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Biomedical subjects

R Dickson

Publications and source records attributed to R Dickson.

At least 19 recordsLinked to original sources
PubMed2007

Pemetrexed disodium for the treatment of malignant pleural mesothelioma: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of pemetrexed disodium in combination with cisplatin for the treatment of unresectable pleural mesothelioma in chemotherapy-naive patients. DATA SOURCES: Electronic databases were searched up to May 2005. REVIEW METHODS: The systematic review was conducted following accepted guidelines. An assessment of the economic submission received from the manufacturer of pemetrexed was also carried out. This comprised two sections, each employing an economic model. One of these models was then reformulated in order to carry out a separate exploration of economic performance. RESULTS: One randomised controlled trial comparing pemetrexed and cisplatin with cisplatin alone, and involving a total study population of 448 patients, met the inclusion criteria. Pemetrexed in combination with cisplatin in this trial showed a 2.8-month gain in median survival compared with cisplatin alone in an intention-to-treat (ITT) population (12.1 and 9.3 months, respectively, p = 0.020, hazard ratio of 0.77). During the trial, increased reporting of severe toxicity in the pemetrexed arm led to a change in the protocol to add folic acid and vitamin B12 supplementation to therapy. For fully supplemented patients (n = 331) the hazard ratio for median survival in favour of pemetrexed plus cisplatin was also comparable (0.75), but of borderline significance between treatment arms (p = 0.051). The trial inclusion criteria restricted recruitment to those with a Karnofsky performance status of 70 or greater (equivalent to ECOG/WHO 0 or 1 scales more widely used in the UK). Quality of life scores using the Lung Cancer Symptom Scale demonstrated significantly greater improvement for pain and dyspnoea for patients in the combination group compared with those in the cisplatin group. In the ITT population, the incidence of serious toxicities with pemetrexed plus cisplatin was higher compared with cisplatin alone. However, the grade 3/4 toxicities of the combination arm, particularly leucopenia, neutropenia and diarrhoea, were found to be greatly improved by the addition of vitamin B12 and folic acid. The existing published economic literature was very limited. The economic evaluation conducted by the study (and that submitted by the manufacturer) suggested that pemetrexed is unlikely to be considered cost-effective at conventionally accepted thresholds in the UK for all patients, mainly because of the high cost of pemetrexed itself compared with cisplatin. These findings were better for some patient subgroups, e.g. especially for fully supplemented (FS) patients with good performance status (0/1) and advanced disease (AD). These findings seem robust. The estimated cost-effectiveness results were for the FS population, incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained = pound59,600; for the FS with AD population, ICER per QALY = pound47,600; for the FS with performance status 0/1 population, ICER per QALY = pound49,800; and for the FS with performance status 0/1 and AD population, ICER per QALY = pound36,700. CONCLUSIONS: The new therapy examined in this document demonstrates an extension of life expectancy and palliation, as measured by time to progression of disease and other end-points. However, the absolute benefit obtained is small, and it needs to be weighed against the benefits of effective palliative care services. The limited benefit was also at the expense of considerable toxicity to patients. The economic evaluation conducted in this study and that of the manufacturers suggest that pemetrexed is not cost-effective at conventional thresholds for all patients. Cost-effectiveness seems better for some patient subgroups, e.g. especially for patients with good performance status and with advanced diseases, where it is estimated the ICER per QALY would be pound36,700. Given the relatively small number of patients with mesothelioma, albeit increasing, the overall budget impact of pemetrexed would be unlikely to be more than pound5 million per year at present costs. Much more research is needed into the optimum chemotherapy for patients with mesothelioma and a clear definition of what constitutes best supportive care.

Antineoplastic Agents↗
PubMed2006

Comparison of conference abstracts and presentations with full-text articles in the health technology assessments of rapidly evolving technologies.

