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

Characterisation of development and electrophysiological mechanisms underlying rhythmicity of the avian lymph heart

Despite significant advances in tissue engineering such as the use of scaffolds, bioreactors and pluripotent stem cells, effective cardiac tissue engineering for therapeutic purposes has remained a largely intractable challenge. For this area to capitalise on such advances, a novel approach may be to unravel the physiological mechanisms underlying the development of tissues that exhibit rhythmic contraction yet do not originate from the cardiac lineage. Considerable attention has been focused on the physiology of the avian lymph heart, a discrete organ with skeletal muscle origins yet which displays pacemaker properties normally only found in the heart. A functional lymph heart is essential for avian survival and growth in ovo. The histological nature of the lymph heart is similar to skeletal muscle although molecular and bioelectrical characterisation during development to assess mechanisms that contribute towards lymph heart contractile rhythmicity have not been undertaken. A better understanding of these processes may provide exploitable insights for therapeutic rhythmically contractile tissue engineering approaches in this area of significant unmet clinical need. Here, using molecular and electrophysiological approaches, we describe the molecular development of the lymph heart to understand how this skeletal muscle becomes fully functional during discrete in ovo stages of development. Our results show that the lymph heart does not follow the normal transitional programme of myogenesis as documented in most skeletal muscle, but instead develops through a concurrent programme of precursor expansion, commitment to myogenesis and functional differentiation which offers a mechanistic explanation for its rapid development. Extracellular electrophysiological field potential recordings revealed that the peak-to-peak amplitude of electrically evoked local field potentials elicited from isolated lymph heart were significantly reduced by treatment with carbachol; an effect that could be fully reversed by atropine. Moreover, nifedipine and cyclopiazonic acid both significantly reduced peak-to-peak local field potential amplitude. Optical recordings of lymph heart showed that the organ’s rhythmicity can be blocked by the HCN channel blocker, ZD7288; an effect also associated with a significant reduction in peak-to-peak local field potential amplitude. Additionally, we also show that isoforms of HCN channels are expressed in avian lymph heart. These results demonstrate that cholinergic signalling and L-type Ca2+ channels are important in excitation and contraction coupling, while HCN channels contribute to maintenance of lymph heart rhythmicity

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

A medial to lateral shift in pre-movement cortical activity in hemi-Parkinson's disease

Objective: Recent evidence suggests that cortical activity associated with voluntary movement is relatively shifted from medial to lateral premotor areas in Parkinson's disease. This shift occurs bilaterally even for unilateral responses. It is not clear whether the shift in processing reflects an overall change in movement strategy, thereby involving alternate cortical areas, or reflects a compensatory change whereby, given the appropriate conditions, less impaired cortical areas are able to provide a similar function in compensation for those areas which are more impaired. This issue was examined in patients with hemi-Parkinson's disease, in whom basal ganglia impairment is most pronounced in one hemisphere. Methods: Fourteen patients with hemi-Parkinson's disease and 15 age-matched control subjects performed a Go/NoGo finger movement task and the contingent negative variation (CNV) was recorded from 21 scalp positions. Results and conclusions: Maximal CNV amplitudes were found over central medial regions for control subjects, but were shifted more frontally for Parkinson's disease patients, reduced in amplitude over the midline and lateralized towards the side ipsilateral to the greatest basal ganglia impairment. This shift in cortical activity from medial to lateral areas in Parkinson's disease patients appears to reflect a compensatory mechanism operating predominantly on the side of greatest basal ganglia impairment. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved

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