Association between high-resolution magnetic resonance vessel wall imaging characteristics and recurrent stroke in patients with intracranial atherosclerotic steno-occlusive disease: A prospective multicenter study.

BACKGROUND: High-resolution magnetic resonance vessel wall imaging (HRMR-VWI) is a promising technique for identifying intracranial vulnerable plaques beyond lumen narrowing. However, the association between HRMR-VWI characteristics and recurrent stroke remains uncertain. AIMS: This study aimed to investigate the association between HRMR-VWI characteristics and recurrent ipsilateral stroke in patients with symptomatic intracranial atherosclerotic steno-occlusive disease (ICAS). METHODS: This multicenter, observational study recruited first-ever acute ischemic stroke patients attributed to ICAS (>50% stenosis or occlusion) within 7 days after onset. Participants were assessed by multiparametric magnetic resonance imaging (MRI) including diffusion-weighted imaging, three-dimension time-of-flight magnetic resonance angiography, and three-dimensional T1-weighted HRMR-VWI. The patients were recommended to receive best medical therapy and were systematically followed up for 12 months. The association between HRMR-VWI characteristics and the time to recurrent ipsilateral stroke was investigated by univariable and multivariable analysis. RESULTS: Two hundred and fifty-five consecutive patients were enrolled from 15 centers. The cumulative 12 month ipsilateral recurrence incidence was 4.1% (95% confidence interval (CI): 1.6-6.6%). Patients with recurrent ipsilateral stroke exhibited higher rates of intraplaque hemorrhage (IPH) (30.0% vs 6.5%) and eccentric plaque (90.0% vs 48.2%), and lower occurrence of occlusive thrombus (10.0% vs 23.7%). Plaque length (5.69 ± 2.21 mm vs 6.67 ± 4.16 mm), plaque burden (78.40 ± 7.37% vs 78.22 ± 8.32%), degree of stenosis (60.25 ± 18.95% vs 67.50% ± 22.09%) and remodeling index (1.07 ± 0.27 vs 1.03 ± 0.35) on HRMR-VWI did not differ between patients with and without recurrent ipsilateral stroke. In the multivariable Cox regression analysis, IPH (hazard ratio: 6.64, 95% CI: 1.23-35.8, p = 0.028) was significantly associated with recurrent ipsilateral stroke after adjustment.Conclusions:Our results suggest intraplaque hemorrhage (IPH) is significantly associated with recurrent ipsilateral stroke and has potential value in the selection of patients for aggressive treatment strategies. DATA ACCESS STATEMENT: Data from this study are available and can be accessed upon request.

Drug-related problems among community-dwelling elderly with ischemic stroke in China.

BACKGROUND: Ischemic stroke incidence is increasing amongst elderly patients in China; this is closely associated with drug-related problems (DRPs). OBJECTIVES: To evaluate the influencing factors of DRPs among elderly patients with a history of ischemic stroke in the Chinese community and the role clinical pharmacists play in providing solutions. MATERIAL AND METHODS: This study was conducted in 2 community health service centers in Putuo District, Shanghai, China, between December 2018 and June 2019. Demographics and clinical characteristics of the 130 selected patients were collected. Drug-related problems were classified using the Pharmaceutical Care Network Europe (PCNE)-DRP V8.03 classification system. The number, types, causes, interventions, and status of DRPs were then analyzed. RESULTS: The average number of DRPs per patient was 1.3, corresponding to 256 causes. "Treatment effectiveness P1" was identified as the most common problem (75.0%). The main causes were "drug selection C1" (33.2%) and "patient-related C7" (30.9%). Antihypertensive drugs, statins, aspirin, and Chinese patent medicines were the top 4 drugs for DRPs. Age, unintentional medication discrepancy and medication compliance were independent predictors of DRPs. Pharmacists provided 339 interventions, mainly "at drug level I3" (38.9%) and "at patient level I2" (30.7%). Most of the interventions (85.5%) were accepted by the patients and 65.9% of the problems were solved. CONCLUSIONS: The number, types and etiology of DRPs in elderly patients with ischemic stroke in our community are diverse and treatment effectiveness is the main cause of their occurrence. Clinical pharmacists play an important role in providing interventions for major causes of DRPs.

