Disrupted functional connectivity between sub-regions in the sensorimotor areas and cortex in migraine without aura.

BACKGROUND: Migraine is a severe and disabling brain disorder, and the exact neurological mechanisms remain unclear. Migraineurs have altered pain perception, and headache attacks disrupt their sensory information processing and sensorimotor integration. The altered functional connectivity of sub-regions of sensorimotor brain areas with other brain cortex associated with migraine needs further investigation. METHODS: Forty-eight migraineurs without aura during the interictal phase and 48 age- and sex-matched healthy controls underwent resting-state functional magnetic resonance imaging scans. We utilized seed-based functional connectivity analysis to investigate whether patients exhibited abnormal functional connectivity between sub-regions of sensorimotor brain areas and cortex regions. RESULTS: We found that patients with migraineurs without aura exhibited disrupted functional connectivities between the sensorimotor areas and the visual cortex, temporal cortex, posterior parietal lobule, prefrontal areas, precuneus, cingulate gyrus, sensorimotor areas proper and cerebellum areas compared with healthy controls. In addition, the clinical data of the patients, such as disease duration, pain intensity and HIT-6 score, were negatively correlated with these impaired functional connectivities. CONCLUSION: In patients with migraineurs without aura, the functional connectivities between the sensorimotor brain areas and other brain regions was reduced. These disrupted functional connectivities might contribute to abnormalities in visual processing, multisensory integration, nociception processing, spatial attention and intention and dysfunction in cognitive evaluation and modulation of pain. Recurrent headache attacks might lead to the disrupted network between primary motor cortex and temporal regions and between primary somatosensory cortex and temporal regions. Pain sensitivity and patient quality of life are closely tied to the abnormal functional connectivity between sensorimotor regions and other brain areas.

Cathepsin K Knockout Exacerbates Haemorrhagic Transformation Induced by Recombinant Tissue Plasminogen Activator After Focal Cerebral Ischaemia in Mice.

Severe haemorrhagic transformation (HT), a common complication of recombinant tissue plasminogen activator (rtPA) treatment, predicts poor clinical outcomes in acute ischaemic stroke. The search for agents to mitigate this effect includes investigating biomolecules involved in neovascularization. This study examines the role of Cathepsin K (Ctsk) in rtPA-induced HT after focal cerebral ischaemia in mice. After knockout of Ctsk, the gene encoding Ctsk, the outcomes of Ctsk+/+ and Ctsk-/- mice were compared 24 h after rtPA-treated cerebral ischaemia with respect to HT severity, neurological deficits, brain oedema, infarct volume, number of apoptotic neurons and activated microglia/macrophage, blood-brain barrier integrity, vascular endothelial growth factor (VEGF) expression and Akt-mTOR pathway activation. We observed that haemoglobin levels, brain oedema and infarct volume were significantly greater and resulted in more severe neurological deficits in Ctsk-/- than in Ctsk+/+ mice. Consistent with our hypothesis, the number of NeuN-positive neurons was lower and the number of TUNEL-positive apoptotic neurons and activated microglia/macrophage was higher in Ctsk-/- than in Ctsk+/+ mice. Ctsk knockout mice exhibited more severe blood-brain barrier (BBB) disruption, with microvascular endothelial cells exhibiting greater VEGF expression and lower ratios of phospo-Akt/Akt and phospo-mTOR/mTOR than in Ctsk+/+ mice. This study is the first to provide molecular insights into Ctsk-regulated HT after cerebral ischaemia, suggesting that Ctsk deficiency may disrupt the BBB via Akt/mTOR/VEGF signalling, resulting in neurological deficits and neuron apoptosis. Ctsk administration has the potential as a novel modality for improving the safety of rtPA treatment following stroke.

Plasma Levels of miR-125b-5p and miR-206 in Acute Ischemic Stroke Patients After Recanalization Treatment: A Prospective Observational Study.