OBJECTIVES: To assess the extent of use of data from conference abstracts and presentations in health technology assessments (HTAs) provided as part of the National Institute for Health and Clinical Excellence (NICE) appraisal process. Also to assess the methodological quality of trials from conference abstracts and presentations, the consistency of reporting major outcomes between these sources and subsequent full-length publications, the effect of inclusion or exclusion of data from these sources on the meta-analysis pooled effect estimates, and the timeliness of availability of data from these sources and full articles in relation to the development of technology assessment reviews (TARs). DATA SOURCES: A survey of seven TAR groups. An audit of published TARs: included all NICE TARs published between January 2000 and October 2004. Case studies of selected TARs. REVIEW METHODS: Analyses of the results of the survey and audit were presented as a descriptive summary and in a tabular format. Sensitivity analyses were carried out to compare the effect of inclusion of data from abstracts and presentations on the meta-analysis pooled effect estimates by including data from both abstracts/presentations and full papers, and data from only full publications, included in the original TAR. These analyses were then compared with meta-analysis of data from trials that have subsequently been published in full. RESULTS: All seven TAR groups completed and returned the survey. Five out of seven groups reported a general policy that included searching for and including studies available as conference abstracts/presentations. Five groups responded that if they included data from these sources they would carry out methodological quality assessment of studies from these sources using the same assessment tools as for full publications, and manage the data from these sources in the same way as fully published reports. All groups reported that if relevant outcome data were reported in both an abstract/presentation and a full publication, they would only consider the data in the full publication. Conversely, if data were only available in conference abstract/presentation, all but two groups reported that they would extract and use the data from the abstract/presentation. In total, 63 HTA reports for NICE were identified. In 20 of 63 TARs (32%) explicit statements were made with regards to inclusion and assessment of data from abstracts/presentations. Thirty-eight (60%) identified at least one randomised controlled trial (RCT) available as a conference abstract or presentation. Of these, 26 (68%) included trials available as abstracts/presentations. About 80% (20/26) of the 26 TARs that included RCTs in abstract/presentation form carried out an assessment of the methodological quality of such trials. In 16 TARs full reports of these trials were used for quality assessment where both abstracts/presentations and subsequent full publications were available. Twenty-three of 63 TARs (37%) carried out a quantitative analysis of results. Of these, ten (43%) included trials that were available as abstracts/presentations in the review; however, only 60% (6/10) of these included data from abstracts/presentations in the data analysis of results. Thirteen TARs evaluated rapidly evolving technologies and only three of these identified and included trial data from conference abstracts/presentations and carried out a quantitative analysis where abstract/presentation data were used. These three TARs were used as case studies. In all three case studies the overall quality of reporting in abstracts/presentations was generally poor. In all case studies abstracts and presentations failed to describe the method of randomisation or allocation concealment. Overall, there was no mention of blinding in 66% (25/38) of the abstracts and in 26% (7/27) of the presentations included in case studies, and one presentation (4%) explicitly stated use of intention-to-treat analysis. Results from one case study demonstrated discrepancies in data made available in abstracts or online conference presentations. Not only were discrepancies evident between these sources, but also comparison of conference abstracts/presentations with subsequently published full-length articles demonstrates data discrepancies in reporting of results. Sensitivity analyses based on one case study indicated a change in significance of effect in two outcome measures when only full papers published to date were included. CONCLUSIONS: There are variations in policy and practice across TAR groups regarding searching for and inclusion of studies available as conference abstracts/presentations. There is also variation in the level of detail reported in TARs regarding the use of abstracts/presentations. Therefore, TAR teams should be encouraged to state explicitly their search strategies for identifying conference abstracts and presentations, their methods for assessing these for inclusion, and where appropriate how the data were used and their effect on the results. Comprehensive searching for trials available as conference abstracts/presentations is time consuming and may be of questionable value. However, there may be a case for searching for and including abstract/presentation data if, for example, other sources of data are limited. If conference abstracts/presentations are to be included, the TAR teams need to allocate additional time for searching and managing data from these sources. Incomplete reporting in conference abstracts and presentations limits the ability of reviewers to assess confidently the methodological quality of trials. Where conference abstracts and presentations are considered for inclusion in the review, the TAR teams should increase their efforts to obtain further study details by contacting trialists. Where abstract/presentation data are included, reviewers should discuss the effect of including data from these sources. Any data discrepancies identified across sources in TARs should be highlighted and their impact discussed in the review. In addition, there is a need to carry out, for example, a sensitivity analysis with and without abstract/presentation data in the analysis. There is a need for research into the development of search strategies specific to identification of studies available as conference abstracts and presentations in TARs. Such strategies may include guidance with regard to identification of relevant electronic databases and appropriate conference sites relevant to certain clinical areas. As there are limited case studies included in this report, analyses should be repeated as more TARs accrue, or include the work of other international HTA groups.

