Simultaneous ischemic regions targeting and BBB crossing strategy to harness extracellular vesicles for therapeutic delivery in ischemic stroke.

Extracellular vesicles (EVs) derived from adipose-derived stem cells (ADSC-EVs) hold great promise for ischemic stroke treatment, but their therapeutic efficacy is greatly limited due to insufficient targeting ability. Previous reports focused on single ischemic targeting or blood-brain barrier (BBB) penetration, precise delivery to the brain parenchyma has not been fully considered. This study leveraged the targeting ability of RGD peptide and the cell penetrating ability of Angiopep-2 peptide to deliver ADSC-EVs precisely to the impaired brain parenchyma. We found that dual-modified EVs (RA-EVs) significantly enhanced the transcellular permeability across BBB in vitro, and not only targeted ischemic blood vessels but also achieved rapid accumulation in the ischemic lesion area after intravenous administration in vivo. RA-EVs further decreased the infarct volume, apoptosis, BBB disruption, and neurobehavioral deficits. RNA sequencing revealed the molecular regulation mechanism after administration. These findings demonstrate that dual-modification optimizes brain parenchymal targeting and highlights the significance of recruitment and penetration as a previously unidentified strategy for harnessing EVs for therapeutic delivery in ischemic stroke.

Post-operative neutrophil-to-lymphocyte ratio and outcome after thrombectomy in acute ischemic stroke.

Background: Neutrophil to lymphocyte ratio (NLR) is a novel inflammatory marker to predict adverse cardiovascular events. However, there is a lack of data on hemorrhagic transformation (HT) and neurological outcome after mechanical thrombectomy in acute ischemic stroke (AIS). We investigated whether NLR before and after thrombectomy for patients with AIS was associated with HT and neurological outcomes. Methods: We performed a retrospective analysis of consecutive patients with anterior circulation AIS who underwent thrombectomy. HT was evaluated by CT within 24 h after thrombectomy. Clinical data had been collected retrospectively; laboratory data were extracted from our electronic hospital information system. NLR was obtained at admission (NLR1) and immediately after thrombectomy (NLR2). The main outcomes were post-interventional intracranial hemorrhage and unfavorable functional status (modified Rankin scale scores of 3-6) 3 months post-stroke. Results: A total of 258 patients with AIS, according to the NIHSS (median 14), were included. NLR2 was higher in patients who developed HT after thrombectomy and unfavorable neurological outcomes 3 months post-stroke (p < 0.001) than in those without HT or favorable outcomes, even after correction for co-factors [Odds Ratio (OR) 1.35 for HT, 95% confidence interval (CI)1.16-1.57, p < 0.001, and 1.85 for unfavorable outcome, 95%CI 1.57-2.17, p < 0.001]. The optimal cutoff value for the NLR2 as an indicator for auxiliary diagnosis of HT and the unfavorable outcome was 8.4 and 8.8, respectively. Conclusion: NLR immediately after thrombectomy is a readily available biomarker of HT and neurological outcomes in patients with AIS.

Multiple-Factor Analyses of Futile Recanalization in Acute Ischemic Stroke Patients Treated With Mechanical Thrombectomy.

Background and Purpose: Acute ischemic stroke (AIS) is a serious threat to the life and health of middle-aged and elderly people. Mechanical thrombectomy offers the advantages of rapid recanalization, but the response of patients to this treatment varies greatly. This study investigated the risk factors for futile recanalization in AIS patients after thrombectomy through multivariate analyses. Methods: A retrospective study was conducted in AIS patients with anterior circulation occlusion from a derivation cohort and a validation cohort who underwent thrombectomy and reperfusion defined as a modified Thrombolysis in Cerebral Infarction (mTICI) score of 2b/3. Using the modified Rankin Scale (mRS) at 90 days after the operation, the patients were divided into two groups, the meaningful recanalization group (mRS ≤ 2), and the futile recanalization group (mRS > 2). Multivariate logistic regression analyses were performed, and the receiver operating characteristic (ROC) curve was used to construct a risk prediction model for futile recanalization. The performance of prediction model was evaluated on the validation cohort. Results: A total of 140 patients in the derivation cohort were enrolled, 46 patients in the meaningful recanalization group and 94 patients in the futile recanalization group. The two groups were significantly different in age, preoperative National Institute of Health Stroke Scale (NIHSS) score, and collateral circulation ASITN/SIR grade (P < 0.05). In multivariate regression analyses, patients' age ≥ 71, NIHSS ≥ 12, and ASITN/SIR ≤ 3 were risk factors for futile recanalization. Hence, an ANA (Age-NIHSS-ASITN/SIR) score scale consisting of age, NIHSS score, and ASITN/SIR grade factors can effectively predict the risk for futile recanalization (area under curve 0.75, 95% CI 0.67-0.83, specificity 67.4%, and sensitivity 73.4%). The proportion of patients with futile recanalization in ANA groups 0, 1, 2, and 3 were 21.05, 56.76, 79.03, and 90.91%, respectively. Furthermore, ANA score scale had also a good performance for predicting futile recanalization on the validation cohort. Conclusions: Old age, high baseline NIHSS, and poor collateral circulation are risk factors for futile recanalization in AIS patients treated with thrombectomy. An ANA score that considers age, NIHSS, and collateral ASITN/SIR can effectively predict the risk for futile recanalization. Further studies with a larger sample size are needed to validate the prognostic value of this combined score for futile recanalization.