INTRODUCTION: Multiple microRNAs (miRNAs) participate in the response to hypoxic/ischemic and ischemia-reperfusion events. However, the expression of these miRNAs in circulation from patients with acute ischemic stroke (AIS) receiving recanalization treatment has not been examined, and whether they are associated with the severity and outcome of stroke is still unknown. MATERIALS AND METHODS: In this prospective cohort study, plasma levels of miR-125b-5p, miR-15a-3p, miR-15a-5p, and miR-206 were measured at 24 hours after thrombolysis with or without endovascular treatment in 94 patients with AIS, as determined by qRT-PCR. Stroke severity was assessed based on National Institutes of Health Stroke Scale (NIHSS) score and infarct lesion. Intracranial haemorrhage (ICH) was recorded. An unfavorable outcome was defined as a modified Rankin Scale score greater than 2 at day 90 after stroke. RESULTS: miR-125b-5p and miR-206 levels were correlated with NIHSS scores (P = .014 and P = .002) and cerebral infarction volumes (P = .025 and P = .030). miR-125b-5p levels were significantly higher in patients with an unfavorable outcome than in patients with a favorable outcome (P = .002) and showed good diagnostic accuracy in discriminating the presence of an unfavorable outcome (area under the curve .735, 95% confidence interval .623-.829, P < .001). No association was found between different miRNAs and ICH. CONCLUSIONS: In AIS patients after thrombolysis with or without endovascular treatment, miR-125b-5p is a novel prognostic biomarker highly associated with an unfavorable outcome. miR-125b-5p and miR-206 levels are associated with stroke severity.

Structural changes of cerebellum and brainstem in migraine without aura.

BACKGROUND: Increasing evidence has suggested that the cerebellum is associated with pain and migraine. In addition, the descending pain system of the brainstem is the major site of trigeminal pain processing and modulation and has been discussed as a main player in the pathophysiology of migraine. Cerebellar and brainstem structural changes associated with migraineurs remain to be further investigated. METHODS: Voxel-based morphometry (VBM) (50 controls, 50 migraineurs without aura (MWoAs)) and diffusion tensor imaging (DTI) (46 controls, 46 MWoAs) were used to assess cerebellum and brainstem anatomical alterations associated with MWoAs. We utilized a spatially unbiased infratentorial template toolbox (SUIT) to perform cerebellum and brainstem optimized VBM and DTI analysis. We extracted the average diffusion values from a probabilistic cerebellar white matter atlas to investigate whether MWoAs exhibited microstructure alterations in the cerebellar peduncle tracts. RESULTS: MWoAs showed decreased fractional anisotropy (FA) in the vermis VI extending to the bilateral lobules V and VI of the cerebellum. We also found higher axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) in the right inferior cerebellum peduncle tract in MWoAs. MWoAs exhibited both reduced gray matter volume and increased AD, MD and RD in the spinal trigeminal nucleus (SpV). CONCLUSION: MWoAs exhibited microstructural changes in the cerebellum and the local brainstem. These structural differences might contribute to dysfunction of the transmission and modulation of noxious information, trigeminal nociception, and conduction and integration of multimodal information in MWoAs. These findings further suggest involvement of the cerebellum and the brainstem in the pathology of migraine without aura.

Association between carotid artery perivascular fat density and cerebral small vessel disease.

Studies aiming to identify the significance of the carotid artery perivascular fat density are limited. The present study investigated the distribution pattern of pericarotid fat and its association with imaging markers of cerebral small vessel disease (CSVD). In total, 572 subjects who underwent both neck computed tomography angiography and cranial magnetic resonance imaging were analyzed. The pericarotid fat density near the origin of the internal carotid artery (ICA) and imaging markers of CSVD, such as lacunes, white matter hyperintensities (WMHs) and dilated perivascular spaces (PVSs), were assessed. We found that an increased pericarotid fat density was associated with the presence of lacunes and a higher WMH grade in all subjects, but in the patients with acute ischemic stroke, there was a difference only among the WMH grades. There was no significant difference in the pericarotid fat density in different grades of PVSs. The patients with acute ischemic stroke had a significantly higher mean pericarotid fat density than those without stroke. In conclusion, our study provides evidence suggesting that an increased pericarotid fat density is associated with the presence and degree of WMHs and lacunes. Our findings suggested that features that appear to extend beyond the vessel lumen of the ICA may be linked to CSVD.

