Clinical subtypes in Parkinson's disease: the impact of MAPT haplotypes.

The H1 haplotype of the MAPT gene influences the risk of PD and has been related to the development of PDD. We evaluated the influence of MAPT haplotypes on the expression of motor features in PD patients. We genotyped, for the MAPT haplotypes H1 and H2, a sample of 181 PD patients with distinct clinical subtypes: tremor dominant and non-tremor dominant (NTD). Our results indicate that the MAPT haplotypes contribute to the expression of motor features of PD. H1 homozygous PD patients are significantly more likely to present a NTD phenotype, a clinical subtype characterized by widespread pathological degeneration, than H2 carriers.

Development and validation of an analytical method based on high performance thin layer chromatography for the simultaneous determination of lamotrigine, zonisamide and levetiracetam in human plasma.

Methods based on HPLC technology are the most frequently adopted for monitoring blood levels of novel antiepileptics. Here a rapid method based on HPTLC was developed for quantitative determination of lamotrigine (LTG), zonisamide (ZNS) and levetiracetam (LVT) in human plasma and compared with HPLC and LC-MS/MS methods. Chromatographic separation was achieved on silical gel 60F(254) plates using ethylacetate:methanol:ammonia (91:10:15v/v/v) as mobile phase. Quantitative analysis was carried out by densitometry at a wavelength of 312, 240 and 210nm for LTG, ZNS and LVT, respectively. Calibration curves were linear over range of 0-200ng for LTG and ZNS and 0-400ng for and LVT. The limit of quantification of LTG, ZNS and LTV was found to be 3.69, 3.7 and 6.85µg/ml, respectively. Intra and inter-assay precision provided relative standard deviations lower than 10% for all three analytes. Correlation and Bland-Altman plot showed general agreement between HPTLC and LC-MS/MS quantification, with a mean bias of -0.25, -0.46 and 0.5µg/ml for LTG ZNS and LVT, respectively. Likewise, comparison between HPLC-UV and LC-MS/MS showed good agreement for all the three compounds analyzed. In conclusion, the proposed HPTLC method is simple, rapid, precise and accurate. It therefore is appropriate for the routine quantification of therapeutic levels of LTG, ZNS and LVT in human plasma.

Genetic polymorphism of Angiotensin-Converting Enzyme is not associated with the development of Parkinson's disease and of L-dopa-induced adverse effects.

Sporadic Parkinson's disease (PD) is a frequent neurodegenerative movement disorder. Both environmental and genetic factors have been studied in the etiology of PD. Among genetic factors, increasing evidences suggest that deletion/insertion (D/I) gene polymorphism of the angiotensin I-converting enzyme (ACE) may be involved in the pathogenesis of PD and in the occurrence of the adverse effects of chronic L-dopa therapy. We investigated this hypothesis by evaluating the frequency of the ACE gene D/I polymorphism in 120 Italian PD patients and 132 controls. Out of the 120 PD patients, 91 were under chronic L-dopa treatment. Our results revealed no difference in ACE I/D genotype (chi(2)=0.79, p=0.66) and allele (chi(2)=0.34, p=0.56) frequencies between PD and controls. We also failed to observe any significant association with the occurrence of L-dopa-induced adverse effects in long-term treated PD patients, thereby excluding the presence of an association between ACE I/D genotypes and the genetic susceptibility to PD and the development of adverse effect of chronic L-dopa therapy.

Antithrombin III metabolism in the pulmonary vessel endothelium.

In 85 patients undergoing aorto-coronary bypass for atherosclerotic coronary disease, we measured the antithrombin III activity levels and the thrombin-antithrombin III complex concentrations in blood from the pulmonary and the radial arteries, taken before the aorto-coronary bypass procedure, with the aim of investigating the role of the pulmonary endothelium in the metabolism of the inhibitor. Results showed significantly lower mean antithrombin III activity levels, expressed as a percentage of normal plasma, in blood from the radial artery with respect to levels from the pulmonary artery (0.78 +/- 0.12 versus 0.80 +/- 0.12, P<0.0001), while no significant difference was found in thrombin-antithrombin III complex concentrations. The results seem to show that the pulmonary endothelium contributes to the antithrombin III metabolism with a 0.023 breakdown rate, corresponding to about a 0.1 fraction of the reported 0.22-0.25 total body catabolic rate, as well as the pulmonary endothelial surface (50-70 m2) corresponding to about a 0.1 fraction of the peripheral vessels' endothelial surface (500-700 m2). The data support the hypothesis of a main endothelial catabolism of antithrombin III.

The COX-2 G/C -765 polymorphism may modulate the occurrence of cerebrovascular ischemia.

In the atherosclerotic plaque, cyclooxygenase-2 (COX-2) catalyzes prostaglandin E formation, which acts as a pro-atherogenic factor. A polymorphism, G/C -765, within the COX-2 promoter region modulates gene expression and the risk of cerebrovascular disease. We have evaluated the relation between COX-2 G/C -765 genotypes and the occurrence of cerebrovascular ischemia. We evaluated the COX-2 G/C -765 polymorphism in 110 consecutive patients with a documented history of acute ischemic cerebrovascular disease, in 110 age-matched and sex-matched subjects without such history, and in a general population (n = 324) from the same ethnical background. The frequency of the COX-2 -765C allele in patients [0.21; 95% confidence interval (CI), 0.16-0.26] was similar to those found in controls (0.28; 95% CI, 0.22-0.34) and in the general population (0.26; 95% CI, 0.23-0.29). Carriers of the CC genotype differed between patients (0.02; 95% CI, 0.00-0.05) and controls [0.10 (95% CI, 0.04-0.16), P = 0.019; odds ratio, 0.17 (95% CI, 0.04-0.79)] or the general population [0.08 (95% CI, 0.05-0.11), P = 0.023; odds ratio, 0.22 (95% CI, 0.05-0.95)]. In a multiple logistic regression analysis adjusted for confounding variables, smoking status (P < 0.001), atrial fibrillation (P = 0.004) and COX-2 G/C-765 polymorphism (P = 0.016) independently contributed to cerebrovascular ischemia, with CC carriers exhibiting a lower risk (odds ratio, 0.07; 95% CI, 0.01-0.61). Our data show an association between the COX-2 G/C-765 gene polymorphism and cerebrovascular ischemia, suggesting that the COX-2 gene is a susceptibility locus for the risk of cerebrovascular ischemic disease.