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Abstract Background Total knee replacement (TKA) is a frequent modality performed in patients with knee osteoarthritis (OA). The aim of this study was to perform a meta-analysis and systematic review to evaluate the efficacy after TKA by gait analysis in patients with OA. Methods PubMed, EMBASE, the Cochrane library, and Web of Science were searched for relevant studies from inception to July 2024. STATA SE 14.0 software was used for statistical analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guideline. Results A total of 2525 reports were identified with 24 studies meeting pre-designed inclusion criteria. Several gait parameters were investigated. In patients with knee OA after TKA, there existed an increase in the Max knee flexion (WMD, 3.12; 95% CI, 0.93 to 5.32; I2 = 73.9%, P

Background Changes in levels of hemoglobin would result in alterations of cerebral blood flow (CBF). However, the impact of hemoglobin on CBF in moyamoya disease (MMD) remains largely unknown. This study sought to determine whether CBF would be influenced by hemoglobin before surgical revascularization and to analyze the relationships between hemoglobin and CBF with clinical outcome after surgery in patients with MMD. Methods and Results We prospectively enrolled adult patients with MMD undergoing surgical revascularization between June 2020 and December 2022. Preoperative CBF was measured in the territories of anterior, middle, and posterior cerebral arteries (ACA, MCA, and PCA, respectively) using 3‐dimensional pseudo‐continuous arterial spin labeling magnetic resonance imaging. Clinical outcome at 1 year after surgery was evaluated using the modified Rankin Scale. A total of 60 patients with MMD were included, with 25% (n=15) experiencing unfavorable outcomes. Patients with MMD exhibited lower CBF (ACA: P=0.007; MCA: P

Abstract Background Glymphatic dysfunction is a crucial pathway for dementia. Alzheimer’s disease (AD) pathologies co-existing with cerebral small vessel disease (CSVD) is the most common pathogenesis for dementia. We hypothesize that AD pathologies and CSVD could be associated with glymphatic dysfunction, contributing to cognitive impairment. Method Participants completed with amyloid PET, diffusion tensor imaging (DTI), and T2 fluid-attenuated inversion-recovery (FLAIR) sequences were included from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). White matter hyperintensities (WMH), the most common CSVD marker, was evaluated from T2FLAIR images and represented the burden of CSVD. Amyloid PET was used to assess Aβ aggregation in the brain. We used diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, the burden of enlarged perivascular spaces (PVS), and choroid plexus volume to reflect glymphatic function. The relationships between WMH burden/Aβ aggregation and these glymphatic markers as well as the correlations between glymphatic markers and cognitive function were investigated. Furthermore, we conducted mediation analyses to explore the potential mediating effects of glymphatic markers in the relationship between WMH burden/Aβ aggregation and cognition. Results One hundred and thirty-three participants along the AD continuum were included, consisting of 40 CN − , 48 CN + , 26 MCI + , and 19 AD + participants. Our findings revealed that there were negative associations between whole-brain Aβ aggregation (r = − 0.249, p = 0.022) and WMH burden (r = − 0.458, p

Abstract. Background:. Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia. In addition to systemic immune/inflammatory effects in response to tumor progression, tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss. However, the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood. Methods:. The yki-gut tumors were induced in fruit flies. Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3 (IGFBP-3) treated cells. Immunoblotting was used to display phenotypes of tumor cells and adipocytes. Quantitative polymerase chain reaction (qPCR) analysis was carried out to examine the gene expression levels such as Acc1, Acly, and Fasn et al . Results:. In this study, it was revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes. IGFBP-3, which is highly expressed in cachectic tumor cells, antagonized insulin/IGF-like signaling (IIS) and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes. Conditioned medium from cachectic tumor cells, such as Capan-1 and C26 cells, contained excessive IGFBP-3 that potently induced lipolysis in adipocytes. Notably, neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes. Furthermore, cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS, ensuring their escape from IGFBP-3-associated growth suppression. Finally, cachectic tumor-derived ImpL2, the IGFBP-3 homolog, also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila. Most importantly, IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients, especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients. Conclusion:. Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.