DNA Methylation Analysis Identifies Differentially Methylated Sites Associated with Early-Onset Intracranial Atherosclerotic Stenosis.

AIM: Studies have suggested that genetic and environmental factors do not account for all risks and mechanisms of intracranial atherosclerotic stenosis (ICAS). DNA methylation may play a role in the progression of ICAS. METHODS: DNA methylation profiles of peripheral blood leucocytes from 7 patients with early-onset ICAS and 7 perfectly matched controls were interrogated for the first time using the Illumina Infinium Human MethylationEPIC BeadChip. Afterward, functional analysis for differentially methylated genes was conducted. In addition, pyrosequencing verification was performed in an independent cohort comprising 21 patients with early-onset ICAS and 21 age- and gender-matched controls. RESULTS: A total of 318 cytosine-phosphate-guanine sites were found to be differentially methylated based on the established standards. Functional analysis annotated differentially methylated sites to atherosclerosis-related processes and pathways, such as the negative regulation of hydrolase activity (GO 0051346), type II diabetes mellitus (KEGG hsa04930), and the insulin signaling pathway (KEGG hsa04910). In addition, a differentially methylated site was also validated, cg22443212 in gene Rnf213, which showed significant hypermethylation in patients with early-onset ICAS compared with controls 59.56% (49.77%, 88.55%) vs. 44.65% (25.07%, 53.21%), respectively; P=0.010). Receiver operating characteristic curve analysis showed that the area under the curve value of cg22443212 was 0.744 (95% confidence interval, 0.586-0.866; P=0.002). CONCLUSIONS: We revealed that altered DNA methylation may play a role in the occurrence and development of ICAS. These results provided new epigenetic insights into ICAS.

Altered Spontaneous Activity and Functional Connectivity in the Posterior Pons of Patients With Migraine Without Aura.

The brainstem has been discussed as the main player in the pathogenesis of migraine. Dysfunctional brainstem nuclei and their abnormal connections to other key brain centers may contribute to headache and other symptoms of migraine. In the present study, 32 patients with migraine without aura (MWoA) and 32 age- and sex-matched healthy controls (HCs) underwent resting-state fMRI scans. We used masked independent analysis (mICA) to investigate whether patients with MWoA exhibited abnormal brainstem nuclei-cortical functional connectivity (FC). The mICA can suppress adjacent physiological noise and prevent results from being driven by the much stronger signals of the surrounding structures. Regional homogeneity (ReHo) was used to investigate whether the brainstem regions with abnormal FC to other brain areas exhibited abnormal regional neuronal activity. Patients with MWoA showed significantly weaker FC between the posterior pons and the left superior parietal lobule, the left middle temporal gyrus, and the left middle frontal gyrus. Furthermore, patients with MWoA exhibited significantly decreased ReHo values in the posterior pons compared with HCs, and the posterior pons ReHo value was significantly negatively correlated with HIT-6 scores in the MWoA group. Patients with MWoA exhibited functional abnormalities in the posterior pons and weakened connections between the posterior pons and several key cortical brain areas involved in pain processing during the resting state. PERSPECTIVE: This study provided increased evidence that the pons is involved in the pathophysiological mechanism of migraine, and weakened connections suggest that the touch and pain sensation of migraine sufferers may not be properly relayed to cortical processing areas, which may be associated with the pathogenesis of MWoA.

Higher Platelet-to-Lymphocyte Ratio Is Associated With Worse Outcomes After Intravenous Thrombolysis in Acute Ischaemic Stroke.

