Opinions over targets for blood pressure control after mechanical thrombectomy in patients with acute ischemic stroke: baseline survey for the ENCHANTED2/MT trial in China.

BACKGROUND: Although guidelines recommend a target blood pressure 185-180/105-110 mmHg after mechanical thrombectomy for acute ischemic stroke (AIS), there is limited randomized evidence to support this level. We surveyed candidate institutions about the approach to blood pressure management in this patient group in preparation for inviting them to participate in the Enhanced Blood Pressure Control after Endovascular Thrombectomy for the Acute Ischemic Stroke Trial (ENCHANTED2/MT). METHODS: Physicians from a professional network of institutions that met mechanical thrombectomy qualification requirements were invited to participate in an online questionnaire covering basic clinical information as well as questions on blood pressure management. RESULTS: We invited 88 sites to participate with 44 (50%) ultimately joining the trial, and a total of 88 physicians finished the survey. The median number of annual mechanical thrombectomy cases performed per site was 89 [IQR 65-150]. Only 38 (43%) institutions strictly adhere to guidelines when managing the blood pressure of mechanical thrombectomy patients. The most popular blood pressure target for reperfusion patients was 140-160 mmHg (n=47, 53%), and <120 mmHg (n=28, 32%). Fewer hospital stroke beds (40 [21-57] vs. 60 [39-110], p = 0.01) and lower proportion of elevated blood pressure after mechanical thrombectomy (25% [10%-50%] vs. 50% [20%-70%], p = 0.02) were related to a more aggressive blood pressure target (<120 mmHg). Urapidil (n=82, 93%) and calcium channel blockers (CCBs) (n = 87, 99%), were the most widely used antihypertensive drugs, respectively. CONCLUSIONS: According to the survey, unstandardized blood pressure management protocols are performed in mechanical thrombectomy patients at institutions across China, which is different from prior survey from another country. More high-quality studies are needed to guide clinical practice.

Intensive blood pressure control after endovascular thrombectomy for acute ischaemic stroke (ENCHANTED2/MT): a multicentre, open-label, blinded-endpoint, randomised controlled trial.

BACKGROUND: The optimum systolic blood pressure after endovascular thrombectomy for acute ischaemic stroke is uncertain. We aimed to compare the safety and efficacy of blood pressure lowering treatment according to more intensive versus less intensive treatment targets in patients with elevated blood pressure after reperfusion with endovascular treatment. METHODS: We conducted an open-label, blinded-endpoint, randomised controlled trial at 44 tertiary-level hospitals in China. Eligible patients (aged ≥18 years) had persistently elevated systolic blood pressure (≥140 mm Hg for >10 min) following successful reperfusion with endovascular thrombectomy for acute ischaemic stroke from any intracranial large-vessel occlusion. Patients were randomly assigned (1:1, by a central, web-based program with a minimisation algorithm) to more intensive treatment (systolic blood pressure target <120 mm Hg) or less intensive treatment (target 140-180 mm Hg) to be achieved within 1 h and sustained for 72 h. The primary efficacy outcome was functional recovery, assessed according to the distribution in scores on the modified Rankin scale (range 0 [no symptoms] to 6 [death]) at 90 days. Analyses were done according to the modified intention-to-treat principle. Efficacy analyses were performed with proportional odds logistic regression with adjustment for treatment allocation as a fixed effect, site as a random effect, and baseline prognostic factors, and included all randomly assigned patients who provided consent and had available data for the primary outcome. The safety analysis included all randomly assigned patients. The treatment effects were expressed as odds ratios (ORs). This trial is registered at ClinicalTrials.gov, NCT04140110, and the Chinese Clinical Trial Registry, 1900027785; recruitment has stopped at all participating centres. FINDINGS: Between July 20, 2020, and March 7, 2022, 821 patients were randomly assigned. The trial was stopped after review of the outcome data on June 22, 2022, due to persistent efficacy and safety concerns. 407 participants were assigned to the more intensive treatment group and 409 to the less intensive treatment group, of whom 404 patients in the more intensive treatment group and 406 patients in the less intensive treatment group had primary outcome data available. The likelihood of poor functional outcome was greater in the more intensive treatment group than the less intensive treatment group (common OR 1·37 [95% CI 1·07-1·76]). Compared with the less intensive treatment group, the more intensive treatment group had more early neurological deterioration (common OR 1·53 [95% 1·18-1·97]) and major disability at 90 days (OR 2·07 [95% CI 1·47-2·93]) but there were no significant differences in symptomatic intracerebral haemorrhage. There were no significant differences in serious adverse events or mortality between groups. INTERPRETATION: Intensive control of systolic blood pressure to lower than 120 mm Hg should be avoided to prevent compromising the functional recovery of patients who have received endovascular thrombectomy for acute ischaemic stroke due to intracranial large-vessel occlusion. FUNDING: The Shanghai Hospital Development Center; National Health and Medical Research Council of Australia; Medical Research Futures Fund of Australia; China Stroke Prevention; Shanghai Changhai Hospital, Science and Technology Commission of Shanghai Municipality; Takeda China; Hasten Biopharmaceutic; Genesis Medtech; Penumbra.