Maraviroc, an inhibitor of chemokine receptor type 5, alleviates neuroinflammatory response after cerebral Ischemia/reperfusion injury via regulating MAPK/NF-κB signaling.

Neuroinflammation is a key factor that contributes to the secondary damage after cerebral ischemia/reperfusion (CI/R) injury. Chemokine receptor type 5 (CCR5) has shown its pro-inflammatory effects during central nervous system (CNS) diseases. However, the role of CCR5 in CI/R injury is still unclear. In this study, we administered maraviroc (MVC, APEXBIO, UK-427857), a CCR5 antagonist, to the middle cerebral artery occlusion (MCAO) mice. In vivo studies showed that MVC was successively intraperitoneally (i.p.) injected with doses (20 mg/kg body weight) for 3 days after mice MCAO. MVC showed its neuroprotective effects in alleviating neurological deficits and infarct volumes after MCAO. The level of apoptosis and inflammation were remarkably decreased by MVC treatment after CI/R injury. Subsequently, primary microglia cells were stimulated with doses of MVC (20 nM) for 12 h after oxygen-glucose deprivation/reoxygenation model (OGD/R) in vitro. MVC significantly increased the viability of primary microglia after OGD/R. The expression of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) in microglia was down-regulated by MVC treatment. Mechanistically, MVC also inhibited the secretion of these cytokines by microglia after OGD stimulation. Furthermore, the key components of NF-κB pathway were measured in vivo and in vitro after MCAO and OGD. MVC significantly inhibited the activity of NF-κB pathway in the above pathological environments. Finally, our data indicated that MVC treatment decreased the activation of JNK signaling pathway after CI/R injury in vivo and in vitro. The JNK activator anisomycin (AN, Beyotime, SC0132) reversed the neuroprotective effects of MVC, indicating that the JNK pathway is involved in the anti-inflammatory and anti-apoptotic mechanisms of MVC in CI/R injury. Our data demonstrated that CCR5 inhibition exhibits neuroprotective effects after CI/R injury. MVC, which is widely used for HIV treatment by its anti-virus effect, is a potential drug for the treatment of ischemic stroke in the future clinical trials. MVC has been widely used in HIV treatment which showed its safety. Based on its anti-inflammatory and anti-apoptotic mechanisms, we speculate that MVC may be a potential drug for treating ischemic stroke in future clinical trials.

Correlation Between Plasma Levels of RIP3 and Acute Ischemic Stroke with Large-Artery Atherosclerosis.

BACKGROUND: Receptor-interacting serine-threonine protein kinase 3 (RIP3) was previously discovered to be an important medium in the occurrence and development of major atherosclerotic cerebral infarction. However, the role of RIP3 in acute ischemic stroke remains unclear. OBJECTIVE: This study aimed to explore the correlation between plasma levels of RIP3 and acute ischemic stroke with large-artery atherosclerosis (LAA). METHODS: This prospective study enrolled 116 patients with LAA, 40 healthy controls, and 30 acute ischemic stroke patients with small-artery occlusion. The patients with LAA were divided according to the quartile of plasma levels of RIP3. A logistic regression model was used for comparison. The ROC curve was performed to evaluate the predictive value. RESULTS: In patients with LAA, the RIP3 levels in patients with poor outcomes as well as neurological deterioration were significantly higher than those with good outcomes (P < 0.001) and without neurological deterioration (P = 0.014). Patients in the highest levels of plasma RIP3 quartile were more likely to have neurological deterioration (OR, 11.07; 95% CI, 1.990-61.582) and poor outcomes (OR, 35.970; 95% CI, 5.392-239.980) compared with the lowest. The optimal cut-off value for neurological deterioration was 1127.75 pg/mL (specificity, 66.7%; sensitivity, 69.2%) and that for poor prognosis was 1181.82 pg/mL (specificity, 89.7%; sensitivity, 62.1%). CONCLUSION: Elevated levels of plasma RIP3 were significantly associated with neurological deterioration and poor prognosis in patients with LAA. A significant increase in plasma RIP3 levels can predict neurological deterioration and the poor prognosis of these patients.

Serum Exosomal mir-340-5p Promotes Angiogenesis in Brain Microvascular Endothelial Cells During Oxygen-Glucose Deprivation.