ObjectiveTo develop and validate radiomics models on non-enhanced CT for discrimination of arteriovenous malformation (AVM) related hematomas from hypertensive intracerebral hematomas.Materials and methodsA total of 571 patients with acute intraparenchymal hematomas and baseline non-enhanced CT scans were retrospectively analyzed, including 297 cases of AVM related hematomas and 274 cases of hypertensive intracerebral hematomas. The patients were divided into training and validation cohorts in a 7:3 ratio with a random seed. A total of 1,688 radiomics features of hematomas were extracted from non-enhanced CT. Then, the least absolute shrinkage and selection operator (LASSO) regression was applied to select features and construct the radiomics models. In this study, a radiomics-based model was constructed that based on the radiomics features only. Furthermore, a combined model was constructed using radiomics features, clinical characteristics and radiological signs by radiologists’ evaluation. In addition, we compared predictive performance of the two models for discrimination of AVM related hematomas from hypertensive intracerebral hematomas.ResultsA total of 67 radiomics features were selected to establish radiomics signature via LASSO regression. The radiomics-based model was constructed with 2 classifiers, support vector machine (SVM) and logistic regression (LR). AUCs of the radiomics-based model in the training set were 0.894 and 0.904, in validation set were 0.774 and 0.782 in SVM classifier and LR classifier, respectively. AUCs of the combined model (combined with radiomics, age and calcification) in the training set were 0.976 and 0.981, in validation set were 0.896 and 0.907 in SVM classifier and LR classifier, respectively. The combined model showed greater AUCs than radiomics-based model in both training set and validation set.ConclusionThe combined model using radiomics, age and calcification showed a satisfactory predictive performance for discrimination of AVM related hematomas from hypertensive intracerebral hematomas and hold great potential for personalized clinical decision.

Senile osteoporosis (SOP) is a prevalent manifestation of age-related bone disorders, resulting from the dysregulation between osteoblast (OB)-mediated bone formation and osteoclast (OC)-mediated bone resorption, coupled with the escalating burden of cellular senescence. Traditional Chinese medicine (TCM) herbs, renowned for their remarkable attributes encompassing excellent tolerability, low toxicity, heightened efficacy, and minimal adverse reactions, have gained considerable traction in OP treatment. Emerging evidence substantiates the therapeutic benefits of various TCM formulations and their active constituents, including Zuogui wan, Fructus Ligustri Lucidi, and Resveratrol, in targeting cellular senescence to address SOP. However, a comprehensive review focusing on the therapeutic efficacy of TCM against SOP, with a particular emphasis on senescence, is currently lacking. In this review, we illuminate the pivotal involvement of cellular senescence in SOP and present a comprehensive exploration of TCM formulations and their active ingredients derived from TCM, delineating their potential in SOP treatment through their anti-senescence properties. Notably, we highlight their profound effects on distinct aging models that simulate SOP and various senescence characteristics. Finally, we provide a forward-looking discussion on utilizing TCM as a strategy for targeting cellular senescence and advancing SOP treatment. Our objective is to contribute to the unveiling of safer and more efficacious therapeutic agents for managing SOP.

Abstract Background Chemokine CXC motif receptor 7 (CXCR7) is an atypical G protein-coupled receptor (GPCR) that signals in a biased fashion. CXCL12/CXCR7 biased signal has been reported to play crucial roles in multiple stages of colorectal cancer (CRC). However, the mechanism of CXCL12/CXCR7 biased signal in promoting CRC progression and metastasis remains obscure. Results We demonstrate that CXCR7 activation promotes EMT and upregulates the expression of Vimentin and doublecortin-like kinase 1 (DCLK1) in CRC cells with concurrent repression of miR-124-3p and miR-188-5p through YAP1 nuclear translocation. Cell transfection and luciferase assay prove that these miRNAs regulate EMT by targeting Vimentin and DCLK1. More importantly, CXCL12/CXCR7/β-arrestin1-mediated biased signal induces YAP1 nuclear translocation, which functions as a transcriptional repressor by interacting with Yin Yang 1 (YY1) and recruiting YY1 to the promoters of miR-124-3p and miR-188-5p. Pharmacological inhibitor of YAP1 suppresses EMT and tumor metastasis upon CXCR7 activation in vivo in tumor xenografts of nude mice and inflammatory colonic adenocarcinoma models. Clinically, the expression of CXCR7 is positively correlated with nuclear YAP1 levels and EMT markers. Conclusions Our studies reveal a novel mechanism and clinical significance of CXCL12/CXCR7 biased signal in promoting EMT and invasion in CRC progression. These findings highlight the potential of targeting YAP1 nuclear translocation in hampering CXCL12/CXCR7 biased signal-induced metastasis of colorectal cancer.