Application of symbolic play test in identification of autism spectrum disorder without global developmental delay and developmental language disorder.

BACKGROUND: Children with autism spectrum disorders (ASD) usually experience difficulty regarding symbolic play. However, studies on whether symbolic play test (SPT) can differentiate between ASD and other developmental disorders are inconsistent, and evaluating the application value of the SPT in the identification of ASD without global developmental delay (GDD) and developmental language disorder (DLD) is necessary. METHODS: A total of 200 children were selected as the research participants. There were 100 cases of ASD without GDD and 100 cases of DLD. All children were tested by SPT and Children Neuropsychological and Behavioral Scale-Revision (CNBS-R2016). Binomial logistic regression was used for multivariate analysis. The receiver operating characteristic (ROC) curve was used to evaluate the value of SPT in identifying ASD without GDD and DLD. RESULTS: SPT equivalent age was lower than chronological age in the two groups, the difference between the ASD without GDD group was greater than that in the DLD group, and the proportion of SPT equivalent age retardation was higher than that in the DLD group; the differences were statistically significant. Logistic regression analysis showed that there was a difference in SPT equivalent age between DLD and ASD without GDD. When the cut-off value of the SPT was 8.5, the largest area under the ROC curve was 0.723, and the sensitivity and specificity for the diagnosis of ASD without GDD were 0.720 and 0.620 respectively. CONCLUSIONS: Symbolic play ability in ASD children is worse than that of DLD children at comparable development levels. SPT may be helpful to distinguish ASD without GDD from children with DLD.

Galcanezumab in patients with episodic migraine: results from the open-label period of the phase 3 PERSIST study.

BACKGROUND: The phase 3 randomized PERSIST study demonstrated the efficacy and tolerability of galcanezumab, a humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody for prevention of episodic migraines. We present findings from the open-label extension (OLE) of PERSIST, which evaluated the long-term efficacy and safety of galcanezumab in patients from China, India, and Russia. METHODS: Patients completing the 3-month double-blind period of PERSIST were eligible for the 3-month OLE. Patients previously randomized to galcanezumab (GMB/GMB group) continued to receive galcanezumab 120 mg at all three visits during the OLE whereas patients randomized to placebo received a 240 mg loading dose of galcanezumab and then two 120 mg doses (PBO/GMB group). The primary outcome was the mean change (from double-blind baseline) in the number of monthly migraine headache days (MHDs) to month 6. Other endpoints included percent reduction in monthly MHDs from double-blind baseline to month 6, functional outcomes, safety and tolerability. RESULTS: Overall, 99% of patients completing the double-blind period entered the OLE, and 96% completed through month 6. Patients in the GMB/GMB group achieved continued improvements in efficacy, with the reduction from baseline in the mean number of monthly MHDs, and slightly increasing from 4.01 days at the end of the double-blind period to 4.62 at the end of the OLE. Of patients who were ≥ 50% responders to galcanezumab at month 3, 66% maintained this response through to month 6. Patients in the PBO/GMB group experienced a rapid reduction in the number of monthly MHDs after initiation of galcanezumab, with a mean reduction from baseline of 4.56 days by month 6. The long-term benefits of galcanezumab were also supported by improvements in other efficacy and functional endpoints. All safety findings were consistent with the known long-term safety profile of galcanezumab; no patients experienced a treatment-related serious adverse event. CONCLUSIONS: Galcanezumab was efficacious and well-tolerated in patients with episodic migraine from China, India and Russia, for up to 6 months. TRIAL REGISTRATION: ClinicalTrisABSTRACT_pals.gov NCT03963232, registered May 24, 2019.

