The Wimpole Street principles.
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Consumer Behavior↗
Biomedical subjects
A Thompson
Publications and source records attributed to A Thompson.
Microarrays for microbiologists.
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Bacteria↗
Location effects of a reporter gene on expression levels and on native protein synthesis in Lactococcus lactis and Saccharomyces cerevisiae.
The engineering of industrially important genetically modified organisms by the integration of heterologous genes into the chromosome is often the method of choice for several reasons concerned with long-term stability, homogeneous population distribution, and the enabling of selection without the addition of antibiotics. However, integration may disrupt endogenous gene expression, giving rise to increased levels of toxic metabolic byproducts or activating otherwise silent genes. The position of integration of a foreign gene in the chromosome can also influence its expression levels, and this effect will be of relevance in terms of optimizing protein production parameters. In this study, we determine how the random integration of a foreign reporter gene might affect expression levels and assess the use of proteome analysis to investigate possible effects on synthesis of endogenous proteins in two important food-relevant microorganisms, Saccharomyces cerevisiae and Lactococcus lactis. Eleven L. lactis integrants carrying the gusA gene were analyzed, and expression levels were found to vary by a factor of threefold in contrast to expression levels of lacZ in 18 S. cerevisiae integrants, which showed a 14-fold variation. Of relevance to industry is whether any changes in expression levels might occur as a consequence of storage of the modified strains. Here it is also shown that the above differences in expression levels were not significantly affected by storage of frozen cultures over a period of several months. Analysis of the protein composition of the yeast and lactococcal integrant strains by separation on one-dimensional (1D) and 2D gels showed no significant variations in position beyond those observed in control samples.
Bacterial Proteins↗
The SF-36 in multiple sclerosis: why basic assumptions must be tested.
OBJECTIVES: To evaluate, in people with multiple sclerosis, two psychometric assumptions that must be satisfied for valid use of the medical outcomes study 36-item short form health survey (SF-36): the data are of high quality and, it is legitimate to generate scores for eight scales and two summary measures using the standard algorithms. METHODS: SF-36 data from 438 people representing the full range of multiple sclerosis were examined (mean age 48; 70% women). Data quality (per cent missing data and computable scale and summary scores) were determined, six scaling criteria were tested to determine the legitimacy of generating the eight SF-36 scale scores using Likert's method of summed ratings, and two scaling criteria were tested to determine the appropriateness of the standard SF-36 algorithms for weighting scale scores to generate two summary measures. RESULTS: Data quality was excellent except in the most disabled subgroup where missing responses reached a maximum of 16.5% and summary scores could only be computed for 72%. There was clear support for the generation of SF-36 scale scores. Item response distributions were symmetric, item mean scores and variances were equivalent, corrected item-total correlations were high (range 0.46-0.85) and similar, and definite scaling success rates exceeded 96%. Nevertheless, there were notable floor or ceiling effects in four of the eight scales. Assumptions for generating two SF-36 summary measures were only partially satisfied. Although principal components analysis suggested a two component model, these components explained less than 60% of the total variance in SF-36 scales, and less than 75% of the variance in five of the eight scales. Moreover, scale to component correlations did not support the use of scale weights derived from United States population data. CONCLUSIONS: When using the SF-36 as a health measure in multiple sclerosis summary scores should be reported with caution.
Activities of Daily Living↗
Overexpression of cyclin D1 moderately increases ploidy in megakaryocytes.
