Dopamine depletion and subcortical dysfunction disrupt cortical synchronization and metastability affecting cognitive function in Parkinson's disease.

Parkinson's disease (PD) is primarily characterized by the loss of dopaminergic cells and atrophy in subcortical regions. However, the impact of these pathological changes on large-scale dynamic integration and segregation of the cortex are not well understood. In this study, we investigated the effect of subcortical dysfunction on cortical dynamics and cognition in PD. Spatiotemporal dynamics of the phase interactions of resting-state blood-oxygen-level-dependent signals in 159 PD patients and 152 normal control (NC) individuals were estimated. The relationships between subcortical atrophy, subcortical-cortical fiber connectivity impairment, cortical synchronization/metastability, and cognitive performance were then assessed. We found that cortical synchronization and metastability in PD patients were significantly decreased. To examine whether this is an effect of dopamine depletion, we investigated 45 PD patients both ON and OFF dopamine replacement therapy, and found that cortical synchronization and metastability are significantly increased in the ON state. The extent of cortical synchronization and metastability in the OFF state reflected cognitive performance and mediates the difference in cognitive performance between the PD and NC groups. Furthermore, both the thalamic volume and thalamocortical fiber connectivity had positive relationships with cortical synchronization and metastability in the dopaminergic OFF state, and mediate the difference in cortical synchronization between the PD and NC groups. In addition, thalamic volume also reflected cognitive performance, and cortical synchronization/metastability mediated the relationship between thalamic volume and cognitive performance in PD patients. Together, these results highlight that subcortical dysfunction and reduced dopamine levels are responsible for decreased cortical synchronization and metastability, further affecting cognitive performance in PD. This might lead to biomarkers being identified that can predict if a patient is at risk of developing dementia.

Association of serum bisphenol AF concentration with depressive symptoms in adolescents: A nested case-control study in China.

BACKGROUND: As an important alternative to bisphenol A (BPA), bisphenol AF (BPAF) is widely used and can be detected in multiple human biological samples. However, there are few studies on neurotoxicity of BPAF at present. In particular, no epidemiological studies have investigated BPAF in relation to depressive symptoms in adolescents. Here, our study aimed to evaluate the associations between serum BPAF concentrations and depressive symptoms in adolescents. METHODS: A nested case-control study within an ongoing longitudinal prospective adolescent cohort that was established in Huaibei, China was conducted. A total of 175 participants who had new-onset depressive symptoms (cases) and 175 participants without depressive symptoms (controls) were included. Serum BPAF concentrations was measured using ultra-high-performance liquid chromatography-tandem mass spectrometry. The associations between BPAF exposure and the risk of depressive symptoms in adolescents were assessed using conditional logistic regression. The dose-response relationship between BPAF level and depressive symptoms was estimated using restricted cubic spline analyses. RESULTS: In this study, the detection rate of serum BPAF was 100%, and the median (interquartile range, IQR) serum BPAF concentration was 5.24 (4.41-6.11) pg/mL in the case group and 4.86 (4.02-5.77) pg/mL in the control group (P = 0.009). Serum BPAF exposure was a risk factor for depressive symptoms (odds ratio (OR)= 1.132, 95% confidence interval (CI):1.013-1.264). After adjustment for all for confounders, compared with the low-exposure group, the high-exposure group had a 2.806-fold increased risk of depressive symptoms (OR=2.806, 95% CI: 1.188-6.626). Stratified analysis by sex revealed that males were more vulnerable to BPAF exposure than females. After adjustment for all confounders, compared with the low-exposure group, the relative risk of depressive symptoms in the high-exposure group was 3.858 (95% CI: 1.118-12.535) for males, however, no significant association between BPAF exposure and depressive symptoms was found in females. In addition, there was a marked linear association between BPAF exposure and the risk of depressive symptoms in the total population and in males. CONCLUSIONS: The adolescents in this study were widely exposed to low levels of BPAF. A significant positive association was found between serum BPAF levels and the risk of depressive symptoms. The association was significantly modified by sex, and males were more vulnerable to BPAF exposure than females.