Implementing a Goal-Directed Care Bundle after Acute Intracerebral Haemorrhage: Process Evaluation for the Third INTEnsive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial Study in China.

BACKGROUND: The third INTEnsive care bundle with blood pressure Reduction in Acute Cerebral Haemorrhage Trial is an ongoing international, multicentre, stepped wedge, cluster-randomized trial to determine the effectiveness of a goal-directed care bundle (early intensive blood pressure [BP] lowering, glycaemic control, treatment of pyrexia, and reversal of anticoagulation), as compared to standard of care, on patient-centred outcomes after acute intracerebral haemorrhage (ICH). An embedded process evaluation aims to identify factors related to the uptake and implementation of the intervention. Herein, we present the process evaluation results for hospital sites in China. METHODS/DESIGN: A mixed methods approach, including surveys, focused group discussions and interviews with clinicians, routine monitoring, and recruitment logs were used to collect data across purposively sampled hospitals. Medical Research Council guidance and normalization process theory were used as theoretical frameworks for design, data analysis, and synthesis. RESULTS: Twenty quantitative surveys were completed with clinicians, and 26 interviews and 2 focus group discussions were conducted during 2019-2020. The care bundle was generally delivered as planned and acceptable by doctors and nurses, but difficulties were reported in achieving the protocol-defined target levels of BP and glycaemic control. Resistance to implementing the care bundle occurred for patients perceived to be at high risk of adverse effects. Common organizational contextual factors that impeded implementation included delayed processes and limited medication supply, while established background care procedures, expertise, and capacity influenced its integration into routine practice. Areas to facilitate implementation included optimizing workflow within available resources, having a dedicated team, and recognizing the potential benefits of the intervention. CONCLUSIONS: Varied established care protocols across sites, different levels of background expertise, and lack of staff capacity impeded the integration of goal-directed care bundle into routine practice for ICH patients in China. Ready identification, and efforts to address, these barriers could facilitate uptake of future guideline-recommended interventions for the management of patients with ICH.

Perfluorooctane sulfonate aggravates CCl4-induced hepatic fibrosis via HMGB1/TLR4/Smad signaling.

Perfluorooctane sulfonate (PFOS) is a widespread environmental pollutant and may cause a variety of adverse health effects. The hepatotoxicity of PFOS has attracted particular attention, given the fact that the liver has one of the highest PFOS accumulations among human tissues. In this study, we revealed that subchronic PFOS exposure may exacerbate carbon tetrachloride (CCl4 )-induced liver fibrosis in animal models. Administration with 1 mg/kg PFOS every other day for 56 days dramatically enhanced CCl4 -mediated liver injury and hepatic stellate cell (HSC) activation. Furthermore, PFOS exposure may promote the activation of high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4) signaling pathway through inducing the secretion of HMGB1 from hepatocytes. PFOS exposure induced the translocation of HMGB1 from the nucleus into the cytoplasm of hepatocytes and cultured BRL-3A cells at a starting concentration of 50 µM. This process is accompanied with concurrent flux of calcium, suggesting a link between calcium signaling and HMGB1 release following PFOS exposure. Finally, we showed that PFOS-exposed conditional medium (PFOS-CM) of hepatocytes may induce the translocation of Smad2/3 in HSCs in a TLR4-dependent manner. Taken together, subchronic PFOS exposure might play a pro-fibrotic role via a HMGB1/TLR4-dependent Smad signaling in HSCs. Our findings for the first time uncovered an involvement of PFOS exposure in liver fibrosis via HMGB1/TLR4/Smad signaling.

Induction of Apoptosis via Inactivating PI3K/AKT Pathway in Colorectal Cancer Cells Using Aged Chinese Hakka Stir-Fried Green Tea Extract.