Ischemic stroke (IS) is a cerebrovascular disease with high morbidity, recurrence, and mortality. The purpose of the present study was to investigate the role and mechanism of human serum exosomes on angiogenesis after IS. The middle cerebral artery occlusion (MCAO) in vivo model and oxygen-glucose deprivation (OGD) in vitro model were established. Human serum exosomes from healthy samples (NC-exo) and IS samples (IS-exo) were injected into MCAO mice. Neurobehavioral tests were performed to assess the extent of neurological deficits. The infarct volume was assessed by 2,3,5-triphenyl tetrazolium chloride (TTC) staining, and the levels of inflammatory cytokines were analyzed by enzyme-linked immunosorbent assay (ELISA). In addition, human serum exosomes were cocultured with brain microvascular endothelial cells (BMECs). Cell Counting Kit-8 (CCK-8), Transwell, and tubule formation assays were performed to investigate the proliferation, migration, invasion, length, and branching of BMECs. The miRNA expression profiles of NC-exo and IS-exo were analyzed by high-throughput sequencing and compared. Bioinformatics and luciferase reporter assays were performed to evaluate the relationship between miR-340-5p and CD147. Serum NC-exo and IS-exo had protective effects on IS injury and promoted BMEC angiogenesis. Interestingly, the protective effect of IS-exo was weaker than that of NC-exo. In addition, miR-340-5p was downregulated in IS-exo, and miR-340-5p accelerated angiogenesis of BMECs after OGD. Mechanistically, CD147 was confirmed as a direct target of miR-340-5p. Finally, miR-340-5p promoted angiogenesis by directly targeting CD147. Serum exosome-derived miR-340-5p promote angiogenesis in OGD-induced BMECs by targeting CD147.

Effects of home medication review on drug-related problems and health-related quality of life among community-dwelling older adults in China.

BACKGROUND: There is a lack of research on the nature of drug-related problems (DRPs) in older adult communities in China and the impact of home medication review on DRP reduction and health-related quality-of-life (HRQoL) improvement. OBJECTIVES: To identify and categorize DRPs in older adults in China and to assess the impact of home medication review. METHODS: The prospective study was conducted in 2 community health service centers in Shanghai, China from December 2018 to December 2019. Eligible patients received a home medication review by a clinical pharmacist to assess for DRPs and adherence, propose pharmaceutical interventions, and measure outcomes of HRQoL. All enrolled patients were followed up for 3 months. RESULTS: Medication use in 412 patients was analyzed. A total of 362 DRPs were identified, an average of 0.88 per patient. Treatment effectiveness was the primary DRP type (249; 68.8%). The most common causes of DRPs were patient-related (35.1%) and drug selection (31.0%). Pharmacists made 733 interventions, an average of 2 per DRP. A total of 82.1% of these interventions were accepted. At a 3-month follow-up, home medication review led to a statistically significant reduction in the mean number of DRPs (0.4 vs. 0.88, P < 0.001) and an increase in medication adherence (1.42 vs. 0.85, P < 0.001). Both HRQoL indicators also improved, EuroQol 5 Dimension scale (0.75 vs. 0.78, P < 0.001) and EuroQol-visual analog scale (70 vs. 77.65, P < 0.001). CONCLUSION: Home medication review is a practical means to optimize drug therapy and improve patients' HRQoL in community settings.

The first reported outbreak of an undetermined species of human infection with spotted fever group Rickettsia in Lu'an, China.

