TMEM16F may be a new therapeutic target for Alzheimer's disease.

TMEM16F is involved in many physiological processes such as blood coagulation, cell membrane fusion and bone mineralization. Activation of TMEM16F has been studied in various central nervous system diseases. High TMEM16F level has been also found to participate in microglial phagocytosis and transformation. Microglia-mediated neuroinflammation is a key factor in promoting the progression of Alzheimer's disease. However, few studies have examined the effects of TMEM16F on neuroinflammation in Alzheimer's disease. In this study, we established TMEM16F-knockdown AD model in vitro and in vivo to investigate the underlying regulatory mechanism about TMEM16F-mediated neuroinflammation in AD. We performed a Morris water maze test to evaluate the spatial memory ability of animals and detected markers for the microglia M1/M2 phenotype and NLRP3 inflammasome. Our results showed that TMEM16F was elevated in 9-month-old APP/PS1 mice. After TMEM16F knockdown in mice, spatial memory ability was improved, microglia polarization to the M2 phenotype was promoted, NLRP3 inflammasome activation was inhibited, cell apoptosis and Aß plaque deposition in brain tissue were reduced, and brain injury was alleviated. We used amyloid-beta (Aß25-35) to stimulate human microglia to construct microglia models of Alzheimer's disease. The levels of TMEM16F, inducible nitric oxide synthase (iNOS), proinflammatory cytokines and NLRP3 inflammasome-associated biomarkers were higher in Aß25-35 treated group compared with that in the control group. TMEM16F knockdown enhanced the expression of the M2 phenotype biomarkers Arg1 and Socs3, reduced the release of proinflammatory factors interleukin-1, interleukin-6 and tumor necrosis factor-α, and inhibited NLRP3 inflammasome activation through reducing downstream proinflammatory factors interleukin-1ß and interleukin-18. This inhibitory effect of TMEM16F knockdown on M1 microglia was partially reversed by the NLRP3 agonist Nigericin. Our findings suggest that TMEM16F participates in neuroinflammation in Alzheimer's disease through participating in polarization of microglia and activation of the NLRP3 inflammasome. These results indicate that TMEM16F inhibition may be a potential therapeutic approach for Alzheimer's disease treatment.

Immunocytes Rapid Responses Post-ischemic Stroke in Peripheral Blood in Patients With Different Ages.

Objectives: To explore the alterations in immune cell composition in peripheral blood in patients with acute ischemic stroke (AIS) based on their age group. Methods: Patients with imaging confirmed AIS were enrolled from April 2019 to January 2020 and were divided into three groups according to their ages: <55 years (group-A), 55-65 years (group-B), and >65 years (group-C). Blood samples were collected immediately when the patients were admitted to our ward prior to any intervention. Flow cytometry was used to analyze immune cell composition in peripheral blood. Results: A total of 41 eligible patients were included for final analysis. Among the three groups, the proportions of CD56+ CD16dim NK cells were least to greatest in group-B, group-A, then group-C, respectively. With increasing age, there was a decrease in the proportion of CD3+ T-cells (group-A vs. group-C, P = 0.016) and CD3+CD4+ T-cells (group-C vs. group-A, P = 0.008; group-C vs. group-B P = 0.026). Meanwhile, no significant differences in proportions of monocytes and B cells were observed. Conclusions: The compositions of immune cells in peripheral blood of AIS patients were distinct when divided by age groups. Differences in immune cell ratios may affect clinical outcomes and foreshadows possible need for customized treatment of AIS in different age groups.

pH-responsive curcumin-based nanoscale ZIF-8 combining chemophotodynamic therapy for excellent antibacterial activity.