Food extract supplements, with high functional activity and low side effects, play a recognized role in the adjunctive therapy of human colorectal cancer. The present study reported a new functional beverage, which is a type of Chinese Hakka stir-fried green tea (HSGT) aged for several years. The extracts of the lyophilized powder of five HSGT samples with different aging periods were analyzed with high-performance liquid chromatography. The major components of the extract were found to include polyphenols, catechins, amino acids, catechins, gallic acid and caffeine. The tea extracts were also investigated for their therapeutic activity against human colorectal cancer cells, HT-29, an epithelial cell isolated from the primary tumor. The effect of different aging time of the tea on the anticancer potency was compared. Our results showed that, at the cellular level, all the extracts of the aged teas significantly inhibited the proliferation of HT-29 in a concentration-dependent manner. In particular, two samples prepared in 2015 (15Y, aged for 6 years) and 2019 (19Y, aged for 2 years) exhibited the highest inhibition rate for 48 h treatment (cell viability was 50% at 0.2 mg/mL). Further, all the aged tea extracts examined were able to enhance the apoptosis of HT-29 cells (apoptosis rate > 25%) and block the transition of G1/S phase (cell-cycle distribution (CSD) from <20% to >30%) population to G2/M phase (CSD from nearly 30% to nearly 10%) at 0.2 mg/mL for 24 h or 48 h. Western blotting results also showed that the tea extracts inhibited cyclin-dependent kinases 2/4 (CDK2, CDK4) and CylinB1 protein expression, as well as increased poly ADP-ribose polymerase (PRAP) expression and Bcl2-associated X (Bax)/B-cell lymphoma-2 (Bcl2) ratio. In addition, an upstream signal of one of the above proteins, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling, was found to be involved in the regulation, as evidenced by the inhibition of phosphorylated PI3K and AKT by the extracts of the aged tea. Therefore, our study reveals that traditional Chinese aged tea (HSGT) may inhibit colon cancer cell proliferation, cell-cycle progression and promoted apoptosis of colon cancer cells by inactivating PI3K/AKT signalling.

Associations of an Abnormal Physiological Score With Outcomes in Acute Intracerebral Hemorrhage: INTERACT2 Study.

BACKGROUND AND PURPOSE: We determined associations of physiological abnormalities (systolic blood pressure, glucose, and body temperature) and warfarin use with outcomes in spontaneous intracerebral hemorrhage. METHODS: Post hoc analyses of INTERACT2 (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial) comparing systolic blood pressure control (<140 versus <180 mm Hg) in 2839 hypertensive patients with intracerebral hemorrhage (onset <6 hours). Multivariable logistic regression defined associations of baseline scores assigned as 0 to 6 per 10 mm Hg systolic blood pressure increase (range, 150-220 mm Hg) and 0 or 1 for serum glucose (≤6.5 versus >6.5 mmol/L), body temperature (≤37.5 °C versus >37.5 °C), and warfarin use (no versus yes) and death or major disability (modified Rankin Scale scores 3-6 at 90 days). RESULTS: Baseline score distribution was 0 (7.7%), 1 (15.6%), 2 (19.0%), 3 (19.1%), 4 (15.2%), 5 (11.6%), 6 (8.9%), and 7 (2.9%). After adjustment for baseline neurological severity and potential confounders, significant linear associations were evident for increasing (per point) score and death or major disability (odds ratio, 1.12 [95% CI, 1.07-1.17]), death (odds ratio, 1.15 [95% CI, 1.07-1.23]), and major disability (odds ratio, 1.10 [95% CI, 1.05-1.15]). CONCLUSIONS: Combination of abnormal physiological parameters and warfarin use is associated with poor outcomes in intracerebral hemorrhage. Effects of their early control is under investigation in INTERACT3 (Intensive Care Bundle With Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial). Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00716079.

Coronavirus Disease 2019 Patients in Earlier Stages Exhaled Millions of Severe Acute Respiratory Syndrome Coronavirus 2 Per Hour.

Coronavirus disease 2019 (COVID-19) patients exhaled millions of severe acute respiratory syndrome coronavirus 2 RNA copies per hour, which plays an important role in COVID-19 transmission. Exhaled breath had a higher positive rate (26.9%, n = 52) than surface (5.4%, n = 242) and air (3.8%, n = 26) samples.

