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Subthalamic nucleus deep brain stimulation for Parkinson's disease in Hong Kong: A prospective territory-wide 2 year follow-up study. - World neurosurgery
We were to assess the effects of bilateral subthalamic nucleus stimulation in Parkinson's patients at the 1st-year and 2nd-year follow-ups. UPDRS motor at Off-Medication (On-DBS) and quality of life assessments (PDQ39) were conducted. The percentage of awake On-time, awake Off-time and L-DOPA requirement were also assessed.We conducted a two-year prospective study of 25 consecutive patients from three DBS referral centers in Hong Kong. They were treated with bilateral stimulation of the subthalamic nucleus. Assessments were performed at 1st-year and 2nd-year intervals after DBS and were compared with the baseline.Eighteen patients completed the two-year outcome assessments. The mean UPDRS motor improvement was 57 % in the first year and 45 % in the second year. PDQ39 showed significant improvement in the quality of life for 2 consecutive years. The L-DOPA requirement decreased 63% and 55.9% respectively. The awake On-time was doubled in the first year and sustained in the second year. Awake Off-time was reduced from 28.1% to 5.9% in the first year and returned to 10.6% in the second year interval. Improvement of UPDRS motor, reduction in awake Off-time and decrement of daily L-DOPA dosage were all the main factors correlated with the improvement in PDQ39 summary index.The effects of Subthalamic nucleus deep brain stimulation in Parkinson's patients in Hong Kong were satisfactory. The results showed that reduction in UPDRS motor, awake off-time and daily L-DOPA dosage were the major drivers of overall improvement in PDQ39.Copyright Â© 2016 Elsevier Inc. All rights reserved.
CD146 defines commitment of cultured annulus fibrosus cells to express a contractile phenotype. - Journal of orthopaedic research : official publication of the Orthopaedic Research Society
Characterization of cells is important for facilitating cell-based therapies for degenerative diseases of intervertebral discs. For this purpose, we analyzed mouse annulus fibrosus cells by flowcytometory to detect phenotypic change in their primary cultures. After examination of sixteen cell surface proteins, we focused on CD146 that solely increased during culture expansion. CD146 is known to be a marker for mesenchymal stem cells and for their vascular smooth muscle commitment with expression of contractile phenotype enhanced by SM22Î±. We sorted CD146+ cells to elucidate their characteristics and the key factors that play a role in this change. Whole cell cultures showed the ability for tripotent differentiation toward mesenchymal lineages, whereas sorted CD146+ cells did not. Expression of CD146 was elevated by addition of transforming growth factor Î²1, and sorted CD146+ cells expressed higher levels of mRNA for SM22Î± and Elastin than did CD146-cells. Morphologically, CD146+ cells more broadly deposited extracellular type I collagen than CD146-cells and showed filamentous actin bundles traversing their cytoplasm and cell-cell junctions. Moreover, CD146+ cells demonstrated significantly higher gel contraction properties than CD146-cells when they were embedded in collagen gels. Human annulus fibrosus CD146+ cells also showed higher contractility. Immunohistochemistry determined CD146+ cells localized to the outermost annulus layers of mouse intervertebral disc tissue with co-expression of SM22Î±. These results suggest that increment of CD146 expression indicates gradual change of cultured annulus fibrosus cells to express a contractile phenotype and that transforming growth factor Î²1 enhances this cellular commitment. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.
