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The postnatal growth of rats involves a developmental phase (0 to approximately 3 weeks), a rapid growth phase ( approximately 3 to approximately 10 weeks), and a slower maturation phase ( approximately 10 weeks+). In this study, we investigated the age-related changes in excitation-contraction (E-C) coupling characteristics of mammalian skeletal muscle, during rapid growth (4-10 weeks) and maturation (10-21 weeks) phases, using single, mechanically skinned fibres from rat extensor digitorum longus (EDL) muscle. Fibres from rats aged 4 and 8 weeks produced lower maximum T-system depolarization-induced force responses and fewer T-system depolarization-induced force responses to 75% run-down than those produced by fibres from rats aged 10 weeks and older. The sensitivity of the contractile apparatus to Ca(2+) in fibres from 4-week rats was significantly higher than that in fibres from 10-week rats; however, the maximum Ca(2+)-activated force per skinned fibre cross-sectional area (specific force) developed by fibres from 4-week rats was on average approximately 44% lower than the values obtained for all the other age groups. In agreement with the age difference in specific force, the MHC content of EDL muscles from 4-week rats was approximately 29% lower than that of 10-week rats. Thus, mechanically skinned fibres from rats undergoing rapid growth are less responsive to T-system depolarization and maximal Ca(2+) activation than fibres from rats at the later stage of maturation or adult rats. These results suggest that during the rapid growth phase in rats, the structure and function of elements involved in E-C coupling in fast-twitch skeletal muscle continue to undergo significant changes.

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Home management is a very common approach to the treatment of illnesses such as malaria, acute respiratory infections, tuberculosis, diarrhoea and sexually transmitted infections, frequently through over-the-counter purchase of drugs from shops. Inappropriate drugs and doses are often obtained, but interventions to improve treatment quality are rare. An educational programme for general shopkeepers and communities in Kilifi District, rural Kenya was associated with major improvements in the use of over-the-counter anti-malarial drugs for childhood fevers. The two main components were workshop training for drug retailers and community information activities, with impact maintained through on-going refresher training, monitoring and community mobilization. This paper presents the cost and cost-effectiveness of the programme in terms of additional appropriately treated cases, evaluating both its measured cost-effectiveness in the first area of implementation (early implementation phase) and the estimated cost-effectiveness of the programme recommended for district-level implementation (recommended district programme). The proportion of shop-treated childhood fevers receiving an adequate amount of a recommended antimalarial rose from 2% to 15% in the early implementation phase, at an economic cost of 4.00 US dollars per additional appropriately treated case (2000 US dollars). If the same impact were achieved through the recommended district programme, the economic cost per additional appropriately treated case would be 0.84 US dollars, varying between 0.37 US dollars and 1.36 US dollars in the sensitivity analysis. As with most educational approaches, the programme carries a relatively high initial financial cost, of 11,477 US dollars (0.02 per capita US dollars) for the development phase and 81,450 US dollars (0.17 per capita US dollars) for the set up year, which would be particularly suitable for donor funding, while the annual costs of 18,129 US dollars (0.04 per capita US dollars) thereafter could be contained within the budget of a typical District. To reach the Abuja target of 60% of those suffering from malaria in sub-Saharan Africa having access to affordable and appropriate treatment within 24 hours, improvements in community-based malaria treatment are urgently required. From these results, policymakers can estimate costs for district-scale shopkeeper training programmes, and will be able to assess their relative cost-effectiveness as comparable evaluations become available from home management interventions in the future. Extrapolation of the results using a simple decision tree model to estimate the cost per DALY averted indicates that the intervention is likely to be considered highly cost-effective in comparison with standard benchmarks for interventions in low-income countries.

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Access to effective treatment would substantially reduce the burden of malaria in sub-Saharan Africa, but resistance to chloroquine, the most commonly used first line drug, is now widespread. There has been considerable debate over the level of chloroquine resistance at which a new first line drug should be adopted. Two issues make this an extremely complex decision: it involves trade-offs in costs and health outcomes over time; and many of the parameters are uncertain. A modelling approach was identified as appropriate for addressing these issues. The costs and effects of changing from chloroquine to sulphadoxine-pyrimethamine (SP) as the first line drug were modelled over 10 years, allowing for growth in drug resistance. Probabilistic sensitivity analysis was used to allow for the high levels of parameter uncertainty. The optimal year of switch was highly dependent on both empirical values, such as initial resistance and resistance growth rates, and on subjective values, such as the time preferences of policy-makers. It was not possible to provide policy-makers with a definitive threshold resistance level at which to switch, but the model can be used as an analytical tool to structure the problem, explore trade-offs, and identify areas for which data are lacking.

