%, respectively. In contrast, the alpha 2-adrenergic agonist clonidine had no significant effects. Both alpha- and beta-adrenergic blockers were used to antagonize the submaximal increase in Vo2 elicited by norepinephrine. As a dose of 10 micrograms.kg-1.min-1, the alpha-adrenergic blocker phentolamine abolished the effects of naphazoline and phenylephrine and reduced norepinephrine-induced Vo2 by 45.5%. The beta-adrenergic blocker propranolol inhibited the norepinephrine-induced Vo2 by 58.8% at 20 micrograms.kg-1.min-1. A combination of the two antagonists blocked 82.5% of the norepinephrine-induced Vo2. Pretreatment of the animal with indomethacin (1 mg/kg), a known inhibitor of prostaglandin cyclooxygenase, had no effect on phenylephrine-elicited Vo2. Taken together, these results indicate that alpha 1-adrenoceptors are directly involved in norepinephrine-induced thermogenesis in non-BAT tissue(s).
Adrenergic alpha-Agonists↗
Chimeric potyvirus-like particles as vaccine carriers.
Presentation of subunit vaccines in a highly ordered aggregate form can result in enhanced immune responses. Coat protein (CP) monomers of a potyvirus (Johnsongrass mosaic virus) when produced in heterologous host expression systems (Escherichia coli, yeast and insect cells) self-polymerized to produce potyvirus-like particles (PVLPs). The N- and C-terminal regions of potyvirus CP are surface-exposed and are not required for assembly. Hybrid CP monomers containing short peptides fused to their N- and/or C-termini, or large target antigens fused to the N-terminus or replacing most of the N- or C-terminal exposed regions retained the ability to assemble into hybrid PVLPs. Such chimeric PVLPs were highly immunogenic in mice and rabbits even in the absence of any adjuvant. Potyvirus CP is highly versatile in accommodating peptides or large antigens and is able to present antigens exposed on the surface of virus-like particles. This, combined with the efficiency of high level bacterial and insect cell expression systems, makes PVLPs an attractive non-pathogenic and non-replicative vaccine carrier.
Animals↗
Genomic organization of the human osteopontin gene: exclusion of the locus from a causative role in the pathogenesis of dentinogenesis imperfecta type II.
Osteopontin (SPP1) is the principal phosphorylated glycoprotein of bone that is also expressed in a limited number of other tissues including dentine. In the current investigation we report the genomic organization of the SPP1 gene, which comprises seven exons, six of which contain coding sequence. The splice sites for exon donor and acceptor positions are in close agreement with previously published consensus sequences. Comparison of the human gene with its murine and bovine counterparts revealed a highly homologous organization. A highly informative short tandem repeat polymorphism isolated at the SPP1 locus showed no recombination with the autosomal dominant disorder dentinogenesis imperfecta type II. Nevertheless, sequencing of each exon in individuals affected by this disorder failed to reveal any disease-specific mutations.
Alleles↗
Vasoconstrictors alter oxygen, lactate, and glycerol metabolism in the perfused hindlimb of a rat kangaroo.
The Tasmanian bettong (Bettongia gaimardi) is a small marsupial rat kangaroo without detectable brown adipose tissue (BAT). The hindlimb was perfused with constant flow at 25 degrees C after cannulation under anesthesia of the femoral artery and vein to one hindlimb. Norepinephrine (NE, 25 nM-2.5 microM) and vasopressin (VP, 10 nM-0.1 microM) each increased perfusion pressure, oxygen consumption (VO2), and lactate and glycerol efflux of the perfused hindlimb. NE-mediated increases in VO2 and the efflux of lactate and glycerol were unaffected by propranolol (10 microM) but were completely blocked by the further addition of phentolamine (10 microM). In contrast, serotonin (5-HT; 0.1-2.5 microM) inhibited VO2 and inhibited lactate efflux. The changes induced by NE, VP, and 5-HT were all rapidly reversed by nitroprusside. These results suggest that resting thermogenesis in bettong hindlimb can be differentially controlled by the vasculature, which may also contribute to the induced VO2. This vascular control of skeletal muscle VO2 appears widespread in homeotherm evolution.
Adrenergic Antagonists↗
Expression and characterisation of equine herpesvirus 1 glycoprotein H using a recombinant baculovirus.
