PINK1 mutations in sporadic early-onset Parkinson's disease.

Pathogenic PINK1 mutations have been described in PARK6-linked Parkinson's disease (PD) patients of Asian origin. However, data on the frequency of PINK1 mutations in sporadic early-onset Parkinson's disease (EOPD) Asian patients are lacking. The objectives of this study were to report the frequency of PINK1 mutations of sporadic EOPD in an Asian cohort comprising of ethnic Chinese, Malays, and Indians, and to highlight a PINK1-positive patient who presented with restless legs symptoms. Eighty consecutive sporadic EOPD patients from the movement disorder clinics of two major tertiary institutions in the country were included. We performed sequence analysis of all the coding and exon-intron junctions of the PINK1 using specific primer sets. In addition, we genotyped polymorphisms detected from the analysis in a group of sporadic PD patients and controls. Three different mutations (two homozygous nonsense and one heterozygous missense) in the putative kinase domain were found in three patients, giving a 3.7% frequency of PINK1 mutations in our EOPD cohort. All the mutations were absent in 200 healthy controls. One patient with a novel homozygous nonsense PINK1 mutation presented unusually with restless legs symptoms. Separately, analysis of the frequency of four PINK1 polymorphisms in a group of sporadic PD and controls did not reveal any significant differences. We highlight a 3.7% frequency of PINK1 mutations in an Asian cohort (ethnic Chinese, Malay, and Indian) of EOPD. The phenotypic spectrum associated with PINK1-positive patients may be wider than previously reported. Polymorphisms of PINK1 do not appear to modulate risk of PD in our population.     

Thick Slices from Tomosynthesis Data Sets: Phantom Study for the Evaluation of Different Algorithms

PURPOSE  

Tomosynthesis is a 3-dimensional mammography technique that generates thin slices separated one to the other by typically 1 mm from source data sets. The relatively high image noise in these thin slices raises the value of 1-cm thick slices computed from the set of reconstructed slices for image interpretation. In an initial evaluation, we investigated the potential of different algorithms for generating thick slices from tomosynthesis source data (maximum intensity projection—MIP; average algorithm—AV, and image generation by means of a new algorithm, so-called softMip). The three postprocessing techniques were evaluated using a homogeneous phantom with one textured slab with a total thickness of about 5 cm in which two 0.5-cm-thick slabs contained objects to simulate microcalcifications, spiculated masses, and round masses. The phantom was examined by tomosynthesis (GE Healthcare). Microcalcifications were simulated by inclusion of calcium particles of four different sizes. The slabs containing the inclusions were examined in two different configurations: adjacent to each other and close to the detector and with the two slabs separated by two 1-cm thick breast equivalent material slabs. The reconstructed tomosynthesis slices were postprocessed using MIP, AV, and softMip to generate 1-cm thick slices with a lower noise level. The three postprocessing algorithms were assessed by calculating the resulting contrast versus background for the simulated microcalcifications and contrast-to-noise ratios (CNR) for the other objects. The CNRs of the simulated round and spiculated masses were most favorable for the thick slices generated with the average algorithm, followed by softMip and MIP. Contrast of the simulated microcalcifications was best for MIP, followed by softMip and average projections. Our results suggest that the additional generation of thick slices may improve the visualization of objects in tomosynthesis. This improvement differs from the different algorithms for microcalcifications, speculated objects, and round masses. SoftMip is a new approach combining features of MIP and average showing image properties in between MIP and AV.     

Analysis of LRRK2 functional domains in nondominant Parkinson disease

A comprehensive sequence analysis of 29 exons that code for the functional domains of LRRK2 in 160 nondominant Parkinson disease (PD) patients was performed. Novel variant screening in a further 470 sporadic PD patients and 630 controls revealed two novel variants (R1067Q and IVS33 + 6 T>A), which are likely to be pathogenic in five patients. One patient presented initially with a typical essential tremor phenotype, expanding the phenotypic spectrum of LRRK2 mutations.     