OBJECTIVE: On May 2, 2017, an outbreak of unexplained fever with rashes was reported in Lu'an, China. In this study, we aimed to identify the possible pathogens, epidemiological characteristics, and risk factors of this outbreak. METHODS: We conducted descriptive field epidemiological studies. Blood samples were tested using an indirect immunofluorescence assay for Rickettsia rickettsii antibody, and nested polymerase chain reaction and gene sequencing assays were performed. RESULTS: We recruited 39 cases who had symptomatic onset from April 20 to June 8, 2017. Among these, 9 were suspected cases, 18 were probable cases, and 12 were confirmed cases. No one died. The main clinical manifestations were fever (100%), rash (100%), fatigue (97.3%), myalgia (83.8%), and anorexia (83.8%). None of the patients died. Thirty-seven patients who were treated with antibiotics during hospitalization showed significant improvement. The cases were distributed across 14 townships in 2 counties. The median age was 59 (43.0-81.0) years, of which 93.3% had a history of tea picking (28/30), and 77.3% (17/22) had a history of tick bites. The mean incubation period was 5.0 days (2.0-13.0 days). Serum IgG titers were higher in convalescent patients than in the general population (p = 0.016). Phylogenetic analysis revealed that the ompA sequences of Rickettsia sp. Lu'an-2018 had an 86.8%-99.0% sequence identity with the 23 strains of Rickettsia found worldwide. CONCLUSIONS: This was the first reported outbreak of an undetermined species of a human infection with the spotted fever group of Rickettsia in China, which might be caused by ticks biting local residents when picking tea.

Nursing postoperative lung cancer patients using continuous positive airway pressure treatment.

OBJECTIVE: This study aimed to investigate the nursing of postoperative lung cancer patients treated with continuous positive airway pressure (CPAP). METHODS: A total of 64 lung cancer patients in our hospital were recruited as the study cohort and randomly divided into a CPAP group and a control group. The patients in the CPAP group (n=30) were administered CPAP, while those in the control group (n=34) were given routine low flow oxygen inhalation, a respiratory stimulant, a bronchodilator, antibiotics, antitussives, anti-inflammatories (glucocorticoids), an apophlegmatisant (ambroxol), basic nutritional support, correcting acidosis, etc. Results: The patients in the CPAP group showed a more significant improvement in their blood gas analysis, and they also had better airway patency and secretion cleaning effects compared with those in the control group. One month after the treatment, the patients in the CPAP group had significantly less inappetence, weight loss, electrolyte disturbance, dyspnea, and pulmonary encephalopathy than the patients in the control group. One week after the treatment, the patients in the CPAP group had higher maximum ventilatory volumes (MVV), higher maximum mid-expiratory flows (MMF), higher forced expiratory volumes in 1s/forced vital capacity (FEV1/FVC), higher peak expiratory flows (PEF), and higher total lung capacity (TLC) than the patients in the control group. CONCLUSION: CPAP can significantly improve postoperative dyspnea in lung cancer patients.

Targeting connexin 43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling.

BACKGROUND: In the central nervous system (CNS), connexin 43 (Cx43) is mainly expressed in astrocytes and regulates astrocytic network homeostasis. Similar to Cx43 overexpression, abnormal excessive opening of Cx43 hemichannels (Cx43Hcs) on reactive astrocytes aggravates the inflammatory response and cell death in CNS pathologies. However, the role of excessive Cx43Hc opening in intracerebral hemorrhage (ICH) injury is not clear. METHODS: Hemin stimulation in primary cells and collagenase IV injection in C57BL/6J (B6) mice were used as ICH models in vitro and in vivo. After ICH injury, the Cx43 mimetic peptide Gap19 was used for treatment. Ethidium bromide (EtBr) uptake assays were used to measure the opening of Cx43Hcs. Western blotting and immunofluorescence were used to measure protein expression. qRT-PCR and ELISA were used to determine the levels of cytokines. Coimmunoprecipitation (Co-IP) and the Duolink in situ proximity ligation assay (PLA) were applied to measure the association between proteins. RESULTS: In this study, Cx43 expression upregulation and excessive Cx43Hc opening was observed in mice after ICH injury. Delayed treatment with Gap19 significantly alleviated hematoma volume and neurological deficits after ICH injury. In addition, Gap19 decreased inflammatory cytokine levels in the tissue surrounding the hematoma and decreased reactive astrogliosis after ICH injury in vitro and in vivo. Intriguingly, Cx43 transcriptional activity and expression in astrocytes were significantly increased after hemin stimulation in culture. However, Gap19 treatment downregulated astrocytic Cx43 expression through the ubiquitin-proteasome pathway without affecting Cx43 transcription. Additionally, our data showed that Gap19 increased Yes-associated protein (YAP) nuclear translocation. This subsequently upregulated SOCS1 and SOCS3 expression and then inhibited the TLR4-NFκB and JAK2-STAT3 pathways in hemin-stimulated astrocytes. Finally, the YAP inhibitor, verteporfin (VP), reversed the anti-inflammatory effect of Gap19 in vitro and almost completely blocked its protective effects in vivo after ICH injury. CONCLUSIONS: This study provides new insight into potential treatment strategies for ICH injury involving astroglial Cx43 and Cx43Hcs. Suppression of abnormal astroglial Cx43 expression and Cx43Hc opening by Gap19 has anti-inflammatory and neuroprotective effects after ICH injury.