Two subtypes of intervertebral disc degeneration distinguished by large-scale population-based study. - The spine journal : official journal of the North American Spine Society
Lumbar disc degeneration (LDD) is a major cause of low back pain, and is a common and disabling condition worldwide. It has been defined and measured by multiple spine magnetic resonance imaging (MRI) features, but the heterogeneity among them has never been fully addressed.This study examined the intercorrelations, risk factor associations, and single nucleotide polymorphism (SNP) heritabilities of lumbar disc MRI features in a large-scale sample to classify the different intervertebral disc phenotypes associated with LDD.A cross-sectional study was conducted consisting of 2,943 volunteers of Southern Chinese origin (mean age: 41.1 years; range: 15-55 years; 59.6% women).The outcome measures were MRI phenotypic spinal patterns and their risk factor profiles in relation to developmental or degenerative origins of disc degeneration.Sagittal T2-weighted MRI of the lumbar spine from L1 to S1 was assessed. The MRI features of lumbar intervertebral disc changes, such as disc signal intensity loss and disc bulges or extrusions, as well as additional imaging phenotypes of end plate changes, high-intensity zones, and bone marrow changes, were evaluated. Blood samples were taken for genotyping using the HumanOmni-ZhongHua-8 BeadChip. Subject demographics, environmental, and lifestyle factors were assessed by questionnaires. Multivariate statistical techniques were used for phenotype evaluation. Polychoric correlations and local regression statistical analyses were performed. The genetic components contributed by common SNPs were estimated by comparing genetic correlations and phenotypic correlations using the Genome-Wide Complex Trait Analysis (GCTA) tool.The study noted that lumbar disc MRI features separated into two groups with differential patterns of risk factor associations. A subset of lumbar disc abnormalities, including end plate changes but also upper lumbar disc bulging and signal intensity loss, may have a developmental origin. Subsequent degenerative changes, typically affecting the lower lumbar discs, then emerge as individuals age and are associated with body mass index.This is the first large-scale study to identify two distinct patterns of lumbar disc alterations, noting degenerative changes and a possible developmental component affecting the lumbar spine. This new classification provides a starting point for a more homogeneous phenotype definition, which may provide greater statistical power and precision in future genetic and epidemiologic studies. In addition, such insights may have direct clinical implications in the prevention, therapeutics, and prognostics of patients with disc degeneration.Copyright Â© 2016 Elsevier Inc. All rights reserved.
Comparison of proteomic datasets from hypertrophic chondrocytes in response to ER stress. - Data in brief
Cartilage proteomics is challenging due to the dominance of poorly soluble matrix components and limited available tissue. Using a "spatial" strategy coupled to MS/MS analysis we have specifically labeled and extracted hypertrophic chondrocytes within the growth plate providing thus a comprehensive proteomic map of normal hypertrophic chondrocytes. Furthermore our established 13del mouse model in which the activation of ER stress did not lead to apoptosis of the hypertrophic cells allowed us to address the natural consequences of ER stress in vivo. Thus our data provide also an overview of proteomic changes occurring in cells under ER stress. Associated with the published study  this dataset article provided the detailed information of experimental designing, methods, features as well as the raw data of mass spectrometry (MS) identification. Furthermore the data presented here allow the reader to assert the extent of proteomic changes occurring under ER stress in hypertrophic chondrocytes as well as address the data technical reproducibility in both wild type and stress condition. The mass spectrometry proteomics data can be fully accessed from the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD002125.
Separation and quantification of lactate and lipid at 1.3â€‰ppm by diffusion-weighted magnetic resonance spectroscopy. - Magnetic resonance in medicine
To separate the spectrally overlapped lactate and lipid signals at 1.3â€‰ppm using diffusion-weighted magnetic resonance spectroscopy (DW-MRS) based on their large diffusivity difference.DW-MRS was applied to the gel phantoms containing lactate and lipid droplets, and to the rat brain tumors. Lactate and lipid signals and their apparent diffusion coefficients were computed from the diffusion-weighted proton spectra. Biexponential fitting and direct spectral subtraction approaches were employed and compared.DW-MRS could effectively separate lactate and lipid signals both in phantoms and rat brain C6 glioma by biexponential fitting. In phantoms, lactate and lipid signals highly correlated with the known lactate concentration and lipid volume fractions. In C6 glioma, both lactate and lipid signals were detected, and the lipid signal was an order of magnitude higher than lactate signal. The spectral subtraction approach using three diffusion weightings also allowed the separation of lactate and lipid signals, yielding results comparable to those by the biexponential fitting approach.DW-MRS presents a new approach to separate and quantify spectrally overlapped molecules and/or macromolecules, such as lactate and lipid, by using the diffusivity difference associated with their different sizes or mobility within tissue microstructure. Magn Reson Med, 2016. Â© 2016 Wiley Periodicals, Inc.Â© 2016 Wiley Periodicals, Inc.