BACKGROUND AND OBJECTIVES: Megakaryocytes undergo a unique cell cycle by which they replicate their complete genome many times in the absence of cytokinesis. In the search for regulators of the endomitotic cell cycle, we previously produced mice transgenic for cyclin D3 to identify this cyclin as able to enhance ploidy and to increase the number of differentiated cells in the megakaryocytic lineage. Of the D-type cyclins, cyclin D3 and to a much lesser extent cyclin D1, are present in megakaryocytes undergoing endomitosis and these cyclins are, respectively, markedly and moderately upregulated following exposure to the ploidy-promoting factor, Mpl-ligand. Our objective was to explore whether cyclin D1 can mimic the effect of cyclin D3 on ploidy in megakaryocytes. DESIGN AND METHODS: We generated transgenic mice overexpressing cyclin D1 in megakaryocytes and analyzed megakaryocyte ploidy, number and platelet levels in these mice and control mice. RESULTS: We show that transgenic mice in which cyclin D1 is overexpressed in megakaryocytes display higher ploidy level than the control mice, with no change in the number of differentiated cells of the megakaryocytic series, or in platelet level. INTERPRETATION AND CONCLUSIONS: Our models support a key role for D-type cyclins in the endomitotic cell cycle, and also indicate that although cyclin D3, from among the D cyclins, is unique in its high levels of expression in megakaryocytes, it is not unique in its ability to promote polyploidization.
Animals↗
Primus (florasulam 50 G/L), a new triazolopyrimidine sulfonanilide herbicide to control broad-leaved weeds in maize when applied in early postemergence (1 to 6 leaf stage of maize). Preliminary results.
OBJECTIVE: PRIMUS was developed in maize in Belgium in 1999 and 2000 in the course of research into limiting or replacing the use of triazines in maize. One of the imperatives of this research was to find the lowest possible residue content (MRL). SELECTIVITY TEST: An application of florasulam, at the dose of 5 g of active substance (a.s.) at the 2 to 3 leaf stage of the maize was found to be selective on 132 (in 1999) and 126 (in 2000) varieties of maize. EFFICACY TEST: Florasulam was tested at doses of between 1 and 5 g a.s./hectare. The treatments were applied in early postemergence at the 3-5 leaf stage of the maize or in 2 separate applications: at the 1 leaf stage with a dose of 2 g a.s. florasulam at the 4 leaf stage with a dose of 2 g a.s. florasulam The herbicide was fully effective on the sensitive flora. A summary of the results is presented. A detailed weed spectrum is defined. PROGRAMMES: Herbicide programmes were developed on the basis of these findings. The results showed that the best partners for florasulam were triketones (sulcotrione and mesotrione) in very low doses. Sulcotrione was applied at doses of 75 to 150 g a.s./ha and mesotrione at 25 to 50 g a.s./ha. Triple mixes of florasulam + triketone + nicosulfuron in very low doses and 1 or 2 applications were also tested. The results were highly encouraging and this work should lead to practical recommendations. PHYTOTOXICITY: Phytotoxicity was observed on some occasions. The phytotoxicity results for the different figures seem, however, to depend more on the climate (difference between daytime and night-time temperatures just before and after the treatment) than on the products tested in the mixes. However, the florasulam + nicosulfuron (sulfonyl-urea antigrasses) may sometimes cause serious problems with selectivity. The phytotoxicity noted in the tests was usually short-lived (30 days). CONCLUSION: The results of the tests show that it is possible to consider replacing atrazine-based programmes with very low doses of modern herbicides applied at early stages of the maize. A mixture of active substances is vital. Repeated very low doses at the 1/2 and 4/5 leaf stages of the maize were found to be the most effective.
Cyclohexanones↗
Double-helical dinuclear bis(dipyrromethene) complexes formed by self-assembly
Bis(dipyrromethene) ligands linked by an alkyl spacer between beta and beta' positions are shown to give helical dimers or monomers, dependent upon the length of the alkyl linker, upon complexation. Ligands consisting of methylene, ethylene, and propylene linkers -(CH(2))(n)()- (n = 1, 2, and 3) give helical dimers, while longer linking chains (n = 4, 5, or 6) give monomers or mixtures of dimers and monomers. X-ray crystal structures of the dimeric zinc complexes (n = 1, 2, and 3) reveal that the angles between dipyrromethene planes and the extent of helicity in the complexes differ as the length of the linker varies. The extent of helicity was assessed and found to be dependent upon the length and, specifically, the conformational preferences of the alkyl spacer unit. The presence of an ethylene linker gave complexes of greatest helicity. The use of a methylene spacer gave less helical structures upon complexation, while propylene spacers gave only slightly helical complexes. Our studies identify the crucial importance that the conformational preferences of the beta-beta' alkyl spacer group plays in the coordination algorithm of self-assembly to form dipyrromethene based complexes.