The associations between serum vitamin D, calcium and uterine fibroids in Chinese women: a case-controlled study.

OBJECTIVE: To investigate the associations between serum vitamin D, calcium and uterine fibroids in a Chinese female population. METHODS: In this case-control study, adult female patients with fibroids (cases) were compared with females without fibroids (controls) in terms of serum 25-hydroxyvitamin D (25OHD) and calcium levels. RESULTS: Out of 546 total participants (mean age, 41.68 ± 5.99 years; 279 with fibroids and 267 without fibroids), only 232 had serum 25OHD levels above the sufficient threshold (>20 ng/ml). In addition, females with fibroids had lower serum 25OHD levels versus those without fibroids. The prevalence of fibroids in females with deficient (<12 ng/ml) and insufficient (12-20 ng/ml) 25OHD levels were significantly higher than in females with sufficient (>20 ng/ml) 25OHD levels. Serum calcium levels were within normal range in both groups. CONCLUSION: Hypovitaminosis D was highly prevalent among a population of Chinese females of reproductive-age, and serum 25OHD levels were lower in female patients with fibroids.

Echinocystic acid provides a neuroprotective effect via the PI3K/AKT pathway in intracerebral haemorrhage mice.

BACKGROUND: Echinocystic acid (EA), a natural extract from plants of Gleditsia sinensis Lam, exhibits anti-inflammatory, antioxidant and analgesic activities in different diseases. In this study, we explored the pharmacological effects of EA on intracerebral haemorrhage (ICH) in a collagenase-induced ICH mouse model. METHODS: EA (50 mg/kg, i.p. q.d) was injected after the establishment of ICH, and we measured the amount of degraded neurons in brain tissue with Fluoro-Jade C staining and the haemorrhagic injury volume with Luxol fast blue staining on day 3 after ICH. We also assessed animal behaviour by rotarod test, claw force test and modified neurological severity score (mNSS) score. The expression of apoptosis-related proteins such as Bcl-2, Bax and cleaved caspase-3 was analysed by Western blot. RESULTS: EA reduced both the death of neurons and the volume of haemorrhagic injury after ICH. The haemorrhage infarct volume of the ICH+EA group was 9.84%±3.32% lower than that in the ICH group of mice (P<0.01). The mNSS score of the ICH+EA treated group was 4.75±0.55 lower than that in the ICH group (P<0.01). With the administration of EA after ICH, the expression of Bcl-2 was upregulated while the Bax level was downregulated. The cleaved caspase-3 level was also significantly decreased. We further investigated the neuroprotective mechanism of EA. Western blot results showed that the expression of P-AKT increased after EA treatment and decreased after LY294002, an inhibitor of the PI3K/AKT pathway, treatment. CONCLUSIONS: EA may provide neuroprotection via activation of the PI3K/AKT pathway. Given the safety of EA has been proven, further studies are required to investigate whether EA is a potential agent for the treatment of ICH.

Design of stroke imaging package study of intracranial atherosclerosis: a multicenter, prospective, cohort study.

BACKGROUND: Intracranial atherosclerosis (ICAS) is a major cause of stroke worldwide. However, much remains unknown regarding its underlying pathophysiology. High-resolution magnetic resonance imaging (HR-MRI) can clearly display intracranial vessel wall lesions in vivo. The aim of stroke imaging package study of ICAS (SIPS-ICAS) study is to explore the stroke mechanisms of symptomatic ICAS, the dynamic changes under aggressive medical treatment and their associations with clinical events using conventional MRI sequences plus HR-MRI. METHODS: This is a multicenter, prospective, cohort study recruiting first-ever acute ischemic stroke patients attributed to intracranial large artery stenosis (>50% or occlusion). Subjects undergo a pre-designed stroke imaging packages at baseline and are recommended to receive aggressive medical treatments. Participants will be followed up for functional outcome, stroke recurrence, and death events at 3, 6 and 12 months and retake HR-MRI imaging at 6 months. RESULTS: Enrollment began in November 2018 and 96 patients have been enrolled as of September 2019. CONCLUSIONS: The SIPS-ICAS study will provide insights into the pathophysiology of ICAS and identify specific imaging markers for risk stratification and prognosis prediction. At the same time, the feasibility and validity of the new stroke imaging package including HR-MRI will be assessed, which is promising for clinical routine use.