Objective: The platelet-to-lymphocyte ratio (PLR) is a new marker of atherosclerotic inflammation and has been identified as a predictive factor in cardiovascular diseases, but its significance in patients with acute ischaemic stroke (AIS) who have undergone intravenous thrombolysis (IVT) is still unknown. Methods: Consecutive patients who were treated with IVT using recombinant tissue plasminogen activator (rtPA) for AIS were included from May 2012 to August 2018. The PLR was calculated according to platelet and lymphocyte counts within 24 h after thrombolysis therapy. Functional outcomes were assessed by the modified Rankin Scale (mRS) at 3 months after thrombolysis. Stroke severity was assessed by National Institutes of Health Stroke Scale (NIHSS) scores. The primary endpoint was an unfavorable outcome (mRS > 2), and the secondary endpoint was death at 3 months. Results: A total of 286 patients were included in the study. The median age was 69.5 (59.0-80.0) years, and 59.1% of patients were men. A total of 120 (42.0%) patients had an unfavorable outcome, and 38 (13.2%) died. Patients with an unfavorable outcome had significantly higher PLR values compared with those with a favorable outcome [172.5 (105.3-239.0) vs. 139 (97.0-194.5), P = 0.008], and the PLR values of the patients who died at 3 months were higher than those of the surviving patients [189.5 (127.5-289.0) vs. 142.0 (98.0-215.5), P = 0.006]. After adjustment for other variables, the PLR was independently associated with the two endpoints: unfavorable outcome (OR 2.220, 95% CI 1.245-3.957, P = 0.007) and death (OR 2.825, 95% CI 1.050-7.601, P = 0.040) at 3 months after thrombolysis. In addition, PLR was correlated with the NIHSS score (R = 0.230, P < 0.001). Conclusions: Higher PLR levels were independently associated with an unfavorable outcome and death at 3 months in AIS patients treated with IVT.

Increased plasma levels of miR-124-3p, miR-125b-5p and miR-192-5p are associated with outcomes in acute ischaemic stroke patients receiving thrombolysis.

BACKGROUND AND AIMS: Circulating microRNAs (miRNAs) have recently emerged as promising biomarkers for acute ischaemic stroke (AIS). However, the expression profiles of miRNAs in AIS patients receiving intravenous thrombolysis, and their associations with outcome have not been investigated. METHODS: In a prospective cohort study, a total of 84 AIS patients, who received intravenous thrombolysis (21.4% received combined reperfusion therapy) and completed 3 month follow-up visits, were included. Favourable and unfavourable outcomes were defined as modified Rankin Scale (mRS) scores of 0-1 and 2-6, respectively. Plasma samples were collected at 24 h after thrombolysis. We used RNA sequencing to study miRNA profiles in 5 patients with unfavourable outcomes and 5 matched patients with favourable outcomes. Differentially expressed miRNAs were further validated in all cohorts using quantitative real-time polymerase chain reaction assays. RESULTS: After identification and validation, we found that miR-124-3p, miR-125b-5p and miR-192-5p levels were higher in patients with unfavourable outcomes than in patients with favourable outcomes. Logistic regressions and receiver-operating characteristic curve analyses demonstrated that these altered miRNAs may function as predictive biomarkers for outcome in AIS patients receiving thrombolysis, whether combined with endovascular thrombectomy or not. In addition, miR-124-3p and miR-125b-5p were closely associated with stroke severity. CONCLUSIONS: A set of circulating microRNAs (miR-124-3p, miR-125b-5p and miR-192-5p) are associated with unfavourable 3 month outcomes and might have clinical utility in AIS patients receiving thrombolysis.

Lack of Correlation Between Intracranial Carotid Artery Modified Woodcock Calcification Score and Prognosis of Patients With Acute Ischemic Stroke After Intravenous Thrombolysis.