Fibrinogen Level Combined With Platelet Count for Predicting Hemorrhagic Transformation in Acute Ischemic Stroke Patients Treated With Mechanical Thrombectomy.

A serious complication of acute ischemic stroke (AIS) after mechanical thrombectomy (MT) is hemorrhagic transformation (HT), which is potentially associated with clinical deterioration. This study examined predictors of HT following MT in AIS patients. Patients with AIS due to large artery occlusion in the anterior circulation, treated with MT and successfully recanalized (modified Thrombolysis in Cerebral Infarction score 2b/3), were studied retrospectively. HT was evaluated by computed tomography (CT) 24 h after MT and was diagnosed and classified into parenchymal hematoma (PH) and hemorrhagic infarction (HI). Multivariate logistic regression models were used to determine the risk factors for HT. Receiver operating characteristic (ROC) curve analysis was performed to determine the predictive utility of risk factors for HT. We enrolled 135 patients: 49 in the HT group and 86 in the non-HT group. The two groups differed significantly in baseline fibrinogen levels (p = 0.003) and platelet counts (p = 0.006). Multivariate logistic regression analyses showed that lower fibrinogen levels [odds ratio (OR), 0.41; 95% CI, 0.23-0.72; p = 0.002] and platelet counts (OR, 0.58; 95% CI, 0.33-0.99; p = 0.048) were independently associated with a higher risk of HT. Together, the binary variates fibrinogen and platelets well-predicted HT (area under the curve, 0.703; specificity, 77.9%; sensitivity, 55.1%). The combination of fibrinogen <2.165 g/L and platelets <171.5 × 109/L was the strongest predictor of HT (OR, 23.17; 95% CI, 5.75-126.80; p < 0.0001). Our study suggests that lower baseline fibrinogen levels and platelet counts may be risk factors for HT in AIS patients following MT and reperfusion. Specifically, the combination of fibrinogen level and platelet count may predict the risk of HT after MT in these patients.

Fiber-Reinforced Cemented Paste Backfill: The Effect of Fiber on Strength Properties and Estimation of Strength Using Nonlinear Models.

This experimental investigation was conducted to research the properties of polypropylene (PP) fiber-reinforced cemented paste backfill (CPB). The unconfined compressive strength (UCS) of the fiber-reinforced CPB showed a significant improvement with average UCS increase ratios of 141.07%, 57.62% and 63.17% at 3, 7 and 28 days, respectively. The macroscopic failure mode and SEM analysis indicated that fibers prevented the formation of large tensile and shear cracks during the pull-out and pull-off failure modes. A linear fitting function for the UCS at a curing time of 3 days and two polynomial fitting functions for the UCS at curing times of 7 and 28 days were established to characterize the relationship between the UCS of the fiber-reinforced and unreinforced CPB. Moreover, based on composite mechanics, nonlinear models related to the UCS and fiber reinforcement index were obtained. The estimated functions containing the fiber reinforcement index λ, which consists of the fiber content and aspect ratio of fiber, could evaluate the UCS. Furthermore, the fiber reinforcement index λ quantifies the enhancement by the fibers. Both estimation results indicated that the UCS values were estimated accurately at curing times of 3, 7 and 28 days in this study. Additionally, the estimation models could be used to guide the strength design of fiber-reinforced CPB. Besides this, the results showed that fiber-reinforced CPB can be used more widely in mine backfills and meets the requirements of controlled low-strength material (CLSM) for broader applications.

Growth, condition, and maturity schedules of an estuarine fish species change in estuaries following increased hypoxia due to climate change.

Understanding challenges posed by climate change to estuaries and their faunas remains a high priority for managing these systems and their communities. Freshwater discharge into a range of estuary types in south-western Australia between 1990 and 2015 is shown to be related to rainfall. This largely accounts for decreases in discharge in this microtidal region being more pronounced on the west coast than south coast, where rainfall decline was less. Results of an oxygen-balance model imply that, as demonstrated by empirical data for the Swan River Estuary, declines in discharge into a range of estuary types would be accompanied by increases in the extent of hypoxia. In 2013-15, growth and body condition of the teleost Acanthopagrus butcheri varied markedly among three permanently open, one intermittently-open, one seasonally-closed and one normally-closed estuary, with average time taken by females to reach the minimum legal length (MLL) of 250 mm ranging from 3.6 to 17.7 years. It is proposed that, in a given restricted period, these inter-estuary variations in biological characteristics are related more to differences in factors, such as food resources and density, than to temperature and salinity. The biological characteristics of A. butcheri in the four estuaries, for which there are historical data, changed markedly between 1993-96 and 2013-15. Growth of both sexes, and also body condition in all but the normally-closed estuary, declined, with females taking between 1.7 and 2.9 times longer to attain the MLL. Irrespective of period, body condition, and growth are positively related. Age at maturity typically increased between periods, but length at maturity declined only in the estuary in which growth was greatest. The plasticity of the biological characteristics of A. butcheri, allied with confinement to its natal estuary and ability to tolerate a wide range of environmental conditions, makes this sparid and comparable species excellent subjects for assessing estuarine "health."