Effects of Exogenous α-Naphthaleneacetic Acid and 24-Epibrassinolide on Fruit Size and Assimilate Metabolism-Related Sugars and Enzyme Activities in Giant Pumpkin.

Size is the most important quality attribute of giant pumpkin fruit. Different concentrations and application frequencies of α-naphthaleneacetic acid (NAA) and 24-epibrassinolide (EBR) were sprayed on the leaves and fruits of giant pumpkin at different growth stages to determine their effects and the mechanism responsible for fruit size increase. NAA+EBR application improved source strength, and further analysis indicated that NAA+EBR markedly boosted net photosynthetic rate (Pn), stomatal conductance (Gs), transpiration rate (Tr) and the expression level and activity of galactitol synthetase (GolS), raffinose synthetase (RS), and stachyose synthetase (STS), resulting in an increase in the synthesis of photoassimilate, especially stachyose. Concomitantly, NAA+EBR spray increased stachyose and sucrose contents throughout pumpkin fruit growth and the concentrations of glucose and fructose at 0 and 20 days post-anthesis (DPA) in peduncle phloem sap, implying that such treatment improved the efficiency of assimilate transport from the peduncle to the fruit. Furthermore, it improved the expression and activity of alkaline α-galactosidase (AGA), facilitating assimilate unloading, providing carbon skeletons and energy for fruit growth, and increasing fruit weight by more than 44.1%. Therefore, exogenous NAA and EBR increased source capacity, transportation efficiency, and sink strength, overall promoting the synthesis and distribution of photoassimilate, ultimately increasing fruit size.

Advances in Research on Bioactivity, Toxicity, Metabolism, and Pharmacokinetics of Usnic Acid In Vitro and In Vivo.

Lichens are among the most widely distributed plants on earth and have the longest growth cycle. Usnic acid is an abundant characteristic secondary metabolite of lichens and the earliest lichen compound used commercially. It has diverse pharmacological activities, such as anti-inflammatory, antibacterial, antiviral, anticancer, antioxidant, and photoprotective effects, and promotes wound healing. It is widely used in dietary supplements, daily chemical products (fodder, dyes, food, perfumery, and cosmetics), and medicine. However, some studies have found that usnic acid can cause allergic dermatitis and drug-induced liver injury. In this paper, the bioactivity, toxicity, in vivo and in vitro metabolism, and pharmacokinetics of usnic acid were summarized. The aims were to develop and utilize usnic acid and provide reference for its future research.

Serum Ceruloplasmin Depletion is Associated With Magnetic Resonance Evidence of Widespread Accumulation of Brain Iron in Parkinson's Disease.

BACKGROUND: Excessive iron accumulation is one of the main pathogeneses of Parkinson's disease (PD). Ceruloplasmin plays an important role in keeping the iron homoeostasis. PURPOSE: To explore the association between serum ceruloplasmin depletion and subcortical iron distribution in PD. STUDY TYPE: Prospective. POPULATION: One hundred and twenty-one normal controls, 34 PD patients with low serum ceruloplasmin (PD-LC), and 28 patients with normal serum ceruloplasmin (PD-NC). SEQUENCE: Enhanced susceptibility-weighted angiography (ESWAN) on a 3 T scanner. ASSESSMENT: Quantitative susceptibility mapping was employed to quantify the regional iron content by using a semi-automatic method. Serum ceruloplasmin concentration was measured from peripheral blood sample. Clinical assessments were conducted by a neurologist. STATISTICAL TESTS: General linear model was used to compare the intergroup difference of region iron distribution among groups, and the statistics was adjusted by Bonferroni method (P < 0.01). Partial correlation analysis was used to detect the association between regional iron distribution and serum ceruloplasmin concentration (P < 0.05). RESULTS: Compared with normal controls, significant iron accumulation in substantia nigra, putamen, and red nucleus was observed in PD-LC, while the only region showing significant iron accumulation was SN in PD-NC. Between PD-NC and PD-LC, the iron accumulation in putamen remained significantly different, which had a negative correlation with serum ceruloplasmin in whole PD patients (r = -0.338, P = 0.008). DATA CONCLUSION: Nigral iron accumulation characterizes PD patients without significant association with serum ceruloplasmin. Differentially, when PD patients appear with reduced serum ceruloplasmin, more widespread iron accumulation would be expected with additionally involving putamen and red nucleus. All these findings provide insightful evidence for the abnormal iron metabolism behind the ceruloplasmin depletion in PD. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: 2.

