Human 13N-ammonia PET studies: the importance of measuring 13N-ammonia metabolites in blood

Dynamic 13N-ammonia PET is used to assess ammonia metabolism in brain, liver and muscle based on kinetic modeling of metabolic pathways, using arterial blood 13N-ammonia as input function. Rosenspire et al. (1990) introduced a solid phase extraction procedure for fractionation of 13N-content in blood into 13N-ammonia, 13N-urea, 13N-glutamine and 13N-glutamate. Due to a radioactive half-life for 13N of 10 min, the procedure is not suitable for blood samples taken beyond 5–7 min after tracer injection. By modifying Rosenspire’s method, we established a method enabling analysis of up to 10 blood samples in the course of 30 min. The modified procedure was validated by HPLC and by 30-min reproducibility studies in humans examined by duplicate 13N-ammonia injections with a 60-min interval. Blood data from a 13N-ammonia brain PET study (from Keiding et al. 2006) showed: (1) time courses of 13N-ammonia fractions could be described adequately by double exponential functions; (2) metabolic conversion of 13N-ammonia to 13N-metabolites were in the order: healthy subjects > cirrhotic patients without HE > cirrhotic patients with HE; (3) kinetics of initial tracer distribution in tissue can be assessed by using total 13N-concentration in blood as input function, whereas assessment of metabolic processes requires 13N-ammonia measurements

Efficacy of psychosocial intervention in patients with mild Alzheimer's disease:the multicentre, rater blinded, randomised Danish Alzheimer Intervention Study (DAISY)

Objective To assess the efficacy at 12 months of an early psychosocial counselling and support programme for outpatients with mild Alzheimer’s disease and their primary care givers. Design Multicentre, randomised, controlled, rater blinded trial. Setting Primary care and memory clinics in five Danish districts. Participants 330 outpatients with mild Alzheimer’s disease and their 330 primary care givers. Interventions Participating dyads (patient and primary care giver) were randomised to control support during follow-up or to control support plus DAISY intervention (multifaceted and semi-tailored counselling, education, and support). Main outcome measures Primary outcomes at 12 months for patients were change from baseline in mini mental state examination (MMSE) score, Cornell depression scale score, and proxy rated European quality of life visual analogue scale (EQ-VAS) score. For care givers, outcomes were change from baseline in geriatric depression scale (GDS 30 items) score and EQ-VAS score. Results Because of multiple testing, statistical significance was set at an adjusted P limit of <0.0005. At 12 months there were no significant differences between the two allocation groups in changes from baseline in the primary and secondary outcomes. However, although non-significant with the adjusted P limit, a small difference was observed for one of the primary patient outcomes (Cornell depression scale score) in patients in favour of the DAISY intervention group before and after adjusting for attrition (P=0.0146 and P=0.0103 respectively). Conclusions The multifaceted, semi-tailored intervention with counselling, education, and support for patients with mild Alzheimer’s disease and their care givers did not have any significant effect beyond that with well structured follow-up support at 12 months after adjustment for multiple comparisons. The small positive effect found in the unadjusted primary outcome addressing depressive symptoms in patients may call for further research focusing on patients with Alzheimer’s disease and comorbid depression. Trial registration ISRCTN74848736

European regulatory agenices should employ full time statisticians

No abstract available

Enterprise Education Competitions: A Theoretically Flawed Intervention?