Paris saponin VII extracted from Trillium tschonoskii induces autophagy and apoptosis in NSCLC cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Trillium tschonoskii Maxim, a perennial herb of the Trilliaceae, has been widely used to treat inflammation, hypertension and cancer. We investigated Paris saponin VII's (PS VII), isolated from Trillium tschonoskii Maxim, function in mediating autophagy and apoptosis in NSCLC cells. MATERIALS AND METHODS: We treated various NSCLC cells with different concentrations of PS Ⅶ and then measure the cell apoptosis by using flow cytometry assays and western blot. Autophagy were investigated by using western blot, transmission electron microscopy and immunofluorescence analysis. We also use a xenograft model of nude mice to measure the effect of PS Ⅶ in vivo. RESULTS: Treatment with PS Ⅶ significantly inhibit NSCLC cell growth, especially for A549 (IC50 = 1.53 µM). Moreover, PS VII induces caspase-dependent apoptosis and autophagy through AMPK-ULK1 pathway. After blocking autophagy by 3-methyladenine (3-MA), PS VII induced cell death was significantly increased. In vivo, the co-treatment with PS VII and 3-MA dramatically inhibited A549 tumor growth in immune deficient mice and has similar inhibition rates as cisplatin group. CONCLUSION: Our results suggest that a combination of PS VII and autophagy inhibitor may be a potential anticancer strategy in the NSCLC therapy.

Predictive value of the THRIVE score for outcome in patients with acute basilar artery occlusion treated with thrombectomy.

BACKGROUND AND PURPOSE: A higher Totaled Health Risks in Vascular Events (THRIVE) score has been shown to predict poor functional outcome in patients with acute ischemic stroke (AIS) and anterior circulation large vessel occlusions undergoing thrombectomy treatment. We attempted to evaluate the value of the THRIVE score in predicting the outcome of thrombectomy treatment in AIS patients with basilar artery occlusion (BAO). METHODS: A total of 68 AIS patients with BAO who underwent thrombectomy treatment from May 2014 to August 2018 were included in the present study. Multivariable logistic regression was performed to determine the predictive value of the THRIVE score for poor functional outcome (defined as modified Rankin Scale score ≥ 3), all-cause mortality, and hemorrhage transformation (HT) at 3 months. RESULTS: A total of 42 (61.8%) participants experienced poor functional outcomes, 25 (36.8%) patients died from all causes, and 21 (30.9%) patients had HT during the 3-month follow-up. Multivariable logistic regression showed that a higher THRIVE score was significantly associated with poor functional outcome (odds ratio [OR] 5.86, 95% confidence interval [CI], 2.28-14.91, p < .001) as well as all-cause mortality (OR 2.40, 95% CI, 1.32-4.34, p = .004) but not HT (p = .607). The C-statistic of the THRIVE score was significantly larger than that of the NIHSS score for predicting poor functional outcome (AUC = 0.913; cutoff > 5; sensitivity, 88.5%; specificity, 83.3%, p = .007) and all-cause mortality (AUC = 0.768; cutoff > 5; sensitivity, 92.0%; specificity, 65.1%, p = .018). CONCLUSIONS: A high THRIVE score was independently associated with an increased risk of poor functional outcome and all-cause mortality in AIS patients with BAO who underwent thrombectomy treatment. Moreover, the THRIVE score appeared to be a better predictor of clinical outcome than the NIHSS score.

Echinocystic acid, a natural plant extract, alleviates cerebral ischemia/reperfusion injury via inhibiting the JNK signaling pathway.