Platelet-rich plasma protects human melanocytes from oxidative stress and ameliorates melanogenesis induced by UVB irradiation.

To investigate the role of platelet-rich plasma (PRP) from different sources in alleviating oxidative stress and ameliorating melanogenesis in UVB-irradiated PIG1 cells, PIG1 cells were irradiated with 80 mJ/cm2 UVB prior to 1% PRP application and the following experiments were taken: the viability of UVB-irradiated PIG1 cells, cellular malondialdehyde (MDA) and reactive oxygen species (ROS) content, and activities of antioxidant enzymes. Western blotting was utilized to detect the expression level of proteins associated with melanin synthesis, apoptosis, and DNA lesions. We found that PRP intervention promoted cell proliferation, reduced MDA and ROS content, increased the activities of series of antioxidant enzymes, and alleviated DNA damages in UVB-damaged PIG1 cells. It is important to note that PRP treatment inhibited UVB-induced melanogenesis via the PI3K/Akt/GSK3ß signal pathway. Therefore, we suppose PRP treatment exerts a protective role through their antioxidation effect on UVB-damaged PIG1 cells and hinders melanogenesis induced by UVB irradiation.

Clinically relevant connectivity features define three subtypes of Parkinson's disease patients.

Parkinson's disease (PD) is characterized by complex clinical symptoms, including classic motor and nonmotor disturbances. Patients with PD vary in clinical manifestations and prognosis, which point to the existence of subtypes. This study aimed to find the fiber connectivity correlations with several crucial clinical symptoms and identify PD subtypes using unsupervised clustering analysis. One hundred and thirty-four PD patients and 77 normal controls were enrolled. Canonical correlation analysis (CCA) was performed to define the clinically relevant connectivity features, which were then used in the hierarchical clustering analysis to identify the distinct subtypes of PD patients. Multimodal neuroimaging analyses were further used to explore the neurophysiological basis of these subtypes. The methodology was validated in an independent data set. CCA revealed two significant clinically relevant patterns (motor-related pattern and depression-related pattern; r = .94, p < .001 and r = .926, p = .001, respectively) among PD patients, and hierarchical clustering analysis identified three neurophysiological subtypes ("mild" subtype, "severe depression-dominant" subtype and "severe motor-dominant" subtype). Multimodal neuroimaging analyses suggested that the patients in the "severe depression-dominant" subtype exhibited widespread disruptions both in function and structure, while the other two subtypes exhibited relatively mild abnormalities in brain function. In the independent validation, three similar subtypes were identified. In conclusion, we revealed heterogeneous subtypes of PD patients according to their distinct clinically relevant connectivity features. Importantly, depression symptoms have a considerable impact on brain damage in patients with PD.

Aberrant Fiber Coherence of Amygdala-Accumbens-Pallidum Pathway Is Associated With Disorganized Nigrostriatal-Nigropallidal Pathway in Parkinson's Disease.