The proportion of 3 classes of lateral throat form.

The aim of this study was to investigate the proportion of 3 Neil's classifications of lateral throat forms and the difference in the length of the lateral throat form between the dentures and the patient's actual anatomy. The classification of lateral throat form was determined by the patient's functional movements, and an implant depth gauge was used to measure the length of the lateral throat form in the patient's mouth and compare it to that of the dentures. One hundred mandibular edentulous patients were measured. The proportion of Neil's Class I lateral throat form was 70%, the proportion of Class II was 25%, and the proportion of Class III was 5%. The mean difference between the actual lateral throat forms and the dentures was 6.7 +/- 2.9 mm at the anterior point of measurement (from the anterior part of the retromolar pad to the mouth floor) and 10.0 +/- 3.7 mm at the posterior point (from the middle of the retromolar pad to the mouth floor). The difference in length between the ridge height of the mouth and the denture was statistically significant (P < .001).

[Correlation between the expression of angiopoietins and their receptor and angiogenesis in gastric cancers].

OBJECTIVE: To explore the effects of angiopoietins (Ang-1 and Ang-2) and Tie-2 expression on microvessel density (MVD) in gastric cancers. METHODS: By using semiquantitative RT-PCR, immunohistochemistry and image analysis system, the expression of Ang-1, Ang-2, Tie-2 mRNA and their proteins were detected in 68 primary gastric cancers and their adjacent normal tissues. Microvessel density (MVD) was figured out based on CD34 immunohistochemical staining. RESULTS: The expression of all Ang-1, Ang -2, Tie-2 mRNA and their proteins was detected in gastric cancers and their paired adjacent gastric mucosa tissues. A negative correlation between Ang-1 protein, Tie-2 mRNA and MVD in gastric cancers was observed (r = -0.440, r = -0.267; P < 0.05), while the relation between Ang-2 mRNA and its protein, Ang-2/Ang-1 protein ratio with MVD were positive (r = 0.319, r = 0.729, r = 0.739; P < 0.05). It was found that MVD in groups with Ang-2 mRNA T/N ratio over 1.2 (the ratio of Ang-2 mRNA in gastric cancers and its adjacent normal mucosa) was higher than that in those with a ratio under 1.2, revealed by analysing the effects of Ang-1 and Ang-2 mRNA T/N ratio on MVD in gastric cancers. CONCLUSION: Ang-1 activates Tie-2 receptor, whereas Ang-2 antagonizes Ang-1 in the angiogenesis, and the Ang-2/Ang-1 ratio determines angiogenesis and tumor growth in gastric cancers. When the expression of Ang-2 is high and Ang-1 is low, the angiogenesis in gastric cancers is promoted, otherwise oppositely. The role of Ang-2 is dominant in the effect of Angs and their receptor on angiogenesis in gastric cancers.

[Dual effect of angiopoietin-2 on angiogenesis in gastric cancer].

OBJECTIVE: To explore the effect of Ang-2 on angiogenesis in gastric cancer. METHODS: The expression of Ang-2 mRNA was analyzed by RT-PCR and the expression of VEGF and CD34 was detected by immunohistochemistry in 36 cases of gastric cancer tissues and their paired adjacent gastric mucosa. RESULTS: The expression of Ang-2 mRNA was found both in gastric cancer and their paired adjacent gastric mucosa; the correlationship between the general expression levels of Ang-2 mRNA and microvessel density (MVD) in gastric cancer tissues was not found. However, in 27 cases whose Ang-2 mRNA expression levels in cancer tissues were lower than those in adjacent gastric mucosa. A significant positive correlation between the expression level of Ang-2 mRNA and MVD in the tumor tissues was found (r = 0.411, P < 0.05). In these 27 cases, the MVD in the gastric cancer tissues with positive VEGF expression (45.45 +/- 10.30) was higher than that with negative VEGF expression (30.15 +/- 8.69, P < 0.05), whereas in the other 9 cases whose expression levels of Ang-2 mRNA in cancer tissues were higher than those in adjacent gastric mucosa, a significant negative correlation between expression level of Ang-2 mRNA and MVD in the tumor tissues (r = -0.758, P < 0.05), but without correlation between the MVD and VEGF. CONCLUSION: Under the conditions that the expression of Ang-2 mRNA in cancer tissues was lower than that in adjacent gastric mucosa, VEGF could promote the sprouting of new vessels along with Ang-2 upregulation. But under the conditions that the expression of Ang-2 mRNA in cancer tissues was higher than that in adjacent gastric mucosa, Ang-2 inhibited angiogenesis. Angiopoietin-2 may play a dual effect on angiogenesis in gastric cancer.