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Antimalarial chemoprophylaxis during pregnancy significantly increases the birth weight of babies born to primigravidae, but coverage in sub-Saharan Africa is very limited. This analysis assessed whether increasing coverage is justified on cost-effectiveness grounds. A standardized modeling framework was used to estimate ranges for the cost per discounted year of life lost averted by weekly chloroquine chemoprophylaxis and intermittent sulfadoxine-pyrimethamine (SP) treatment for primigravidae in an operational setting with moderate to high malaria transmission. The SP regimen was found to be more cost-effective than the chloroquine regimen, because of both lower costs and higher compliance. Both regimens appear to be a good value for money in comparison with other methods of malaria control and based on rough cost-effectiveness guidelines for low-income countries, even with high levels of drug resistance. However, extending the SP regimen to all gravidae and increasing the number of doses per pregnancy could make the intervention significantly less cost-effective.

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Residual house-spraying (RHS) has been the mainstay of South African malaria prevention for more than 50 years, but it has been argued that insecticide-treated bednets (ITBN) could be a more effective and appropriate method of control. To provide a rational basis for choosing between the interventions, a trial was conducted during 1998 and 1999 in northern KwaZulu-Natal to collect comparable data on the effectiveness, acceptability and cost of the two interventions. The current practice of house-spraying once a year was compared with ITBN, distributed free to households and retreated annually at several specific centres. The base case results show ITBN to be significantly more effective in preventing malaria cases than RHS (overall adjusted rate ratio of 0.69), and also more costly, with an incremental economic cost per person of ITBN compared with RHS of R8.68 (US$1.42) per year, giving a gross incremental cost per case averted of R111 ($18) (1999 prices). Estimating the number of deaths averted, based on the average case fatality rate, gave a gross incremental cost per death averted of R11 718 ($1915). The additional cases averted were estimated to lead to drug cost savings of around R1 ($0.16) per capita per year, giving a net cost per case averted of R98 ($16), and net cost per death averted of R10 377 ($1696). Although the finding that the economic costs of ITBN were higher than those for RHS was relatively robust to parameter variations, the extent of the cost margin was sensitive to changes in the price and useful life of the net, and the price of the insecticide. Moreover, a switch to ITBN could lead to net financial savings if the price per net fell below $3.57 (R21.85), or if a change in policy allowed a significant reduction in the number of permanent full-time malaria control staff. In view of the greater effectiveness of ITBN, policy makers may view ITBN as a cost-effective use of resources, even if the economic costs are higher. If ITBN are implemented, close monitoring will be required of use, retreatment and useful life of nets, and resistance to insecticides, to assess any change over time in relative cost-effectiveness, and any threat to the role of the programme as a barrier to the spread of malaria transmission to other areas.

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BACKGROUND: Pancreatic anastomotic failure has historically been regarded as one of the most feared complications after pancreaticoduodenectomy. METHODS: We reviewed our recent experience (59 cases), March 1994 to December 1998, with pancreaticoduodenectomy and compared preoperative and intraoperative characteristics as well as outcomes in those patients who experienced (n = 10) versus those who did not experience a postoperative pancreatic leak (n = 49). Information was retrospectively collected from hospital records, office records, and interviews with patients. RESULTS: The clinical leak rate in this series was 8.5%. There were no significant differences in preoperative or intraoperative characteristics comparing those with versus those without a postoperative pancreatic leak. Only 1 of 10 patients with a postoperative pancreatic leak required reoperation to manage the leak. Those with a pancreatic leak had more other postoperative complications (median 2 versus 0 complications per patient, P = 0.01) and longer hospital duration compared with those without a leak (median 13 versus 23 days, P<0.01). Overall mortality in the series was 3.4%; no mortalities occurred as a result of a pancreatic leak. CONCLUSIONS: In the 1990s pancreatic anastomotic leak remains a potentially lethal problem after pancreaticoduodenectomy. Pancreatic leakage after pancreaticoduodenectomy is associated with other postoperative complications and a longer hospital stay.