Echinocystic acid (EA) was found to possess antiviral, anti-inflammatory and antioxidation activities. A recent study showed the antiapoptotic effects of EA on acute myocardial infarction. In this study, we demonstrated the potential neuroprotective effects of EA on cerebral ischemia/reperfusion (I/R) injury in mice. Intraperitoneal injection of EA 1 h before ischemia significantly reduced the cerebral infarct volume and neurological deficit after 60 min of ischemia and 24 h of reperfusion. The neuroprotective effects of EA occurred in a dose-dependent manner. Then, we explored the mechanisms of neuroprotection by EA. This compound exerted antiapoptotic activity by upregulating the level of Bcl-2 and simultaneously downregulating the levels of cleaved caspase-3 and Bax. Furthermore, EA also possessed anti-inflammatory activity and prevented the excessive phosphorylation of NF-κB (p-P65) and the increase in IL-1ß and IL-6 levels. Finally, our data indicated that EA treatment decreased the level of phosphorylated JNK in vivo, and the JNK activator anisomycin (AN) reversed the neuroprotective effects of EA, indicating that the JNK pathway is involved in the antiapoptotic and anti-inflammatory mechanisms of EA. In summary, our findings suggest that EA provides neuroprotective effects through its antiapoptotic and anti-inflammatory activities by inhibiting the JNK signaling pathway in cerebral I/R injury. Due to its safety and lack of toxicity, EA is a potential candidate for the treatment of ischemic stroke in future clinical trials.

ESE1 expression correlates with neuronal apoptosis in the hippocampus after cerebral ischemia/reperfusion injury.

Epithelial-specific ETS-1 (ESE1), a member of the ETS transcription factor family, is widely expressed in multiple tissues and performs various functions in inflammation. During neuroinflammation, ESE1 promotes neuronal apoptosis; however, the expression and biological functions of ESE1 remain unclear after cerebral ischemia/reperfusion. We performed in vivo and in vitro experiments to explore the role of ESE1 in cerebral ischemic injury. A modified four vessel occlusion method was used in adult Sprague-Dawley rats. At 6, 12, 24, 48, and 72 hours after model induction, the hippocampus was collected for analysis. Western blot assays and immunohistochemistry showed that the expression of ESE1, phosphorylated p65 and active caspase-3 was significantly up-regulated after ischemia. Double immunofluorescence staining indicated that ESE1 and NeuN were mostly co-located in the hippocampus after ischemia. Furthermore, ESE1 was also co-expressed with active caspase-3. PC12 cells were stimulated with cobalt chloride (CoCl2) to establish a chemical hypoxia model. After ESE1 knockdown by siRNA for 6 hours, cell viability was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assays. The levels of ESE1, phosphorylated p65 and active caspase-3 were also remarkably increased in PC12 cells after CoCl2 stimulation. After ESE1 knockdown, PC12 cell viability was increased after hypoxia. siRNA knockdown of ESE1 decreased the level of p-p65 and active caspase-3 after CoCl2 stimulation. These data reveal that ESE1 levels are elevated in the hippocampus after cerebral ischemia/reperfusion injury. This may play a role in neuronal apoptosis via activation of the nuclear factor-κB pathway.

Inhibition of Connexin43 hemichannels with Gap19 protects cerebral ischemia/reperfusion injury via the JAK2/STAT3 pathway in mice.

