471 research outputs found
Cyclodextrin-complexed curcumin exhibits anti-inflammatory and antiproliferative activities superior to those of curcumin through higher cellular uptake (vol 80, vol 1021, 2010)
Retraction notice to âCyclodextrin-complexed curcumin exhibits anti-inflammatory and antiproliferative activities superior to those of curcumin through higher cellular uptakeâ [Biochem. Pharmacol. 80 (2010) 1021â1032].Non peer reviewe
Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance
In Parkinsonâs disease (PD) and dementia with Lewy bodies (DLB) α-synuclein (αS) pathology is seen that displays a predictable topographic distribution. There are two staging/categorization systems, i.e. Braakâs and McKeithâs, currently in use for the assessment of αS pathology. The aim of these diagnostic strategies in pathology is, in addition to assess the stage/severity of pathology, to assess the probabilities of the related clinical symptomatology i.e. dementia and extrapyramidal symptoms (EPS). Herein, we assessed the applicability of these two staging/categorization systems and the frequency of dementia and EPS in a cohort of 226 αS-positive-subjects. These subject were selected from a large autopsy sample (n = 1,720), irrespective of the clinical presentation, based on the detection of αS-immunoreactivity (IR) in one of the most vulnerable nuclei; in the dorsal motor nucleus of vagus, substantia nigra and basal forebrain. The frequency of αS-IR lesions in this large cohort was 14% (248 out of 1,720). If applicable, each of the 226 subjects with all required material available was assigned a neuropathological stage/category of PD/DLB and finally the neuropathological data was analyzed in relation to dementia and EPS. 83% of subjects showed a distribution pattern of αS-IR that was compatible with the current staging/categorization systems. Around 55% of subjects with widespread αS pathology (Braakâs PD stages 5â6) lacked clinical signs of dementia or EPS. Similarly, in respect to those subjects that fulfilled the McKeith criteria for diffuse neocortical category and displaying only mild concomitant Alzheimerâs disease-related pathology, only 48% were demented and 54% displayed EPS. It is noteworthy that some subjects (17%) deviated from the suggested caudo-rostral propagation suggesting alternative routes of progression, perhaps due to concomitant diseases and genetic predisposition. In conclusion, our results do indeed confirm that current staging/categorization systems can readily be applied to most of the subjects with αS pathology. However, finding that around half of the subjects with abundant αS pathology remain neurologically intact is intriguing and raises the question whether we do assess the actual disease process
Genome-wide meta-analysis of short-tandem repeats for Parkinsonâs disease risk using genotype imputation
Idiopathic Parkinsonâs disease is determined by a combination of genetic and environmental factors. Recently, the first genome-wide association study on short-tandem repeats in Parkinsonâs disease reported on eight suggestive short-tandem repeat-based risk loci (α = 5.3 Ă 10â6), of which four were novel, i.e. they had not been implicated in Parkinsonâs disease risk by genome-wide association analyses of single-nucleotide polymorphisms before. Here, we tested these eight candidate short-tandem repeats in a large, independent Parkinsonâs disease caseâcontrol dataset (n = 4757). Furthermore, we combined the results from both studies by meta-analysis resulting in the largest Parkinsonâs disease genome-wide association study of short-tandem repeats to date (n = 43 844). Lastly, we investigated whether leading short-tandem repeat risk variants exert functional effects on gene expression regulation based on methylation quantitative trait locus data in human âpost-mortemâ brain (n = 142). None of the eight previously reported short-tandem repeats were significantly associated with Parkinsonâs disease in our independent dataset after multiple testing correction (α = 6.25 Ă 10â3). However, we observed modest support for short-tandem repeats near CCAR2 and NCOR1 in the updated meta-analyses of all available data. While the genome-wide meta-analysis did not reveal additional study-wide significant (α = 6.3 Ă 10â7) short-tandem repeat signals, we identified seven novel suggestive Parkinsonâs disease short-tandem repeat risk loci (α = 5.3 Ă 10â6). Of these, especially a short-tandem repeat near MEIOSIN showed consistent evidence for association across datasets. CCAR2, NCOR1 and one novel suggestive locus identified here (LINC01012) emerged from colocalization analyses showing evidence for a shared causal short-tandem repeat variant affecting both Parkinsonâs disease risk and cis DNA methylation in brain. Larger studies, ideally using short-tandem repeats called from whole-sequencing data, are needed to more fully investigate their role in Parkinsonâs disease
Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies
We have developed a novel real-time quaking-induced conversion RT-QuICbased assay to detect alpha-synuclein aggregation in brain and cerebrospinal fluid from dementia with Lewy bodies and Parkinsonâs disease patients. This assay can detect alpha-synuclein aggregation in Dementia with Lewy bodies and Parkinsonâs disease cerebrospinal fluid with sensitivities of 92% and 95%, respectively, and with an overall specificity of 100% when compared to Alzheimer and control cerebrospinal fluid. Patients with neuropathologically confirmed tauopathies (progressive supranuclear palsy; corticobasal degeneration) gave negative results. These results suggest that RT-QuiC analysis of cerebrospinal fluid is potentially useful for the early clinical assessment of patients with alpha-synucleinopathies
Expression of reduced amounts of structurally altered aggrecan in articular cartilage chondrocytes exposed to high hydrostatic pressure
Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies
Several studies have confirmed the α-synuclein real-time quaking-induced conversion (RT-QuIC) assay to have high sensitivity and specificity for Parkinson's disease. However, whether the assay can be used as a robust, quantitative measure to monitor disease progression, stratify different synucleinopathies and predict disease conversion in patients with idiopathic REM sleep behaviour disorder remains undetermined. The aim of this study was to assess the diagnostic value of CSF α-synuclein RT-QuIC quantitative parameters in regard to disease progression, stratification and conversion in synucleinopathies. We performed α-synuclein RT-QuIC in the CSF samples from 74 Parkinson's disease, 24 multiple system atrophy and 45 idiopathic REM sleep behaviour disorder patients alongside 55 healthy controls, analysing quantitative assay parameters in relation to clinical data. α-Synuclein RT-QuIC showed 89% sensitivity and 96% specificity for Parkinson's disease. There was no correlation between RT-QuIC quantitative parameters and Parkinson's disease clinical scores (e.g. Unified Parkinson's Disease Rating Scale motor), but RT-QuIC positivity and some quantitative parameters (e.g. Vmax) differed across the different phenotype clusters. RT-QuIC parameters also added value alongside standard clinical data in diagnosing Parkinson's disease. The sensitivity in multiple system atrophy was 75%, and CSF samples showed longer T50 and lower Vmax compared to Parkinson's disease. All RT-QuIC parameters correlated with worse clinical progression of multiple system atrophy (e.g. change in Unified Multiple System Atrophy Rating Scale). The overall sensitivity in idiopathic REM sleep behaviour disorder was 64%. In three of the four longitudinally followed idiopathic REM sleep behaviour disorder cohorts, we found around 90% sensitivity, but in one sample (DeNoPa) diagnosing idiopathic REM sleep behaviour disorder earlier from the community cases, this was much lower at 39%. During follow-up, 14 of 45 (31%) idiopathic REM sleep behaviour disorder patients converted to synucleinopathy with 9/14 (64%) of convertors showing baseline RT-QuIC positivity. In summary, our results showed that α-synuclein RT-QuIC adds value in diagnosing Parkinson's disease and may provide a way to distinguish variations within Parkinson's disease phenotype. However, the quantitative parameters did not correlate with disease severity in Parkinson's disease. The assay distinguished multiple system atrophy patients from Parkinson's disease patients and in contrast to Parkinson's disease, the quantitative parameters correlated with disease progression of multiple system atrophy. Our results also provided further evidence for α-synuclein RT-QuIC having potential as an early biomarker detecting synucleinopathy in idiopathic REM sleep behaviour disorder patients prior to conversion. Further analysis of longitudinally followed idiopathic REM sleep behaviour disorder patients is needed to better understand the relationship between α-synuclein RT-QuIC signature and the progression from prodromal to different synucleinopathies
Routine versus on demand removal of the syndesmotic screw; a protocol for an international randomised controlled trial (RODEO-trial)
Background: Syndesmotic injuries are common and their incidence is rising. In case of surgical fixation of the syndesmosis a metal syndesmotic screw is used most often. It is however unclear whether this screw needs to be removed routinely after the syndesmosis has healed. Traditionally the screw is removed after six to 12 weeks as it is thought to hamper ankle functional and to be a source of pain. Some studies however suggest this is only the case in a minority of patients. We therefore aim to investigate the effect of retaining the syndesmotic screw on functional outcome. Design: This is a pragmatic international multicentre randomised controlled trial in patients with an acute syndesmotic injury for which a metallic syndesmotic screw was placed. Patients will be randomised to either routine removal of the syndesmotic screw or removal on demand. Primary outcome is functional recovery at 12 months measured with the Olerud-Molander Score. Secondary outcomes are quality of life, pain and costs. In total 194 patients will be needed to demonstrate non-inferiority between the two interventions at 80% power and a significance level of 0.025 including 15% loss to follow-up. Discussion: If removal on demand of the syndesmotic screw is non-inferior to routine removal in terms of functional outcome, this will offer a strong argument to adopt this as standard practice of care. This means that patients will not have to undergo a secondary procedure, leading to less complications and subsequent lower costs.Peer reviewe
Routine versus on demand removal of the syndesmotic screw; a protocol for an international randomised controlled trial (RODEO-trial) (vol 19, 35, 2018)
Peer reviewe
Relational color constancy in achromatic and isoluminant images
Relational color constancy, which refers to the constancy of perceived relations between surface colors under
changes in illuminant, may be based on the computation of spatial ratios of cone excitations. As this activity
need occur only within rather than between cone pathways, relational color constancy might be assumed to be
based on relative luminance processing. This hypothesis was tested in a psychophysical experiment in which
observers viewed simulated images of Mondrian patterns undergoing colorimetric changes that could be attributed
either to an illuminant change or to a nonilluminant change; the images were isoluminant, achromatic,
or unmodified. Observers reliably discriminated the two types of changes in all three conditions, implying
that relational color constancy is not based on luminance cues alone. A computer simulation showed
that in these isoluminant and achromatic images spatial ratios of cone excitations and of combinations of cone
excitations were almost invariant under illuminant changes and that discrimination performance could be predicted
from deviations in these ratios.Biotechnology and Biological Sciences Research Council (BBSRC
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