Abstract C-X-C motif chemokine receptor 7 (CXCR7) is a newly discovered atypical chemokine receptor that binds to C-X-C motif chemokine ligand 12 (CXCL12) with higher affinity than CXCR4 and is associated with the metastasis of colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs) have been known to promote tumor progression. However, whether CAFs are involved in CXCR7-mediated metastasis of CRC remains elusive. We found a significant positive correlation between CXCR7 expression and CAF activation markers in colonic tissues from clinical specimens and in villin-CXCR7 transgenic mice. RNA sequencing revealed a coordinated increase in the levels of miR-146a-5p and miR-155-5p in CXCR7-overexpressing CRC cells and their exosomes. Importantly, these CRC cell-derived miR-146a-5p and miR-155-5p could be uptaken by CAFs via exosomes and promote the activation of CAFs through JAK2–STAT3/NF-κB signaling by targeting suppressor of cytokine signaling 1 (SOCS1) and zinc finger and BTB domain containing 2 (ZBTB2). Reciprocally, activated CAFs further potently enhanced the invasive capacity of CRC cells. Mechanistically, CAFs transfected with miR-146a-5p and miR-155-5p exhibited a robust increase in the levels of inflammatory cytokines interleukin-6, tumor necrosis factor-α, transforming growth factor-β, and CXCL12, which trigger the epithelial–mesenchymal transition and pro-metastatic switch of CRC cells. More importantly, the activation of CAFs by miR-146a-5p and miR-155-5p facilitated tumor formation and lung metastasis of CRC in vivo using tumor xenograft models. Our work provides novel insights into CXCR7-mediated CRC metastasis from tumor–stroma interaction and serum exosomal miR-146a-5p and miR-155-5p could serve as potential biomarkers and therapeutic targets for inhibiting CRC metastasis.

Abstract Background White matter hyperintensities (WMHs) are one of the hallmarks of cerebral small vessel disease (CSVD), but the pathological mechanisms underlying WMHs remain unclear. Recent studies suggest that extracellular fluid (ECF) is increased in brain regions with WMHs. It has been hypothesized that ECF accumulation may have detrimental effects on white matter microstructure. To test this hypothesis, we used cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as a unique CSVD model to investigate the relationships between ECF and fiber microstructural changes in WMHs. Methods Thirty-eight CADASIL patients underwent 3.0 T MRI with multi-model sequences. Parameters of free water (FW) and apparent fiber density (AFD) obtained from diffusion-weighted imaging (b = 0 and 1000 s/mm2) were respectively used to quantify the ECF and fiber density. WMHs were split into four subregions with four levels of FW using quartiles (FWq1 to FWq4) for each participant. We analyzed the relationships between FW and AFD in each subregion of WMHs. Additionally, we tested whether FW of WMHs were associated with other accompanied CSVD imaging markers including lacunes and microbleeds. Results We found an inverse correlation between FW and AFD in WMHs. Subregions of WMHs with high-level of FW (FWq3 and FWq4) were accompanied with decreased AFD and with changes in FW-corrected diffusion tensor imaging parameters. Furthermore, FW was also independently associated with lacunes and microbleeds. Conclusions Our study demonstrated that increased ECF was associated with WM degeneration and the occurrence of lacunes and microbleeds, providing important new insights into the role of ECF in CADASIL pathology. Improving ECF drainage might become a therapeutic strategy in future.

AimWhite matter hyperintensities (WMH) and lacunes were important features of cerebral small vessel disease (CSVD), which contributes to 25% of ischemic strokes and 45% of dementias. Currently, the underlying mechanisms of WMH and lacunes are not clear, and the role of hemodynamic changes is not fully investigated. In this study, we aimed to measure the cerebral blood flow (CBF) and arterial transit in CSVD patients and to investigate their association with WMH and lacunes.MethodsWe retrospectively analyzed the prospectively collected database of CSVD patients. Ninety-two CSVD patients with complete imaging data were included. We used arterial spin labeling (ASL) with post-labeling delay time (PLD) of 1,525 ms and 2,025 ms to measure CBF respectively, and the difference between CBFPLD1.5 and CBFPLD2.0 was recorded as δCBF. We performed regression analysis to understand the contribution of CBF, δCBF to CSVD imaging markers.ResultsWe found that CBF derived from both PLDs was associated with WMH volume and the presence of lacune. CBFPLD1.5 was significantly lower than CBFPLD2.0 in CSVD patients, and δCBF was correlated with WMH volume but not the presence of lacune. Furthermore, CBFPLD2.0 and δCBF were both associated with WMH in multiple regression analyses, suggesting an independent effect of delayed arterial transit. On an exploratory basis, we also investigated the relationship between venous disruption on δCBF, and we found that δCBF correlated with deep medullary veins score.ConclusionBoth CBF and arterial transit were associated with WMH. ASL with multiple PLDs could provide additional hemodynamic information to CSVD-related studies.