Effect of fermentation bed on bacterial growth in the fermentation mattress material and cecum of ducks.

The composition of microorganisms in the gastrointestinal tract is closely related to the intestinal microenvironments and the exterior growth environments of host. In this study, 16S rDNA sequencing technology was adopted to investigate the influence of fermentation bed on the cecum microorganisms of ducks. Two feeding density treatment groups were set up, including group A (n = 4brids/m2) and group B (n = 6brids/m2). Samples were collected from the intermediate core fermentation layer (10-20 cm) of the fermented mattress materials and from the intestinal contents of ducks at 4, 6 and 8 weeks, respectively. Results showed that Bacteroidetes (20.12-27.17%) and Ruminococcaceae UCG-014 (2.97-10.1%) were the predominant microorganisms in duck cecum, while the Truepera (5.08-6.29%), Pricia (4.44-5.44%) and Luteimonas (3.62-4.99%) were the dominant microorganisms in fermentation mattress material. The cecum bacteria exhibited great difference among different growth periods of the ducks. Increasing the stocking density of ducks had a negative effect on the beneficial bacteria in the cecum. The microbial populations in fermentation mattress material were very different from that in the cecal. In summary, our findings can provide a scientific data for the rational use of fermentation bed feeding mode in poultry production.

Disparities between Asian and Non-Asian Thrombolyzed Acute Ischemic Stroke Patients in the Enhanced Control of Hypertension and Thrombolysis Stroke Trial.

BACKGROUND AND PURPOSE: As outcomes for acute ischemic stroke (AIS) vary according to clinical profile and management approaches, we aimed to determine disparities in clinical outcomes between Asian and non-Asian participants of the international, Enhanced Control of Hypertension and Thrombolysis Stroke study (ENCHANTED). METHODS: ENCHANTED was a multicenter, prospective, partial-factorial, randomized, open trial of low-dose (0.6 mg/kg) versus standard-dose (0.9 mg/kg) alteplase, and intensive (target systolic blood pressure [SBP] 130-140 mm Hg) or guideline-recommended (<180 mm Hg) BP management, in thrombolysis-eligible AIS patients. Logistic regression models were used to examine the associations with outcomes of death or disability (modified Rankin scale [mRS] scores 2-6), major disability (mRS 3-5), death, and intracranial hemorrhage (ICH), with adjustment prognostic factors, alteplase dose, and mean SBP over 1-24 h. RESULTS: Among 4,551 thrombolyzed AIS patients (mean age 66.7 years, 37.8% female), there were 65.4% Asians who were younger, fewer female, and with less atrial fibrillation, hypercholesterolemia, premorbid symptoms, and concomitant antihypertensive, antithrombotic and statin treatment, and more prior stroke, compared to non-Asians. Frequencies of hypertension, coronary artery disease, and diabetes mellitus were comparable between groups. Asian patients were less likely to be admitted to an acute stroke unit and receive early mobilization by a therapist or rehabilitation but more likely to receive intensive care. There were no significant differences between Asians and non-Asians in functional outcome (defined by mRS scores 2-6 or 3-5; adjusted odds ratio [OR] 1.00, 95% confidence interval [CI] 0.85-1.19 [p = 0.958] and OR 0.95, 95% CI 0.80-1.13 [p = 0.572], respectively), or death (OR 1.25, 95% CI 0.95-1.65; p = 0.116), despite Asians having greater odds of ICH (OR 1.51, 95% CI 1.23-1.86; p = 0.0001) and neurological deterioration within 24 h (OR 1.58, 95% CI 1.18-2.12; p = 0.002). CONCLUSIONS: Within the context of an international clinical trial of thrombolyzed AIS patients, demography, risk factors, management, and odds of early neurological deterioration and ICH, all differ between Asian and non-Asian participants. However, patterns of functional recovery are similar between these major regional groups.

Brain Imaging Signs and Health-Related Quality of Life after Acute Ischemic Stroke: Analysis of ENCHANTED Alteplase Dose Arm.

