Nomogram Prediction for Lower Extremity Deep Vein Thrombosis in Acute Ischemic Stroke Patients Receiving Thrombolytic Therapy.

This study developed and evaluated a tailored nomogram to predict the potential occurrence of early lower extremity deep vein thrombosis (LDVT) in patients receiving thrombolytic therapy. We performed several logistic analyses on the training cohort and created a corresponding nomogram to forecast early LDVT. The classification accuracy and the accuracy of predicted probabilities of the multiple logistic regression model were evaluated using area under the curve (AUC) and the calibration graph method. According to the multivariate logistic regression model homocysteine, previous history of hypertension and atrial fibrillation, indirect bilirubin, age, and sex was identified as independent determinants of early LDVT. The nomogram was constructed using these variables. The calibration plots showed a good agreement between the predicted and observed LDVT possibilities in the training and validation cohorts with AUCs being 0.833 (95% CI: 0.774-0.892) and 0.907 (95% CI: 0.801-1.000), respectively. Our nomogram offers clinicians a tool for predicting the individual risk of LDVT in the early stage of acute ischemic stroke in patients receiving thrombolytic therapy, which could lead to early intervention.

Value of electrophysiological indicators in differential diagnosis of parkinson's disease and multiple system atrophy.

BACKGROUND: We evaluated the value of electrophysiological indicators by external anal sphincter electromyography (EAS-EMG), sympathetic skin response (SSR), R-R interval variation (RRIV), and Bulbocavernosus Reflex (BCR) in differential diagnosis of multiple system atrophy (MSA) and Parkinson's disease (PD). METHODS: A total of 41 patients with MSA and 32 patients with PD were enrolled. The electrophysiological changes of autonomic dysfunction were assessed with BCR, EAS-EMG, SSR, and RRIV, and the abnormal rate of each indicator was calculated. The diagnostic value of each indicator was analyzed with ROC curve. RESULTS: The incidence rate of autonomic dysfunction in MSA group was significantly higher than that in PD group (p < 0.05). The abnormal rates of BCR and EAS-EMG indicators in MSA group were higher than those in PD group (p < 0.05). The abnormal rates of SSR and RRIV indicators in MSA group and PD group were high; however, there was no significant difference between MSA and PD groups (p > 0.05). The sensitivity of BCR combined with EAS-EMG indicators in differential diagnosis of MSA and PD were 92.3% in males and 86.7% in females, respectively, and the specificity was 72.7% in males and 90% in females, respectively. CONCLUSIONS: Combined analysis of BCR and EAS-EMG has high sensitivity and specificity for differential diagnosis of MSA and PD.

Metformin, Rapamycin, or Nicotinamide Mononucleotide Pretreatment Attenuate Cognitive Impairment After Cerebral Hypoperfusion by Inhibiting Microglial Phagocytosis.

Vascular cognitive impairment (VCI) is the second leading form of dementia after Alzheimer's disease (AD) plaguing the elder population. Despite the enormous prevalence of VCI, the biological basis of this disease has been much less well-studied than that of AD, with no specific therapy currently existing to prevent or treat VCI. As VCI mainly occurs in the elderly, the role of anti-aging drugs including metformin, rapamycin, and nicotinamide mono nucleotide (NMN), and the underlying mechanism remain uncertain. Here, we examined the role of metformin, rapamycin, and NMN in cognitive function, white matter integrity, microglial response, and phagocytosis in a rat model of VCI by bilateral common carotid artery occlusion (BCCAO). BCCAO-induced chronic cerebral hypoperfusion could cause spatial working memory deficits and white matter lesions (WMLs), along with increasing microglial activation and phagocytosis compared to sham-operated rats. We found the cognitive impairment was significantly improved in BCCAO rats pretreated with these three drugs for 14 days before BCCAO compared with the vehicle group by the analysis of the Morris water maze and new object recognition tests. Pretreatment of metformin, rapamycin, or NMN also increased myelin basic protein (MBP, a marker for myelin) expression and reduced SMI32 (a marker for demyelinated axons) intensity and SMI32/MBP ratio compared with the vehicle group, suggesting that these drugs could ameliorate BCCAO-induced WMLs. The findings were confirmed by Luxol fast blue (LFB) stain, which is designed for staining myelin/myelinated axons. We further found that pretreatment of metformin, rapamycin, or NMN reduced microglial activation and the number of M1 microglia, but increased the number of M2 microglia compared to the vehicle group. Importantly, the number of MBP+/Iba1+/CD68+ microglia was significantly reduced in the BCCAO rats pretreated with these three drugs compared with the vehicle group, suggesting that these drugs suppress microglial phagocytosis. No significant difference was found between the groups pretreated with metformin, rapamycin, or NMN. Our data suggest that metformin, rapamycin, or NMN could protect or attenuate cognitive impairment and WMLs by modifying microglial polarization and inhibiting phagocytosis. The findings may open a new avenue for VCI treatment.