Journal Article↗
X-ray crystallographic and (13)C NMR investigations of the effects of electron-withdrawing groups on a series of pyrroles
A series of pyrroles substituted with various electron-withdrawing groups (EWGs) on the N atom have been synthesized and full characterization including X-ray crystal structures obtained. Analysis of (13)C chemical shifts and X-ray crystal structures reveals that a trend between decreased aromaticity and the strength of the EWG exists. Experimental results regarding alternative mechanisms of nucleophilic substitution reactions can thus be rationalized.
Journal Article↗
Amyloidogenicity and neurotoxicity of peptides corresponding to the helical regions of PrP(C).
An alpha-helical to beta-sheet conformational change in the prion protein, PrP(C), is believed to be causative in transmissible spongiform encephalopathies. Recent nuclear magnetic resonance structures of PrP(C) have identified three helical regions in the normal full-length protein. We have synthesised peptides corresponding to these helical regions (PrP144-154, helical region one; PrP178-193, helical region two; and PrP198-218, helical region three). Circular dichroism results show that the peptide corresponding to helical region one is unstructured, while peptides corresponding to the second and third helical regions have a high propensity to form beta-sheet structure in a pH-dependent manner in aqueous solutions. Peptides corresponding to the second helical region, PrP180-193 and PrP178-193, are the only ones that form amyloid by electron microscopy and congo red birefringence. PrP178-193 and the amyloidogenic Alzheimer's disease Abeta25-25 peptide were found to promote Cu (II)-induced lipid peroxidation and cytotoxicity in primary neuronal cultures, while PrP144-154, PrP198-218 and the nonamyloidogenic Abeta1-28 had no effect on Cu (II) toxicity. There was no increase in toxicity induced by PrP178-193 in cultures treated with Fe (II) or hydrogen peroxide, indicating a preferential modulatory effect on Cu (II) toxicity by PrP178-193. The data suggest that the PrP178-193 peptide has both structural and bioactive properties in common with Abeta25-35 and that the second putative helical region of PrP could be involved in modulation of Cu (II)-mediated toxicity in neurons during prion disease.
Amyloid beta-Peptides↗
Cancer among people living in rural and remote Indigenous communities in Queensland.
OBJECTIVE: To describe the pattern of cancer among people living in rural and remote Indigenous communities in Queensland and to consider what implications the results have for cancer control. DESIGN AND SETTING: Descriptive analysis of data on incidence and mortality from the population-based Queensland Cancer Registry for the years 1982-1996. MAIN OUTCOME MEASURES: Age-standardised incidence and mortality rates for different cancer sites. RESULTS: The pattern of cancer was different from that found in the Queensland population as a whole. Of all the cancer sites, cervical cancer showed the biggest difference: the age-standardised incidence was 4.7 times the State average (95% CI, 3.2-6.6) and the mortality rate was 13.4 times the State average (95% CI, 7.8-21.4). Rates of lung cancer and other smoking-related cancers, although not as high as those for cervical cancer, were also significantly higher than the Queensland average, while rates for prostate and colorectal cancer were significantly lower. CONCLUSION: The cancers that are over-represented among Indigenous people are amenable to preventive measures. The cancer burden among Indigenous people could be reduced by lowering the prevalence of smoking and improving participation in cervical cancer screening and follow-up of screening-detected abnormalities.