BACKGROUND AND PURPOSE: The influence of specific brain lesions on health-related quality of life (HRQoL) after acute ischemic stroke (AIS) is uncertain. We aimed to identify imaging predictors of poor HRQoL in alteplase-treated participants of the alteplase dose arm of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: ENCHANTED was an international trial of low- versus standard-dose intravenous alteplase in AIS patients, with functional outcome (modified Rankin scale [mRS]) and HRQoL on the 5-dimension European Quality of Life Scale (EQ-5D) assessed at 90 days post-randomization. Brain images were analyzed centrally by trained assessors. Multivariable logistic regression was undertaken in the study population randomly divided (2:1) into training (development) and validation (performance) groups, with age (per 10-year increase), ethnicity, baseline National Institutes of Health Stroke Scale (NIHSS) score, diabetes mellitus, premorbid function (mRS score 0 or 1), and proxy respondent, forced into all models. Data are presented with odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Eight prediction models were developed and validated in 2,526 AIS patients (median age 67.5 years; 38.4% female; 61.7% Asian) with complete brain imaging and 90-day EQ-5D utility score data. The best performance model included acute ischemic changes in the right (OR 1.69, 95% CI: 1.24-2.29) and deep (OR 1.50, 95% CI: 1.03-2.19) middle cerebral artery (MCA) regions. Several background features of brain frailty - atrophy, white matter change, and old infarcts - were significantly associated with adverse physical but not emotional HRQoL domains. CONCLUSIONS: In thrombolysed AIS patients, right-sided and deep ischemia within the MCA territory predict poor overall HRQoL, whilst features of old cerebral ischemia are associated with reduced physical HRQoL.

A combination of Citrus reticulata peel and black tea inhibits migration and invasion of liver cancer via PI3K/AKT and MMPs signaling pathway.

Liver cancer, one of the most common malignancies, is the second leading cause of cancer death in the world. The citrus reticulate peel and black tea have been studied for their beneficial health effects. In spite of the many studies have been reported, the underlying molecular mechanisms underlying its health benefits are still not fully understood. In present study, we developed a unique citrus reticulate peel black tea (CRPBT) by combined citrus reticulate peel and black tea and assessed its active ingredients, anti-oxidant and anti-liver cancer effects in vitro. The results suggested that CRPBT exhibited antioxidant capacity and effectively inhibited proliferation and migration of liver cancer cells in a dose- and time- dependent manner. Mechanistically, CRPBT significantly down-regulated phosphorylation of PI3K and AKT, and up-regulated the ratio of Bax/Bcl-2, and suppressed the expression of MMP2/9, N-cadherin and Vimetin proteins in liver cancer cells. Taken together, CRPBT has good effect on inhibiting migration, invasion, proliferation, and inducing apoptosis in liver cancer cells.

Preventative and Therapeutic Potential of Flavonoids in Peptic Ulcers.

Peptic ulcer disease is a common gastrointestinal tract disorder that affects up to 20% of the population of the world. Treatment of peptic ulcer remains challenging due to the limited effectiveness and severe side effects of the currently available drugs. Hence, natural compounds, owing to their medicinal, ecological, and other safe properties, are becoming popular potential candidates in preventing and treating peptic ulcers. Flavonoids, the most abundant polyphenols in plants, exhibit gastroprotective effects against peptic ulcer both in vivo and in vitro. In this review, we summarized the anti-ulcer functions and mechanisms, and also the bioavailability, efficacy, and safety, of flavonoid monomers in the gastrointestinal tract. Flavonoids exerted cytoprotective and rehabilitative effects by not only strengthening defense factors, such as mucus and prostaglandins, but also protecting against potentially harmful factors via their antioxidative, anti-inflammatory, and antibacterial activities. Although controlled clinical studies are limited at present, flavonoids have shown a promising preventable and therapeutic potential in peptic ulcers.

A Mitochondrion-Localized Two-Photon Photosensitizer Generating Carbon Radicals Against Hypoxic Tumors.