Prognostic implications of PPL expression in ovarian cancer.

Periplakin (PPL) is a main member in plakin family, which plays important role in cellular adhesion complexes supporting and cytoskeletal integrity supplying. PPL was reported to be a potential biomarker candidate for several types of cancers. However, the biological functions and underlying mechanisms of PPL in ovarian cancer (OV) remain unclear. In the present study, we used GEPIA 2, Human Protein Atlas, Oncomine, LinkedOmics, Kaplan-Meier Plotter, STRING, CytoHubba plug-in and TIMER to determine the associations among PPL expression, prognosis, and immune cell infiltration in OV. RT-qPCR and IHC analysis were conducted to validated the role of PPL in an independent OV cohort. Compared with the normal ovary tissues, the levels of PPL mRNA and protein expression were both obviously higher in OV tumors from multiple datasets (P < 0.05), and a poor survival was observed to be strongly correlated with high PPL expression (P < 0.05). Moreover, the results were further validated by RT-qPCR and IHC analysis in an independent OV cohort. A gene-clinical nomogram was constructed, including PPL mRNA expression and clinical factors in TCGA. Functional network analysis suggested that PPL participates in the important pathways like Wnt signaling pathway, MAPK signaling pathway. Ten hub genes (LAMC2, PXN, LAMA3, LAMB3, LAMA5, ITGA3, TLN1, ACTN4, ACTN1, and ITGB4) were identified to be positively associated with PPL. Furthermore, PPL expression was negatively correlated with infiltrating levels of CD4+ T cell, macrophages, neutrophils, and dendritic cells. In conclusion, PPL may be an unfavorable prognostic biomarker candidate in OV, which was also correlated with immune infiltrating and function in immunotherapy response.

Application of bulbocavernosus reflex combined with anal sphincter electromyography in the diagnosis of MSA and PD.

BACKGROUND: Multiple system atrophy (MSA) and Parkinson's disease (PD) are characterized by abnormal changes in the extrapyramidal system and autonomic nervous system. The two diseases are consistent in some clinical manifestations and few objective indicators for preclinical prediction. METHOD: The value of anal sphincter electromyography (EAS-EMG) in the diagnosis of MSA has been recognized by researchers, while the bulbocavernosus reflex (BCR) has been found to be of great significance in the diagnosis of PD and MSA. In this study, the diagnostic value of BCR combined with EAS-EMG in patients with MSA and PD was further discussed. RESULTS: Forty-three patients with MSA, 120 patients with PD and 40 normal controls were recruited, and the BCR and EAS-EMG were evaluated. The average duration, average amplitude, percentage of polyphasic waves, satellite potential, phase pattern and amplitude of strong contraction were observed. The results showed that the abnormal rate of BCR in the control group was 0%, and the abnormal rate of EAS-EMG was 2.5%; these differences were statistically significant compared with the MSA group (BCR 90.9%, EAS-EMG 93.9%). For patients with PD, there were some significant differences in BCR and EAS-EMG between the control group and the PD group. CONCLUSION: Our study revealed that BCR combined with EAS-EMG detection can provide an objective electrophysiological basis for the diagnosis of MSA and PD, which is beneficial for the early treatment of disease.

ZNF76 predicts prognosis and response to platinum chemotherapy in human ovarian cancer.

