Clinical and genomic-based decision support system to define the optimal timing of allogeneic hematopoietic stem-cell transplantation in patients with myelodysplastic syndromes

Statistical Scienc

Role of lipid peroxidation and the glutathione-dependent antioxidant system in the impairment of endothelium-dependent relaxations with age

1. Age-related changes in the blood prooxidant-antioxidant state, as well as its influence on the relaxant responses to acetylcholine (ACh) were studied in the tail artery from 6-, 24- and 30-month-old Sprague-Dawley (SD) rats. 2. Malondialdehyde (MDA) plasma levels increased 2 and 3 times in 24- and 30-month-old rats, respectively, when compared with 6-month-old rats (0.43±0.09 μM). This increase was accompanied by an induction of 6-phosphogluconate dehydrogenase (6PG-DH) and glutathione reductase (GR) activities in red blood cells from 24-month-old rats. In 30-month-old rats, a further induction of these enzymatic activities, as well as glucose-6-phosphate dehydrogenase (G6P-DH) and glutathione peroxidase (GPx) activities was observed. 3. No differences with age were found in the concentration-response curves to ACh in isolated tail artery segments from 6- and 24-month-old rats precontracted with 0.3 μM noradrenaline (NA). However, a decrease in sensitivity to ACh-induced relaxation was observed in 30-month-old rats; EC(30) values were 3.5 (1.3–8.0)×10(−7) M and 18.1 (8.9–30.1)×10(−7) M for 6- and 30-month-old rats, respectively. Moreover, a decrease in maximum ACh relaxation (10 μM) was found in 30-month-old rats in comparison with that obtained in 6-month-old rats (58.5±3.9% and 42.5±3.4% of previous NA contraction, respectively). 4. Incubation of tail artery segments with MDA (0.5, 1 or 10 μM) caused a reduction of ACh-induced relaxations that was different in the three ages. Thus, the reduction of ACh-induced relaxations became significant with 0.5 μM MDA in 6-, with 1 μM MDA in 24-, and with 10 μM MDA in 30-month-old rats. In addition, MDA did not cause a shift in the concentration-response curve to ACh, but a decrease in the maximum response. 5. Superoxide dismutase (SOD; 150 u ml(−1), a superoxide anion scavenger) reversed the inhibitory effect of MDA on ACh-induced relaxations at all ages studied. 6. We conclude that: (1) ageing produces an increase in lipid peroxidation process, as indicated by the increase in MDA plasma levels, that is accompanied by an induction of lipid peroxide detoxification enzymes; (2) the changes in prooxidant-antioxidant equilibrium with age contribute, at least partially, to the impairment of the relaxant responses evoked by ACh; and (3) the effect of MDA appears to be mediated by superoxide anion at all ages studied

Long-term prognosis of epilepsy, prognostic patterns and drug resistance : a population-based study

Background and purpose: Seizures in most people with epilepsy remit but prognostic markers are poorly understood. There is also little information on the long-term outcome of people who fail to achieve seizure control despite the use of two antiepileptic drugs (drug resistance). Methods: People with a validated diagnosis of epilepsy in whom two antiepileptic drugs had failed were identified from primary care records. All were registered with one of 123 family physicians in an area of northern Italy. Remission (uninterrupted seizure freedom lasting 2 years or longer) and prognostic patterns (early remission, late remission, remission followed by relapse, no remission) were determined. Results: In all, 747 individuals (381 men), aged 11 months to 94 years, were followed for 11 045.5 person-years. 428 (59%) were seizure-free. The probability of achieving 2-year remission was 18% at treatment start, 34% at 2 years, 45% at 5, 52% at 10 and 67% at 20 years (terminal remission, 60%). Epilepsy syndrome and drug resistance were the only independent predictors of 2- and 5-year remission. Early remission was seen in 101 people (19%), late remission in 175 (33%), remission followed by relapse in 85 (16%) and no remission in 166 (32%). Treatment response was the only variable associated with differing prognostic patterns. Conclusion: The long-term prognosis of epilepsy is favourable in most cases. Early seizure remission is not invariably followed by terminal remission and seizure outcome varies according to well-defined patterns. Prolonged seizure remission and prognostic patterns can be predicted by broad syndromic categories and the failure of two antiepileptic drugs