Adult↗
PubMed2005

Percutaneous transluminal coronary angioplasty with stents versus coronary artery bypass grafting for people with stable angina or acute coronary syndromes.

BACKGROUND: Coronary artery bypass graft surgery (CABG) replaces obstructed vessels with ones from other parts of the body. Alternatively, obstructions are remodelled using catheter-based techniques such as percutaneous coronary angioplasty with the use of stents. Though less invasive, stenting techniques are limited by the re-narrowing of treated vessels (restenosis). We examined evidence on cardiac-related outcomes occurring after CABG or stenting, with implications for resource use, resource allocation and informing patient choice. OBJECTIVES: To examine evidence from randomised controlled trials (RCTs) on benefit of stents or CABG in reducing cardiac events in people with stable angina or acute coronary syndrome (ACS). SEARCH STRATEGY: CENTRAL (Issue 2 2004), EMBASE (1990 to 2004), MEDLINE (1990 to 2004) and handsearching to July 2004. SELECTION CRITERIA: Only RCTs comparing stents used with PTCA with CABG were included. Participants were adults with stable angina or ACS and unstable angina and had either single or multiple vessel disease. Published and unpublished sources were considered. DATA COLLECTION AND ANALYSIS: Outcomes included composite event rate (major adverse cardiac event, event free survival), death, acute myocardial infarction (AMI), repeat revascularisation and binary restenosis as well as information on design and baseline characteristics. Quality assessment was completed independently. Meta-analyses are presented as odds ratios, 95% confidence intervals (CI) using a fixed-effect model. Heterogeneity between trials was assessed. MAIN RESULTS: Nine studies (3519 patients) were included. Four RCTs included patients with multiple vessel disease, five focused on single vessel disease. Four studies reported beyond 1 year. No statistical differences were observed between CABG and stenting for meta-analysis of mortality or AMI, but there was heterogeneity. Composite cardiac event and revascularisation rates were lower for CABG than for stents. Odds ratios resulting from meta-analysis of event rate data at 1 year were, odds ratio 0.43 (95% CI 0.35 to 0.54) and at 3 years, odds ratio 0.37 (95% CI 0.29 to 0.48). Odds ratios for revascularisation at 1 year were, odds ratio 0.18 (95% CI 0.13 to 0.25) and at 3 years, odds ratio 0.09 (95% CI 0.02 to 0.34). Binary restenosis at 6 months (single vessel trials) favoured CABG, odds ratio 0.29 (95% CI 0.17 to 0.51). AUTHORS' CONCLUSIONS: CABG is associated with reduced rates of major adverse cardiac events, mostly driven by reduced repeat revascularisation. However, the RCT data are limited by follow-up, unrepresentative samples and rapid development of both surgical techniques and stenting. Research on real-world patient population or patient level data meta-analyses may identify risk factors and groupings who may benefit most from one strategy over the other.