Ovarian cancer (OV) is the most lethal gynecologic malignancy. One major reason of the high mortality of the disease is due to platinum-based chemotherapy resistance. Increasing evidence reveal the important biological functions and clinical significance of zinc finger proteins (ZNFs) in OV. In the present study, the relationship between the zinc finger protein 76 (ZNF76) and clinical outcome and platinum resistance in patients with OV was explored. We further analyzed ZNF76 expression via multiple gene expression databases and identified its functional networks using cBioPortal. RT-qPCR and IHC assay shown that the ZNF76 mRNA and protein expression were significantly lower in OV tumor than that in normal ovary tissues. A strong relationship between ZNF76 expression and platinum resistance was determined in patients with OV. The low expression of ZNF76 was associated with worse survival in OV. Multivariable analysis showed that the low expression of ZNF76 was an independent factor predicting poor outcome in OV. The prognosis value of ZNF76 in pan-cancer was validated from multiple cohorts using the PrognoScan database and GEPIA 2. A gene-clinical nomogram was constructed by multivariate cox regression analysis, combined with clinical characterization and ZNF76 expression in TCGA. Functional network analysis suggested that ZNF76 was involved in several biology progressions which associated with OV. Ten hub genes (CDC5L, DHX16, SNRPC, LSM2, CUL7, PFDN6, VARS, HSD17B8, PPIL1, and RGL2) were identified as positively associated with the expression of ZNF76 in OV. In conclusion, ZNF76 may serve as a promising prognostic-related biomarker and predict the response to platinum in OV patients.

Interleukin-10 level is associated with post-stroke depression in acute ischaemic stroke patients.

BACKGROUND: Interleukin-10 (IL-10) is a pathophysiological factor in acute ischaemic stroke (AIS) and is relevant to mood disorders after stroke. We evaluated the predictive value of IL-10 in patients with post-stroke depression (PSD). METHODS: A total of 350 stroke patients were recruited at baseline, and 151 AIS patients were screened and completed a 1-month follow-up. Serum IL-10 levels were measured within 24 h of admission. We used the 17-item Hamilton Depression Scale (HAMD-17) to evaluate depression symptoms; PSD was defined as an HAMD score ≥ 7. RESULTS: Fifty-one (33.8%) patients showed a more serious stroke degree, larger infarction volume, and poorer daily life activities and prognosis (P < 0.05) and were diagnosed with PSD at the 1-month follow-up. Their IL-10 level decreased significantly compared to the non-PSD group (P < 0.001). After adjusting for confounders, IL-10 could be used as an independent predictor for PSD with an adjusted odds ratio (OR) of 0.615 (95% CI 0.410-0.923, P = 0.019). In addition, the optimal cut-off value of IL-10 was 0.615 pg/mL based on an area under the receiver operating characteristic curve of 0.692 (95% CI 0.604-0.781, P < 0.001), demonstrating that IL-10 could predict the occurrence of PSD. Moreover, IL-10 was an indicator of stroke severity, living ability, and functional outcomes (P < 0.05). LIMITATIONS: IL-10 was only measured upon admission; dynamic changes need to be further monitored. This was also a single-centre study with a relatively small sample. CONCLUSIONS: Lower IL-10 levels may be used to predict PSD.

Key Signaling Pathways in Aging and Potential Interventions for Healthy Aging.

Aging is a fundamental biological process accompanied by a general decline in tissue function. Indeed, as the lifespan increases, age-related dysfunction, such as cognitive impairment or dementia, will become a growing public health issue. Aging is also a great risk factor for many age-related diseases. Nowadays, people want not only to live longer but also healthier. Therefore, there is a critical need in understanding the underlying cellular and molecular mechanisms regulating aging that will allow us to modify the aging process for healthy aging and alleviate age-related disease. Here, we reviewed the recent breakthroughs in the mechanistic understanding of biological aging, focusing on the adenosine monophosphate-activated kinase (AMPK), Sirtuin 1 (SIRT1) and mammalian target of rapamycin (mTOR) pathways, which are currently considered critical for aging. We also discussed how these proteins and pathways may potentially interact with each other to regulate aging. We further described how the knowledge of these pathways may lead to new interventions for antiaging and against age-related disease.

Estrogen administration attenuates post-stroke depression by enhancing CREB/BDNF/TrkB signaling in the rat hippocampus.

