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Periodicals as Topic↗
Biomedical subjects
R Smith
Publications and source records attributed to R Smith.
NMR structure of C-terminally tagged gramicidin channels.
A biotin group was covalently attached to the C terminus of gramicidin A (gA) through a linker arm comprising a glycine residue with either one (gAXB) or two caproyl groups (gAXXB). High-resolution two-dimensional NMR spectroscopy was used to determine the structure of these modified gA analogues and [Lys16]gramicidin A (gA-Lys) in sodium dodecyl-d25 sulphate micelles. Gated gA ion channels based on linking a receptor group to these gA analogues have been used recently as a component in a sensing device. The conformations of the gA backbones and amino acid side chains of lysinated gA and biotinylated gA in detergent micelles were found to be almost identical to that of native gA, i.e. that of an N-terminal to N-terminal (head to head) dimer formed by two right-handed, single-stranded beta 6.3 helices. The biotin tail of the gAXB and gAXXB and the lysine extremity of gA-Lys appeared to lie outside the micelle. Thus it appears that the covalent attachment of functional groups to the C terminus of gA does not disrupt the peptide's helical configuration. Further, single channel measurements of all three gA analogues showed that functioning ion channels were preserved within a membrane environment.
Biotin↗
Effect of open peer review on quality of reviews and on reviewers' recommendations: a randomised trial.
OBJECTIVES: To examine the effect on peer review of asking reviewers to have their identity revealed to the authors of the paper. DESIGN: Randomised trial. Consecutive eligible papers were sent to two reviewers who were randomised to have their identity revealed to the authors or to remain anonymous. Editors and authors were blind to the intervention. MAIN OUTCOME MEASURES: The quality of the reviews was independently rated by two editors and the corresponding author using a validated instrument. Additional outcomes were the time taken to complete the review and the recommendation regarding publication. A questionnaire survey was undertaken of the authors of a cohort of manuscripts submitted for publication to find out their views on open peer review. RESULTS: Two editors' assessments were obtained for 113 out of 125 manuscripts, and the corresponding author's assessment was obtained for 105. Reviewers randomised to be asked to be identified were 12% (95% confidence interval 0.2% to 24%) more likely to decline to review than reviewers randomised to remain anonymous (35% v 23%). There was no significant difference in quality (scored on a scale of 1 to 5) between anonymous reviewers (3.06 (SD 0.72)) and identified reviewers (3.09 (0.68)) (P=0.68, 95% confidence interval for difference - 0.19 to 0.12), and no significant difference in the recommendation regarding publication or time taken to review the paper. The editors' quality score for reviews (3.05 (SD 0.70)) was significantly higher than that of authors (2.90 (0.87)) (P<0.005, 95%confidence interval for difference - 0.26 to - 0.03). Most authors were in favour of open peer review. CONCLUSIONS: Asking reviewers to consent to being identified to the author had no important effect on the quality of the review, the recommendation regarding publication, or the time taken to review, but it significantly increased the likelihood of reviewers declining to review.
Decision Making↗
Opening up BMJ peer review.
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Peer Review, Research↗
Health-related quality-of-life measures for children.
Our purpose is to report the development and psychometric properties of a generic computer-delivered measure of health-related quality of life (HRQL) suitable for children aged 6 to 11 years, the Exeter HRQL scale (EHRQL). The theoretical model adopted is based on a definition of HRQL which assumes that HRQL is the result of discrepancies between an individual's actual self and ideal self. The EHRQL consists of 16 pictures, each of which is rated twice, first in terms of "like me" and second as "I would like to be". The difference between these scores is assumed to be indicative of HRQL. The EHRQL is delivered using a Macintosh Powerbook and takes approximately 20 min. Data are reported for 60 children with asthma (mean age = 8.93 years) and 69 healthy children (mean age = 7.49 years). In addition, children with asthma completed the Childhood Asthma Questionnaire (CAQ) and a measure of self-efficacy. For children with asthma, significant correlations were found between discrepancy scores and 3 of the 4 subscales of the CAQ. In addition, higher discrepancies were found for children with asthma compared with healthy children (p < 0.05). The EHRQL has acceptable internal reliability, and these data provide preliminary support for the theoretical assumption that HRQL reflects perceived discrepancies between an individual's actual self and ideal self. The measure also distinguished, as predicted, between children with asthma and healthy children. Methodological refinements to the EHRQL are suggested.
Asthma↗
A novel 8-bp insertion in codon 281 of p53 in a patient with acute lymphoblastic leukaemia and 2 separate leukaemic clones. Mutations in brief no. 219. Online.