Functional disruption of the neurovascular unit may lead to aggravation of ischemic cerebral injury. Connexin43 (Cx43)-dependent gap junctional channels (GJCs) are critical in maintaining brain homeostasis. However, excessive opening of hemichannels (HCs) after cerebral ischemia may cause apoptosis and finally lead to amplification of ischemic injury. Previous studies indicated that Cx43 mimetic peptides Gap26 and Gap27 may protect cerebral ischemic injury, but the latest studies showed they also inhibit the opening of GJCs, which are beneficial for neuroprotection. Recent studies showed that Gap19 is a new specific inhibitor of Cx43 HCs. We investigated the role of Gap19 on cerebral ischemia/reperfusion (I/R) injury in a mouse model of middle cerebral artery occlusion (MCAO). Ventricle-injected Gap19 significantly alleviated infarct volume, neuronal cell damage and neurological deficits after ischemia, the neuroprotective effect of Gap19 was significant stronger than Gap26. Post-treatment with TAT-Gap19 still provided neuroprotection when it was administered intraperitoneally at 4 h after reperfusion. In addition, we found that Gap19 decreased the levels of cleaved caspase-3 and Bax and increased the level of Bcl-2, suggesting the anti-apoptotic activity of specifically blocking the Cx43 HCs. Furthermore, our data indicate that Gap19 treatment increased the levels of phosphorylated JAK2 and STAT3 both in vivo and in vitro. Gap19 inhibited hemichannel activity assessed by dye uptake in astrocytes. And we detected that pSTAT3 co-localized with Cx43 together in astrocytes after oxygen glucose deprivation (OGD) injury. Finally, AG490, a blocker of the JAK2/STAT3 pathway, could reverse the neuroprotective effects of Gap19 both in vivo and in vitro. Our experiment investigated the anti-apoptotic activity of Gap19, the specific inhibitor of Cx43 HCs, and the potential mechanisms. Our results demonstrated that Gap19 plays an anti-apoptotic role via activating the JAK2/STAT3 pathway after cerebral I/R injury, indicating that specific blocking of Cx43 HCs is a potential target for ischemic stroke.

Pyoderma gangrenosum around an ileostoma: A case report.

RATIONALE: Pyoderma gangrenosum (PG) is a rare postoperative complication of enterostomy, mostly developing from dermatitis, which may have serious consequence. PATIENT CONCERNS: A patient with lower rectal cancer receiving low anterior resection (LAR) and protective ileostomy was initially diagnosed with dermatitis, which very quickly developed to PG, though no medical or familial history was found. DIAGNOSIS: We diagnosed the patient with peristoaml dermatitis starting from a tiny skin ulceration, but corrected the diagnosis to PG because of the rapid development and severe consequences. INTERVENTIONS: Routine stoma care did not improve the condition, so we performed 2 terms of debridement, the closure of the stoma and autologous skin transplantation before finally solving the problem. OUTCOMES: The patient was discharged 60 days after the first surgery and 5 days after the last one. After 18 months of follow-up, the patient kept in a stable condition. LESSONS: Medical staff should not neglect peristoaml dermatitis because of its common occurrence. Once the situation develops beyond the doctors' expectation, more efforts should be made to treat it, even expand debridement if possible.

Inhibition of Connexin 43 Hemichannels Alleviates Cerebral Ischemia/Reperfusion Injury via the TLR4 Signaling Pathway.

Connexin 43 (Cx43) widely exists in all components of the neurovascular unit (NVU) and is a constituent of gap junctions and hemichannels. In physiological states, gap junctions are open for regular intercellular communication, and the hemichannels present low open probability in astrocytes. After cerebral ischemia, a large number of hemichannels are unusually opened, leading to cell swelling and even death. Most known hemichannel blockers also inhibit gap junctions and sequentially obstruct normal electrical cell-cell communication. In this study, we tested the hypothesis that Gap19, a selective Cx43-hemichannel inhibitor, exhibited neuroprotective effects on cerebral ischemia/reperfusion (I/R). An obvious improvement in neurological scores and infarct volume reduction were observed in Gap19-treated mice after brain ischemia induced by middle cerebral artery occlusion (MCAO). Gap19 treatment attenuated white matter damage. Moreover, Gap19 treatment suppressed the expression of Cx43 and Toll-like receptor 4 (TLR4) pathway-relevant proteins and prevented the overexpression of tumour necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). To further explore downstream signaling, we established an in vitro model-oxygen glucose deprivation (OGD) to simulate ischemic conditions. Immunofluorescence staining showed that Cx43 co-existed with TLR4 in astrocytes. The hemichannel activity was increased after OGD and Gap19 could inhibit this effect on astrocytes. Gap19 substantially improved relative cell vitality and decreased the expression of Cx43, TLR4 and inflammatory cytokines in vitro. In addition, in the lipopolysaccharide (LPS) stimulation OGD model, Gap19 also exhibited a protective effect via inhibiting TLR4 pathway activation. In summary, our results showed that Gap19 exerted a neuroprotective effect after stroke via inhibition of the TLR4-mediated signaling pathway.