Competition for adhesion between probiotics and human gastrointestinal pathogens in the presence of carbohydrate

The adhesion of Lactobacillus rhamnosus GG to human enterocyte-like Caco-2 cells was not inhibited by eight carbohydrates tested, namely N-acetyl-glucosamine, galactose, glucose, fructose, fucose, mannose, methyl-alpha-D-mannopyranoside and sucrose. The degree of hydrophobicity predicted the adhesion of L. rhamnosus GG to Caco-2 cells. L. rhamnosus GG, however, was able to compete with Escherichia coli and Salmonella spp. of low hydrophobicity and high adhesin-receptor interaction for adhesion to Caco-2 cells. The interference of adhesion of these gastrointestinal (GI) bacteria by L. rhamnosus GG was probably through steric hindrance, and the degree of inhibition was related to the distribution of the adhesin receptors and hydrophobins on the Caco-2 surface. A Carbohydrate Index for Adhesion (CIA) was used to depict the binding property of adhesins on bacteria surfaces. CIA was defined as the sum of the fraction of adhesion in the presence of carbohydrates, with reference to the adhesion measured in the absence of any carbohydrate. The degree of competition for receptor sites between Lactobacillus casei Shirota and GI bacteria is a function of their CIA distance. There were at least two types of adhesins on the surface of L. casei Shirota. The study provides a scientific basis for the screening and selection of probiotics that compete with selective groups of pathogens for adhesion to intestinal surfaces. It also provides a model for the characterisation of adhesins and adhesin-receptor interactions.     

The G2019S LRRK2 mutation is uncommon in an Asian cohort of Parkinson's disease patients

A common heterozygous leucine-rich repeat kinase 2 (LRRK2) mutation 6055G > A transition (G2019S) accounts for about 3-7% of familial Parkinson's disease (PD) and 1-1.6% sporadic PD in a number of European populations. To determine the prevalence of the G1019S mutation in our Asian population, we conducted genetic analysis of this mutation in 1000 PD and healthy controls. The G2019S mutation was not detected in any of our study subjects. The prevalence of G2019S mutation is rare (< 0.1%) in our population, suggesting that occurrence of this mutation may vary amongst different ethnic races. This has important clinical implication when implementing guidelines for genetic testing.     

Case-control study of UCHL1 S18Y variant in Parkinson's disease.

A recent meta-analysis observed a greater significant inverse association of the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y variant with Parkinson's disease (PD) for Asian (predominantly Japanese) populations compared with Caucasian populations. We performed an independent case-control study in 335 PD and 341 control subjects with data from a Chinese population to investigate the age-of-onset effect of the UCHL1 variant in PD. The Y/Y and Y/S genotypes were less frequent in the PD young-onset group than in controls and the frequency of the Y alleles was higher in young controls compared to young-onset PD (age at examination 相似文献   

Fragile X premutation alleles in SCA, ET, and parkinsonism in an Asian cohort

Among 367 subjects, the authors analyzed 167 patients with essential tremor, sporadic progressive cerebellar ataxia, multiple-system atrophy, and atypical parkinsonism and 200 healthy control subjects for FMR1 premutation alleles. None of the subjects carried alleles within the premutation range. These findings suggest that in the absence of other supportive clinical or imaging features, the cost-effectiveness of routine fragile X tremor/ataxia syndrome screening in this Asian cohort with movement disorders was low.     

Adherens junction breakdown in the periderm following cadmium administration in the chick embryo: distribution of cadherins and associated molecules

BACKGROUND: The teratogenic metal cadmium (Cd) has been found to cause ventral body wall defects similar to human omphalocele when administered to post-gastrulation chick embryos prior to body wall folding. From 4h after Cd, affected embryos demonstrate varying degrees of cell junction breakdown and desquamation in the periderm. We examined the effect of Cd on tissue and cell distribution of cadherins and their intracellular associates. METHODS: Chicks were explanted and given 50microl of 50microM Cd solution at 60h incubation (Hamburger-Hamilton stage 16-17). To examine peridermal junctions, embryos were processed into resin and ultra-thin sections examined by transmission electron microscopy (TEM). Tissue was processed into paraffin and 6microm sections treated according to standard protocols for immunohistochemical detection of L-CAM, pan-cadherin, beta-catenin, alpha-1 and alpha-2 catenin. To examine actin distribution, frozen sections were cut at 10-20microm, stained with oragon green phalloidin and nuclei counter-stained with propidium iodide. RESULTS: The overall tissue distribution of L-CAM, pan-cadherin and the alpha-catenins did not appear to be altered following Cd. However, beta-catenin changed from its normal sub-membranous location to a more general cytoplasmic distribution, with translocation to the nucleus in both peridermal and ectodermal cells. Similarly, actin distribution in the periderm in embryos demonstrating cell junction breakdown was markedly altered, with clumping and disorganization after 4h. CONCLUSIONS: Although L-CAM is distributed normally after Cd, post-translational modification may occur causing breakdown of its normal association with the catenins and actin, and allowing beta-catenin to translocate to the nucleus in peri-ectodermal tissue, mimicking the canonical Wnt pathway.