Angina Pectoris↗
PubMed2004

Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical and cost-effectiveness of zaleplon, zolpidem and zopiclone (Z-drugs) compared with benzodiazepines. DATA SOURCES: Electronic databases, reference lists of retrieved articles and pharmaceutical company submissions. REVIEW METHODS: Randomised controlled trials (RCTs) that compared either benzodiazepines to the Z-drugs or any two of the non-benzodiazepine drugs in patients with insomnia were included in the review. Data on the following outcome measures were considered: sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse effects and rebound insomnia. A search was also undertaken for any study designs that evaluated issues related to adverse events (e.g. dependency and withdrawal symptoms). Full economic evaluations that compared two or more options and considered both costs and consequences including cost-effectiveness, cost-utility analysis or cost-benefit analysis undertaken in the context of high-quality RCTs were considered for inclusion in the review. RESULTS: Twenty-four studies, involving a total study population of 3909 patients, met the inclusion criteria. These included 17 studies comparing a Z-drug with a benzodiazepine and seven comparing a Z-drug with another Z-drug. The diversity of possible comparisons and the range of outcome measures in the review may be confusing. Outcomes were rarely standardised and, even when reported, differed in interpretation. In addition, variations in assessment and variety in the level of information provided make study comparisons difficult. As a result, meta-analysis has been possible on only a small number of outcomes. However, some broad conclusions might be reached based on the limited data provided. The existing published economic literature in this area is very limited. No relevant economic evaluations were identified for inclusion in the review. The industry submissions did not include detailed evidence of cost-effectiveness. Given the lack of robust clinical evidence, no economic model describing the costs and benefits of the newer hypnotic drugs for insomnia was developed. The systematic review provided in this report suggests that an agnostic approach to cost-effectiveness is required at this stage. In the short-term, no systematic evidence is available concerning significant outcome variations between either the different classes of drugs or between individual drugs within each class. Within this short-term horizon, the one element that does vary significantly is the acquisition cost of the individual drugs. CONCLUSIONS: The short-acting drugs seem equally effective and safe with minor differences that may lead a prescriber to favour one over another in different patients. There is no evidence that one is more cost-effective than any other. Analysis of the additional costs to the NHS, depending on the rate of change from benzodiazepine prescriptions to Z-drug prescriptions, at current levels of hypnotic prescribing, range from GBP2 million to GBP17 million per year. There are clear research needs in this area; in particular, none of the existing trials adequately compare these medications. It is suggested that further consideration should be given to a formal trial to allow head-to-head comparison of some of the key drugs in a double-blind RCT lasting at least 2 weeks, and of sufficient size to draw reasonable conclusions. We would also recommend that any such trial should include a placebo arm. It should also collect good-quality data around sleep outcomes and in particular quality of life and daytime drowsiness. We do not believe that any formal study of risk of dependency is feasible at present. Finally, the management of long-term insomnia is suggested for further investigation: considering the frequency of this symptom and its recurring course, the short-term trial of medication and lack of long-term follow-up undermine attempts to develop evidence-based guidelines for the use of hypnotics in this condition, or indeed for its whole management.

Adult↗
PubMed2004

Coronary artery stents: a rapid systematic review and economic evaluation.

OBJECTIVES: To assess the effectiveness and cost-effectiveness of the use of coronary artery stents in patients with coronary heart disease (CHD). DATA SOURCES: Electronic databases. REVIEW METHODS: The review was conducted following accepted guidelines for conducting systematic reviews. Randomised controlled trials that include comparisons of percutaneous transluminal coronary angioplasty (PTCA) versus PTCA with stent, stent versus coronary artery bypass graft (CABG), and drug-eluting stents (DES) versus non-DES in patients with CAD in native or graft vessels and those with stable angina or acute coronary syndrome (ACS) and unstable angina were also included. Data on the following outcome measures were included in the review: combined event rate or event-free survival, death, acute myocardial infarction, target vessel revascularisation, repeat treatment (PTCA, stent or CABG) and binary restenosis. An economic model was developed based on extrapolation of trends in mortality and revascularisation from clinical trials data to a 5-year time horizon. RESULTS: The inclusion criteria were fulfilled by 50 studies comparing the use of stents with PTCA, six comparing stents with CABG and 12 comparing DES eluting stents with non-DES. No studies were identified that compared DES with PTCA or DES with CABG. Existing quality of life data suggest that revascularisation procedures reduce the patient's quality of life for a short period only. Stents were found to be more effective than PTCA in preventing adverse events and revascularisations. In multiple-vessel disease there was no evidence of a difference in mortality (at 1 year) between patients treated surgically and those receiving a stent. Patients treated surgically required fewer revascularisations. There is no evidence of a difference in mortality between patients receiving DES and those treated with bare metal stents at 1 year. A reduction in event rate at 9 and 12 months was found in patients treated with DES. This event rate is primarily made up of increased revascularisation rates in patients treated with bare metal stents. Two-year outcome data from one study indicate that this benefit of DES continues over the longer term. The economic model proved sufficient to indicate long-term trends in cost-effectiveness. CABG was found initially to be more expensive than bare metal stenting in multivessel disease and may have higher immediate risks, but over time the cost differential is reduced and long-term outcomes favour CABG over stenting. A similar situation was found for DES versus CABG in multiple-vessel disease. However, DES may not generally be considered a cost-effective alternative to bare metal stenting in single-vessel disease by policy makers as substantially higher costs are involved with a very small outcome benefit. CONCLUSIONS: DES might be considered cost-effective if the additional cost (compared with ordinary stents) was substantially reduced, the outcome benefits from the use of DES were much improved, and/or its use were targeted on the subgroups of patients with the highest risks of requiring reintervention. Long-term clinical studies are needed that focus on significant outcomes such as mortality. Further research should consider: the differences among plain stents; head-to-head comparisons within DES, CABG compared with DES; and the evaluation of newer non-DES against DES. Evaluation of the effects of revascularisation procedures and especially repeat revascularisation procedures on the patient's quality of life would also be useful, as would the development and testing of risk assessment tools to identify patients likely to need further revascularisations.