We report a novel p53 insertion in a case of aggressive acute lymphoblastic leukaemia in a 16 year old male, in which 2 separate leukaemic clones were previously identified by T-cell receptor sigma and immunoglobulin heavy chain gene rearrangement studies. Initial p53 mutation screening of blast cells from 29 patients with acute leukaemia by PCR-denaturing gradient gel electrophoresis showed that 2 had a silent codon 213 polymorphism and only the index case had a somatic mutation identified to be an 8 bp insertion in codon 281 (5'CCGGGGGG-3'). This insertion was associated with the second, more aggressive clone which underwent clonal evolution and became resistant to cytotoxic chemotherapy. With an allele-specific primer in PCR, we were able to demonstrate the presence of this clone as a minority at disease presentation, and in 2 of 3 collections of peripheral blood progenitor cells.
Adolescent↗
The mucosal adjuvant effects of cholera toxin and immune-stimulating complexes differ in their requirement for IL-12, indicating different pathways of action.
Adjuvants that can improve mucosal vaccine efficacy are much warranted. In this comparative study between cholera toxin (CT) and immune-stimulating complexes (ISCOM) we found that, contrary to CT, ovalbumin (OVA)-ISCOM were poor inducers of mucosal anti-OVA IgA responses, but induced similar or better systemic immunity following oral immunizations. The addition of CT to the oral OVA-ISCOM protocol did not stimulate local anti-OVA IgA immunity, nor did it change the quality or magnitude of the systemic responses. Both vectors recruited strong innate immunity, but only OVA-ISCOM could directly induce IL-12, demonstrable at the protein and mRNA levels. CT had no inhibitory effects on lipopolysaccharide/IFN-gamma-induced IL-12 mRNA expression or IL-12 production. Furthermore, adjuvanticity of CT was unaffected in IL-12-deficient mice, while OVA-ISCOM showed partly impaired adjuvant effects by the lack of IL-12. CT abrogated the induction of oral tolerance stimulated by antigen feeding in these mice. In addition, CT did not alter TGF-beta levels, suggesting that the immunomodulating effect of CT was independent of IL-12 as well as TGF-beta production. Taken together, these findings indicate that mucosal adjuvanticity of CT and ISCOM are differently dependent on IL-12, suggesting that separate and distinct antigen-processing pathways are involved.
Adjuvants, Immunologic↗
Losartan therapy for Raynaud's phenomenon and scleroderma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial.
OBJECTIVE: To compare the efficacy and tolerability of losartan, an antagonist of angiotensin II receptor type 1, with nifedipine for the treatment of primary and secondary Raynaud's phenomenon (RP) in a pilot study. METHODS: In a randomized, parallel-group, controlled trial, patients with primary RP (n = 25) or RP secondary to systemic sclerosis (SSc [scleroderma]; n = 27) were allocated to receive 12 weeks' treatment with either losartan (50 mg/day) or nifedipine (40 mg/day). Primary outcome variables were the severity and frequency of RP episodes and findings on vascular measurements, including thermography and laser Doppler flowmetry. Serum levels of soluble adhesion molecules, endothelin 1, fibrinogen, von Willebrand factor, and procollagen type I N-terminal propeptide (PINP) were also measured. RESULTS: There was a reduction in the severity of RP episodes following treatment with losartan and with nifedipine, but this effect was greater in the losartan arm of the study (P<0.05): episode frequency was reduced only in the losartan group (P<0.01 versus baseline). Symptomatic improvement was associated with a significant reduction in soluble vascular cell adhesion molecule 1 and PINP (P<0.01). Subgroup analysis suggested that although these biochemical changes occurred mainly in SSc patients, the clinical benefit was greater in the primary RP group. CONCLUSION: This study confirms the tolerability of short-term treatment of RP with losartan, and our data suggest its clinical benefit. Further evaluation of this drug as a long-term treatment for SSc-associated RP should be considered, since it may have additional disease-modifying potential.
Adult↗
Identification and grouping of Dichelobacter nodosus, using PCR and sequence analysis.
Dichelobacter nodosus is the causative agent of ovine foot rot, a disease that is a constant economic burden for many Western sheep ranches. Vaccination is one method of treating foot rot. A higher and more specific immune response is observed when monovalent vaccines are used to treat foot rot, as compared to multivalent vaccines, which incorporate all 10 major New Zealand D. nodosus serogroups. There is no single assay for specifically identifying and grouping D. nodosus for the purpose of incorporating only the desired serogroup(s) in a vaccine. A polymerase chain reaction (PCR)-based assay was used to specifically identify and group D. nodosus from a foot rot lesion. Identification and grouping was determined by predicted fragment size analysis and nucleotide sequence information. The PCR approach vastly improves the accuracy in identifying and grouping D. nodosus from a foot rot lesion.
Animals↗
Vertebral bone mineral density, content and area in 8789 normal women aged 33-73 years who have never had hormone replacement therapy.