A previous study demonstrated that 17ß-estradiol (E2), which is an antidepressant, can ameliorate post-stroke depression (PSD); however, the underlying mechanisms governing this remain largely unknown. Therefore, the present study developed a PSD model in rats, which was induced by left middle cerebral artery occlusion followed by exposure to chronic mild stress for 2 weeks. The results revealed that the activity of the cAMP response element-binding protein (CREB), a cellular transcription factor, and the associated brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) signaling were all attenuated in the hippocampus in PSD rats. The depression-like behaviors were significantly improved after treatment with E2, along with increased CREB and the BDNF/TrkB signaling activity. These results provide novel insight into the molecular basis of PSD, and suggest the potential involvement of CREB/BDNF/TrkB signaling in E2-mediated improvement of PSD in rats.

2-BFI attenuates ischemic injury by modulating mTOR signaling and neuroinflammation in rats.

Ischemic stroke is one of the major diseases that cause mortality and morbidity of human beings, but there is still lack of effective treatment and prevention. We found that 2-(2-Benzofuranyl)-2-Imidazoline (2-BFI) is potently protective against stroke and acute inflammatory immune disease. Moreover, the mammalian target of rapamycin (mTOR) signaling contributes effectively to the modulation of post-stroke neuroinflammatory response. However, whether the protection of 2-BFI against ischemic injury is through mTOR-mediated neuroinflammatory response remains unestablished. Here, we used 2-BFI to treat ischemic rats induced by distal middle cerebral artery occlusion (dMCAO). We found that 2-BFI administration after dMCAO improved the neurological deficits and decreased the infarct volume. 2-BFI reduced phosphorylation of mTOR and p70S6, increased IL-10 and TGF-ß, and decreased IFN-γ levels in ischemic rats. Our results demonstrated that 2-BFI attenuates ischemic injury by inhibiting the activation of mTOR signaling and modulating neuroinflammation after stroke in rats.

White Matter Hypoperfusion Associated with Leukoaraiosis Predicts Intracranial Hemorrhage after Intravenous Thrombolysis.

OBJECTIVES: White matter hyperintensity is common in patients receiving intravenous thrombolysis. Some studies have expressed concern about the increased risk of hemorrhagic transformation and poor prognosis for those patients with pre-existing leukoaraiosis. The purpose of this study was to evaluate hypoperfusion associated with leukoaraiosis before thrombolysis using CT perfusion and to explore whether chronic white matter hypoperfusion increases risks of intracranial hemorrhage and poor clinical prognosis. MATERIALS AND METHODS: We collected 175 patients underwent intravenous thrombolysis with complete CT perfusion data and follow-up MRI between June 2017 and January 2020. We measured cerebral blood flow, cerebral blood volume, mean transit time and transit time to the peak at both periventricular and subcortical layers in the cerebral hemisphere contralateral to the stroke. The differences of white matter perfusion were compared between groups with different leukoaraiosis severity. Univariate analysis was used to compare in incidence of hemorrhagic transformation and poor prognosis between the hypoperfusion and normal perfusion groups. Further, we examined association between white matter hypoperfusion and intracranial hemorrhage after thrombolysis using logistic regression. RESULTS: The length of periventricular transit time to the peak was independently associated with a higher risk of intracranial hemorrhage after thrombolysis (OR=4.740, 95%CI=1.624-13.837, P=0.004). The best predictive value was 4.012. But there was no significant difference in poor prognosis at 3 months between hypoperfusion (periventricular transit time to the peak≥4.012 s) and normal perfusion (periventricular transit time to the peak<4.012 s) group. CONCLUSIONS: Image presentations of white matter hypoperfusion reflected the severity of leukoaraiosis. White matter hypoperfusion was independently associated with intracranial hemorrhage after intravenous thrombolysis. However, hypoperfusion would not increase the risk of poor prognosis.

Efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke: a multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Ischemic stroke is a leading cause of morbidity and mortality. Thrombolytic therapy improves disability and survival rates; however, to be effective, it must be given within 4.5 h of onset. Moreover, thrombolytic therapy is frequently contraindicated. Therefore, alternative therapeutic options are required. In China, cinepazide maleate injection has been shown to improve the cerebral collateral circulation and further reduce disability in stroke patients; however, very few studies investigating this therapy have been conducted to date. Therefore, this study aimed to further confirm the efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke. METHODS: Patients with acute ischemic stroke were administered an intravenous infusion of 320 mg cinepazide maleate or placebo once daily for 14 days. All patients were also administered basic therapy (citicoline sodium). The primary efficacy endpoint was the proportion of patients with a modified Rankin scale (mRS) ≤2 on day 90. Secondary efficacy endpoints included Barthel Index ≥95. Safety was evaluated by recording all adverse events (AEs), monitoring laboratory parameters and vital signs, and electrocardiogram. RESULTS: In total, 937 patients with an acute ischemic stroke were included, with a mean (standard deviation, SD) National Institutes of Health Stroke Scale score of 8.8 (2.4) and a mean (SD) stroke onset of 30.9 (11.4) hours prior. Following treatment for 90 days, the proportion of patients with an mRS score ≤ 2 was significantly higher in the cinepazide maleate group than in the control group (60.9% vs. 50.1%; p = 0.0004). Moreover, the proportion of patients with a Barthel Index of ≥95 on day 90 was also significantly higher in the cinepazide maleate group than in the control group (53.4% vs. 46.7%; p = 0.0230). There were no statistically significant differences in safety parameters between the cinepazide maleate and control groups. CONCLUSIONS: The results of this study show that cinepazide maleate injection is superior to placebo in improving neurological function and activities of daily living, reducing disability, and promoting functional recovery in patients with acute ischemic stroke. Cinepazide maleate injection was safe and well tolerated with no unexpected AEs reported. TRIAL REGISTRATION: Chinese Clinical Trial Registry CTR20160292 and ChiCTR1900023827 . Retrospectively registered June 13, 2019.

Hypermethylation of Single CpG Dinucleotides at the Promoter of CXCL13 Gene Promoting Cell Migration in Cervical Cancer.

BACKGROUND: Chemokine 13 (CXCL13) and its chemokine receptor 5 (CXCR5) are involved in the onset of various types of cancer. However, their role in cervical cancer (CC) remains unknown. OBJECTIVE: To investigate the role of chemokine 13 (CXCL13) and its receptor in CC. METHODS: The expression of CXCL13/CXCR5 and the infiltration of CXCR5+CD8+ T cells in CC, cervical intraepithelial neoplasia (CIN), normal cervical epithelial (NCE) tissues, and in CC cell lines were analysed and the associated clinical significance was determined. In vitro, CXCL13 overexpression and DNA methyltransferase inhibition (through S110) were used to investigate the biological function and the underlying mechanism that regulates CXCL13 expression. Tumor growth and liver metastasis were also evaluated in the xenogenous subcutaneously implant model. RESULTS: CXCL13/CXCR5 expression levels and the infiltration of CXCR5+CD8+ T cells were significantly decreased in CC tissues compared with CIN and NCE tissues. CXCL13 downregulation was significantly correlated with the FIGO stages, lymph node metastasis, interstitial infiltration depth, and pathological grade. The overexpression of CXCL13 suppressed CC cell migration. CXCL13 downregulation was associated with hypermethylation in CC cell lines, and primary tumor biopsies. Furthermore, a CpG dinucleotide at the HIF-1a transcription factor motifs in the promoter element of CXCL13 was consistently methylated in CC cells and associated with HIF-1a. CXCL13 overexpression and S110 treatment dramatically repressed tumor growth and liver metastasis in the xenograft model; whereas it's low expression increased the risk of death in CC patients. CONCLUSION: DNA methylation-dependent CXCL13 downregulation may promote cervical carcinogenesis and progression.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio as Potential Predictors of Prognosis in Acute Ischemic Stroke.

