The choice of algorithm will be dependent on the study aim. Individuals outside the United Kingdom may find it more useful to use the multinomial results, which can be used with different country-specific tariff valuations. However, these algorithms should not replace prospective collection of utility data.
The in situ mouse brain perfusion method for measuring blood-brain barrier permeability was adapted to assess transport of solutes at the blood-brain and blood-eye barriers. The procedure was checked with radiolabeled markers in oxygenated bicarbonate-buffered fluid infused for 30 to 120 secs via a carotid artery. Vascular flow estimated with diazepam was 2.2-fold lower in the eye than in the brain. The vascular volume and the integrity markers sucrose and inulin indicated that a perfusion flow rate of 2.5 mL/min preserved the physical integrity of these organs. However, the brain vasculature integrity was more sensitive to acute perfusion pressure than the eye vasculature. The functional capacities of blood barriers were assessed with D-glucose; its transport followed Michaelis-Menten kinetics with an apparent K m of 7.6 mmol/L and a V max of 23 lmol/sec per g in the brain, and a K m of 22.9 mmol/L and a V max of 40 lmol/sec per g in the eye. The transport of cholesterol to the brain and eye was significantly enhanced by adding the Abca1 inhibitor probucol, suggesting an Abca1-mediated efflux at the mouse brain and eye blood barriers. Thus in situ carotid perfusion is suitable for elucidating transport processes at the blood-brain and blood-eye barriers.
BackgroundDespite the considerable health impact of coeliac disease (CD), reliable estimates of the impact of diagnosis on health care use and costs are lacking.AimsTo quantify the volume, type and costs, in a United Kingdom primary care setting, of healthcare resources used by individuals diagnosed with CD up to ten years before and after diagnosis, and to estimate medical costs associated with CD.MethodsA cohort of 3,646 CD cases and a parallel cohort of 32,973 matched controls, extracted from the General Practice Research Database (GPRD) over the period 1987–2005 were used i) to evaluate the impact of diagnosis on the average resource use and costs of cases; ii) to assess direct healthcare costs due to CD by comparing average resource use and costs incurred by cases vs. controls.ResultsAverage annual healthcare costs per patient increased by £310 (95% CI £299, £320) after diagnosis. CD cases experienced higher healthcare costs than controls both before diagnosis (mean difference £91; 95% CI: £86, £97) and after diagnosis (mean difference £354; 95% CI: £347, £361). These differences were driven mainly by higher test and referral costs before diagnosis, and by increased prescription costs after diagnosis.ConclusionsThis study shows significant additional primary care costs associated with coeliac disease. It provides novel evidence that will assist researchers evaluating interventions in this area, and will challenge policymakers, clinicians, researchers and the public to develop strategies that maximise the health benefits of the resources associated with this disease.
Cystamine has shown significant neuroprotective properties in preclinical studies of Parkinson's disease (PD) and Huntington's disease (HD). Cysteamine, its FDA-approved reduced form, is scheduled to be tested for clinical efficacy in HD patients. Here, we studied the key cystamine metabolites, namely cysteamine, hypotaurine and taurine, as well as cysteine, in order to identify which one is more distinctively responsible for the neuroprotective action of cystamine. After a single administration of cystamine (10, 50 or 200 mg/kg), naïve mice were perfused with phosphate-buffered saline (PBS) at 1, 3, 12, 24 or 48 h post-injection and brain and plasma samples were analyzed by two distinct HPLC methods. Although plasma levels remained under the detection threshold, significant increases in cysteamine brain levels were detected with the 50 and 200 mg/kg doses in mice perfused 1 and 3 h following cystamine injection. To further assess cysteamine as the candidate molecule for pre-clinical and clinical trials in PD, we evaluated its capacity to cross the blood brain barrier. Using an in situ cerebral perfusion technique, we determined that the brain transport coefficient (Clup) of cysteamine (259 lM) was 0.15 ± 0.02 lL/g/s and was increased up to 0.34 ± 0.07 lL/g/s when co-perfused in the presence of cysteine. Taken together, these results strongly suggest that cysteamine is the neuroactive metabolite of cystamine and may further support its therapeutic use in neurodegenerative diseases, particularly in HD and PD.
We investigated the expression and function of Abca1 in wild-type C57BL/6, abca1(+/+), and abca1(-/-) mice brain capillaries forming the blood-brain barrier (BBB). We first demonstrated by quantitative RT-PCR and Western immunoblot that Abca1 was expressed and enriched in the wild-type mouse brain capillaries. In abca1(-/-) mice, we reported that the lack of Abca1 resulted in an 1.6-fold increase of the Abcg4 expression level compared to abca1(+/+) mice. Next, using the in situ brain perfusion technique, we showed that the [(3)H]cholesterol brain uptake clearance (Cl(up), μl/s/g brain), was significantly increased (107%) in abca1(-/-) mice compared to abca1(+/+) mice, meaning that the deficiency of Abca1 conducted to a significant decrease of the cholesterol efflux at the BBB level. In addition, the co-perfusion of probucol (Abca1 inhibitor) with [(3)H]cholesterol resulted in an increase of [(3)H]cholesterol Cl(up) (115%) in abca1(+/+) but not in abca1(-/-) mice, meaning that probucol inhibited selectively the efflux function of Abca1. In conclusion, our results demonstrated that Abca1 was expressed in the mouse brain capillaries and that Abca1 functions as an efflux transporter through the mouse BBB.
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