There have been few studies about the association between intracranial carotid artery calcification (ICAC) and acute ischemic stroke (AIS) prognosis after intravenous thrombolysis (IVT). We aimed to analyze the association between ICAC and prognosis (including symptomatic intracranial hemorrhage (sICH), functional outcome and death) of AIS patients treated with IVT. In this retrospective study, we consecutively included 232 AIS patients treated with IVT between April 2012 and December 2018. ICAC was evaluated using the modified Woodcock calcification visual score on non-enhanced cranial computed tomography scans. Poor functional outcome was defined as a modified Rankin Scale score > 2 at 3 months. We found that the modified Woodcock calcification score was associated with ICH, poor outcome, and death in univariable analyses on the symptomatic side and/or bilaterally. However, after adjustment for other different covariates, the results showed no significant difference. We documented that the presence and severity of ICAC did not significantly modify the beneficial effects of rtPA treatment in AIS.

Comprehensive analysis of differentially expressed profiles of long non-coding RNAs and messenger RNAs in kaolin-induced hydrocephalus.

BACKGROUNDS: The pathophysiology of hydrocephalus induced brain damage remains unclear. Long non-coding RNAs (lncRNAs) have been demonstrated to be implicated in many central nervous system diseases. However, the roles of lncRNAs in hydrocephalus injury are poorly understood. METHODS: The present study depicted the expression profiles of lncRNAs and messenger RNAs (mRNAs) in C57BL/6 mice with kaolin-induced hydrocephalus and saline controls using high-throughput RNA sequencing. Afterward, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify potential targets that correlated with hydrocephalus. In addition, co-expression networks and cis- and trans-regulation were predicted using bioinformatics methods. Finally, representative lncRNAs and mRNAs were further validation using quantitative real-time polymerase chain reaction. RESULTS: A total of 1575 lncRNAs and 1168 mRNAs were differentially expressed (DE) in hydrocephalus. GO and KEGG analyses indicated several immune and inflammatory response-associated pathways may be important in the hydrocephalus. Besides, functional enrichment analysis based on co-expression network showed several similar pathways, such as chemokine signaling pathway, phagosome, MAPK signaling pathway and complement and coagulation cascade. Cis-regulation prediction revealed 5 novel lncRNAs might regulate their nearby coding genes, and trans-regulation revealed several lncRNAs participate in pathways regulated by transcription factors, including BPTF, FOXM1, NR5A2, P2RX5, and NR6A1. CONCLUSIONS: In conclusion, our results provide candidate genes involved in hydrocephalus and suggest a new perspective on the modulation of lncRNAs in hydrocephalus.

Cerebellar functional abnormalities in early stage drug-naïve and medicated Parkinson's disease.

Parkinson's disease (PD) is a progressive neurological degenerative disorder characterized by impaired motor function and non-motor dysfunctions. While recent studies have highlighted the role of the cerebellum in PD, our understanding of its role in PD remains limited. In the present study, we used resting-state fMRI to evaluate dysfunctions within the cerebellum in PD patients treated with medication and drug-naïve PD patients. We applied amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) analysis methods. Thirty-one patients with early stage PD (22 drug-naïve and 9 medicated patients) and 31 gender- and age-matched healthy controls were recruited in this study. ALFFs increased in the left cerebellar areas (lobules VI/VIIb/CruI/CruII and the dentate gyrus) and right cerebellar areas (lobules VI/VIIb/VIIIa/CruI/CruII and the dentate gyrus) of all PD patients and in the left and right cerebellar areas (lobules VI/VIIb/CruI and the dentate gyrus) of drug-naive PD patients but were not significantly changed in medicated PD patients. DC increased in the right cerebellar areas of all PD patients and medicated PD patients. All PD patients and all drug-naive PD patients showed significantly weaker functional connectivity (FC) between the left cerebellum and the left medial frontal gyrus. However, FC was significantly stronger between the right cerebellum and the left precentral and right middle occipital gyri in the medicated PD patients than in controls. Furthermore, a correlation analyses revealed that ALFF z scores in the left cerebellum (lobule VI) and right cerebellum (lobule VI/CruI and dentate gyrus) were negatively correlated with Mini-Mental State Examination (MMSE) scores in all PD patients and drug-naive patients. These results indicate that the cerebellum plays an important role in PD, mainly by exerting a compensatory effect in early stage PD. Additionally, antiparkinsonian medication would modified PD-induced changes in local neural activity and FC in PD patients. The results of this study offer novel insights into the roles of the cerebellum in early stage drug-naïve PD.

