Characterization of a multi-copy gene for a major stage-specific cysteine proteinase of Leishmania mexicana

AbstractImcpb, a gene from Leishmania mexicana that encodes a major cysteine proteinase in the parasite, has been cloned and sequenced. LmCPb is related more to cysteine proteinases from Trypanosoma brucel and Trypanosoma cruzi than to a previously characterized cysteine proteinase, LmCPa, of L. mexicana. It contains a long C-terminal extension characteristic of similar enzymes of T. brucei and T. cruzi. The gene is multi-copy and tandemly arranged. Imcpb RNA levels are developmentally regulated with steady state levels being high in amastigotes, low in metacyclic promastigotes and undetectable in multiplicative promastigotes. This variation correlates with and may account for the stage-specific expression of LmCPb enzyme activity

The clinical and cost-effectiveness of patient education models for diabetes : a systematic review and economic evaluation

Description of the proposed service This systematic review examines the clinical and cost-effectiveness of patient education models for adults with Type 1 or Type 2 diabetes. Epidemiology and background Diabetes mellitus (diabetes) is characterised by a state of chronic hyperglycaemia (raised blood sugar). There are two main types of diabetes: Type 1 and Type 2. Type 1 diabetes is an autoimmune condition involving a process of destruction of the beta cells of the pancreas, leading to severe insulin deficiency. About one-fifth of patients with diabetes in England and Wales have Type 1 diabetes. Type 2 diabetes is characterised by insulin resistance and relative insulin deficiency and is linked to being overweight or obese, and to physical inactivity. Type 2 diabetes primarily affects people aged over 40 years. The basic target in the treatment of diabetes is the normalisation of blood glucose levels. Poor control of diabetes can in the short term result in diabetic ketoacidosis, a serious and potentially fatal condition, and in the long term can increase the risk of complications such as diabetic retinopathy and nephropathy. However, studies have shown that good diabetic control is associated with a reduced risk of these complications. Diabetic control is affected by both lifestyle factors such as diet, and by pharmacological treatments, and the management of diabetes is largely the responsibility of patients. A key component in empowering patients to manage their own diabetes is education. Education of patients with diabetes is considered a fundamental aspect of diabetes care and aims to empower patients by improving knowledge and skills. Structured educational programmes for diabetes self-management are often multifaceted interventions providing patients with information not only about diabetes but also management issues such as diet, exercise, self-monitoring of blood glucose and medication use. Methods A systematic review of the literature and an economic evaluation were undertaken. Data sources Electronic databases were searched, including the Cochrane Library, MEDLINE, EMBASE, PubMed, Science Citation Index, Web of Science Proceedings, DARE and HTA databases, PsychINFO, CINAHL, NHS Economic Evaluation Database and EconLit. References of all retrieved articles were checked for relevant studies, and experts were contacted for advice and peer review and to identify additional published and unpublished references. Sponsor submissions to the National Institute for Clinical Excellence were reviewed. Study selection Studies were included if they fulfilled the following criteria: Interventions: educational interventions compared with usual care or another educational intervention. Participants: adults with Type 1 or Type 2 diabetes mellitus. Outcomes: must report glycated haemoglobin, hypoglycaemic episodes, diabetic complications or quality of life. Other reported outcomes from included studies were discussed. Evaluation of outcomes >12 months from inception of intervention. Design: randomised clinical trials (RCTs), and controlled clinical trial (CCTs) with a concurrent control were included. Reporting: studies were only included if they reported sufficient detail of the intervention to be reproducible (e.g. topics covered, who provided the education, how many sessions were available). Studies in non-English language or available only as abstracts were excluded. Titles and abstracts were checked by two reviewers. Full texts of selected studies were assessed for inclusion by one reviewer and checked by a second. Differences in opinion were resolved through discussion. Data extraction and quality assessment Data extraction and quality assessment were undertaken by one reviewer and checked by a second, with any disagreement resolved through discussion involving a third reviewer if necessary. The quality of included studies was assessed in accordance with Centre for Reviews and Dissemination Report 4. Data synthesis Data on clinical effectiveness were synthesised through a narrative review with tabulation of results from included studies. Studies were too diverse to be combined in a meta-analysis. Cost-effectiveness analyses were reported in a narrative review. Number and quality of studies Searches identified 24 studies comparing education with either a control group or with another educational intervention. These were 18 RCTs and six CCTs. Four studies included adults with Type 1 diabetes, 16 studies included adults with Type 2 diabetes and four studies included adults with either Type 1 or Type 2 diabetes. The quality of reporting and methodology of the studies was generally poor by today’s standards with only two RCTs reporting adequate randomisation procedures and none demonstrating adequate allocation concealment. Economic evaluations Literature searches identified only two studies reporting cost-effectiveness results: one cost-utility analysis and one cost-effectiveness analysis using intermediate outcomes only. Summary of benefits Studies of education in Type 1 diabetes suggest that education programmes offered as a part of intensified treatment interventions can result in significant and long-lasting improvements in metabolic control and reductions in complications. These are studies in which education is part of a package of care also including treatment changes (for example diet and insulin) and therefore it is not possible to draw conclusions about potential effects of education per se in Type 1 diabetes. Diverse educational programmes in Type 2 diabetes did not yield consistent results. Although some trials reported significant improvements in metabolic control and/or quality of life or other psychological outcomes, many others did not report significant effects of educational interventions. No clear characterisation is possible as to what features of education may be beneficial in this patient group. Studies that included patients with either Type 1 or Type 2 diabetes also produced mixed results with only poorer quality studies reporting significant effects. Costs Literature searches identified a small number of studies offering cost data in relation to patient education models. These were all studies undertaken outside the UK and they covered a variety of methodologies. We are not able to generalise from these studies as to the cost-effectiveness of patient education models. Patient education models will predominantly consist of direct costs for resource inputs to particular education packages, for example staff time (diabetes specialist nurse, dietitian and/or consultant) and education materials. The Dose Adjustment for Normal Eating (DAFNE) intervention is estimated to cost approximately £545 per person attending. Costs per life year gained Owing to the absence of accurate data on health outcomes, we are not able to provide cost-effectiveness summary statistics. The evidence base does indicate that improved glycaemic control is likely to have a positive impact on the incidence of long-term diabetic complications. Therefore, where the costs associated with patient education are assumed to be in the region of £500–600 per patient, the benefits over time would have to be very modest to offer an attractive cost-effectiveness profile for the intervention. The submission from the DAFNE study group predicts a scenario in which the DAFNE intervention results in cost savings and added health benefits over time, when compared with usual practice. Implications The main implication for the NHS would be staff time, particularly of diabetes specialist nurses, but also dietitians. Provision of increased education may be hindered by a shortage of trained specialist nurses, which will take some years to resolve. Future research needs The paucity of high-quality trials that have tested education per se in diabetes reveals a need for more research. Such research should focus on RCTs with clear designs based on explicit hypotheses and with a range of outcomes evaluated after long follow-up intervals. In order to draw conclusions about the effects of education alone, such trials should manipulate only education rather than confounding education with other factors