The efficacy of photodynamic therapy is typically reliant on the local concentration and diffusion of oxygen. Due to the hypoxic microenvironment found in solid tumors, oxygen-independent photosensitizers are in great demand for cancer therapy. We herein report an iridium(III) anthraquinone complex as a mitochondrion-localized carbon-radical initiator. Its emission is turned on under hypoxic conditions after reduction by reductase. Furthermore, its two-photon excitation properties (λex =730 nm) are highly desirable for imaging. Upon irradiation, the reduced form of the complex generates carbon radicals, leading to a loss of mitochondrial membrane potential and cell death (IC50light =2.1 µm, IC50dark =58.2 µm, PI=27.7). The efficacy of the complex as a PDT agent was also demonstrated under hypoxic conditions in vivo. To the best of our knowledge, it is the first metal-complex-based theranostic agent which can generate carbon radicals for oxygen-independent two-photon photodynamic therapy.

Interaction of Blood Pressure Lowering and Alteplase Dose in Acute Ischemic Stroke: Results of the Enhanced Control of Hypertension and Thrombolysis Stroke Study.

OBJECTIVE: To determine the extent to which the effects of intensive blood pressure (BP) lowering are modified by doses of alteplase in thrombolysis-eligible acute ischemic stroke (AIS) patients. METHODS: Prespecified analyses of the Enhanced Control of Hypertension and Thrombolysis Stroke Study for patients enrolled in both arms: (i) low-dose (0.6 mg/kg body weight) or standard-dose (0.9 mg/kg) alteplase and (ii) intensive (target systolic BP [SBP] 130-140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) BP management. The primary outcome was functional recovery, measured by a shift in scores on modified Rankin scale at 90 days. The safety outcome was any intracranial hemorrhage (ICH). RESULTS: There were 925 participants (mean age 67 years, 39% female, 77% Asian) randomized to both arms: 242 randomly assigned to guideline/standard-dose (GS); 234 to guideline/low-dose (GL); 227 to intensive/standard-dose (IS); and 222 to intensive/low-dose (IL). Overall, average SBP levels within 24 h were lower in the low-dose compared to standard-dose alteplase group (146 and 144 vs. 151 and 150 mm Hg, for GS and GL vs. IS and IL, respectively, p < 0.0001). There was no heterogeneity of the effects of BP lowering (intensive vs. guideline) on functional recovery between standard-dose (OR 0.81, 95% CI 0.59-1.12) and low-dose alteplase (1.06, 0.77-1.47; p = 0.25 for interaction). Similar results were observed for ICH (p = 0.50 for interaction). CONCLUSIONS: In thrombolysis-treated patients with predominantly mild-to-moderate severity AIS, intensive BP lowering neither improve functional recovery, either with low- or standard-dose intravenous alteplase, nor beneficially interact with low-dose alteplase in reducing ICH. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov (NCT01422616).

Nrf2 Signaling Elicits a Neuroprotective Role Against PFOS-mediated Oxidative Damage and Apoptosis.

Perfluorooctanesulfonate (PFOS) may cause neurotoxicity through the initiation of oxidative stress. In the current study, we investigated the role of anti-oxidant nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in PFOS-induced neurotoxicity. We found that human neuroblastoma SH-SY5Y cells exhibited significant apoptotic cell death following PFOS exposure, and this process was accompanied with apparent accumulation of reactive oxidative species (ROS). In addition, we revealed that PFOS exposure caused marked activation of Nrf2 pathway and the expression of Nrf2 transcription target heme oxygenase-1. We further found that pre-treatment with ROS scavenger N-acetyl-L-cysteine (NAC) dramatically ameliorated PFOS-induced ROS production and Nrf2 signaling. In keeping with these findings, western blot and Cell Counter Kit-8 analyses revealed that pre-incubation with NAC suppressed PFOS-induced expression of pro-apoptotic proteins and impairment of neuronal viability. Moreover, antagonizing Nrf2 pathway with Nrf2 inhibitor brusatol resulted in increased ROS production and enhanced PFOS-induced expression of apoptosis related proteins. Finally, we showed that PFOS exposure altered mitochondrial transmembrane potential and disrupted normal mitochondrial morphology in SH-SY5Y cells. Whereas treatment with NAC ameliorated PFOS-induced mitochondrial disorders, co-incubation with brusatol augmented PFOS-induced mitochondrial deficits, consequently contributing to neuronal apoptosis. These results manifest that Nrf2 pathway plays a protective role in PFOS-induced neurotoxicity, providing new insights into the prevention and treatment of PFOS-related toxicities.