BACKGROUND: Motor disturbances in Parkinson's disease (PD) mainly result from the degeneration of classic motor pathways. Given that the specific limbic pathway participates in movements, it is reasonable to consider that limbic pathway have the pathologic potential of motor disturbance in PD. PURPOSE: To explore the white matter changes of limbic and motor pathways and their relations in PD patients. STUDY TYPE: Prospective. POPULATION: 39 PD patients and 55 normal controls. SEQUENCE: Sagittal 3D T1 -weighted fast spoiled gradient recalled sequence, diffusion-weighted spin echo-echo planar imaging sequence on a 3T scanner. ASSESSMENT: Probabilistic tractography was used to reconstruct the motor pathways (nigrostriatal-nigropallidal and basal ganglia-motor cortex pathways) and limbic pathway (amygdala-accumbens-pallidum pathway). White matter alterations of these pathways were evaluated by fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), neurite density (NDI), and orientation dispersion (ODI). Clinical assessment was conducted by a neurologist. STATISTICAL TESTS: Group comparisons were performed using unpaired t-tests. Pearson or Spearman correlation was used to explore the relationships between variables. RESULTS: Compared with normal controls, PD patients showed decreased ODI as well as increased MD and AD in the bilateral nigrostriatal-nigropallidal pathway (P < 0.05), decreased FA in left basal ganglia-motor cortex pathway (P < 0.05), and decreased ODI in left limbic pathway (P < 0.05). MD and AD in the left nigrostriatal-nigropallidal pathway was negatively correlated with FA in left basal ganglia-motor cortex pathway (r = -0.597, P < 0.05 and r = -0.433, P < 0.05, respectively). MD in the left nigrostriatal-nigropallidal pathway was significantly correlated with ODI in the left limbic pathway (r = -0.404, P < 0.05). ODI was associated with AD within each hemisphere of the nigrostriatal-nigropallidal pathway (r = -0.591, P < 0.05 for left; r = -0.589, P < 0.05 for right). DATA CONCLUSION: The relationship between the degenerated motor pathways and aberrant limbic pathway suggest the existence of neuronal modulation between motor and limbic pathways, providing novel evidence of the neuromechanism for motor disruption in PD patients. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1 J. MAGN. RESON. IMAGING 2020;52:1799-1808.

Alteration of Brain Functional Connectivity in Parkinson's Disease Patients with Dysphagia.

Dysphagia is a common non-primary symptom of patients with Parkinson's disease. The aim of this study is to investigate the underlying alterations of brain functional connectivity in Parkinson's disease patients with dysphagia by resting-state functional magnetic resonance imaging. We recruited 13 Parkinson's disease patients with dysphagia and ten patients without dysphagia, diagnosed by videofluoroscopic study of swallowing. Another 13 age and sex-matched healthy subjects were recruited. Eigenvector centrality mapping was computed to identify functional connectivity alterations among these groups. Parkinson's disease patients with dysphagia had significantly increased functional connectivity in the cerebellum, left premotor cortex, the supplementary motor area, the primary motor cortex, right temporal pole of superior temporal gyrus, inferior frontal gyrus, anterior cingulate cortex and insula, compared with patients without dysphagia. This study suggests that functional connectivity changes in swallowing-related cortexes might contribute to the occurrence of dysphagia in Parkinson's disease patients.

IDSSR: An Efficient Pipeline for Identifying Polymorphic Microsatellites from a Single Genome Sequence.

Simple sequence repeats (SSRs) are known as microsatellites, and consist of tandem 1-6-base motifs. They have become one of the most popular molecular markers, and are widely used in molecular ecology, conservation biology, molecular breeding, and many other fields. Previously reported methods identify monomorphic and polymorphic SSRs and determine the polymorphic SSRs via experimental validation, which is potentially time-consuming and costly. Herein, we present a new strategy named insertion/deletion (INDEL) SSR (IDSSR) to identify polymorphic SSRs by integrating SSRs with nucleotide insertions/deletions (INDEL) solely based on a single genome sequence and the sequenced pair-end reads. These INDEL indexes and polymorphic SSRs were identified, as well as the number of repeats, repeat motifs, chromosome location, annealing temperature, and primer sequences, enabling future experimental approaches to determine the correctness and polymorphism. Experimental validation with the giant panda demonstrated that our method has high reliability and stability. The efficient SSR pipeline would help researchers obtain high-quality genetic markers for plants and animals of interest, save labor, and reduce costly marker-screening experiments. IDSSR is freely available at https://github.com/Allsummerking/IDSSR.