Objective: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been emerging as the novel inflammatory biomarkers for determining the prognosis of various diseases. This study aimed to investigate the individual and joint effects of NLR and PLR on functional outcomes of acute ischemic stroke (AIS). Methods: Our study involved 448 eligible patients with first-ever AIS. Clinical and laboratory data were collected on admission within 72 h from stroke onset. Unfavorable functional outcome was defined as a modified Rankin Scale score of 3-6 at 3 months after AIS. Cox proportional hazard model and spline regression models was used to estimate the effect of NLR and PLR on risk of adverse outcomes after the last patient who completed a 3-months follow-up was enrolled. Results: After adjusting confounders, NLR were significantly associated with the unfavorable functional outcomes (P-trend < 0.001). So were PLR (P-trend < 0.001). NLR was discovered to have higher predictive value than PLR (AUC = 0.776, 95%CI = 0.727-0.825, P < 0.001; AUC = 0.697, 95%CI = 0.641-0.753, P < 0.001). The optimal cutoff values for NLR and PLR was 3.51 and 141.52, respectively. Stratified analysis performed by cox proportional hazard model showed that high level of NLR and PLR (NLR ≥ 3.51, PLR ≥ 141.52) presented the highest risk of unfavorable functional outcomes (adjusted HR, 3.77; 95% CI: 2.38-5.95; P < 0.001). Followed by single high level of NLR (adjusted HR, 2.32; 95% CI: 1.10-4.87; P = 0.027). Single high level of PLR (NLR < 3.51, PLR ≥ 141.52) also showed higher risk than low level of the combination, but it did not reach statistical significance (adjusted HR, 1.42; 95% CI: 0.75-2.70; P = 0.285). No obvious additive [relative excess risk due to interaction (RERI) not significant] or multiplicative (adjusted HR, 0.71; 95%CI: 0.46-1.09; P = 0.114) interaction was found between the effects of NLR and PLR on the risk of unfavorable functional outcomes. Conclusion: This study demonstrated that both NLR and PLR were independent predictors of 3-months functional outcomes of AIS. They may help to identify high-risk patients more forcefully when combined together.

Striatal overexpression of ß-arrestin2 counteracts L-dopa-induced dyskinesia in 6-hydroxydopamine lesioned Parkinson's disease rats.

Prolonged administration of Levodopa (L-dopa) therapy can generate L-dopa-induced dyskinesia (LID). Accumulating evidence indicates that hyper-activation of the dopamine D1 receptor (D1R) and the cAMP signaling cascade in the medium spiny neurons (MSNs) of the striatum are involved in LID. Previous studies have shown that striatal ß-arrestin2 overexpression significantly reduces LID severity and have indicated that ß-arrestin2 may play a causal role in the dyskinesia sensitization process. L-dopa-induced changes in the expression of signaling molecules and other proteins in the striatum were examined immunohistochemically and by western blot. A rAAV (recombinant adeno-associated virus) vector was used to overexpress and ablate ß-arrestin2. We found that striatal overexpression of AAV-mediated ß-arrestin2 produced less severe AIMs (abnormal involuntary movements) in response to L-dopa, whereas selective deletion of ß-arrestin2 in the striatal neurons dramatically enhanced the severity of dyskinesia induced by L-dopa. Furthermore, no significant improvements in motor behavior (FFT: forelimb functional test) were seen with the inhibition or overexpression of ß-arrestin2. Finally, overexpression of ß-arrestin2 diminished L-dopa-induced D1R and phosphor-DARPP32/ERK levels. Viral deletion of ß-arrestin2 markedly enhanced the key biochemical markers in the direct pathway. We found that increased availability of ß-arrestin2 ameliorated dyskinesia severity with no influence on the anti-Parkinsonian action of L-dopa, suggesting a promising approach for controlling LID in Parkinson's disease. In addition, overexpression of ß-Arrestin2 prevented the development of LID by inhibiting G protein-dependent D1R and phosphor-DARPP32/ERK signaling in dyskinetic rats.

Serum interleukin-33 as a novel marker for long-term prognosis and recurrence in acute ischemic stroke patients.