Adult↗
Nuclear magnetic resonance studies of helical dipyrromethene-zinc complexes
[formula: see text] Analysis of helical chirality within dinuclear dipyrromethene-Zn(II) complexes has been achieved with the use of 1H NMR spectroscopy. The use of AgFOD and chiral lanthanide shift reagents gives fully resolved resonances attributable to two diastereomeric helical complexes.
Journal Article↗
Ubiquitination of free cyclin D1 is independent of phosphorylation on threonine 286.
Cyclin D1 binds and regulates the activity of cyclin-dependent kinases (CDKs) 4 and 6. Phosphorylation of the retinoblastoma protein by cyclin D1.CDK4/6 complexes during the G(1) phase of the cell cycle promotes entry into S phase. Cyclin D1 protein is ubiquitinated and degraded by the 26 S proteasome. Previous studies have demonstrated that cyclin D1 ubiquitination is dependent on its phosphorylation by glycogen synthase kinase 3beta (GSK-3beta) on threonine 286 and that this phosphorylation event is greatly enhanced by binding to CDK4 (Diehl, J. A., Cheng, M. G., Roussel, M. F., and Sherr, C. J. (1998) Genes Dev. 12, 3499-3511). We now report an additional pathway for the ubiquitination of free cyclin D1 (unbound to CDKs). We show that, when unbound to CDK4, a cyclin D1-T286A mutant is ubiquitinated. Further, we show that a mutant of cyclin D1 that cannot bind to CDK4 (cyclin D1-KE) is also ubiquitinated in vivo. Our results demonstrate that free cyclin D1 is ubiquitinated independently of its phosphorylation on threonine 286 by GSK-3beta, suggesting that, as has been shown for cyclin E, distinct pathways of ubiquitination lead to the degradation of free and CDK-bound cyclin D1. The pathway responsible for ubiquitination of free cyclin D1 may be important in limiting the effects of cyclin D1 overexpression in a variety of cancers.
Animals↗
Iloprost and cisaprost for Raynaud's phenomenon in progressive systemic sclerosis.
OBJECTIVES: To assess the effects and toxicity of the following agents:Prostaglandin analogues together with other agents proposed for the treatment of Raynaud's phenomenom (RP) in scleroderma. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, and Medline up to 1996 using the Cochrane Collaboration search strategy developed by Dickersin et al.(1994). Key words included: raynaud's or vasospasm, scleroderma or progressive systemic sclerosis or connective tissue disease or autoimmune disease. Current Contents were searched up to and including April 7, 1997. All bibliographies of articles retrieved were searched and key experts in the area were contacted for additional and unpublished data. The initial search strategy included all languages. SELECTION CRITERIA: All randomized controlled trials comparing prostaglandin analogues versus placebo were eligible if they reported clinical outcomes within the start of therapy, and if the dropout rate was less than 35%. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two reviewers (DF, AT). Peto's odds ratios were calculated for all dichotomous outcomes and a weighted mean difference was calculated for all continuous outcomes. A fixed effects or random effects model was used if the data were homogeneous or heterogeneous, respectively. MAIN RESULTS: Seven randomized trials and 332 patients were included. Five of the seven trials were of parallel design. Five trials compared I.V. Iloprost and one trial studied p.o. Iloprost and another p.o. Cisaprost. Some trials were dose finding trials so various doses of Iloprost were used. Due to different efficacies of I.V. Iloprost, oral Iloprost and oral Cisaprost, the overall efficacy of these drugs was somewhat diluted. Intravenous Iloprost appears to be effective in the treatment of secondary Raynaud's phenomenon. REVIEWER'S CONCLUSIONS: Intravenous Iloprost is effective in the treatment of Raynaud's phenomenon secondary to scleroderma at decreasing the frequency and severity of attacks and preventing or healing digital ulcers. The effect seems to be prolonged after the intravenous infusion is given. Oral Iloprost may have less efficacy than intravenous Iloprost. However, Cisaprost has minimal or no efficacy when given orally for the treatment of Raynaud's phenomenon secondary to scleroderma.