The vertebral bone mineral density (BMD), bone mineral content (BMC) and bone area of the lumbar spine were measured using a bone densitometer in 8789 women aged 33-73 years who had had no previous hormone replacement therapy (HRT). The overall relationship between BMD and age was analyzed on a year-by-year basis, and comprised three separate regions that could each be described by a straight line: 33-46 years (gradient = 0.00166 g cm(-2)/year), 47-63 years (gradient = 0.0121 g cm(-2)/year) and 64-73 years (gradient = 0.0045 g cm(-2)/year). Above the age of 50 years our results were higher than the BMD in most previous reports. In those 3198 women who knew the time of their last menstrual period (mean age 49.25 years, SD 4. 83) bone loss was most rapid in the first 10 menopausal years. In the whole group, the relationship between BMC and age was found to be similar to that of BMD, with three distinct regions, including a rapid drop between the ages of 47 and 63 years (gradient 0.781 g/year). Bone area showed a much more gradual (though significant) decrease with age. Based on WHO definitions and using BMD as an indicator, the percentage of women with osteoporosis varied from zero in the younger age group to about 30% of women aged over 70 years; in contrast, where BMC was used, although the trend with age had a similar shape, the percentages at each year were about half those derived from the corresponding BMD values. Osteopenia derived in the same way occurred in about 50% of women over 70 years using either BMD or BMC. The results presented here provide a reliable local reference range for lumbar spine bone densitometry measurements. They also show that for this site BMD and BMC cannot be used interchangeably to define osteoporosis.
Absorptiometry, Photon↗
Phenotypic and molecular heterogeneity in fibrodysplasia ossificans progressiva.
Fibrodysplasia (myositis) ossificans progressiva (FOP) is an extremely rare inherited disorder in which progressive ossification of major striated muscles, often following injury, is associated with abnormal skeletal patterning. Altered expression of bone morphogenetic proteins may be a contributory cause. To examine this hypothesis, we compared the patterns of expression of bone morphogenetic proteins (BMPs) mRNAs from lymphoblastoid cell lines from two small multigenerational families with autosomal dominant transmission of FOP. Although affected members of both families showed the characteristic phenotype of FOP, one family was more severely affected than the other. Expression of mRNAs for BMP-1, 2, 3, 5, and 6 mRNAs were not detected within the more severely affected family, but BMP-4 mRNA was expressed in affected but not unaffected members of this family. The results of linkage exclusion analysis using a highly polymorphic microsatellite marker near the BMP-4 gene were consistent with linkage of FOP and BMP-4 in this family. Within the less severely affected family, affected and unaffected members showed similar levels of mRNA expression of BMPs 1, 2, 4, and 5, and linkage of FOP to the BMP-4 gene was excluded. It is concluded that clinical, radiographic, and biochemical data in these two families with FOP establish clinical and molecular heterogeneity and also suggest the possibility of genetic heterogeneity.
Adolescent↗
Predicting risk of preterm delivery by second-trimester measurement of maternal plasma corticotropin-releasing hormone and alpha-fetoprotein concentrations.
OBJECTIVE: Many women who have preterm labor have abnormally high plasma concentrations of the placental peptide corticotropin-releasing hormone and the fetal product alpha-fetoprotein in early pregnancy. This study was designed to evaluate the ability of these biochemical tests and a clinical risk factor score to prospectively discriminate pregnancies at high risk for preterm delivery. STUDY DESIGN: Eight hundred sixty women were studied prospectively from the early second trimester until delivery. A risk factor score for preterm delivery was calculated from the clinical history and maternal plasma corticotropin-releasing hormone and alpha-fetoprotein concentrations were measured by radioimmunoassay between 17 and 30 weeks' gestation. The risk factor score, corticotropin-releasing hormone concentration, and alpha-fetoprotein concentration for each woman were expressed as individual odds or likelihood ratios for preterm delivery and as a combined risk estimate derived from the 3 tests. RESULTS: Sixty women had preterm deliveries (n = 37 spontaneous labor, n = 23 planned deliveries), and these women had significantly higher concentrations of corticotropin-releasing hormone (median 1.92 multiples of the median) and alpha-fetoprotein (median 1.32 multiples of the median) than did women with term deliveries (median 1.00 multiples of the median, P <.001 for both tests), with these abnormalities being evident from early in the second trimester. The risk factor score was >/=10 in 28% of women with preterm delivery and 7% of women with term delivery. The combination of all 3 markers resulted in a higher detection rate and a higher positive predictive value than the risk factor score, corticotropin-releasing hormone concentration, or alpha-fetoprotein concentration alone, correctly discriminating 37% of women who would have preterm deliveries with a false-positive rate of 5%. The positive predictive value was also 37% (odds of being affected given a positive result were 1:1.7). CONCLUSIONS: The combination of measurement of maternal plasma corticotropin-releasing hormone and alpha-fetoprotein concentrations in the second trimester with risk factor scoring provides a more accurate indicator of the risk of preterm delivery than does risk factor scoring alone. This method of risk assessment may therefore be of use in targeting prevention strategies.