OBJECTIVES: Interleukin-33, a newly identified member of interleukin-1 family, had been confirmed to play a crucial role in regulating inflammatory responses in various disease. However, the exact role of interleukin-33 in the disease process of acute ischemic stroke still remains unclear. This study aims to demonstrate the relationship between interleukin-33 levels and long-term functional outcome as well as ischemic stroke recurrence. METHODS: Three hundred and four first-ever acute ischemic stroke patients were recruited and basic information and history of all subjects taken within 72 hr on admission. The functional outcome was estimated by Barthel index. The multivariate logistic regression was used to analyze the prognosis, while the Cox proportional hazard model was applied to assess the recurrence risk. RESULTS: Out of 304 subjects, 259 patients successfully completed scheduled two-year follow-up. We found that higher interleukin-33 levels correlated positively with better prognosis as compared with those with lower interleukin-33 levels who presented with poorer outcome (62.45 ± 20.50 ng/ml vs. 51.58 ± 19.16 ng/ml, p < .001). After adjustment of all confounders, interleukin-33 was associated with the one-year prognosis with an adjusted odds ratio of 0.956 (95% confidence interval, 0.937-0.976, p < .001). Furthermore, interleukin-33 levels were also closely related to recurrent ischemic stroke with an adjusted hazard ratio of 0.979 (95% confidence interval, 0.961-0.997, p = .025). CONCLUSIONS: IL-33 can be used to predict the long-term outcomes and ischemic stroke recurrence in first-ever acute ischemic stroke patients.

The Prognostic Value of Serum Cytokines in Patients with Acute Ischemic Stroke.

The inflammatory response is an unavoidable process and contributes to the destruction of cerebral tissue during the acute ischemic stroke (AIS) phase and has not been addressed fully to date. Insightful understanding of correlation of inflammatory mediators and stroke outcome may provide new biomarkers or therapeutic approaches for ischemic stroke. Here, we prospectively recruited 180 first-ever AIS patients within 72 hrs after stroke onset. We used the National Institutes of Health Stroke Scale (NIHSS) to quantify stroke severity and modified Rankin scale (mRS) to assess the 3-month outcome for AIS patients. Initially, we screened 35 cytokines, chemokines, and growth factors in sera from 75 AIS patients and control subjects. Cytokines that were of interest were further investigated in the 180 AIS patients and 14 heathy controls. We found that IL-1RA, IL-1ß, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, IL-15, EGF, G-CSF, Flt-3L, GM-CSF and Fractalkine levels were significantly decreased in severe stroke patients. In particular, IL-1ß, IL-4, IL-5, IL-7, IL-9, IL-10, IL-15, G-CSF and GM-CSF were significantly reduced in AIS patients with poor outcome, compared to those with good prognosis. IL-6 was notably higher in the poor outcome group. Only IL-9 level decreased in the large infarct volume group. After adjusting for confounders, we found that IL-5 was an independent protective factor for prognosis in AIS patients with an adjusted OR of 0.042 (P = 0.007), whereas IL-6 was an independent risk predictor for AIS patients with an adjusted OR of 1.293 (P = 0.003). Our study suggests the levels of serum cytokines are related to stroke severity, short-term prognosis and cerebral infarct volume in AIS patients.

[Proliferation of MicroRNA-365 and E74-like Factor 4 in Cervical Cancer Cells and Its Clinical Significance].

Objective To investigate the expressions,roles,and clinical significance of microRNA-365(miR-365)and E74-like factor 4(ELF4)in cervical cancer. Methods The expressions of miR-365 in normal cervical tissues(n=34),cervical intraepithelial neoplasia 1(CIN 1)(n=31),cervical intraepithelial neoplasia2-3(CIN 2-3)(n=37),squamous cell carcinoma of the cervix(SCC)(n=33),and three cervical cancer cell lines(C33A cells,Hela cells,and SiHa cells)were detected by real-time quantitative polymerase chain reaction(qPCR).Bioinformatic prediction and luciferase reporter gene assay were performed to verify whether ELF4 was a direct target of miR-365.Western blot and immunohistochemistry were used to detect ELF4 expression in cervical cancer cells and in different pathological cervix tissues.CCK8 assay was used to detect the effect of overexpression or inhibition of miR-365 on the proliferation of cervical cancer cells at different time points.The relationships among the miR-365 expression,ELF4 expression,and clinicopathological parameters of cervical cancer were analyzed by correlation analysis. Results qPCR results showed that compared with the normal cervical cell HcerEpic,the expressions of miR-365 in CIN1,CIN2-3,and cervical cancer tissues gradually decreased with the increased pathologic grade,and its expressions also decreased in different cervical cancer cell lines.The luciferase reporter gene assay confirmed that ELF4 was the direct target of miR-365.Western blot showed that the expression of ELF4 increased in all three cervical cancer cell lines compared with normal cervical epidermal cell(P=0.013,P=0.002,P=0.004).Immunohistochemistry showed that ELF4 expression was up-regulated in CIN and cervical cancer tissues.CCK8 assay showed that overexpression of miR-365 inhibited cell proliferation,while inhibition of miR-365 promoted the proliferation of three cervical cancer cells(P<0.05).Further analysis confirmed that there was a negative correlation between the expression levels of miR-365 and ELF4 in CIN2-3 and SCC(r=-0.351,P=0.045;r=-0.349,P=0.035).Clinical analysis showed that the expressions of both miR-365 and ELF4 were correlated with tumor size,pathological grade,and clinical stage in SCC(all P < 0.05).Conclusion The decreased expression of miR-365 in human cervical cancer cells relieves its inhibitory effect on ELF4,which promotes the proliferation of cervical cancer cells and the formation of tumor.

