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.

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.

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.

Lipopolysaccharide reduces gonadotrophin-releasing hormone (GnRH) gene expression: role of RFamide-related peptide-3 and kisspeptin.

RFamide-related peptide (RFRP)-3 reduces luteinising hormone (LH) secretion in rodents. Stress has been shown to upregulate the expression of the RFRP gene (Rfrp) with a concomitant reduction in LH secretion, but an effect on expression of the gonadotrophin-releasing hormone (GnRH) gene (Gnrh1) has not been shown. We hypothesised that lipopolysaccharide (LPS)-induced stress affects expression of Rfrp, the gene for kisspeptin (Kiss1) and/or Gnrh1, leading to suppression of LH levels in rats. Intracerebroventricular injections of RFRP-3 (0.1, 1, 5 nmol) or i.v. LPS (15µgkg-1) reduced LH levels. Doses of 1 and 5 nmol RFRP-3 were then administered to analyse gene expression by in situ hybridisation. RFRP-3 (5 nmol) had no effect on Gnrh1 or Kiss1 expression. LPS stress reduced GnRH and Kiss1 expression, without affecting Rfrp1 expression. These data indicate that LPS stress directly or indirectly reduces Gnrh1 expression, but this is unlikely to be due to a change in Rfrp1 expression.

[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.

Guillain-Barré syndrome in southern China: retrospective analysis of hospitalised patients from 14 provinces in the area south of the Huaihe River.

OBJECTIVES: The clinical and epidemiological profiles of Guillain-Barré syndrome (GBS) in southern China have yet to be fully recognised. We aimed to investigate the subtypes of GBS in southern China, compare the clinical features of demyelinating form with that of axonal form and test whether preceding infections and age have influence on the clinical phenotype, disease course and severity of GBS. METHODS: Medical records of patients with a diagnosis of GBS admitted to 31 tertiary hospitals, located in 14 provinces in southern China, from 1 January 2013 to 30 September 2016, were collected and retrospectively reviewed. RESULTS: Finally. 1056 patients, including 887 classic GBS and 169 variants, were enrolled. The 661 classic patients with available electromyographic data were grouped as having acute inflammatory demyelinating polyneuropathy (AIDP, 49.0%), acute motor axonal neuropathy (AMAN, 18.8%), inexcitable (0.9%) and equivocal (31.3%). In contrast to AIDP, patients with AMAN were characterised by earlier nadir (P=0.000), higher Hughes score at nadir (P=0.003) and at discharge (P=0.000). Preceding upper respiratory infections were identified in 369 (34.9%) patients, who were more inclined to develop AIDP (P=0.000) and Miller-Fisher syndrome (P=0.027), whereas gastrointestinal infection were found in 89 (8.4%) patients, who were more prone to develop AMAN (P=0.000), with more severe illness (P=0.001) and longer hospital stay (P=0.009). Children (≤15 years) and the elderly (≥56 years) were more severe at nadir, the elderly had the longest hospital stay (P=0.023). CONCLUSION: AIDP is the predominant form in southern China, which is different from data of northern China. The different subtypes, preceding infection and age of onset can partially determine the disease progression, severity and short-term recovery speed of GBS. CLINICAL TRIAL REGISTRATION: ChiCTR-RRC-17014152.

Correlation of Changes in Leukocytes Levels 24 Hours after Intravenous Thrombolysis With Prognosis in Patients With Acute Ischemic Stroke.