Label-Free Quantitative Proteomics Reveals Survival Mechanisms Developed by Hypertrophic Chondrocytes under ER Stress. - Journal of proteome research
Emerging evidence implicates ER stress caused by unfolded mutant proteins in chondrocytes as the underlying pathology of chondrodysplasias. ER stress is triggered in hypertrophic chondrocytes (HCs) in a mouse model (13del) of metaphyseal chondrodysplasia type Schmid (MCDS) caused by misfolded mutant collagen X proteins, but the HCs do not undergo apoptosis; rather chondrocyte differentiation is altered, causing skeletal abnormality. How 13del HCs can escape from apoptosis and survive ER stress is not understood. Here we compared the proteomes of HCs isolated from 13del growth plates with normal HCs using a label-free quantitative mass spectrometry approach. Pathway enrichment analyses of differentially expressed proteins showed significant changes in glycolysis and ER-mitochondria pathways in 13del HCs as well as in ATDC5 cell lines expressing wt and 13del collagen X. In vivo, we showed expression of mitochondrial calcium channels was reduced while mitochondrial membrane polarity was maintained in 13del chondrocytes, while in vitro, glucose uptake was maintained. We propose 13del HCs survive by a mechanism whereby changes in ER-mitochondria communication reduce import of calcium coupled to maintenance of mitochondrial membrane polarity. These findings provide the initial insights into our understanding of growth plate changes caused by protein misfolding in the pathogenesis of chondrodysplasias.
Biomarker-based prognostic stratification of young adult glioblastoma. - Oncotarget
While the predominant elderly and the pediatric glioblastomas have been extensively investigated, young adult glioblastomas were understudied. In this study, we sought to stratify young adult glioblastomas by BRAF, H3F3A and IDH1 mutations and examine the clinical relevance of the biomarkers. In 107 glioblastomas aged from 17 to 35 years, mutually exclusive BRAF-V600E (15%), H3F3A-K27M (15.9%), H3F3A-G34R/V (2.8%) and IDH1-R132H (16.8%) mutations were identified in over half of the cases. EGFR amplification and TERTp mutation were only detected in 3.7% and 8.4% in young adult glioblastomas, respectively. BRAF-V600E identified a clinically favorable subset of glioblastomas with younger age, frequent CDKN2A homozygous deletion, and was more amendable to surgical resection. H3F3A-K27M mutated glioblastomas were tightly associated with midline locations and showed dismal prognosis. IDH1-R132H was associated with older age and favorable outcome. Interestingly, tumors with positive PDGFRA immunohistochemical expression exhibited poorer prognosis and identified an aggressive subset of tumors among K27M mutated glioblastomas. Combining BRAF, H3F3A and IDH1 mutations allowed stratification of young adult glioblastomas into four prognostic subgroups. In summary, our study demonstrates the clinical values of stratifying young adult glioblastomas with BRAF, H3F3A and IDH1 mutations, which has important implications in refining prognostic classification of glioblastomas.
Combination genetic signature stratifies lower-grade gliomas better than histological grade. - Oncotarget
We studied if combination genetic signature potentially stratifies lower-grade gliomas better than histology by investigating 214 lower-grade gliomas for IDH1/2 and TERTp mutations, 1p/19q codeletion and EGFR amplification as to their impact on prognostication. Prognostic association of grading was independent of other prognostic variables including age, histological type, IDH1/2, 1p/19q and TERTp status. No single marker, including IDH1/2, superseded grading in prognostication, indicating grading was still a very important tool. Prognosis was most favorable in 31.7% of patients with IDH1/2 mutation and either 1p/19q codeletion or TERTp mutation (IDHmut-OT), intermediate in 45.8% of patients with IDH1/2 mutation only (IDHmut) and 16.9% of patients without any of the alterations (IDHwt), and poorest in 5.6% of patients with wild-type IDH1/2 and either TERTp mutation or EGFR amplification (IDHwt-ET). Our results suggested not all IDH1/2 wild-type lower-grade gliomas are aggressive and additional biomarkers are required to identify glioblastoma-equivalent tumors. Multivariate analysis revealed independent prognostic values of grading and genetic signature. Grade II IDHwt-ET gliomas exhibited shorter survival than IDH1/2 mutated grade III gliomas, suggesting combination genetic signature potentially superseded grading in prognostication. In summary, biomarker-based stratification is useful in the diagnosis and prognostication of lower-grade gliomas, and should be used together with grading.