The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus : a systematic review and economic evaluation

Background The two main types of diabetes are type 1 (formerly called insulin-dependent diabetes) and type 2 (formerly called non-insulin-dependent diabetes). In type 1, insulin is always required because the insulin-producing islet cells in the pancreas have been destroyed. In type 2, the pancreas can still produce insulin, and treatment is initially with diet and exercise, but the disease often progresses, with deteriorating control and rising blood glucose levels, and a need next for oral hypoglycaemic agents (OHAs), and later for insulin in about 30%. The aim of insulin therapy is to reduce blood glucose to normal levels, without going too low and causing hypoglycaemia. Insulin currently has to be given by injection. There are various types according to duration of action – short, intermediate and long. Short- and long-acting insulin both come in two forms: traditional and the newer analogues. The traditional form of short-acting insulin is known as soluble. It is given by injection using an insulin pen, or a syringe and needle. Insulin can also be given by continuous subcutaneous infusion by an insulin pump, usually only in selected patients with type 1 diabetes. Objective The aim was to review the clinical effectiveness and cost-effectiveness of a new technology, the inhaled insulin, Exubera® (Pfizer and Sanofi-Aventis in collaboration with Nektar Technologies), a short-acting insulin. Methods A systematic literature review was conducted and economic modelling carried out. Literature searches were done up to November 2005. The industry model, EAGLE, was used for modelling. Results Clinical effectiveness Nine trials of inhaled insulins were found, but only seven used the Exubera form of inhaled insulin. The other two used inhaled insulins that have not yet been licensed. There were five trials in type 1 and two in type 2 diabetes. Inhaled insulin is clinically effective, and is as good as short-acting soluble insulin in controlling blood glucose. The frequency of hypoglycaemia is similar. It works slightly more quickly than soluble insulin. None of the published trials compared it with short-acting analogues, which would have provided a better comparison since they also work slightly more rapidly than soluble. There is also a problem in most of the trials in that patients were on combinations of short-acting, and either long- or intermediate-acting insulin, and both were changed, making it more difficult to assess the effects of only the change from soluble to inhaled insulin. The only significant difference between inhaled and soluble insulin in the trials was in patient preference. Most patients preferred inhaled to injected short-acting insulin, and this has some effect on quality of life measures. However, there could be some bias operating in the trials. The control groups mostly used syringes and needles, rather than pens. As pens are more convenient, their use might have narrowed the patient satisfaction difference. The manufacturer, Pfizer, argues that this patient preference could lead to improved control in some type 1 patients, through improved compliance with treatment, and in some type 2 patients poorly controlled on oral agents, because a switch to insulin therapy would be more acceptable if people could use inhaled rather than injected insulin. These assertions are unproven. There were no trials of inhaled insulin against continuous subcutaneous insulin infusion (CSII). Safety Concern has been raised about the long-term effects of inhaled insulin in the lung. So far, no serious adverse effects have been seen, but until many thousands of people have used inhaled insulin for many years, one cannot rule out some uncommon or rare, but serious, adverse effects. Cost-effectiveness The manufacturer's model (EAGLE) appears to be a high-quality one. However, the results depend more on the assumptions fed into the model than on the model itself. The key assumptions are the size of the gain in quality of life utility from inhaling rather than injecting insulin, the effect of having an inhaled option on the willingness to start insulin among people with poor diabetic control on oral drugs, and the effect on glycaemic control. We consider that the assumptions used in the industry submission make the cost-effectiveness appear better than it really would be. The manufacturer's submission assumed utility gains of 0.036–0.075 in patients with type 1 diabetes, and 0.027–0.067 in those with type 2, based on an unpublished utility elicitation study sponsored by the manufacturer. We thought that these gains were optimistic and that gains of 0.02 or less were more likely, on average. However, patients with particular problems with injection sites might have more to gain, although they might also be a group with much to gain from CSII. A key factor is the cost of inhaled insulin. Much more insulin has to be given by inhaler than by injection, and so the cost of inhaled insulin is much higher than injected. The extra cost depends on dosage, but ranges from around £600 to over £1000 per patient per year. Conclusion The inhaled insulin, Exubera, appears to be effective and safe, but the cost is so much more that it is unlikely to be cost-effective