Background: Small vessel disease (SVD) is highly prevalent in the elderly and associated with an increased risk of dementia and stroke. SVD may have disturbed cerebrospinal fluid (CSF) flow, which can compromise waste clearance and accelerate disease progression. Methods: We retrospectively included 146 SVD patients from a prospectively collected dataset, with one- or two-year follow-up data in 61 patients. The coupling strength between the global blood-oxygen-level-dependent (gBOLD) signal and CSF inflow was used to reflect CSF dynamics. We performed regression analyses to investigate the association between the gBOLD-CSF coupling index and the severity of SVD and vascular risk factors. Longitudinal analysis was carried out to investigate causal relationships. Results: Patients with severe SVD had significantly decreased gBOLD-CSF coupling (β = −0.180, p = 0.032). Dilation of perivascular spaces in the basal ganglia area (β = −0.172, p = 0.033) and diabetes (β = −0.204, p = 0.014) were associated with reduced gBOLD-CSF coupling. In longitudinal analyses, diabetes was associated with faster decline in gBOLD-CSF coupling (β = 0.20, p = 0.039), while perivascular space (PVS) dilation in the centrum semiovale showed a opposite relationship (β = −0.20, p = 0.041). The gBOLD-CSF coupling could not predict SVD progression. Conclusion: Altered CSF flow is associated with the severity of SVD.

Assessing glymphatic function using in-vivo imaging method is of great value for understanding its contribution to major brain diseases. In the present study, we aim to validate the association between a variety of risk factors and a potential index of glymphatic function—Diffusion Tensor Image Analysis Along the Perivascular Space (ALPS index). We enrolled 142 subjects from communities and performed multi-modality magnetic resonance imaging scans. The ALPS index was calculated from diffusion tensor imaging data, and its associations with demographic factors, vascular factors were investigated using regression analyses. We found that the ALPS index was negatively associated with age (β = −0.284, p < 0.001). Compared to males, females had significantly higher ALPS index (β = −0.243, p = 0.001). Hypertensive subjects had significantly lower ALPS index compared to non-hypertensive subjects (β = −0.189, p = 0.013). Furthermore, venous disruption could decrease ALPS index (β = −0.215, p = 0.003). In general, our results are in consistent with previous conceptions and results from animal studies about the pathophysiology of glymphatic dysfunction. Future studies utilizing this method should consider introducing the above-mentioned factors as important covariates.

Lenticulostriate arteries (LSAs) supply blood to important subcortical areas and are, therefore, essential for maintaining the optimal functioning of the brain’s most metabolically active nuclei. Past studies have demonstrated the potential for quantifying the morphology of LSAs as biomarkers of vascular fragility or underlying arteriopathies. Thus, the current study aims to evaluate the morphological features of LSAs, their potential value in cerebrovascular risk stratification, and their concordance with other vascular risk factors in community-dwelling elderly people. A total of 125 community-dwelling elderly subjects who underwent a brain MRI scan were selected from our prospectively collected imaging database. The morphological measures of LSAs were calculated on the vascular skeletons obtained by manual tracing, and the number of LSAs was counted. Additionally, imaging biomarkers of small vessel disease were evaluated, and the diameters of major cerebral arteries were measured. The effects of vascular risk factors on LSA morphometry, as well as the relationship between LSA measures and other imaging biomarkers, were investigated. We found that smokers had shorter (p = 0.04) and straighter LSAs (p < 0.01) compared to nonsmokers, and the presence of hypertension is associated with less tortuous LSAs (p = 0.03) in community-dwelling elderly. Moreover, the middle cerebral artery diameter was positively correlated with LSA count (r = 0.278, p = 0.025) and vessel tortuosity (r = 0.257, p = 0.04). The posterior cerebral artery diameter was positively correlated with vessel tortuosity and vessel length. Considering the scarcity of noninvasive methods for measuring small artery abnormalities in the brain, the LSA morphological measures may provide valuable information to better understand cerebral small vessel degeneration during aging.