Humans↗
Ketanserin for Raynaud's phenomenon in progressive systemic sclerosis.
OBJECTIVES: To assess the effects and toxicity of the following agent: ketanserin versus placebo proposed for the treatment of Raynaud's phenomenon (RP) in scleroderma. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, and Medline up to 1996 using the Cochrane Collaboration search strategy developed by Dickersin et al.(1994). Key words included: Raynaud's or vasospasm, scleroderma or progressive systematic sclerosis or connective tissue disease or autoimmune disease. Current Contents were searched up to and including April 7, 1997. All bibliographies of articles retrieved were searched and key experts in the area were contacted for additional and unpublished data. The initial search strategy included all languages. SELECTION CRITERIA: All randomized controlled trials comparing ketanserin versus placebo were eligible if they reported clinical outcomes of interest. Trials with dropout rates greater than 35% were excluded. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two reviewers (DF, AT). Peto's odds ratios (OR) were calculated for all dichotomous outcomes, and a weighted mean difference (WMD) was carried out on all continuous outcomes. A fixed effects or random effects model were used if the data was homogeneous or heterogeneous, respectively. MAIN RESULTS: Three trials and 66 patients were included. The proportion improved was significantly better in the group on ketanserin with an odds ratio (OR) of 4.80 (95% CI 1.33, 17.37). However, when comparing ketanserin to placebo, the decrease in severity of RP attacks favoured placebo but this was not statistically significant. Side effects were significantly more common in the group using active treatment with an OR of 5.96 (95% CI 1.61, 22.06). Frequency of attacks did not change, but the duration of attacks decreased significantly in the ketanserin group. REVIEWER'S CONCLUSIONS: Ketanserin may have some efficacy in the treatment of Raynaud's phenomenon secondary to scleroderma. Overall, ketanserin is not significantly different from placebo for the treatment of Raynaud's phenomenon except for some decrease in the duration of attacks and more subjects improved on ketanserin compared to placebo. However, there were more side effects. It can be concluded that ketanserin treatment in Raynaud's phenomenon secondary to scleroderma is not clinically beneficial.
Humans↗
Cyclofenil for Raynaud's phenomenon in progressive systemic sclerosis.
OBJECTIVES: To assess the effects and toxicity of Cyclofenil versus placebo for the treatment of Raynaud's phenomenon (RP) in scleroderma. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, and Medline up to 1996 using the Cochrane Collaboration search strategy developed by Dickersin et al.(1994). Key words included: Raynaud's or Vasospasm, Scleroderma or Progressive Systematic Sclerosis or Connective Tissue Disease or Autoimmune Disease. Current Contents were searched up to and including April 7, 1997. All bibliographies of articles retrieved were searched and key experts in the area were contacted for additional and unpublished data. The initial search strategy included all languages. SELECTION CRITERIA: All randomized trials comparing cyclofenil versus placebo were eligible if they reported any clinical outcomes within the trial. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two reviewers (DF, AT). Peto's odds ratio (OR) was calculated for all dichotomous outcomes, and a weighted mean difference was calculated for all continuous outcomes. A fixed effects or random effects model was used if the data were homogeneous or heterogeneous respectively. MAIN RESULTS: One trial with 38 patients was included. There was a trend for Cyclofenil to demonstrate more improvement and more dropouts compared to placebo, but there were no statistically significant differences. REVIEWER'S CONCLUSIONS: Cyclofenil is not effective in the treatment of Raynaud's phenomenon secondary to scleroderma.
Cyclofenil↗
Prazosin for Raynaud's phenomenon in progressive systemic sclerosis.