Serum levels of endocan and endoglin are associated with large-artery atherosclerotic stroke.

BACKGROUND: Accumulating evidence has suggested that endocan and endoglin may play important roles in cardiovascular disease. However, no previous study has focused on these circulating levels in patients with large-artery atherosclerotic (LAA) stroke. METHODS: Serum levels of endocan and endoglin in 114 patients with LAA stroke and 114 age- and sex-matched controls were measured by ELISA. Serum samples from patients were available on day 1, day 6 and in the 4th week after ischaemic stroke(IS). Stroke severity was determined based on the NIHSS score and the stroke volume. An unfavourable outcome was defined as a mRS score>2 on day 90 after IS. RESULTS: The endocan levels were significantly higher in patients with LAA stroke compared with the controls (p=0.001), and after adjustment for other factors (p=0.001). In addition, higher endocan levels were independently associated with unfavourable outcomes on both day 1 and day 6 after IS (p=0.018 and p=0.011). Endoglin levels were decreased on day 6 (p=0.002) and then recovered in the 4th week after IS. No correlation was found between endocan or endoglin and stroke severity. CONCLUSIONS: Endocan levels are higher in patients with LAA stroke and can help in predicting the short-term unfavourable outcome. Endoglin levels are changed after stroke.

Brain functional changes in patients with botulism after illegal cosmetic injections of botulinum toxin: A resting-state fMRI study.

BACKGROUND: Botulinum toxin type A (BoNT-A) is generally considered safe and is widely used to treat a variety of clinical conditions involving muscle hyperactivity and for cosmetic purposes. However, the effects of BoNT-A poisoning (botulism) on brain function are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we investigated brain functions in 9 patients who received illegal cosmetic injections of botulinum and 18 matched controls by combining the analysis methods of regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) based on resting-state fMRI. Compared with the controls, the patients with botulism exhibited significantly reduced ReHo values in the left posterior lobe of the cerebellum extending to the right anterior lobe of the cerebellum, as well as in the right anterior lobe of the cerebellum extending to the parahippocampal gyrus and right posterior lobe of the cerebellum. The patients with botulism also showed weakened ALFF values in the right anterior lobe of the cerebellum extending to the left anterior lobe of the cerebellum and right posterior lobe of the cerebellum, as well as in the right anterior lobe of the cerebellum. CONCLUSIONS/SIGNIFICANCE: The results indicate that BoNT-A may modulate cerebral activation in specific areas, which may play roles in both the adverse effects of botulism and the mechanism underlying clinical treatment with BoNT-A.

Rivaroxaban does not influence hemorrhagic transformation in a diabetes ischemic stroke and endovascular thrombectomy model.

Managing endovascular thrombectomy (ET) in diabetic ischemic stroke (IS) with novel anticoagulants is challenging due to putative risk of intracerebral hemorrhage. The study evaluates increased hemorrhagic transformation (HT) risk in Rivaroxaban-treated diabetic rats post ET. Diabetes was induced in male Sprague-Dawley rats by intraperitoneal injection of 60 mg/kg streptozotocin. After 4-weeks, rats were pretreated orally with 30 mg/kg Rivaroxaban/saline; prothrombin time was monitored. IS and ET was induced after 1 h, by thread-induced transient middle cerebral artery occlusion (tMCAO) that mimicked mechanical ET for proximal MCA occlusion at 60 min. After 24 h reperfusion, infarct volumes, HT, blood-brain barrier (BBB) permeability, tight junction at peri-ischemic lesion and matrix metalloproteinase-9 (MMP-9) activity was measured. Diabetic rats seemed to exhibit increased infarct volume and HT at 24 h after ET than normal rats. Infarct volumes and functional outcomes did not differ between Rivaroxaban and diabetic control groups. A significant increase in HT volumes and BBB permeability under Rivaroxaban treatment was not detected. Compared to diabetic control group, neither the occludin expression was remarkably lower in the Rivaroxaban group nor the MMP-9 activity was higher. Together, Rivaroxaban does not increase HT after ET in diabetic rats with proximal MCA occlusion, since Rivaroxaban has fewer effects on post-ischemic BBB permeability.