Diagnostic accuracy of contrast-enhanced ultrasound in assessing the therapeutic response to radio frequency ablation for liver tumors: systematic review and meta-analysis.

BACKGROUND: To review the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) used to detect residual or recurrent liver tumors after radiofrequency ablation (RFA). This technique uses contrast-enhanced computer tomography or/and contrast-enhanced magnetic resonance imaging as the gold standard of investigation. METHODS: MEDLINE, EMBASE, and COCHRANE were systematically searched for all potentially eligible studies comparing CEUS with the reference standard that follows RFA. Risk of bias and applicability concerns were addressed by adopting the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Pooled point estimates for sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratios (DOR) with 95% CI were computed before plotting the sROC (summary receiver operating characteristic) curve. Meta-regression and subgroup analysis were used to identify the source of the heterogeneity that was detected. Publication bias was evaluated using Deeks' funnel plot asymmetry test. RESULTS: Ten eligible studies on 1162 lesions that occurred between 2001 and 2016 were included in the final analysis. The quality of the included studies assessed by the QUADAS-2 tool was considered reasonable. The pooled sensitivity and specificity of CEUS in detecting residual or recurrent liver tumors had the following values: 0.90 (95% CI 0.85-0.94) and 1.00 (95% CI 0.99-1.00), respectively. Overall DOR was 420.10 (95% CI 142.30-1240.20). The sources of heterogeneity could not be precisely identified by meta-regression or subgroup analysis. No evidence of publication bias was found. CONCLUSION: This study confirmed that CEUS exhibits high sensitivity and specificity in assessing therapeutic responses to RFA for liver tumors.

CD8+ T cells are predominantly protective and required for effective steroid therapy in murine models of immune thrombocytopenia.

Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder characterized by autoantibodies targeting platelet surface proteins, most commonly GPIIbIIIa (αIIbß3 integrin), leading to platelet destruction. Recently, CD8(+) cytotoxic T-lymphocytes (CTLs) targeting platelets and megakaryocytes have also been implicated in thrombocytopenia. Because steroids are the most commonly administered therapy for ITP worldwide, we established both active (immunized splenocyte engraftment) and passive (antibody injection) murine models of steroid treatment. Surprisingly, we found that, in both models, CD8(+) T cells limited the severity of the thrombocytopenia and were required for an efficacious response to steroid therapy. Conversely, CD8(+) T-cell depletion led to more severe thrombocytopenia, whereas CD8(+) T-cell transfusion ameliorated thrombocytopenia. CD8(+) T-regulatory cell (Treg) subsets were detected, and interestingly, dexamethasone (DEX) treatment selectively expanded CD8(+) Tregs while decreasing CTLs. In vitro coculture studies revealed CD8(+) Tregs suppressed CD4(+) and CD19(+) proliferation, platelet-associated immunoglobulin G generation, CTL cytotoxicity, platelet apoptosis, and clearance. Furthermore, we found increased production of anti-inflammatory interleukin-10 in coculture studies and in vivo after steroid treatment. Thus, we uncovered subsets of CD8(+) Tregs and demonstrated their potent immunosuppressive and protective roles in experimentally induced thrombocytopenia. The data further elucidate mechanisms of steroid treatment and suggest therapeutic potential for CD8(+) Tregs in immune thrombocytopenia.

Regionally progressive accumulation of iron in Parkinson's disease as measured by quantitative susceptibility mapping.