OBJECTIVE: Leukocytes play a crucial role in inflammation and immune response. This study aims to demonstrate the value of changes in leukocytes levels 24 hours after intravenous thrombolysis to predict prognosis in acute ischemic stroke (AIS). METHODS: From Jan 2016 to Oct 2017, the patients who suffered AIS to our center within 4.5 hours of symptom onset were all treated with recombinant tissue-type plasminogen activator. Data from 213 AIS patients were analyzed. Patients were divided into 4 groups: persistent leukocytosis (PL), transient leukocytosis (TL), leukocytosis 24 hours (L24H) and no leukocytosis (NL). By comparison, the factors with statistically significant were selected in pairwise multiple comparisons. Good clinical outcome was defined as the Modified Rankin Scale score of 2 or lower. Multivariate logistic regression was used to assess the association of the indicators with clinical outcome. RESULTS: By pairwise multiple comparisons, PL and L24H had higher baseline National Institutes of Health Stroke Scale (NIHSS) score than NL and were likely to lead poor clinical outcomes. TL had a better prognosis than L24H. As the results of multivariable analyses shown, PL and L24H were risk factors to poor functional outcomes (odds ratio [OR] = 2.668, 95% confidence interval [CI] = 1.139-6.249, P = .024; OR = 6.648, 95%CI = 2.048-21.584, P = .002). CONCLUSION: Persistent leukocytosis and leukocytosis 24 hours both had higher baseline NIHSS scores, more serious stroke and were more likely to lead to unfavorable outcome. Therefore, changes in leukocytes levels 24 hours after intravenous thrombolysis could be predicted the short-term functional outcome of AIS patients.

Soluble lectin-like oxidized low-density lipoprotein receptor-1 as a novel biomarker for large-artery atherosclerotic stroke.

BACKGROUND: Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) has been shown associated with the progression of atherosclerosis in endothelial cells. We sought to assess whether the baseline serum sLOX-1 levels are correlated with the presence and short-term functional outcome of large-artery atherosclerotic (LAA) stroke. METHODS: The study recruited 241 subjects, including 148 consecutive patients with acute ischemic stroke with the subtype of LAA and 93 non-stroke controls. Clinical and laboratory data, including serum concentration of sLOX-1, were collected within 24 h of admission, and the severity of LAA stroke patients was evaluated by National Institutes of Health Stroke Scale score. And functional outcome was assessed by modified Rankin Scale three months after stroke. The association between sLOX-1 level and the functional outcome at three months was analyzed by multiple logistic regression models. RESULTS: Serum levels of sLOX-1 in the LAA stroke patients were significantly higher as compared to normal controls (2.48 ± 0.93 ng/ml vs. 2.22 ± 0.79 ng/ml in the controls, t = 2.301, p = 0.022). The levels of serum sLOX-1 in patients with good outcome were significantly lower than those with poor outcome (2.39 ± 0.94 ng/ml vs. 2.77 ± 0.84 ng/ml, p = 0.032). After adjusting for potential confounders, sLOX-1 was still an independent predictor for the function outcome with an adjusted OR of 3.39 (95% CI, 1.61-7.11, p = 0.001). CONCLUSIONS: The serum sLOX-1 level was higher in patients with LAA stroke, and it was an independent predictor of functional outcome in patients with LAA ischemic stroke.

Neutrophil-to-Lymphocyte Ratio Is a Prognostic Marker in Acute Ischemic Stroke.

BACKGROUND: Neutrophil-to-lymphocyte ratio is an independent predictor of mortality in patients with acute ischemic stroke. However, it is uncertain whether neutrophil-to-lymphocyte ratio is related with functional outcome and recurrent ischemic stroke. In this study, we aimed to investigate the relationship of neutrophil-to-lymphocyte ratio with stroke severity, functional outcome, and recurrent ischemic stroke after acute ischemic stroke. METHODS: A total of 280 patients with acute ischemic stroke were included in the study. Patients were divided into 3 groups according to the neutrophil-to-lymphocyte ratio value (<2, 2-3, >3). Demographic, clinical, and laboratory data were collected for all patients. We evaluated the association between neutrophil-to-lymphocyte ratio and (1) stroke severity on admission, (2) functional outcome at 3 months, and (3) recurrent ischemic stroke. Regression analyses were performed, adjusting for confounders. RESULTS: After adjustment for potential confounders, neutrophil-to-lymphocyte ratio was associated with an increased risk of stroke severity on admission (odds ratio [OR] 1.364, 95% confidence interval [CI] 1.101-1.690, P = .005) and primary unfavorable outcome (OR 1.455, 95% CI 1.083-1.956, P = .013). After a median of 1.13 years (interquartile range.91-1.42) of follow-up, neutrophil-to-lymphocyte ratio was associated with recurrent ischemic stroke after adjustment (hazard ratio 1.499, 95% CI 1.161-1.935, P = .002). CONCLUSIONS: Our study suggests that neutrophil-to-lymphocyte ratio is associated with stroke severity on admission, primary unfavorable functional outcome, and recurrent ischemic stroke in patients with acute ischemic stroke.