The demand for including enterprise in the education system, at all levels and for all pupils is now a global phenomenon. Within this context, the use of competitions and competitive learning activities is presented as a popular and effective vehicle for learning. The purpose of this chapter is to illustrate how a realist method of enquiry – which utilises theory as the unit of analysis – can shed new light on the assumed and unintended outcomes of enterprise education competitions. The case developed here is that there are inherent flaws in assuming that competitions will ‘work’ in the ways set out in policy and guidance. Some of the most prevalent stated outcomes – that competitions will motivate and reward young people, that they will enable the development of entrepreneurial skills, and that learners will be inspired by their peers – are challenged by theory from psychology and education. The issue at stake is that the expansion of enterprise education policy into primary and secondary education increases the likelihood that more learners will be sheep dipped in competitions, and competitive activities, without a clear recognition of the potential unintended effects. In this chapter, we employ a realist-informed approach to critically evaluate the theoretical basis that underpins the use of competitions and competitive learning activities in school-based enterprise education. We believe that our findings and subsequent recommendations will provide those who promote and practice the use of competitions with a richer, more sophisticated picture of the potential flaws within such activities.Peer reviewedFinal Published versio

Clinical applicability of current pharmacokinetic models: Splanchnic elimination of 5-fluorouracil in cancer patients

What can be inferred from limited clinical data by using current models of hepatic elimination? We examined this question by analyzing previously published data on the steady-state uptake of the anticancer agent 5-fluorouracil (5-FU) in seven cancer patients in terms of the venous equilibration model, the undistributed and distributed forms of the sinusoidal perfusion model, and the convection-dispersion model. Because of appreciable extrasplanchnic removal of 5-FU, the value of the steady infusion rate was not used in our analysis. When the data from all patients were pooled by plotting the measured hepatic venous concentration against the measured hepatic arterial concentration, the high concentration data fell on a limiting straight line of slope 1, indicating that at high dose rates elimination of 5-FU in both the liver and gastrointestinal tract was close to saturation. The intercept of this line gave a model-independent estimate of V max /Q= 48.0± 11.6 (SD) μM for the pooled data set, where V max is the maximum splanchnic elimination rate of 5-FU, and Q is the hepatic blood flow. The low concentration data points fell on a limiting straight line through the origin, from which model-dependent values of the Michaelis constant were determined. The venous equilibration model gave K m =9.4 μM , while the undistributed sinusoidal perfusion model gave K m * =26,5 μM. With these values of K m , both models fit the pooled data equally well. These methods were applied to analyses of the five individual data sets which contained sufficiently high concentration data points. The resulting mean values were V max /Q=41.0±5.1 (sem) μM, K m =8.4±1.3μM and K m * =23.2±3.2 μM. However, the splanchnic region is a highly heterogeneous organ system, for which an undistributed analysis provides no more than an upper bound on the Michaelis constant K m + ( K m + ⩽ K m * ). A perfusion model distributed to represent total splanchnic elimination is developed in the Appendix. Using previous estimates of the degree of functional heterogeneity in the liver alone, this model yields K m + values for individual patients which have a mean of 20.3±2.8 μM .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45038/1/10928_2005_Article_BF01062135.pd

Impairment of the Organization of Locomotor and Exploratory Behaviors in Bile Duct-Ligated Rats

Hepatic encephalopathy (HE) arises from acute or chronic liver diseases and leads to several problems, including motor impairment. Animal models of chronic liver disease have extensively investigated the mechanisms of this disease. Impairment of locomotor activity has been described in different rat models. However, these studies are controversial and the majority has primarily analyzed activity parameters. Therefore, the aim of the present study was to evaluate locomotor and exploratory behavior in bile duct-ligated (BDL) rats to explore the spatial and temporal structure of behavior. Adult female Wistar rats underwent common bile duct ligation (BDL rats) or the manipulation of common bile duct without ligation (control rats). Six weeks after surgery, control and BDL rats underwent open-field, plus-maze and foot-fault behavioral tasks. The BDL rats developed chronic liver failure and exhibited a decrease in total distance traveled, increased total immobility time, smaller number of rearings, longer periods in the home base area and decreased percentage of time in the center zone of the arena, when compared to the control rats. Moreover, the performance of the BDL rats was not different from the control rats for the elevated plus-maze and foot-fault tasks. Therefore, the BDL rats demonstrated disturbed spontaneous locomotor and exploratory activities as a consequence of altered spatio-temporal organization of behavior