Abstract Background Activation of CXCL12/CXCR4 axis has been found to be associated with invasion and metastasis in many cancers. However, the underlying mechanism remains elusive. Increasing data highlight that non-coding RNAs are linked to CRC progression. Methods The effects of CXCR4 were investigated using villin-CXCR4 transgenic mice model by flow cytometry assay, immunohistochemistry, and Western blot. The mechanism was explored through bioinformatics, luciferase reporter assay and RNA immunoprecipitation assay. Results We found that high CXCR4 expression exacerbated colitis-associated cancer in villin-CXCR4 transgenic mice. CXCR4 +/− Apc min/+ compound mutant mice demonstrated higher colorectal tumorigenesis than Apc min/+ mice. Furthermore, overexpression of CXCR4 was found to promote the epithelial-mesenchymal transition (EMT) and infiltration of myeloid-derived suppressor cells (MDSCs) and macrophages in colonic tissue, accelerating colitis-associated and Apc mutation-driven colorectal tumorigenesis and progression. Notably, miR-133a-3p was found to be significantly decreased in HCT116 cells overexpressing CXCR4 by miRNA sequencing. miR-133a-3p was proved to target RhoA, which is involved in cytoskeletal reorganization that drive cell motility. Importantly, CXCL12/CXCR4-induced upregulation of lncRNA XIST functioned as a ceRNA to sponge miR-133a-3p, thereby liberating the repression of RhoA by miR-133a-3p. The negative correlation of miR-133a-3p with RhoA was also confirmed in human CRC tissues and CXCR4 +/− mice. Conclusions Our findings revealed the critical role of CXCR4 in promoting progression of inflammatory colorectal cancer through recruiting immunocytes and enhancing cytoskeletal remodeling by lncRNA XIST/ miR-133a-3p/ RhoA signaling. These results provide novel potential therapeutic targets for hindering CXCL12/CXCR4-induced CRC progression.

Mounting evidence demonstrates a close relationship between sleep disturbance and mood disorders, including major depression disorder (MDD) and bipolar disorder (BD). According to the classical two-process model of sleep regulation, circadian rhythms driven by the light–dark cycle, and sleep homeostasis modulated by the sleep–wake cycle are disrupted in mood disorders. However, the exact mechanism of interaction between sleep and mood disorders remains unclear. Recent discovery of the glymphatic system and its dynamic fluctuation with sleep provide a plausible explanation. The diurnal variation of the glymphatic circulation is dependent on the astrocytic activity and polarization of water channel protein aquaporin-4 (AQP4). Both animal and human studies have reported suppressed glymphatic transport, abnormal astrocytes, and depolarized AQP4 in mood disorders. In this study, the “glymphatic dysfunction” hypothesis which suggests that the dysfunctional glymphatic pathway serves as a bridge between sleep disturbance and mood disorders is proposed.

Background: The dilation of perivascular space (PVS) has been widely used to reflect brain degeneration in clinical brain imaging studies. However, PVS characteristics exhibit large differences in healthy subjects. Such variations need to be better addressed before PVS can be used to reflect pathological changes. In the present study, we aim to investigate the potential influence of several related factors on PVS dilation in healthy elderly subjects.Methods: One-hundred and three subjects (mean age = 59.5) were retrospectively included from a prospectively collected community cohort. Multi-modal high-resolution magnetic resonance imaging and cognitive assessments were performed on each subject. Machine-learning based segmentation methods were employed to quantify PVS volume and white matter hyperintensity (WMH) volume. Multiple regression analysis was performed to reveal the influence of demographic factors, vascular risk factors, intracranial volume (ICV), major brain artery diameters, and brain atrophy on PVS dilation.Results: Multiple regression analysis showed that age was positively associated with the basal ganglia (BG) (standardized beta = 0.227, p = 0.027) and deep white matter (standardized beta = 0.220, p = 0.029) PVS volume. Hypertension was positively associated with deep white matter PVS volume (standardized beta = 0.234, p = 0.017). Furthermore, we found that ICV was strongly associated with the deep white matter PVS volume (standardized beta = 0.354, p < 0.001) while the intracranial artery diameter was negatively associated with the deep white matter PVS volume (standardized beta = −0.213, p = 0.032).Conclusions: Intracranial volume has significant influence on deep white matter PVS volume. Future studies on PVS dilation should include ICV as an important covariate.