OBJECTIVES: To determine the effects and toxicity of prazosin versus placebo proposed for the treatment of Raynaud's phenomenon (RP) in scleroderma. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, and Medline up to December 1996 using the Cochrane Collaboration search strategy developed by Dickersin et al.(1994). Key words included: Raynaud's or vasospasm, scleroderma or progressive systemic sclerosis or connective tissue disease or autoimmune disease. Current Contents were searched up to and including April 7, 1997. All bibliographies of articles retrieved were searched and key experts in the area were contacted for additional and unpublished data. The initial search strategy included all languages. SELECTION CRITERIA: Randomized controlled trials comparing prazosin versus placebo were eligible if they reported clinical outcomes from the start of therapy. Trials with a greater than 35% dropout were excluded. Trials were included if patients with diffuse or limited scleroderma were the subjects. If patients with other connective tissue diseases or primary Raynaud's were included, the trial was used if the data on the scleroderma patients could be extracted from the paper. DATA COLLECTION AND ANALYSIS: All data were abstracted by two independent and trained reviewers (DF, AT), and verified by a third reviewer (JP). Each trial was assessed independently by the same two reviewers for its quality using a validated quality assessment tool (Jadad 1996). Peto's odds ratios were calculated for all dichotomous outcomes and a weighted mean difference was carried out on all continuous outcomes. Fixed effects and random effects model were used if the data was homogeneous or heterogeneous, respectively. MAIN RESULTS: Two trials with a total of 40 patients were included. Prazosin has been found in two randomized controlled cross-over trials to be more effective than placebo in the treatment of Raynaud's secondary to scleroderma. However, the positive response is modest and side effects are not rare in those taking prazosin. REVIEWER'S CONCLUSIONS: Prazosin is modestly effective in the treatment of Raynaud's phenomenon secondary to scleroderma.
Adrenergic alpha-Antagonists↗
Clinical improvement as reflected in measures of function and health-related quality of life following treatment with leflunomide compared with methotrexate in patients with rheumatoid arthritis: sensitivity and relative efficiency to detect a treatment effect in a twelve-month, placebo-controlled trial. Leflunomide Rheumatoid Arthritis Investigators Group.
OBJECTIVE: To examine correlations between clinical improvement as defined by the American College of Rheumatology (ACR) responder analysis and clinical improvement as determined by 4 function and/or health-related quality of life measures, and to estimate the sensitivity and relative efficiency of these measures compared with changes in the tender joint count in patients with rheumatoid arthritis (RA). METHODS: A 52-week, multicenter, double-blind controlled trial was conducted to compare treatment with leflunomide (n = 182), methotrexate (n = 180), or placebo (n = 118) in patients with active RA. ACR response rates and improvement in scores on the Health Assessment Questionnaire (HAQ), Problem Elicitation Technique (PET), and Medical Outcomes Survey Short Form 36 (SF-36) were compared in 438 of the patients. RESULTS: In comparing leflunomide with placebo, the patient global assessment, HAQ disability index, and SF-36 bodily pain scale were most responsive to treatment group differences. The modified HAQ (M-HAQ), PET Top 5, SF-36 physical component score, physician global assessment, pain intensity scale, and SF-36 physical functioning scale were more responsive to treatment group differences than was the tender joint count. In comparing methotrexate with placebo, the patient and physician global assessments were most responsive. These 2 measures, as well as the pain intensity scale and the C-reactive protein level, were more responsive to treatment group differences than was the tender joint count, while the SF-36 mental health component score was least responsive. A close correlation between changes in the M-HAQ and HAQ scores indicated that the M-HAQ was similarly responsive to change over time. Improvements in the PET, SF-36 physical component score, bodily pain, and physical functioning scales correlated with the ACR responder status. CONCLUSION: Both disease-specific and generic measures of function and health-related quality of life detect improvements in RA patients. Using both types of measures for evaluating therapies will identify discernible changes that are important to patients, and will facilitate comparisons across different disease states.
Anti-Inflammatory Agents, Non-Steroidal↗
Treatment of focal spasticity with botulinum toxin: effect on the 'positive support reaction'.
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Adolescent↗