Does Prior Antiplatelet Treatment Increase the Risk of Hemorrhagic Transformation and Unfavorable Outcome on Day 90 after Intravenous Thrombolysis in Acute Ischemic Stroke Patients?

BACKGROUND: The effect of prior antiplatelet (AP) therapy on the risk of hemorrhagic transformation (HT), and on functional outcomes of acute ischemic stroke (AIS) after intravenous thrombolysis (IVT), is not known. We performed a retrospective analysis to determine whether history of AP therapy is associated with post-thrombolysis HT and poor prognosis in AIS patients. METHODS: Data pertaining to 145 patients with AIS, who underwent IVT between October 2008 and January 2015, were analyzed. The patients were divided into 2 groups based on whether or not they had received prior AP therapy. Neurological outcomes at 24 hours and 3 months after IVT therapy were assessed. Intergroup difference in cost of treatment was also evaluated. A multivariate logistic regression model was used to identify independent predictors of post-thrombolysis HT. RESULTS: Among 145 patients, 23 (15.8%) had received prior AP therapy. On multivariate analyses, older age (odds ratio [OR]: 1.084; confidence interval [CI], 1.028-1.144) and prior AP therapy (OR: 3.318; CI, 1.172-9.398) were found to be independent predictors of HT. CONCLUSION: In this study, prior AP therapy was independently associated with post-thrombolysis HT in AIS.

Glial scar formation occurs in the human brain after ischemic stroke.

Reactive gliosis and glial scar formation have been evidenced in the animal model of ischemic stroke, but not in human ischemic brain. Here, we have found that GFAP, ED1 and chondroitin sulphate proteoglycans (CSPG) expression were significantly increased in the cortical peri-infarct regions after ischemic stroke, compared with adjacent normal tissues and control subjects. Double immunolabeling showed that GFAP-positive reactive astrocytes in the peri-infarct region expressed CSPG, but showed no overlap with ED1-positive activated microglia. Our findings suggest that reactive gliosis and glial scar formation as seen in animal models of stroke are reflective of what occurs in the human brain after an ischemic injury.

Differential lesion patterns on T2-weighted magnetic resonance imaging and fluid-attenuated inversion recovery sequences in cryptogenic stroke patients with patent foramen ovale.

BACKGROUND: The present study aimed to determine lesion patterns and the stroke mechanisms in cryptogenic ischemic stroke patients with patent foramen ovale (PFO) on T2-weighted magnetic resonance imaging (T2WI) and fluid-attenuated inversion recovery (FLAIR) sequences combined. METHODS: In this retrospective study, 38 patients with cryptogenic stroke and an isolated PFO compared with 51 cryptogenic stroke patients without PFO were evaluated and their characteristics of lesion patterns on T2WI and FLAIR sequences combined were investigated. The number, distribution of small ischemic lesions, and the frequency of multiple small ischemic lesions were analyzed between the 2 groups. RESULTS: Thirty-two of 38 patients had a total of 341 small ischemic lesions in cryptogenic stroke patients with PFO versus 24 of 51 patients with 156 small ischemic lesions in patients without PFO, and, 8.97±7.91 and 3.19±4.82 ischemic lesions per person, respectively. Multiple small ischemic lesions occurred more frequently in cryptogenic stroke patients with PFO (25 of 38 patients, 66%) than in patients without PFO (16 of 51 patients, 31%; P=.001). Subcortical frontal and parietal small lesions were more frequent in cryptogenic stroke patients with PFO (28 of 38 patients, 74%) than in patients without PFO (18 of 51 patients, 35%; P<.0001). CONCLUSIONS: Multiple small ischemic lesions and subcortical frontal and parietal small lesions were significantly associated with cryptogenic stroke patients with PFO, suggesting that paradoxical embolism may be the mechanism of PFO-associated cryptogenic stroke patients.