Propensity Score-Matched Analysis of Lesion Patterns in Stroke Patients With Patent Foramen Ovale and Patients With Spontaneous Intracranial Artery Dissection.

Aims: To investigate the relationship between clinical and imaging features of stroke patients with patent foramen ovale (PFO) and those with spontaneous intracranial artery dissection (SIAD). Materials and methods: We retrospectively examined both clinical and imaging results of 40 stroke patients with PFO and 29 with SIAD. To reduce selection bias, we conducted a propensity score-matching analysis. The patients' propensity scores were estimated using a logistic regression model based on the following variables: age, sex, hypertension, diabetes mellitus, hypercholesterolemia, cigarette smoking, stroke histories, and their NIHSS scores. We compared the pattern of cerebral DWI lesions between patients with PFO and those with SIAD. Results: After propensity score matching, 21 pairs of patients were selected. Clinical characteristics of the 2 groups were well matched. The distribution of DWI lesion patterns differed between the 2 groups. Single lesions (cortical or subcortical) were more frequently observed in the PFO group than in the SIAD group (P = 0.026). Multiple lesions in one vascular territory occurred more frequently in the SIAD group than in the PFO group (P = 0.035). Conclusion: The present study suggests that lesion patterns observed from DWI of patients with PFO and SIAD might provide clues to the etiology of infarcts. Single lesions (cortical or subcortical) might be a typical feature of PFO associated strokes, while multiple lesions in one vascular territory might be a specific feature of SIAD associated strokes.

A comparison of contrast transthoracic echocardiography and contrast transcranial Doppler in cryptogenic stroke patients with patent foramen ovale.

OBJECTIVE: In recent years, increasing attention has been paid to cryptogenic stroke (CS) caused by the patent foramen ovale (PFO). This study aims to compare contrast transthoracic echocardiography (cTTE) and contrast transcranial Doppler (cTCD) to determine whether cTTE is more suitable and reliable than cTCD for clinical use. METHODS: From March 2017 to May 2018, patients who suffered from migraines, stroke, hypomnesis, or asymptomatic stroke found casually were included in our study. Patients with CS were semirandomly divided into two groups (cTTE and cTCD) according to the date of the outpatient visit. Patients with either of the examination above found positive were selected to finish transesophageal echocardiography (TEE). RESULTS: In our study, the sensitivities of group cTTE positive (group cTTE+) and group cTCD positive (group cTCD+) did not have any statistical difference (89% vs. 80%, p = 0.236). Focusing on group cTCD+, we discovered that the semiquantitative shunt grading was not correlated with whether a PFO was present or not (p = 0.194). However, once the PFO has been diagnosed, the shunt grading was shown to be related to the width of the gaps (p = 0.032, pdeviation  = 0.03). CONCLUSION: Both cTTE and the cTCD can be used for preliminary PFO findings. The semiquantitative shunt grading of cTCD and cTTE can suggest the size of the PFO and the next course of treatment. The cTTE may be more significant to a safe PFO (a PFO does not have right-to-left shunts, RLSs). Combining cTTE and TEE could help diagnose PFO and assess CS risk.