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There is increasing evidence that endogenous glycogen depletion may affect excitation-contraction (E-C) coupling events in vertebrate skeletal muscle. One approach employed in physiological investigations of E-C coupling involves the use of mechanically skinned, single fibre preparations obtained from tissues stored under paraffin oil, at room temperature (RT: 20-24 degrees C) and 4 degrees C for several hours. In the present study, we examined the effect of these storage conditions on the glycogen content in three muscles frequently used in research on E-C coupling: rat extensor digitorum longus (EDL) and soleus (SOL) and toad iliofibularis (IF). Glycogen content was determined fluorometrically in homogenates prepared from whole muscles, stored under paraffin oil for up to 6 h at RT or 4 degrees C. Control muscles and muscles stored for 0.5 and 6 h were also analysed for total phosphorylase (Phos(total)) and phosphorylase a (Phos a) activities. No significant change was observed in the glycogen content of EDL and SOL muscles stored at RT for 0.5 h. In rat muscles stored at RT for longer than 0.5 h, the glycogen content decreased to 67.6% (EDL) and 78.7% (SOL) of controls after 3 h and 25.3% (EDL) and 37.4% (SOL) after 6 h. Rat muscles stored at 4 degrees C retained 79.0% (EDL) and 92.5% (SOL) of glycogen after 3 h and 75.2% (EDL) and 61.1% (SOL) after 6 h. The glycogen content of IF muscles stored at RT or 4 degrees C for 6 h was not significantly different from controls. Phos(total) was unchanged in all muscles over the 6 h period, at both temperatures. Phos a was also unchanged in the toad IF muscles, but in rat muscles it decreased rapidly, particularly in EDL (4.1-fold after 0.5 h at RT). Taken together these results indicate that storage under paraffin oil for up to 6 h at RT or 4 degrees C is accompanied by minimal glycogen loss in toad IF muscles and by a time- and temperature-dependent glycogen loss in EDL and SOL muscles of the rat.

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BACKGROUND: Information on the cost-effectiveness of malaria control is needed for the WHO Roll Back Malaria campaign, but is sparse. We used mathematical models to calculate cost-effectiveness ratios for the main prevention and treatment interventions in sub-Saharan Africa. METHODS: We analysed interventions to prevent malaria in childhood (insecticide-treated nets, residual spraying of houses, and chemoprophylaxis) and pregnancy (chloroquine chemoprophylaxis and sulfadoxine-pyrimethamine intermittent treatment), and to improve malaria treatment (improved compliance, improved availability of second-line and third-line drugs, and changes in first-line drug). We developed models that included probabilistic sensitivity analysis to calculate ranges for the cost per disability-adjusted life year (DALY) averted for each intervention in three economic strata. Data were obtained from published and unpublished sources, and consultations with researchers and programme managers. FINDINGS: In a very-low-income country, for insecticide treatment of existing nets, the cost-effectiveness range was US$4-10 per DALY averted; for provision of nets and insecticide treatment $19-85; for residual spraying (two rounds per year) $32-58; for chemoprophylaxis for children $3-12 (assuming an existing delivery system); for intermittent treatment of pregnant women $4-29; and for improvement in case management $1-8. Although some interventions are inexpensive, achieving high coverage with an intervention to prevent childhood malaria would use a high proportion of current health-care expenditure. INTERPRETATION: Cost-effective interventions are available. A package of interventions to decrease the bulk of the malaria burden is not, however, affordable in very-low-income countries. Coverage of the most vulnerable groups in Africa will require substantial assistance from external donors.

PIP: This paper examines the cost-effectiveness of malaria control using an innovative modeling approach based on probabilistic sensitivity analysis in sub-Saharan Africa. The variables included in the study were interventions for preventing malaria in childhood (insecticide-treated nets, residual spraying of houses and chemoprophylaxis), preventing malaria in pregnancy (chloroquine chemoprophylaxis and sulfadoxine-pyrimethamine intermittent treatment), and improving treatment for uncomplicated malaria (better compliance, improved availability of second- and third-line drugs, and changes in first-line drugs). Effectiveness was calculated in terms of disability-adjusted life years (DALY) formula. The cost data were obtained through published and unpublished literature, program budgets, price catalogues, and consultation with researchers and program managers. Results showed that in a very-low-income country, the cost-effectiveness range of insecticide-treated nets was US$19-85. If only insecticide treatment was required, the range would be decreased to US$4-10 per DALY averted. Cost effectiveness was $32-58 for residual spraying (two rounds per year), $3-12 for children's chemoprophylaxis, $4-29 for intermittent treatment of pregnant women, and $1-8 for improvement in case management. Cost-effectiveness analysis helped identify interventions that would result in the effective use of resources, but information on total costs was also needed in order to assess affordability. Furthermore, coverage of the most vulnerable groups in Africa would require substantial assistance from external donors.