Serum levels of galectin-1, galectin-3, and galectin-9 are associated with large artery atherosclerotic stroke.

The aim of this study was to assess the expression patterns of serum galectin-1 (Gal-1), galectin-3 (Gal-3), galectin-9 (Gal-9), and galectin-3 binding protein (Gal-3BP) and their associations with stroke outcome in large artery atherosclerotic (LAA) stroke. The serum levels of Gal-1, Gal-3, Gal-9, and Gal-3BP were measured by ELISA in 130 patients with LAA stroke and 130 age- and sex-matched controls. Serum samples were collected from the patients on day 1, day 6, and in the 4th week after ischaemic stroke (IS). An unfavourable outcome was defined as a modified Rankin Scale score of >2 on day 90 after IS. Our results indicated that the Gal-3 and Gal-9 levels were higher in patients with LAA stroke than in controls. A higher Gal-3 level was independently associated with an unfavourable outcome both on day 1 and day 6 after IS. In addition, Gal-9 and Gal-1 levels were upregulated on day 6 and in the 4th week after IS, respectively. For Gal-3BP, no difference was detected between patients and controls and no predictive value was found in patients. In conclusion, these findings suggest that the serum levels of Gal-1, Gal-3, and Gal-9 may be associated with LAA stroke.

Anti-atherosclerotic potential of baicalin mediated by promoting cholesterol efflux from macrophages via the PPARγ-LXRα-ABCA1/ABCG1 pathway.

BACKGROUND: Atherosclerosis (AS) is associated with severe cardiovascular disease. The anti-inflammatory, anti-oxidation, and lipid regulating properties of baicalin suggest potential as an anti-atherosclerotic agent. We therefore investigated whether baicalin can protect against the development of atherosclerosis in an AS rabbit model and explored the underling mechanisms in THP-1 macrophages. METHODS AND RESULTS: In vivo, treatment with baicalin markedly decreased atherosclerotic lesion sizes and lipid accumulation in AS rabbit carotid arteries. Western blotting revealed that the protein expression levels of both peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptor alpha (LXRα) were up-regulated in the baicalin group compared with the model group. In vitro, baicalin restricted oxidized-low density lipoprotein (ox-LDL)-induced intracellular lipid accumulation and foam cell formation in THP-1 macrophages. Molecular data showed that baicalin significantly increased the expression levels of PPARγ, LXRα, ATP binding cassette transporters (ABC) A1 and ABCG1. Cell transfection experiments (including PPARγ and LXRα siRNAs) suggested that the effects of baicalin are mediated by the PPARγ-LXRα signalling pathway, which stimulates the expression of ABCA1 and ABCG1. CONCLUSION: These results suggest that baicalin potentially exerts anti-atherosclerosis effects, possibly through the PPARγ-LXRα-ABCA1/ABCG1 pathway, by promoting efflux of cholesterol from macrophages and delaying the formation of foam cells.

High serum levels of sclerostin and Dickkopf-1 are associated with acute ischaemic stroke.

