Rare Variants in PLXNA4 and Parkinson's Disease.

Approximately 20% of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset familial PD followed by frequency assessment in 975 PD cases and 1014 ethnically-matched controls and linkage analysis to identify potentially causal variants. Based on the predicted penetrance and the frequencies, a variant in PLXNA4 proved to be the best candidate and PLXNA4 was screened for additional variants in 862 PD cases and 940 controls, revealing an excess of rare non-synonymous coding variants in PLXNA4 in individuals with PD. Although we cannot conclude that the variant in PLXNA4 is indeed the causative variant, these findings are interesting in the light of a surfacing role of axonal guidance mechanisms in neurodegenerative disorders but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance

Loss of thalamic serotonin transporters in early drug-naïve Parkinson’s disease patients is associated with tremor: an [123I]β-CIT SPECT study

In vitro studies revealed serotonin transporter (5-HTT) decline in Parkinson’s disease (PD). Yet, few studies investigated thalamic 5-HTT in vivo and its effect on PD heterogeneity. We analyzed thalamic [123I]β-CIT binding (mainly reflecting 5-HTT binding) in 32 drug-naïve PD patients and 13 controls with SPECT. Twenty-six patients were examined twice (17 months apart). Based on UPDRS scores, we identified subgroups of patients with moderate/severe tremor (PDT) and without tremor (PDWT) at the time of clinical diagnosis. Additionally, depressive symptoms were evaluated using the Beck Depression Inventory (BDI) at baseline. Mean thalamic specific to non-specific [123I]β-CIT binding ratio was lower in patients when compared to controls, and further decreased during follow-up. At baseline, average thalamic ratio was significantly lower in the PDT than in the PDWT subgroup. No correlation was found between BDI scores and thalamic binding ratios. Our findings show decline of [123I]β-CIT binding to thalamic 5-HTT in PD and its possible contribution to tremor onset

Aortic valve replacement with pulmonary homografts. Early experience

The increasing use of the aortic homograft as aortic valve substitute and the limited availability of donor valves prompted us to consider the pulmonary homograft as an alternative substitute for aortic valve replacement. The aim of our study is to compare the ultrastructural and biomechanical properties of pulmonary homograft leaflets with those of their aortic counterpart and to present the early results of using the pulmonary homograft for aortic valve replacement. Light and transmission electron microscopy have shown that pulmonary homograft leaflets are thinner than the aortic with a lesser content of elastic tissue in the ventricularis layer. However there were no substantial differences in the ultrastructure. Uniaxial tensile tests were done on 69 cusps from human pulmonary and aortic valves using an Instron testing machine. The strain at 200 KPa was found to be similar for both pulmonary and aortic leaflets (8.20% +/- 2.87% versus 8.98% +/- 1.90%) cut circumferentially. Radial strips appear to be more extensible in pulmonary leaflets than in aortic (32.6% +/- 7.5% and 28.6% +/- 11.1%, respectively). The ultimate tensile strength for circumferential strips was found to be similar for both aortic and pulmonary valves (1460 +/- 857 kPa versus 1450 +/- 689 kPa), but there was relatively little difference between the radial strips (295 +/- 95 kPa versus 252 +/- 104 kPa). A total of 123 patients whose ages ranged between 13 and 78 years received either fresh antibiotic sterilized or cryopreserved pulmonary homografts for aortic valve replacement. The pulmonary homograft was inserted in place of the patient's diseased aortic valve by using one of two different techniques: freehand in the subcoronary position or as a "short cylinder" inside the aortic root. There was three hospital deaths (2.43%; 70% confidence limits = 1.08% to 4.83%). Cumulative follow-up was 184 patient-years (range 1 to 39 months). All surviving patients have been followed up with serial color flow Doppler echocardiography. There were no late deaths. Actuarial late survival was 97.5% (70% confidence limits = 95.7% to 98.6%) at 3 years. Four patients (2.2%/pt-yr) underwent reoperation because of severe aortic regurgitation (1, 4, 12, and 15 months after the operation) because of technical problems (mismatch in size between the pulmonary homograft and aortic anulus) in three patients and probably because of graft rejection in one patient. At 3 years the actuarial rate of freedom from reoperation was 95.5% (70% confidence limits = 92.7% to 97.3%). Mild aortic regurgitation has been detected in three patients (2.6%). No patients incurred thromboembolic episodes or infective endocarditis.(ABSTRACT TRUNCATED AT 400 WORDS