Recent small subcortical infarcts (RSSIs) can occur in different brain regions. Distinct etiologies might be involved for RSSIs in different locations and could further affect RSSI cavitation and functional outcomes. In this study, we aim to analyze the baseline clinical and imaging characteristics associated with the occurrence and cavitation of RSSIs in different locations. We retrospectively include patients who presented with RSSIs from a database for cerebral small vessel disease. Detailed information, including demographic, clinical, laboratory, and radiological data, were collected. We identify baseline RSSIs on diffusion-weighted images and divide them into brainstem, subcortical white matter, and basal ganglia region groups. Cavitation is evaluated on follow-up T2 fluid-attenuated inversion recovery (FLAIR) images. Statistical analysis is performed to determine factors associated with the occurrence and cavitation of RSSIs in different locations. We find that patients with brainstem RSSIs have a higher proportion of diabetes (64.1%) compared to patients with subcortical white matter (27.3%, P < 0.001) and basal ganglia region RSSIs (35.2%, P = 0.006) and have higher levels of HbA1c (7.20%) compared to patients with subcortical white matter (6.10%, P = 0.001) and basal ganglia region RSSIs (6.20%, P = 0.003). In addition, patients with brainstem RSSIs have higher NIHSS scores than patients with subcortical white matter RSSIs (2 vs 0, P = 0.001). Patients with subcortical white matter RSSIs have higher a white matter hyperintensity (WMH) burden compared to patients with basal ganglia region RSSIs (21.64 cm3 vs 11.10 cm3, P = 0.004). Follow-up analysis demonstrates that basal ganglia region RSSIs are less likely to cavitate than subcortical white matter RSSIs (61.4% vs 83.6%, P = 0.010), and contacting with WMH is associated with the cavitation of subcortical white matter RSSIs (OR: 101.760, P = 0.003). Our study demonstrates that RSSIs in different locations are associated with different clinical and imaging characteristics. Furthermore, cavitation of RSSIs might be affected by local lesion features and the surrounding environment rather than general demographic and clinical factors.

Background: Large core is associated with poor outcome in acute ischemic stroke (AIS) patients. It is unclear whether endovascular treatment (EVT) could bring benefits to patients with core volume ≥70 ml before treatment. We aimed to compare the impact of EVT with intravenous thrombolysis (IVT) on the outcome in patients with core volume ≥70 ml.Methods: We included consecutive anterior circulation AIS patients who underwent MR or CT perfusion within 6 h post stroke onset, which revealed a core ≥70 ml before reperfusion therapy. Good outcome was defined by modified Rankin Scale of 0 to 2 at 90-day. Reperfusion was defined as a reduction in hypoperfusion volume of ≥70% between baseline and 24 h.Results: One hundred four patients were included. Among them, 76 received IVT only, and 28 received EVT. After adjusting for age, NIHSS score, baseline core volume and onset to imaging time, patients in EVT group were more likely to achieve good outcome compared to IVT patients (OR, 3.875; 95% Cl 1.068–14.055, p = 0.039). More patients in EVT group achieved recanalization (84.0 vs. 58.5%, p = 0.027) and reperfusion (66.7 vs. 33.3%, p = 0.010) than in IVT group. Reperfusion also independently predicted good outcome (OR, 7.718; 95% Cl 1.713-34.772, p = 0.008). All patients with good outcome achieved recanalization at 24 h.Conclusions: Our data indicated that patients with core volume ≥70 ml might still benefit from EVT, which was related to its high reperfusion rate.

Cerebral venous collagenosis played a role in the pathogenesis of white matter hyperintensities (WMHs) through venous ischemia. Since pathological changes of veins from intramural stenosis to luminal occlusion is a dynamic process, we aimed to create a deep medullary veins (DMVs) visual grade on susceptibility-weighted images (SWI) and explore the relationship of DMVs and WMHs based on venous drainage regions. We reviewed clinical, laboratory and imaging data from 268 consecutive WMHs patients and 20 controls. SWI images were used to observe characteristics of DMVs and a brain region-based DMVs visual score was given by two experienced neuroradiologists. Fluid attenuated inversion recovery (FLAIR) images were used to calculate WMHs volume. Logistic-regression analysis and partial Pearson’s correlation analysis were used to examine the association between the DMVs score and WMHs volume. We found that the DMVs score was significantly higher in WMHs patients than in controls (p < 0.001). Increased DMVs score was independently associated with higher WMHs volume after adjusting for total cholesterol level and number of lacunes (p < 0.001). Particularly, DMVs scores were correlated with regional PVHs volumes in the same brain region most. The newly proposed DMVs grading method allows the clinician to monitor the course of DMVs disruption. Our findings of cerebral venous insufficiency in WMHs patients may help to elucidate the pathogenic mechanisms and progression of WMHs.