BACKGROUND AND AIMS: Sclerostin and Dickkopf-1 (Dkk-1) are potent antagonists of Wnt signalling and might therefore play important roles in cardiovascular disease. We investigated whether serum sclerostin and Dkk-1 levels are associated with acute ischaemic stroke and specific stroke subtypes. METHODS: Serum levels of sclerostin and Dkk-1 were measured by ELISA on day 1 and on day 6 after stroke in 62 patients with large artery atherosclerotic (LAA) stroke, on day 1 after stroke in 62 age- and gender-matched patients with small-artery occlusion (SAO) stroke and on admission in 62 healthy controls. Stroke severity was determined based on the National Institutes of Health Stroke Scale (NIHSS) and by measuring stroke volume on diffusion-weighted imaging. Outcome was measured by the modified Rankin Scale (mRS) on day 90. RESULTS: Compared with controls, serum sclerostin and Dkk-1 levels were significantly higher in both patients with LAA stroke and with SAO stroke, and no difference was detected between the stroke subtypes. Sclerostin and Dkk-1 levels remained stable between the first and sixth day after stroke in the patients with LAA stroke. Receiver operating characteristic curve analysis was used to evaluate sclerostin and Dkk-1 as markers of a high risk of stroke and produced area under curve values of 0.773 and 0.776. Adjusted logistic regression showed that serum sclerostin and Dkk-1 levels remained as independent markers of stroke. No correlations were found between sclerostin or Dkk-1 levels and stroke severity or stroke outcome. CONCLUSIONS: High serum levels of sclerostin and Dkk-1 are associated with acute ischaemic stroke.

Angiopoietin-like protein 4 serum levels and gene polymorphisms are associated with large artery atherosclerotic stroke.

BACKGROUND: Angiopoietin-like protein 4 (ANGPTL4) is a central player in lipid metabolism and atherosclerosis and may thus be involved in ischaemic stroke. However, no study in humans has investigated the association of ANGPTL4 gene polymorphisms or serum levels with ischaemic stroke. METHODS: We investigated the influence of the tagged single nucleotide polymorphisms (tSNPs) rs4076317 (c.207C>G) and rs1044250 (c.797C>T; T266M) of the ANGPTL4 gene on ischaemic stroke risk in a large group of 712 large artery atherosclerotic (LAA) stroke patients and 828 controls. In addition, we examined the association of the serum ANGPTL4 levels with lipid metabolism, LAA stroke severity and ischaemic volume in a sample of 302 LAA stroke patients and 307 controls. RESULTS: The findings reveal that rs4076317 exerts a co-dominant effect on lower serum TG levels compared with common homozygotes. Fewer stroke cases were homozygous for variants of rs4076317 compared with the controls (7.0% vs. 10.9%). The serum ANGPTL4 levels in patients were significantly higher than those in the controls in a univariate manner (P=0.001) and after adjustment for other risk factors (1.463 [1.215-1.835]; P<0.001). Consistently, the ANGPTL4 levels were statistically correlated with higher NIHSS scores (r=0.172, P=0.003) and larger lesion volumes (r=0.124, P=0.031). CONCLUSION: We concluded that the tagged SNPs and high serum levels of ANGPTL4 are associated with LAA stroke and the lipid characteristics.

Histochemical studies on intestinal metaplasia adjacent to gastric cardia adenocarcinoma in subjects at high-incidence area in Henan, north China.

AIM: To characterize the histochemical type and pattern of intestinal metaplasia (IM) adjacent to gastric cardia adenocarcinoma (GCA) and distal gastric cancer (GC) in Linzhou, Henan Province, China. METHODS: Alcian-blue-periodic acid Schiff and high iron diamine-Alcian blue histochemical methods were performed on 142 cases of IM, including 49 cases of GCA and 93 cases of GC. All the patients were from Linzhou, Henan Province, China, the highest incidence area for both GCA and squamous cell carcinoma. Radio- or chemotherapy was not applied to these patients before surgery. RESULTS: The detection rate of IM in tissues adjacent to GCA tissues was 44.9%, which was significantly lower than that in GC tissues (80.64%, P<0.01). The rates of both incomplete small intestinal and colonic IM types identified by histochemistry in GCA tissues (31.82% and 63.64%, respectively) were significantly higher than those in GC (5.33% and 21.33%, respectively, P<0.01). CONCLUSION: IM in GCA and GC should be considered as a separate entity. Further research is needed to evaluate whether neoplastic progression of IM is related to its mucin profile in GCA.