Angioplasty, Balloon, Coronary↗
PubMed2003

Comparative efficacy of thrombolytics in acute myocardial infarction: a systematic review.

BACKGROUND: The comparative clinical effectiveness of new (reteplase, tenecteplase) vs. older (alteplase, streptokinase) thrombolytic agents in the treatment of acute myocardial infarction is uncertain. AIM: To examine 30-35 day mortality and major adverse effects of thrombolytic agents in the treatment of acute myocardial infarction. DESIGN: Systematic review of randomized controlled trials comparing the clinical efficacy of included drug regimens. METHODS: We searched MEDLINE, EMBASE, Science Citation Index/Web of Science from 1980 to December 2001, and the Cochrane Library (2001, Issue 4). Reference lists of included studies and a number of medical journals were hand searched. Randomized controlled trials that compared any two of the included drugs provided to patients in the early stages of acute myocardial infarction, were included. Outcome measures included: mortality, bleeding, stroke, reinfarction, allergy and anaphylaxis. RESULTS: We found 14 studies, total study population 142 907. For available comparisons (all alteplase vs. streptokinase, reteplase vs. streptokinase or alteplase, tenecteplase vs. alteplase), meta-analysis showed no significant differences in mortality at 30-35 days. The GUSTO-I study showed an apparent benefit of accelerated alteplase over streptokinase, but its inclusion or exclusion made little difference. Total stroke and haemorrhagic stroke rates were lower for streptokinase than for all alteplase combined (total stroke, OR 1.29, 95%CI 1.13-1.46; haemorrhagic stroke OR 1.83, 95%CI 1.14-2.93). DISCUSSION: All thrombolytic drugs appear to be of similar efficacy in reducing mortality, and the apparent benefits of accelerated alteplase in GUSTO-I are consistent with this. Whether accelerated alteplase is sufficiently different from other regimens of administering alteplase to be excluded from a meta-analysis, and whether more weight should be placed on a meta-analysis than on a single trial, are matters for debate.

Fibrinolytic Agents↗
PubMed2002

Excision duodenoplasty: a new technique for congenital duodenal obstruction.

Slow anastomotic function is a common problem in the management of congenital duodenal obstruction. We describe a simple technique of excision duodenoplasty (ED) that results in a fixed open anastomosis, which facilitates early commencement of feeds and discharge from hospital. A retrospective case-note review (1981-2000) was undertaken to compare the results of ED with side-to-side duodenoplasty (SSD) and diamond-shaped anastomosis (DD). The outcome measures were days to commencement of feeds, duration of total parenteral nutrition (TPN), and length of hospital stay. In ED a 1.0 to 1.5-cm elliptical segment of dilated duodenum is excised. A longitudinal incision is made in the smaller distal duodenum. A side-to-side one-layer anastomosis is performed. The wall of the proximal duodenal stump is thick, and excision of the ellipse keeps the anastomosis open by preventing apposition of the opposing walls. This facilitates good drainage across the anastomosis. The time to onset of feeding was longer after SSD (median 7 days) compared to ED (5 days) and DD (5 days). The total duration of TPN was also longer for SSD (9 days) in comparison to ED (7 days) and DD (7 days). Although the duration of hospital stay was more for SSD (18 days) than ED (13 days) and DD (16 days), this difference was not statistically significant. The ED technique thus gives an equally good result as DD and a better result than SSD. It is simple to perform and to teach.

Analysis of Variance↗
PubMed2001

A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B.