Risk factors for seizures and antiepileptic drug-associated adverse effects in high-grade glioma patients: A multicentre, retrospective study in Hong Kong. - Surgical practice
The aim of this present study was to determine the frequency, as well as risk factors, for seizures and antiepileptic drug (AED)-associated adverse effects among high-grade glioma (HGG) patients.A multicentre, retrospective study of adult Chinese Hong Kong patients from three neurosurgical centres diagnosed with supratentorial HGG between 1 January 2001 and 31 December 2010 was performed.A total of 198 patients, with a mean age of 55â€‰years (range: 18-88) and a mean follow up of 15 months, was recruited. Most suffered from glioblastoma multiforme (GBM) (63 per cent) followed by anaplastic astrocytoma (25 per cent). Median overall survival for patients with GBM was 8â€‰months, and 11â€‰months for those with grade III gliomas. Prophylactic AED was prescribed in 165 patients (83 per cent), and 64 per cent of patients were continued until end of life or last follow up. A total of 112 patients (57 per cent) experienced seizures at a mean duration of 8â€‰months postoperatively (range: 1â€‰day-75â€‰months). Independent predictors for seizures were a diagnosis of GBM [adjusted odds ratio (OR): 2.33, 95 per cent confidence interval (CI): 1.21-4.52] and adjuvant radiotherapy (adjusted OR: 2.97, 95 per cent CI: 1.49-6.62). One-fifth of patients (21 per cent) experienced AED adverse effects, with idiosyncratic cutaneous reactions and hepatotoxicity most frequently observed. An independent predictor for adverse effects was exposure to aromatic AED, such as phenytoin, carbamazepine and phenobarbital (adjusted OR: 3.32, 95 per cent CI: 1.32-8.40).Antiepileptic drug prescription for primary seizure prophylaxis is both pervasive and prolonged for HGG patients. Seizures occur frequently, but most were delayed and none were life threatening. Judicious prescription of AED is required, especially when a significant proportion of patients experience adverse effects. Patients with a diagnosis of GBM and exposure to radiotherapy are at risk. We suggest, contrary to present practice, that primary seizure prophylaxis be given only during the perioperative period and resumed when they occur. We also recommend avoidance of aromatic AED due to their association with idiosyncratic adverse effects.
Ictal high-frequency oscillations and hyperexcitability in refractory epilepsy. - Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology
High-frequency oscillations (HFOs, 80-500Hz) from intracranial electroencephalography (EEG) may represent a biomarker of epileptogenicity for epilepsy. We explored the relationship between ictal HFOs and hyperexcitability with a view to improving surgical outcome.We evaluated 262 patients with refractory epilepsy. Fifteen patients underwent electrode implantation, and surgical resection was performed in 12 patients using a semi-prospective design. Ictal intracranial EEGs were examined by continuous wavelet transform (CWT). Significant ictal HFOs were denoted by normalized wavelet power above the 50th percentile across all channels. Each patient underwent functional mapping with cortical electrical stimulation. Hyperexcitability was defined as the appearance of afterdischarges or clinical seizures after electrical stimulation (50Hz, biphasic, pulse width=0.5ms, 5s, 5mA).Among the group of patients achieving Engel Class I/II outcome at 1+ year, the mean proportion of significant ictal HFOs among resected channels for any given patient was 69% (33.3-100%). The respective figures for conventional frequency ictal patterns (CFIPs), hyperexcitability, and radiological lesion were 68.3% (26.3-100%), 39.6% (0-100%), and 52.8% (0-100%). Statistical significance was only achieved with ictal HFOs when comparing patients with Engel Class I/II outcomes versus III/IV outcomes (12.6% vs. 4.2%, the number of channels as the denominator, p=0.005). Further analysis from all patients irrespective of the surgical outcome showed that ictal HFOs co-occurred with CFIP (p<0.001), hyperexcitability (p<0.001), and radiological lesion (p<0.001). The combination of ictal HFOs/hyperexcitability improved the sensitivity from 66.7% to 100%, and the specificity from 66.7% to 75% when compared with ictal HFOs or hyperexcitability alone.We confirmed the utility of ictal HFOs in determining surgical outcome. Ictal HFOs are affiliated to cortical hyperexcitability, which may represent a pathological manifestation of epileptogenicity.Presurgical evaluation of refractory epilepsy may incorporate both ictal HFOs and cortical stimulation in determining epileptogenic foci.Copyright Â© 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
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