[Investigation of a family with Kennedy disease by genetic analysis].

OBJECTIVE: To report on a Chinese family from Wenzhou with genetically confirmed Kennedy disease and describe its clinical and genetic features. METHODS: The clinical phenotype and the level of relevant biochemical markers were assessed. To determine the number of CAG repeats in the exon 1 of androgen receptor (AR) gene, genomic DNA was extracted from peripheral blood samples of the family members, amplified by PCR and identified by DNA sequencing. RESULTS: The proband showed predominantly proximal limb weakness, fasciculation, muscle atrophy, gynecomastia, sexual dysfunction and increased serum creatine kinase. Myopathy and neuropathy were identified by electromyography. Two other affected males and 2 affected female carriers were identified to carry an expanded CAG repeat in the AR gene. The numbers of CAG repeats were found to be 43 in the proband, 43 and 42 in the other two affected males, one of which had similar clinical symptoms to the proband. CONCLUSION: The family was diagnosed with Kennedy disease by analysis of the AR gene.

Identification of Tau and SOD1 gene mutation in a small Chinese Han pedigree of adult amyotrophic lateral sclerosis.

We report the clinical profile, and a brief investigation of SOD1 and Tau gene mutation from a small Chinese Han pedigree of adults with amyotrophic lateral sclerosis (ALS), which consisted of 32 familial members with 6 affected individuals spanning five generations, and presenting autosomal dominant genetic mode. The mean age of onset was 36.6 ± 15.9 years, and disease duration was 6 months to more than 5 years, the average survival was 16.1 ± 8.2 months. There were 5 patients with an early disease onset, rapid progressive course and short survival, and 1 patient with late onset, slow progressive course and long survival in the kindred. ALS patients began to suffer with weakness and muscle atrophy in one side of a lower extremity, which then spread to the upper extremity, the opposite side and bulbar muscles. All patients had spinal onset type. Muscle stretch reflexes were absent or weak in the upper limbs and accentuation in the lower limbs; pathological signs in the lower limbs were positive. Electromyography disclosed ongoing denervation muscle potentials in the four extremities. Brain and spinal MRI did not show any abnormal signal. A 5 exons mutation of SOD1 in all affected individuals was identified using SSCP. Polymorphisms of partial risk regions in 3',5' UTR, and in introns 9, 10, 11, 12 of the Tau gene in the affected and normal family members and in 70 healthy controls were examined by DNA sequencing. Routine exons mutation of SOD1 was not detected, but one single nucleotide polymorphism of A to G at 138278 at 3' UTR of the Tau gene was shown to significantly over-express in fALS familial members.

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.

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.

TGF-beta 1 codon 10 polymorphism is associated with cerebral SVD.

BACKGROUND: To clarify the role of inflammation in the pathogenesis of cerebral small vessel disease (SVD), we investigated whether the gene encoding transforming growth factor-beta 1(TGF-beta 1) is a risk factor for cerebral SVD as a whole, and for two different SVD subtypes. METHODS: TGF-beta 1 codon10 (T+29C) genotype was determined in 441 Chinese patients (313 male and 128 female) with cerebral SVD and 450 control subjects (326 male and 124 female). Cerebral SVD patients were retrospectively classified into two groups based on neuroimaging findings: lacunar infarction group with 112 patients and ischaemic leukoaraiosis group with 329 patients. RESULTS: Subjects carrying TT homozygote were susceptible to cerebral SVD [adjusted odds ratio (OR) =1.44, 95% confidence interval (CI), 1.05-1.98; P=0.026]. Further analysis of SVD subtypes revealed a moderate association with the ischaemic leukoaraiosis group [OR= 1.60, 95% CI, 1.14-2.25; P=0.007]. CONCLUSIONS: Codon 10 of TGF-beta 1 might be a risk factor for SVD, specifically in ischaemic leukoaraiosis phenotype.

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.