The progression of Parkinson's disease (PD) seems to vary according to the disease stage, which greatly influences the management of PD patients. However, the underlying mechanism of progression in PD remains unclear. This study was designed to explore the progressive pattern of iron accumulation at different stages in PD patients. Sixty right-handed PD patients and 40 normal controls were recruited. According to the disease stage, 45 patients with Hoehn-Yahr stage ≤ 2.5 and 15 patients with Hoehn-Yahr stage ≥ 3 were grouped into early-stage PD (EPD) and late-stage PD (LPD) groups, respectively. The iron content in the cardinal subcortical nuclei covering the cerebrum, cerebellum and midbrain was measured using quantitative susceptibility mapping (QSM). The substantia nigra pars compacta (SNc) showed significantly increased QSM values in the EPD patients compared with the controls. In the LPD patients, while the SNc continued to show increased QSM values compared with the controls and EPD patients, the regions showing increased QSM values spread to include the substantia nigra pars reticulata (SNr), red nucleus (RN) and globus pallidus (GP). Our data also indicated that iron deposition was more significant in the GP internal segment (GPi) than in the GP external segment. No other regions showed significant changes in QSM values among the groups. Therefore, we were able to confirm a regionally progressive pattern of iron accumulation in the different stages of PD, indicating that iron deposition in the SNc is affected exclusively in the early stages of the disease, while the SNr, RN and GP, and particularly the GPi segment, become involved in advanced stages of the disease. This is a preliminary study providing objective evidence of the iron-related progression in PD. Copyright © 2016 John Wiley & Sons, Ltd.

Influence of regional iron on the motor impairments of Parkinson's disease: A quantitative susceptibility mapping study.

PURPOSE: Because the roles of striatal-thalamo-cortical and cerebello-thalamo-cortical circuits in the heterogeneous motor impairments of Parkinson's disease (PD) are becoming recognized, this study was designed to investigate the relationships between regional iron in the cardinal subcortical nuclei in these circuits and the different motor impairments. MATERIALS AND METHODS: Sixty-two PD patients and 40 normal subjects were included and accepted for Enhanced T2 -Star Weighted Angiography Scanning (3.0T). According to the Unified Parkinson's Disease Rating Scale, patients were divided into tremor-dominant (PD-TD) and akinetic/rigid-dominant groups (PD-AR). The intergroup differences of magnetic susceptibility in those cardinal nuclei were measured. Correlation analyses between magnetic susceptibility and motor impairments were performed in all patients. RESULTS: Nigral magnetic susceptibility significantly increased for each PD group compared with controls (P < 0.001 for PD-TD; P = 0.001 for PD-AR). Magnetic susceptibility in the dentate nucleus (DN) and red nucleus (RN) for the PD-TD patients were significantly increased compared with controls (P < 0.001 and P = 0.004, respectively). Magnetic susceptibility in these regions was also significantly correlated with tremor severity (r = 0.444, P = 0.001 for DN; r = 0.418, P = 0.001 for RN). Significant correlation between caudate magnetic susceptibility and akinetic/rigid severity were observed (r = -0.322, P = 0.015). CONCLUSION: This study provides evidence that nigral iron accumulation is a common characteristic in PD, while iron accumulation in the DN and RN is correlated with tremor symptoms. Our data also indicate that caudate iron content may be a potential marker for akinetic/rigid progression. LEVEL OF EVIDENCE: 3 J. MAGN. RESON. IMAGING 2017;45:1335-1342.

Abnormal baseline brain activity in Parkinson's disease with and without REM sleep behavior disorder: A resting-state functional MRI study.

PURPOSE: To investigate the differences in spontaneous brain activity between Parkinson's disease (PD) patients with rapid eye movement sleep behavior disorder (RBD), PD patients without RBD, and normal controls, which may shed new light on the neural mechanism of RBD. MATERIALS AND METHODS: Eighteen PD patients with RBD, 16 patients without RBD, and 19 age- and gender-matched normal controls underwent clinical assessment and functional magnetic resonance imaging (fMRI) with a 3.0T scanner. Resting-state fMRI scans were collected using an echo planar imaging sequence. Amplitude of low-frequency fluctuations (ALFF) were calculated to measure spontaneous brain activity in each subject. RESULTS: Compared with PD patients without RBD, patients with RBD exhibited significantly decreased ALFF values (P < 0.001, cluster level) in primary motor cortex extending to premotor cortex. Compared with normal controls, PD patients exhibited decreased ALFF values (P < 0.001, cluster level) in caudate and putamen (P < 0.001, cluster level), and increased ALFF values (P = 0.03, cluster level) in prefrontal cortex. CONCLUSION: The altered spontaneous brain activity in motor cortex may contribute to the pathogenesis of RBD in PD patients, which further supports the idea that the pathophysiology of RBD involves not only midbrain dysfunction but also cerebral cortex abnormalities. Our findings provide additional insight into the neural mechanism of RBD and may drive future research to develop better treatment. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. MAGN. RESON. IMAGING 2017;46:697-703.