Seventy-seven liver transplant candidates were enrolled in a multicenter study in which patients were treated with lamivudine (100 mg daily) without the adjunctive use of hepatitis B immune globulin. Treatment was begun while patients awaited liver transplantation and continued after transplantation. All were hepatitis B surface antigen (HBsAg) positive, and 61% had detectable hepatitis B e antigen (HBeAg) and HBV DNA when treatment was begun. Forty-seven underwent liver transplantation and 30 did not. Median study participation was 38 months (range, 2.7-48.5) in the transplanted patients and 26 months (range, 0.1-37) in the nontransplanted group. Twenty-five of 42 (60%) transplanted patients with 12 or more weeks of posttransplantation follow-up were HBsAg negative at the last study visit. At treatment week 156, 13 of 22 (59%) remained HBsAg negative, and all 9 reinfected patients were HBV-DNA positive before treatment. In the nontransplanted patients, HBeAg was initially detectable in 20 of 27 (74%) but this decreased to 3 of 17 (18%) after 104 weeks of treatment, and significant improvement in biochemical parameters was observed. HBV-DNA polymerase mutants were detected in 15 (21%) and 6 (20%) of the transplanted and nontransplanted patients, respectively. When compared with historical cohorts, lamivudine-treated patients appeared to have improved survival, and transplanted patients had a decrease in the rate of recurrent HBV infection. Lamivudine therapy was partially effective in preventing recurrent HBV infection when given before and after transplantation. Thus, future trials using a combination of HBIg and lamivudine are needed to assess the optimal prophylactic therapy.

Adult↗
PubMed2000

Effects of treatment for intestinal helminth infection on growth and cognitive performance in children: systematic review of randomised trials.

OBJECTIVE: To summarise the effects of anthelmintic drug treatment on growth and cognitive performance in children. DATA SOURCES: Electronic databases: Cochrane Infectious Diseases Group controlled trial register, Cochrane controlled trials register, Embase, and Medline. Citations of all identified trials. Contact with the World Health Organization and field researchers. REVIEW METHODS: Systematic review of randomised controlled trials in children aged 1-16 that compared anthelmintic treatment with placebo or no treatment. Assessment of validity and data abstraction conducted independently by two reviewers. MAIN OUTCOME MEASURES: Growth and cognitive performance. RESULTS: Thirty randomised controlled trials in more than 15 000 children were identified. Effects on mean weight were unremarkable, and heterogeneity was evident in the results. There were some positive effects on mean weight change in the trials reporting this outcome: after a single dose (any anthelmintic) the pooled estimates were 0.24 kg (95% confidence interval 0.15 kg to 0. 32 kg; fixed effects model assumed) and 0.38 kg (0.01 kg to 0.77 kg; random effects model assumed). Results from trials of multiple doses showed mean weight change in up to one year of follow up of 0.10 kg (0.04 kg to 0.17 kg; fixed effects) or 0.15 kg (0.00 to 0.30; random effects). At more than one year of follow up, mean weight change was 0.12 kg (-0.02 kg to 0.26 kg; fixed effects) and 0.43 (-0.61 to 1. 47; random effects). Results from studies of cognitive performance were inconclusive. CONCLUSIONS: There is some limited evidence that routine treatment of children in areas where helminths are common has effects on weight gain, but this is not consistent between trials. There is insufficient evidence as to whether this intervention improves cognitive performance.

Adolescent↗
PubMed2000

Reconstitution of higher plant chloroplast chaperonin 60 tetradecamers active in protein folding.

Unlike the GroEL homologs of eubacteria and mitochondria, oligomer preparations of the higher plant chloroplast chaperonin 60 (cpn60) consist of roughly equal amounts of two divergent subunits, alpha and beta. The functional significance of these isoforms, their structural organization into tetradecamers, and their interactions with the unique binary chloroplast chaperonin 10 (cpn10) have not been elucidated. Toward this goal, we have cloned the alpha and beta subunits of the ch-cpn60 of pea (Pisum sativum), expressed them individually in Escherichia coli, and subjected the purified monomers to in vitro reconstitution experiments. In the absence of other factors, neither subunit (alone or in combination) spontaneously assembles into a higher order structure. However, in the presence of MgATP, the beta subunits form tetradecamers in a cooperative reaction that is potentiated by cpn10. In contrast, alpha subunits only assemble in the presence of beta subunits. Although beta and alpha/beta 14-mers are indistinguishable by electron microscopy and can both assist protein folding, their specificities for cpn10 are entirely different. Similar to the authentic chloroplast protein, the reconstituted alpha/beta 14-mers are functionally compatible with bacterial, mitochondrial, and chloroplast cpn10. In contrast, the folding reaction mediated by the reconstituted beta 14-mers is only efficient with mitochondrial cpn10. The ability to reconstitute two types of functional oligomer in vitro provides a unique tool, which will allow us to investigate the mechanism of this unusual chaperonin system.