Leukoaraiosis is associated with increased risk of cognitive impairment, but its pathophysiological pathway is unclear. The aim of the present study was to determine whether brain structural damage or cerebral blood supply better correlated with the global cognitive outcome in subjects with leukoaraiosis. Seventy-five subjects with leukoaraiosis were included in present study, with age ranged from 43 to 85 years, with mean white matter hyperintensities (WMH) volume 30.69 ± 24.35 mL. Among them, 19(25.33%) subjects presented with cerebral microbleeds (CMB) and 40 (53.33%) subjects presented with lacunes. These participants received arterial spin labeling perfusion MRI, diffusion-tensor imaging (DTI) and diffusion Kurtosis imaging. We analyzed the cerebral blood flow (CBF) by dividing the brain tissue into three regions: WMH, normal appearing white matter (NAWM) and cortex. After adjusting for age and gender, the CBF of NAWM was significantly correlated with fractional anisotropy (FA) (r = 0.336, p = 0.004) and mean diffusion (MD) (r = -0.271, p = 0.020) of NAWM, while there lacked of association between CBF of cortex and mean kurtosis (MK) of cortex (r = -0.015, p = 0.912). Meanwhile, both NAWM-FA (r = -0.443, p < 0.001) and NAWM-MD (r = 0.293, p = 0.012), as well as cortex-MK (r = -0.341, p = 0.012) was significantly correlated with WMH volume. Univariate regression analysis demonstrated that global cognitive function was significantly associated with mean FA or MD of both WMH and NAWM, and cortex-CBF, but neither with the cortex-MK, nor the presences of CMB or lacunes. Finally, multiple linear regression analysis revealed that global cognitive function was independently associated with NAWM-FA (standardized β = 0.403, p < 0.001) and WMH-FA (Standardized β = 0.211, p = 0.017), but not with the cortex-CBF. A model that contained NAWM-FA, WMH-FA and years of education explained 49% of the variance of global cognitive function. Cerebral perfusion status might have a significant impact on the maintenance of white matter integrity in subjects with leukoaraiosis. Global cognitive function was more strongly associated with white matter integrity than with blood supply. DTI parameters, especially FA could serve as a potent imaging indicator for detecting the invisible alteration of white matter integrity and implying its potential cognitive relevance.

Asymmetric medullary veins (AMV) are frequently observed in stroke patients and single-echo susceptibility weighted imaging (SWIs) is the main technique in detecting AMV. Our study aimed to investigate which echo time (TE) on single-echo susceptibility is the optimal echo for visualizing AMV and to compare the ability in detecting AMV in stroke patients between SWIs and multi-echo susceptibility weighted imaging (SWIc).Twenty patients with middle cerebral artery stroke were included. SWI was acquired by using a multi-echo gradient-echo sequence with six echoes ranging from 5 ms to 35.240 ms. Three different echoes of SWIs including SWIs1 (TE = 23.144 ms), SWIs2 (TE = 29.192 ms) and SWIs3 (TE = 35.240 ms) were reconstructed. SWIc was averaged using the three echoes of SWIs. Image quality and venous contrast of medullary veins were compared between SWIs and SWIc using peak signal-to-noise ratio (PSNR), mean opinion score (MOS), contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR). The presence of AMV was evaluated in each SWIs (1-3) and SWIc.SWIs2 had the highest PSNR, MOS and CNR and SWIs1 had the highest SNR among three different echoes of SWIs. No significant difference was found in SNR between SWIs1 and SWIs2. PSNR, MOS and CNR in SWIc were significantly increased by 27.9%, 28.2% and 17.2% compared with SWIs2 and SNR in SWIc was significantly increased by 32.4% compared with SWIs1. 55% of patients with AMV were detected in SWIs2, SWIs3 and SWIc, while 50% AMV were found in SWIs1.SWIs using TE around 29ms was optimal in visualizing AMV. SWIc could improve image quality and venous contrast, but was equal to SWIs using a relative long TE in evaluating AMV. These results provide the technique basis for further research of AMV in stroke.