Adolescent↗
A central theory of preterm and term labor: putative role for corticotropin-releasing hormone.
Near the end of human pregnancy the concentration of placental corticotropin-releasing hormone in maternal blood rises exponentially. The rate of elevation of corticotropin-releasing hormone and its duration through time have been linked to the time of onset of labor. Paradoxically, although glucocorticoids are known to inhibit corticotropin-releasing hormone production within the hypothalamic-pituitary-adrenal axis, cortisol actually increases corticotropin-releasing hormone levels in several areas outside the hypothalamus, including the placenta. Placental corticotropin-releasing hormone may be an important component of a system that controls the normal maturation of the fetus and signals the initiation of labor. Abnormal elevations in corticotropin-releasing hormone, which may be a hormonal response to stressors arising in either the mother, placenta, or fetus, may prove to participate in the premature onset of parturition.
Corticotropin-Releasing Hormone↗
Corticotropin-releasing hormone and the fetoplacental clock: an Australian perspective.
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Animals↗
Use of a three-dimensional magnetic sensor in vestibular testing.
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Electromagnetic Fields↗
Three-dimensional kinematics of the forefoot, rearfoot, and leg without the function of tibialis posterior in comparison with normals during stance phase of walking.
BACKGROUND: Many studies have shown that lack of functional activity of tibialis posterior leads to changes in the longitudinal arch and affects the motion of the foot. A quantitative description of the affects on the motion of the foot in detail has not been reported. OBJECTIVE: To describe three-dimensional motion of the leg, rearfoot and forefoot with tibialis posterior dysfunction during stance phase of walking in comparison with normals. This study compared one case without the function of tibialis posterior with the ensemble average of 10 normals (five males, five females). METHODS: Subjects with 10, 12 mm retroreflective markers placed on their right leg, rearfoot and forefoot, performed five trials of walking at self-selected speed on a 10 m walkway. A four-camera three-dimensional motion analysis system and a synchronized force platform were used to record three-dimensional motions of the segments and force variables during stance phase of walking. RESULTS: The patterns and range of motion of the rearfoot relative to the leg, and the forefoot relative to the rearfoot demonstrated some differences between the tibialis posterior dysfunction case and normals. Most of the major differences occurred from just prior to heel-off through to toe-off, the period when a stable arch would be required. CONCLUSION: The observed differences in the three-dimensional foot motions of the tibialis posterior dysfunction case compared with normals during walking were consistent with the expected mechanical consequences of a foot without the function of tibialis posterior. The one exception was the inversion of the rearfoot which remained normal. RELEVANCE: Tibialis posterior dysfunction has been recognized as one of the significant impairments of the musculoskeletal system which affects normal walking. Dynamic investigation adds an understanding of how the muscle controls the foot during walking which is essential information for the diagnosis and the adjustment of treatment and rehabilitation for a tibialis posterior dysfunction case.
Adult↗
Enadoline, a selective kappa-opioid receptor agonist shows potent antihyperalgesic and antiallodynic actions in a rat model of surgical pain.
Enadoline is a highly selective and potent kappa-opioid receptor agonist. This report describes and compares the activities of enadoline and morphine in a rat model of postoperative pain. A 1 cm incision through the muscle and skin of the plantar surface of the right hind paw induced thermal hyperalgesia as well as static and dynamic allodynia lasting at least 2 days. Postoperative testing was carried out using the plantar test for thermal hyperalgesia, von Frey hairs for static allodynia and light stroking with a cotton bud for dynamic allodynia. A single i.v. dose of enadoline 15 min before surgery dose-dependently (1-100 microg/kg) blocked the development of thermal hyperalgesia as well as static and dynamic allodynia for over 24 h with respective MEDs of < or = 1, 10 and 10 microg/kg. The administration of enadoline (100 microg/kg, i.v.), 1 h after surgery, completely blocked the maintenance of the hyperalgesic and allodynic responses, but its duration of action was much shorter (2 h) than when administered before surgery. Previous studies have shown that administration of morphine (1-6 mg/kg, s.c.) 0.5 h before surgery can prevent the development of thermal hyperalgesia with a MED of < or =1 mg/kg, but it has little effect on static allodynia. In the present study similar administration of morphine (1-3 mg/kg), unlike enadoline, had no effect on the development of dynamic allodynia. Morphine dose-dependently (1-6 mg/kg, s.c.) potentiated isoflurane-induced sleeping time and respiratory depression in the rat. However, whilst enadoline also (1-1000 microg/kg, i.v.) potentiated isoflurane-induced sleeping time, it did not cause respiratory depression. It is suggested that enadoline may possess therapeutic potential as a pre-emptive antihyperalgesic and antiallodynic agent.
Anesthesia Recovery Period↗