Black tea affects obesity by reducing nutrient intake and activating AMP-activated protein kinase in mice.

The effects of certain tea components on the prevention of obesity in humans have been reported recently. However, whether Yinghong NO. 9 black tea consumption has beneficial effects on obesity are not known. Here, we obtained a Yinghong NO. 9 black tea infusion (Y9 BTI) and examined the anti-obesity effects of its oral administration. ICR mice were fed a standard diet supplemented with Y9 BTI at 0.5, 1.0, or 2.0 g/kg body weight for two weeks, and the body weight were recorded. HE staining was used to evaluate the effect of Y9 BTI on mice liver. Western blot analysis was used to detect the expression levels of related proteins in the mice liver and adipose. We found that the body weights of the mice in the control group were significantly higher than those of the mice in the middle and high dose groups. The results of western blot showed that Y9 BTI up-regulated the expression of liver kinase B1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK) and also increased in AMPK phosphorylation (p-AMPK) and LKB1 phosphorylation (p-LKB1). Y9 BTI significantly down-regulated Fas Cell Surface Death Receptor(FAS) and activated the phosphorylation of acetyl-CoA carboxylase (ACC). Furthermore, Y9 BTI (2.0 g/kg BW) down-regulated the expression of three factors (IL-1ß, Cox-2, and iNOS). Altogether, Y9 BTI supplementation reduced the feed intake of mice and may prevent obesity by inhibiting lipid absorption. These results suggest that Y9 BTI may regulate adipogenic processes through the LKB1/AMPK pathway.

Dietary fiber intake reduces risk for Barrett's esophagus and esophageal cancer.

BACKGROUND: Observational studies suggest an association between dietary fiber intake and risk of Barrett's esophagus and esophageal cancer. However, the results are inconsistent. OBJECTIVE: To conduct a meta-analysis of observational studies to assess this association. DESIGN: All eligible studies were identified by electronic searches in PubMed and Embase through February 2015. Dose-response, subgroup, sensitivity, and publication bias analyses were performed. RESULTS: A total of 15 studies involving 16,885 subjects were included in the meta-analysis. The pooled odds ratio for the highest compared with the lowest dietary fiber intake was 0.52 (95% CI, 0.43-0.64). Stratified analyses for tumor subtype, study design, geographic location, fiber type, publication year, total sample size, and quality score yielded consistent results. Dose-response analysis indicated that a 10-g/d increment in dietary fiber intake was associated with a 31% reduction in Barrett's esophagus and esophageal cancer risk. Sensitivity analysis restricted to studies with control for conventional risk factors produced similar results, and omission of any single study had little effect on the overall risk estimate. CONCLUSIONS: Our findings indicate that dietary fiber intake is inversely associated with risk of Barrett's esophagus and esophageal cancer. Further large prospective studies are warranted.

A Study of GWAS-Supported Variants of rs9943582 in a Chinese Han Population with Ischemic Stroke: No Associations with Disease Onset and Clinical Outcomes.

BACKGROUND: The variant rs9943582 of APLNR (apelin receptor) was identified by a large-scale study to be associated with an increased risk of ischemic stroke in a Japanese population. We conducted this study to investigate the association between the variant and age of onset and clinical outcomes of ischemic stroke in a Chinese population. METHODS: Improved multiple ligase detection reaction was used to genotype the variant. We compared the mean age at ischemic stroke onset with one-way ANOVA. The Kaplan-Meier method, log-rank test, and Cox proportional hazards regression models were performed to analyze the association between the variant and clinical outcomes (recurrence and death). RESULTS: A total of 916 ischemic stroke patients were recruited for the study. For age at ischemic stroke onset, no significant association was identified with the variant in any genetic model. In addition, the variant was not strongly associated with recurrence and death risk of ischemic stroke, as shown by the results. CONCLUSIONS: The findings indicated that the variant rs9943582 was not associated with age at onset and clinical outcomes of ischemic stroke. However, evidence from well-designed studies with larger and in different ethnic populations are warranted to further explore the effects of APLNR on the ischemic stroke onset and clinical outcomes.