Adenosine Triphosphate↗
PubMed2000

Anthelmintic drugs for treating worms in children: effects on growth and cognitive performance.

BACKGROUND: Helminth (worm) infections are widespread and are thought to contribute to poor nutritional status, anaemia, and impaired growth and learning in children. OBJECTIVES: To summarise the effects of anthelmintic drug treatment in children in relation to their growth and cognitive performance. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, Embase and the reference lists of articles. We also contacted experts in the field. SELECTION CRITERIA: Randomised and quasi-randomised trials of drug treatment compared with placebo or no drug treatment for intestinal helminths in children. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by two reviewers. Study authors were contacted for additional information. MAIN RESULTS: Thirty trials involving more than 1500 children were included. There was potential for bias from inadequate concealment of allocation. Studies varied in relation to target groups, drugs administered and treatment regimens. Compared to placebo or no drug treatment, drug treatment for helminths was associated with some positive effects on change in weight, height and skinfold thickness. However there was significant heterogeneity between the results of the trials. There were some positive effects on mean weight change in the trials reporting this outcome; after a single dose (any anthelminth) the pooled estimate was 0.24 kg, (95% CI 0.15 to 0.32; fixed effects model assumed); and 0.38 kg (95% CI 0.00 to 0.77; random effects model assumed). Results from trials giving multiple doses showed mean weight change under one year of follow up of 0.10 kg (95% CI 0.04 to 0.17; fixed effects assumed); or 0.15 (95% CI 0.00 to 0.30; random effects assumed). At more than one year of follow up, mean weight change was 0.12 kg (95% CI -0.02 to 0.26; fixed effects assumed) and 0.43 (95% CI -0.61 to 1.47; random effects model assumed). Results from studies of cognitive performance were mixed and inconclusive. REVIEWER'S CONCLUSIONS: There is some limited evidence that routine treatment of children in areas where helminths are common has small effects on weight gain, but this is not consistent between trials. There is insufficient evidence to know whether this intervention improves cognitive performance. Our interpretation of these results is that the current public health programme investments in this intervention, based on the expectation that there will be an improvement in growth and learning, are not based on consistent or reliable evidence.

Adolescent↗
PubMed1998

Molecular cloning and functional characterization of murine sphingosine kinase.

Sphingosine-1-phosphate (SPP) is a novel lipid messenger that has dual function. Intracellularly it regulates proliferation and survival, and extracellularly, it is a ligand for the G protein-coupled receptor Edg-1. Based on peptide sequences obtained from purified rat kidney sphingosine kinase, the enzyme that regulates SPP levels, we report here the cloning, identification, and characterization of the first mammalian sphingosine kinases (murine SPHK1a and SPHK1b). Sequence analysis indicates that these are novel kinases, which are not similar to other known kinases, and that they are evolutionarily conserved. Comparison with Saccharomyces cerevisiae and Caenorhabditis elegans sphingosine kinase sequences shows that several blocks are highly conserved in all of these sequences. One of these blocks contains an invariant, positively charged motif, GGKGK, which may be part of the ATP binding site. From Northern blot analysis of multiple mouse tissues, we observed that expression was highest in adult lung and spleen, with barely detectable levels in skeletal muscle and liver. Human embryonic kidney cells and NIH 3T3 fibroblasts transiently transfected with either sphingosine kinase expression vectors had marked increases (more than 100-fold) in sphingosine kinase activity. The enzyme specifically phosphorylated D-erythro-sphingosine and did not catalyze the phosphorylation of phosphatidylinositol, diacylglycerol, ceramide, D,L-threo-dihydrosphingosine or N, N-dimethylsphingosine. The latter two sphingolipids were competitive inhibitors of sphingosine kinase in the transfected cells as was previously found with the purified rat kidney enzyme. Transfected cells also had a marked increase in mass levels of SPP with a concomitant decrease in levels of sphingosine and, to a lesser extent, in ceramide levels. Our data suggest that sphingosine kinase is a prototypical member of a new class of lipid kinases. Cloning of sphingosine kinase is an important step in corroborating the intracellular role of SPP as a second messenger.

3T3 Cells↗