Altered brain network centrality in depressed Parkinson's disease patients.

BACKGROUND: Depression is a relatively common and serious nonmotor symptom of Parkinson's disease (PD), which reduces the quality of patients' life. Although disturbances in some related brain networks have been reported, the pathophysiology of depression in PD is still unclear. Here, we aim to investigate whole-brain functional connectivity patterns in depressed PD patients. METHODS: We recruited 17 PD patients diagnosed with major depressive disorder, 17 PD patients without depression, and 17 healthy control subjects. Resting-state functional MRI and eigenvector centrality mapping were used to identify functional connectivity alterations among these groups. RESULTS: Results showed that depressed PD patients had decreased functional connectivity in the left dorsolateral prefrontal cortex and right superior temporal gyrus and increased functional connectivity in the right posterior cingulate cortex, compared to nondepressed patients. In addition, there was a significant negative correlation between functional connectivity and depression scores in the posterior cingulate cortex. CONCLUSIONS: This study suggests that functional connectivity changes in certain nodes of brain networks might contribute to depression in patients with PD.

External validation and clinical evaluation of the International Prognostic Score of Thrombosis for Essential Thrombocythemia (IPSET-thrombosis) in a large cohort of Chinese patients.

OBJECTIVES: In patients with essential thrombocythemia (ET), vascular complications contribute to both morbidity and mortality. To better predict the occurrence of thrombotic events, an International Prognostic Score of thrombosis for ET (IPSET-thrombosis) was recently developed. We hereby presented an external validation and analysis of this model in a large Cohort of Chinese Patients. METHODS: We retrospectively evaluated the characteristics and risk factors for thrombosis in 970 Chinese patients with ET and estimated the clinical implications of the IPSET-thrombosis model. RESULTS: The median follow-up was 49 months (range, 0-360). Chinese ET patients had similar clinical characteristics as Caucasian patients. Similar to the IPSET-thrombosis study, our multivariate analysis revealed age >60 (HR = 1.949), previous thrombosis (HR = 2.484), JAK2V617F mutation (HR = 1.719), and cardiovascular risk factors (HR = 1.877) as independent risk factors for thrombosis. We confirmed that the above risk factors in IPSET-thrombosis, when compared with traditional risk factors (e.g., age ≥60 and previous thrombotic events), were more predictive of thrombotic events (C-index 0.714 vs. 0.647). Classification by IPSET-thrombosis risk groups revealed different cumulative thrombosis-free survival (P < 0.001). For treatment, patients in the intermediate- and high-risk group derived clinical benefit from cytoreductive agents (P < 0.05), but those in the low-risk group did not (P = 0.446). The lower risk of thrombosis on cytoreductive therapy was related to decrease in leukocyte count during the disease course. CONCLUSIONS: We validate the reproducibility of IPSET-thrombosis in Chinese ET patients and provide key clinical implications.

Greater loss of white matter integrity in postural instability and gait difficulty subtype of Parkinson's disease.

