Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats

Corticotropin-releasing factor(1) (CRF(1)) antagonists may be effective in the treatment of anxiety disorders with fewer side effects compared with classic benzodiazepines. The behavioral effects of DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] and its effects on the hypothalamic-pituitary-adrenal (HPA) axis were related to its levels in plasma and estimated occupancy of central CRF(1) receptors. DMP904 (10-30 mg/kg, p.o.) and alprazolam (10 mg/kg, p.o.) increased time spent in open arms of an elevated-plus maze. In addition, acutely or chronically (14 days) administered DMP904 (1.0-30 mg/kg, p.o.) and acute alprazolam (1.0-3.0 mg/kg, p.o.) significantly reduced exit latency in the defensive withdrawal model of anxiety in rats, suggesting that tolerance may not develop to the anxiolytic-like effects of DMP904 in this model of anxiety. Acutely, DMP904 reversed the stress-induced increase in plasma corticosterone levels in defensive withdrawal at doses of 3.0 mg/kg and higher. These doses also resulted in levels of DMP904 in plasma similar to (for anxiolytic-like effects) or 4-fold higher (for effects on the HPA axis) than the in vitro IC(50) value for binding affinity at CRF(1) receptors and greater than 50% occupancy of CRF(1) receptors. Unlike alprazolam, DMP904 did not produce sedation, ataxia, or chlordiazepoxide-like subjective effects (as measured by locomotor activity, rotorod performance, and chlordiazepoxide discrimination assays, respectively) at doses at least 3-fold higher than anxiolytic-like doses. In conclusion, anxiolytic-like effects and effects on the stress-activated HPA axis of DMP904 in the defensive withdrawal model of anxiety required 50% or greater occupancy of central CRF(1) receptors. This level of CRF(1) receptor occupancy resulted in fewer motoric side effects compared with classic benzodiazepines.     

World health system performance revisited: the impact of varying the relative importance of health system goals

Background

In 2002, the World Health Organization published a health system performance ranking for 191 member countries. The ranking was based on five indicators, with fixed weights common to all countries.

Methods

We investigate the feasibility and desirability of using mathematical programming techniques that allow weights to vary across countries to reflect their varying circumstances and objectives.

Results

By global distributional measures, scores and ranks are found to be not very sensitive to changes in weights, although differences can be large for individual countries.

Conclusions

Building the flexibility of variable weights into calculation of the performance index is a useful way to respond to the debates and criticisms appearing since publication of the ranking.     

A generic model for the assessment of disease epidemiology: the computational basis of DisMod II

Reliable and comparable analysis of risks to health is key for preventing disease and injury. Causal attribution of morbidity and mortality to risk factors has traditionally been conducted in the context of methodological traditions of individual risk factors, often in a limited number of settings, restricting comparability.     

Population health metrics: crucial inputs to the development of evidence for health policy

Valid, reliable and comparable measures of the health states of individuals and of the health status of populations are critical components of the evidence base for health policy. We need to develop population health measurement strategies that coherently address the relationships between epidemiological measures (such as risk exposures, incidence, and mortality rates) and multi-domain measures of population health status, while ensuring validity and cross-population comparability.     

Breast and cervical cancer survival: making sense of ‘league tables’

During 1998, the Department of Health proposed to use survival rates of cervical and breast cancer in the 1989/90 incidence cohort as indicators of care. Valid interpretation was of concern within Trent and the Trent Cancer Registry responded by performing additional analyses. Trent Cancer Registry registrations for 1989/90 were re-analysed and the stability of districts' ranks for that cohort was investigated using random simulation techniques. Stability of ranks across more recent cohorts was investigated and attempts made to use all available information.The Department of Health's analyses were confirmed by our re-analysis of the 1989/90 cohort: Rotherham residents appeared to have the "worst" survival for cervical cancer, and Sheffield residents for breast cancer, although not statistically significantly so. Random simulations indicated that ranks based on a single cohort are not stable: for example Sheffield (ranked tenth for 1-y breast cancer survival) was ranked third or better in 6% of randomisations. Ranks were also unstable across cohorts: for example Rotherham 1-y cervical cancer survival was ranked tenth for 1989/90, fifth for 1991/92 and tenth for 1993/94. Analysis of 3-y running averages provided better information than the league table approach. Most districts improved over time, to different degrees, and similar sized gaps remained between the "best" and the "worst" districts. This analysis illustrates the need to be circumspect when interpreting "league tables" based on a single year or cohort analysis. League tables are based on ranks: clearly a large difference in rank may reflect only trivial (ie medically unimportant) differences in actual outcome. Lack of a statistically significant difference in survival between two districts does not mean their survival is equivalent. Even for a common cancer, like breast cancer, rankings were unstable from cohort to cohort. At the Registry we propose to perform these trend analyses routinely in future, adjusting, when possible, for the effects of deprivation and stage at diagnosis.     

Abnormal surfactant composition and activity in severe bronchiolitis

A prospective study of infants under 1 y of age, ventilated for severe viral bronchiolitis, was carried out in four paediatric intensive care units in order to study surfactant activity and composition in this condition. Lung lavage fluid from 24 infants with bronchiolitis, 19 with bronchiolitis and sepsis or cardiac failure and 12 controls were analysed by the “click test” for surfactant activity and for phospholipids. Surfactant activity was present in all controls, but in only 2 of the 24 infants with bronchiolitis alone. The presence of phosphatidylglycerol correlated perfectly with the click test, suggesting that reduced activity is due to changes in surfactant lipid composition. In those with bronchiolitis plus coexisting disease, surfactant activity and phosphatidylglycerol were absent in only half. Surfactant activity and phosphatidylglycerol re-appeared by extubation. Severe viral bronchiolitis is associated with an absence of surfactant activity and PG, which resolves by clinical recovery. Infants with coexisting conditions are not always surfactant deficient. Surfactant administration is likely to be beneficial, but requires a selective approach.     

Lipohemarthrosis of the knee: a review of recent experiences

The radiographs of 268 patients with knee trauma were retrospectively reviewed. In 15 patients with intraarticular fracture, the images demonstrated fat-fluid levels. In 28 other patients with intraarticular fracture, only joint effusion without a fat-fluid level was depicted. The presence of a fat-fluid level in the knee indicated fracture in all patients in whom it was seen. The absence of such a level, however, did not exclude intraarticular fracture.