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The efficacy and relative cost-effectiveness of insecticide-treated nets (ITNs) for the control of malaria in children under 5 years of age have recently been demonstrated by several large-scale trials. However, it has been suggested that long-term use of ITNs in areas of high transmission could lead to mortality rebound in later childhood, which would reduce the cost-effectiveness of the intervention, and at the extreme could lead to negative overall effects. A model is presented in which the cost and disability adjusted life years (DALYs) per child aged 1-119 months were estimated for a sub-Saharan African population with and without an ITN intervention. The rebound rate, defined as the percentage increase in age-specific all-cause mortality and malaria specific-morbidity, was varied to estimate the threshold at which the intervention was no longer cost-effective. Rebound was considered over two possible age ranges: 5-9 years and 3-6 years. With mortality and morbidity reductions due to ITNs in children aged 1-59 months and rebound in the 5-9 years age class, one could be reasonably certain that the cost per DALY averted is below $150 up to a rebound rate of 39%. Up to an 84% rebound rate it is highly likely that the intervention will be DALY-averting, that is the DALYs averted by the intervetion outweigh DALYs incurred through rebound effects. These thresholds are sensitive to the age range over which reductions and rebound in morbidity and mortality occur. With reductions confined to children aged 1-35 months and rebound in the 3-6 years age class, the cost per DALY is highly likely to fall below $150 only up to a 2.5% rebound rate, and with a rate in excess of 11% one can no longer be reasonably certain that the intervention is DALY-averting. These rates apply to the whole population. If there is no rebound amongst children who did not comply with the intervention, the actual increases in morbidity and mortality required to reach these thresholds amongst compliers would be much higher. The age range over which rebound occurs is a critical determinant of the thresholds at which one can no longer be reasonably certain that ITNs remain cost-effective in the long term. Based on empirical estimates of age-specific malaria mortality in sub-Saharan Africa, it appears unlikely that this threshold rate would be reached if rebound occurs over the 5-9 years age range. By contrast, if rebound occurs over the ages of 3-6 years, the increase in mortality rates required to reach this threshold falls within the observed range of malaria-specific mortality rates for this age group. It is essential that long-term surveillance is included as part of ITN interventions, with particular attention to the age range over which rebound may occur.

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This review assesses the range and quality of the evidence base on the cost-effectiveness of malaria prevention and treatment in sub-Saharan Africa. Fourteen studies are reviewed, covering insecticide-treated nets, residual spraying, chemoprophylaxis for children, chemoprophylaxis or intermittent treatment for pregnant women, a hypothetical vaccine, and changing the first line drug for treatment. The available evidence provides some guidance to decision-makers. However, the potential to inform policy debates is limited by the gross lack of information on the costs and effects of many interventions, the very small number of cost-effectiveness analyses available, the lack of evidence on the costs and effects of packages of measures, and the problems in generalizing or comparing studies that relate to specific settings and use different methodologies and outcome measures.

PIP: This article reviews the range and quality of the evidence based on the cost-effectiveness of malaria prevention and treatment in sub-Saharan Africa. About 14 studies were analyzed, covering insecticide-treated nets, residual spraying, chemoprophylaxis for children, chemoprophylaxis or intermittent treatment for pregnant women, a hypothetical vaccine, and changing the first line drug for treatment. Results of the analyses demonstrate that highly cost-effective interventions exist for both prevention and treatment; that approaches to improving treatment are likely to be highly cost-effective; and that given the uncertainty and variation involved, the choice between childhood preventive interventions is not clear-cut due to the considerable overlap in their cost-effectiveness ranges. The review also cites several challenges in using cost-effectiveness estimates for policy-making. In conclusion, evidence from economic evaluations can assist policy-makers in identifying interventions representing the best value for money. Available studies provide some guidance to decision-makers. However, the current potential of economic evaluation to inform policy debates is limited by: the gross lack of information on the costs and effects of many interventions; the very small number of cost-effectiveness analyses available; the lack of evidence on the costs and effects of packages of measures; and the problems generalizing or comparing studies that relate to specific settings and use different methodologies and outcome measures.

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We have designed, fabricated, and tested an improved digital sonomicrometer for two-point ultrasound measurements in the experimental cardiology laboratory. The system design incorporates state-of-the-art analog and digital circuitry and demonstrates 1) capability for either analog or digital output; 2) a resolution of +/- 0.15 mm, readily adjustable to +/- 0.03 mm as required; 3) excellent stability; 4) low cost; and 5) ease of operation by untrained personnel. The device was calibrated in vitro and successfully evaluated by making measurements of contractile motion in the myocardium of the open-chest dog.

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