A recombinant baculovirus capable of expressing the glycoprotein H (gH) gene of equine herpesvirus 1 (EHV-1) was constructed. EHV-1 gH gene products in recombinant baculovirus infected insect cells were identified as 105 kDa and 110 kDa species compared with a 115 kDa product detected in EHV-1 infected mammalian cells. The extent of N-glycosylation of EHV-1 gH in both insect and mammalian cells was indicated by a shift in apparent molecular weights after PNGase F treatment to 90 kDa and 95 kDa forms, which compared with the predicted value of 90 kDa for the unglycosylated polypeptide. The recombinant EHV-1 gH was recognised by equine sera demonstrating that EHV-1 gH is a target for the immune system of the natural host. However, while the recombinant EHV-1 gH product from infected insect cells was immunogenic in mice, it did not induce a neutralizing antibody response against EHV-1.
Animals↗
High level production of potyvirus-like particles in insect cells infected with recombinant baculovirus.
The full length gene for the coat protein (CP) of the potyvirus, Johnsongrass mosaic virus, was incorporated into recombinant baculovirus and expressed in insect cells. Western blot and Coomassie-stained polyacrylamide gel electrophoresis analysis of infected insect cells demonstrated that CP was produced in large quantity. Electron microscopic examination of these cells showed the presence of numerous potyvirus-like particles in the cytoplasm. Morphologically the particles resembled potyvirus particles assembled in vitro in the absence of viral RNA and those found in Escherichia coli expressing the recombinant CP gene.
Animals↗
Protective immunity induced in squirrel monkeys with recombinant apical membrane antigen-1 of Plasmodium fragile.
Saimiri sciureus boliviensis monkeys were immunized with the Plasmodium fragile form of the merozoite apical membrane antigen-1 produced using the baculovirus expression system and combined with Montanide ISA 720 adjuvant. Following three immunizations, monkeys were challenged with 10,000 P. fragile trophozoite parasites. Antibody titers determined by fluorescence microscopy indicated an enhanced response following the second immunization. Four of five control animals had parasite counts > 5% 18-26 days following challenge. Four of five immunized monkeys had reduced levels of maximum parasitemia or delays in accumulated parasite counts, suggestive of protection. Rechallenge of the animals with P. falciparum resulted in three of four adjuvant control animals developing patent parasitemia whereas none of five immunized animals were infected, suggesting some level of heterologous protection.
Adjuvants, Immunologic↗
Treacher Collins syndrome: correlation between clinical and genetic linkage studies.
Treacher Collins syndrome (TCOF1) is an autosomal dominant disorder of craniofacial development in which there is considerable variability in the clinical manifestations. The TCOF1 locus has previously been mapped to chromosome 5q32-33.2 and markers flanking the disease locus identified. In the current investigation we have analysed eight short tandem repeat polymorphisms for linkage to TCOF1 in a large family with multiple affected individuals. Linkage analysis suggested that TCOF1 in this family was linked to markers in the region 5q32-33.2. We have used the results to make diagnostic predictions in certain mildly affected and apparently unaffected individuals.
Chromosome Mapping↗
Protective immunity to rotavirus-induced diarrhoea is passively transferred to newborn mice from naive dams vaccinated with a single dose of a recombinant adenovirus expressing rotavirus VP7sc.
VP7sc is a novel rotavirus antigen engineered for presentation at the cell surface. Several recombinant viruses were constructed in which VP7sc was inserted into the E3 region of the human type 5 adenovirus (Ad5) genome and expression and transport of the antigen was monitored in cultured 293 cells. The recombinant virus showing the greatest level of expression (Ad5/7.4) was then used to determine whether antibodies to VP7sc could be induced in a nonhuman host. BALB/c and CBA/H mice were inoculated with Ad5/7.4 by iv, ip, oral and intranasal routes and serum antibody levels were assayed by ELISA. All vaccinated animals seroconverted but, depending on the route of vaccination, not all animals showed a significant secondary response following re-inoculation. The ability of Ad5/7.4 to induce protective immunity in mice was also examined using several vaccination regimes. A single dose of Ad5/7.4 given intranasally to dams not previously exposed to rotavirus was sufficient to induce immunity which could be passively transferred to protect suckling neonates. Recombinant adenoviruses expressing protective antigens therefore may provide an alternative to the use of attenuated rotaviruses in the development of a vaccine against gastroenteritis.
Adenoviruses, Human↗