Transcription factor c-Jun plays a key role in controlling epithelium cell proliferation, apoptosis and differentiation. However, molecular mechanism and biological functions of c-Jun in squamous differentiation and the progression of esophageal squamous cell carcinoma (ESCC) remain elusive. In this study, we found that c-Jun bound directly to the promoter region, and activated the transcription of differentiation-associated genes including cystatin A, involucrin and SPRR3 in vivo. Ectopic expression of c-Jun enhanced SPRR3 transactivation in KYSE450 cells. Conversely, TAM67, a dominant negative mutant of c-Jun, inhibited SPRR3 transactivation. c-Jun increased expression of SPPR3 mainly via a PKC/JNK pathway in response to TPA in KYSE450 cells. Furthermore, c-Jun was remarkably reduced in esophageal cancer. Interestingly, cystatin A, involucrin and SPRR3 were significantly downregulated as well, and associated with differentiation grade. Expression of c-Jun was correlated with the expression of these genes in normal epithelium and ESCC. Importantly, the expression of these genes was remarkably decreased during the malignant transformation from normal epithelium to low-grade intraepithelial neoplasia (LGIN) or high-grade intraepithelial neoplasia (HGIN). The expression of cystatin A and involucrin was significantly reduced from LGIN to HGIN. These results suggest c-Jun was involved in the regulation of differentiation-associated genes in ESCC. These genes might serve as the potential markers in distinguishing normal epithelium from esophageal squamous intraepithelial neoplasia.

Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction and cardiomyocyte apoptosis. Oxidative stress is suggested to be the major contributor to the development of DCM. This study was intended to evaluate the protective effect of low molecular weight fucoidan (LMWF) against cardiac dysfunction in diabetic rats. Type 2 diabetic goto-kakizaki rats were untreated or treated with LMWF (50 and 100 mg/kg/day) for three months. The establishment of DCM model and the effects of LMWF on cardiac function were evaluated by echocardiography and isolated heart perfusion. Ventricle staining with H-E or Sirius Red was performed to investigate the structural changes in myocardium. Functional evaluation demonstrated that LMWF has a beneficial effect on DCM by enhancing myocardial contractility and mitigating cardiac fibrosis. Additionally, LMWF exerted significant inhibitory effects on the reactive oxygen species production and myocyte apoptosis in diabetic hearts. The depressed activity of superoxide dismutase in diabetic heart was also improved by intervention with LMWF. Moreover, LMWF robustly inhibited the enhanced expression of protein kinase C β, an important contributor to oxidative stress, in diabetic heart and high glucose-treated cardiomyocytes. In conclusion, LMWF possesses a protective effect against DCM through ameliorations of PKCβ-mediated oxidative stress and subsequent cardiomyocyte apoptosis in diabetes.

BACKGROUND: It has been found that gap junction-associated intracellular Ca(2+) [Ca(2+)](i) disturbance contributes to the arrhythmogenesis and hyperconstriction in diseased heart. However, whether functional gaps are also involved in the regulation of normal Ca(2+) signaling, in particular the basal [Ca(2+)](i) activities, is unclear. METHODS AND RESULTS: Global and local Ca(2+) signaling and gap permeability were monitored in cultured neonatal rat ventricular myocytes (NRVMs) and freshly isolated mouse ventricular myocytes by Fluo4/AM and Lucifer yellow (LY), respectively. The results showed that inhibition of gap communication by heptanol, Gap 27 and flufenamic acid or interference of connexin 43 (Cx43) with siRNA led to a significant suppression of LY uptake and, importantly, attenuations of global Ca(2+) transients and local Ca(2+) sparks in monolayer NRVMs and Ca(2+) sparks in adult ventricular myocytes. In contrast, overexpression of rat-Cx43 in NRVMs induced enhancements in the above measurements, and so did in HEK293 cells expressing rat Cx43. Additionally, membrane-permeable inositol 1,4,5-trisphosphate (IP(3) butyryloxymethyl ester) and phenylephrine, an agonist of adrenergic receptor, could relieve the inhibited Ca(2+) signal and LY uptake by gap uncouplers, whereas blockade of IP(3) receptor with xestospongin C or 2-aminoethoxydiphenylborate mimicked the effects of gap inhibitors. More importantly, all these gap-associated effects on Ca(2+) signaling were also found in single NRVMs that only have hemichannels instead of gap junctions. Further immunostaining/immunoblotting single myocytes with antibody against Cx43 demonstrated apparent increases in membrane labeling of Cx43 and non-junctional Cx43 in overexpressed cells, suggesting functional hemichannels exist and also contribute to the Ca(2+) signaling regulation in cardiomyocytes. CONCLUSIONS: These data demonstrate that Cx43-associated gap coupling plays a role in the regulation of resting Ca(2+) signaling in normal ventricular myocytes, in which IP(3)/IP(3) receptor coupling is involved. This finding may provide a novel regulatory pathway for mediation of spontaneous global and local Ca(2+) activities in cardiomyocytes.