BACKGROUND: Patients with the postural instability and gait difficulty (PIGD) subtype of Parkinson disease (PD) are at a higher risk of dysfunction and are less responsive to dopamine replacement therapy. The PIGD subtype was found to largely associate with white matter lesions, but details of the diffusion changes within these lesions have not been fully investigated. Voxel-based analysis for diffusion tensor imaging data is one of the preferred measures to compare diffusion changes in each voxel in any part of the brain. METHODS: PD patients with the PIGD (n=12) and non-PIGD subtypes (n=12) were recruited to compare diffusion differences in fractional anisotropy, axial diffusivity, and radial diffusivity with voxel-based analysis. RESULTS: Significantly reduced fractional anisotropy in bilateral superior longitudinal fasciculus, bilateral anterior corona radiata, and the left genu of the corpus callosum were shown in the PIGD subtype compared with the non-PIGD subtype. Increased radial diffusivity in the left superior longitudinal fasciculus was found in the PIGD subtype with no statistical differences in axial diffusivity found. CONCLUSIONS: Our study confirms previous findings that white matter abnormalities were greater in the PIGD subtype than in the non-PIGD subtype. Additionally, our findings suggested: (1) compared with the non-PIGD subtype, loss of white matter integrity was greater in the PIGD subtype; (2) bilateral superior longitudinal fasciculus may play a critical role in microstructural white matter abnormalities in the PIGD subtype; and (3) reduced white matter integrity in the PIGD subtype could be mainly attributed to demyelination rather than axonal loss.

Retrospective analysis of 1,226 Chinese patients with haemophilia in a single medical centre.

Haemophilia A (HA) and B (HB) are X-linked congenital disorders caused by deficiencies of Factor VIII and FIX. Being the world's most populous country, China potentially has a large population of haemophilia patients. During the last decade, no studies have been published regarding the clinical information of haemophilia in China. A retrospective study was conducted in patients with HA and HB referred to Tianjin Haemophilia Centre between 2002 and 2012. We identified 1,226 males with haemophilia (1,019 HA and 207 HB). The results revealed that activate partial thromboplastin time was negatively correlated plasma factor level of person with haemophilia. Our data did not offer sufficient evidence of any relationship existed between disease severity and risk or site of haemorrhage. There was a trend toward a higher inhibitor incidence induced by plasma-derived factor VIII products, than by recombinant FVIII (rFVIII) alone. It seemed that second generation of rFVIII more likely developed inhibitor, and first generation of rFVIII was nevertheless more closely connected to high-titer inhibitor. We found that delay in diagnosis and blood-borne infections were significantly reduced, while the joint deformity rate did not decrease despite the wide variety of products to choose from in this decade. The development of inhibitor still remains a major challenge in replacement therapy in haemophilia.

Lack of association between NR3C1 polymorphism and glucocorticoid resistance in Chinese patients with immune thrombocytopenia.

Resistance to glucocorticoids (GCs) is a tricky problem in therapy for immune thrombocytopenia (ITP). As GCs exert their effects through glucocorticoid receptor (GR), being a GR gene, NR3C1 is thought to connect with individual differences in GC responsiveness during GCs treatments. We analyzed the frequency of three novel single nucleotide polymorphisms (SNPs) of NR3C1 in ITP patients and evaluated the role of these genetic variants in GCs therapy. Four hundred and seventy-three patients with ITP and 160 healthy controls were recruited. Patients were allocated into GCs-responsive (n = 358) and -non-responsive group (n = 115). All subjects of the three groups were genotyped by the PCR-RFLP (restriction fragment length polymorphism) method for the BclI, N363S and ER22/23EK polymorphisms. Assess the statistical differences of genotypes between ITP and controls, and those between GCs- responsive and non-responsive groups. In healthy controls, BclI-GG/GC/CC occurred with 0.581/0.35/0.069 frequency. In ITP patients, BclI-GG/GC/CC was found with 0.617/0.353/0.03 frequency. There was no statistically differences between ITP and controls (p = 0.070). In GCs-responsive and -non-responsive group, BclI-GG, GC, CC occurred with frequencies of 0.628/0.352/0.02 and 0.583/0.357/0.061, respectively. No correlations in the variants of BclI was found between the GCs-responsive and -non-responsive group (p = 0.086). Neither N363S nor ER22/23EK polymorphism was observed in all 636 participants. The BclI polymorphism is not related to the response of GCs in patients with ITP. Furthermore, we did not observe N363S and ER22/23EK polymorphism in Chinese Han population.