Nuclear Magnetic Resonance and Hyperfine Structure

Contains reports on four research projects

Corrections to the universal behavior of the Coulomb-blockade peak splitting for quantum dots separated by a finite barrier

Building upon earlier work on the relation between the dimensionless interdot channel conductance g and the fractional Coulomb-blockade peak splitting f for two electrostatically equivalent dots, we calculate the leading correction that results from an interdot tunneling barrier that is not a delta-function but, rather, has a finite height V and a nonzero width xi and can be approximated as parabolic near its peak. We develop a new treatment of the problem for g much less than 1 that starts from the single-particle eigenstates for the full coupled-dot system. The finiteness of the barrier leads to a small upward shift of the f-versus-g curve at small values of g. The shift is a consequence of the fact that the tunneling matrix elements vary exponentially with the energies of the states connected. Therefore, when g is small, it can pay to tunnel to intermediate states with single-particle energies above the barrier height V. The correction to the zero-width behavior does not affect agreement with recent experimental results but may be important in future experiments.Comment: Title changed from ``Non-universal...'' to ``Corrections to the universal...'' No other changes. 10 pages, 1 RevTeX file with 2 postscript figures included using eps

Force balance and membrane shedding at the Red Blood Cell surface

During the aging of the red-blood cell, or under conditions of extreme echinocytosis, membrane is shed from the cell plasma membrane in the form of nano-vesicles. We propose that this process is the result of the self-adaptation of the membrane surface area to the elastic stress imposed by the spectrin cytoskeleton, via the local buckling of membrane under increasing cytoskeleton stiffness. This model introduces the concept of force balance as a regulatory process at the cell membrane, and quantitatively reproduces the rate of area loss in aging red-blood cells.Comment: 4 pages, 3 figure

The effectiveness and cost-effectiveness of computed tomography screening for coronary artery disease : systematic review

Coronary heart disease (CHD) is one of the main causes of mortality and morbidity in the UK and other Western countries. The disease can be asymptomatic until the first event, which may be a fatal myocardial infarction (heart attack). Half of all heart attacks occur in people who have had no prior warning of coronary disease, and almost half will die from the first attack. Risk scores based on well-known factors such as age, blood pressure, smoking, cholesterol and diabetes have been used to assess risk, but are imperfect: not all high-risk people develop heart disease, and many low-risk people do. Indeed, depending on which cut-off is used to define high risk, most heart attacks occur in low-risk people, because the number of people at low risk is much greater than the number at high risk. There is therefore a need for a better way of identifying those at risk so that they can treat themselves with lifestyle measures, or receive drug therapy such as statins and antihypertensive drugs as appropriate. Computed tomography (CT) is a form of radiological imaging that can detect calcium deposits in the coronary arteries. This calcification is a marker for CHD, and so CT imaging could be a way of detecting asymptomatic but serious CHD. CT is quick and non-invasive, but does involve a relatively large radiation dose

Fast shower simulation in the ATLAS calorimeter

The time to simulate pp collisions in the ATLAS detector is largely dominated by the showering of electromagnetic particles in the heavy parts of the detector, especially the electromagnetic barrel and endcap calorimeters. Two procedures have been developed to accelerate the processing time of electromagnetic particles in these regions: (1) a fast shower parameterisation and (2) a frozen shower library. Both work by generating the response of the calorimeter to electrons and positrons with Geant 4, and then reintroduce the response into the simulation at runtime. In the fast shower parameterisation technique, a parameterisation is tuned to single electrons and used later by simulation. In the frozen shower technique, actual showers from low-energy particles are used in the simulation. Full Geant 4 simulation is used to develop showers down to ~1 GeV, at which point the shower is terminated by substituting a frozen shower. Judicious use of both techniques over the entire electromagnetic portion of the ATLAS calorimeter produces an important improvement of CPU time. We discuss the algorithms and their performance in this paper