Antimicrobial photodynamic therapy (aPDT) is a highly attractive therapy due to its advantages of being a non-antibiotic procedure for reducing drug-resistant microbes. Curcumin (CCM) has been considered as a natural photosensitizer for PDT with prominent antibacterial, antifungal, and anti-proliferative activity. However, its excellent biological and pharmacological activities are limited because of its low solubility, rapid metabolization and instability. Herein, we reported a promising agent based on CCM-incorporated into zeolitic imidazolate framework-8 (ZIF@CCM). The as-prepared nanoparticle exhibited high drug loading capability (11.57%) and drug loading encapsulation (82.76%). Additionally, ZIF@CCM displayed a pH-responsive drug release behavior and chemophotodynamic therapy for excellent antibacterial activity. The underlying mechanism elucidated that Zn2+ released from ZIF-8 increased the permeability of the bacterial cell membrane with leakages of K+. The overproduction of extracellular ROS further resulted in the disrupted bacterial cell membrane and distorted bacterial morphology. Thus, ZIF@CCM-mediated photodynamic activation might be a promising treatment strategy for microbial inactivation.

pH and light-responsive polycaprolactone/curcumin@zif-8 composite films with enhanced antibacterial activity.

Food packaging materials, especially biodegradable polymer composites incorporated with natural antimicrobial agents with excellent antibacterial activities, are in high demand and attracted immense attention. Herein, a polycaprolactone/curcumin@zeolitic imidazolate framework-8 (PCL/Cur@ZIF-8) composite film with enhanced antibacterial activity was developed. Curcumin, a natural photosensitizer, was loaded in the highly porous nanocrystals ZIF-8 to improve its poor water solubility and stability. The integral structure of Cur@ZIF-8 was maintained well in the PCL matrix even at the highest loading of 35% (w/w), and all composite films had good light transmittance at 420-430 nm. The PCL/Cur@ZIF-8 composite films responded to the acidic growth environment of bacteria by releasing zinc ions and curcumin molecules. Furthermore, upon blue light irradiation (420-430 nm, 2.2 mW/cm2 ), curcumin molecules generated singlet oxygen. With the synergistic effects of zinc ions and singlet oxygen, the composite films exhibited a 99.9% reduction of Escherichia coli and Staphylococcus aureus strains when the amount of Cur@ZIF-8 loading was more than 15% (w/w), as well as a strong anti-adhesion effect on bacteria. Moreover, bacterial resuscitation tests indicated that the composite films exhibited 99.9% reduction in the adhered bacteria population through treatment with photodynamic sterilization. This is the first study presenting that the incorporated curcumin ZIF-8 nanoparticles in the matrix of polymer are pH and light responsive for anti-adhesion of bacteria, which is of great potential application as antibacterial packaging material for the food industry. PRACTICAL APPLICATION: A novel, biodegradable, pH, and light-responsive composite film was developed for antibacterial activity. Natural photosensitizer curcumin was encapsulated in ZIF-8 nanocrystals (Cur@ZIF-8) as the antimicrobial agent. With the synergistic effects of Zn2+ and singlet oxygen, the composite film exhibited a 99.9% reduction of Escherichia coli and Staphylococcus aureus strains, and a strong anti-adhesion property toward bacteria. This composite film is of great potential application as an antibacterial packaging material that enhances the shelf life of fruits, meat, and so on.

Cerebral venous sinus thrombosis due to external compression of internal jugular vein.

Cerebral venous sinus thrombosis (CVST) is a special subtype of stroke that may be life-threatening in severe cases. CVST has distinct risk factors and is frequently overlooked because of its initially nonspecific clinical presentation. We herein describe a 72-year-old man who developed CVST in the right lateral sinus. Despite the absence of common risk factors in this patient, he developed external compression of the bilateral internal jugular veins by a lateral mass of the C1 vertebra and expansion of the carotid artery. Because of his elevated D-dimer and fibrinogen concentrations, which are associated with ongoing activation of the coagulation system, the patient underwent treatment with batroxobin combined with anticoagulation. Recanalization of the sinus was achieved, and his high intracranial pressure and papilledema remarkably decreased. We conclude that external compression of the internal jugular veins, which can be identified with three-dimensional computed tomography venography, may be an important risk factor for CVST.

Normobaric Oxygen May Ameliorate Cerebral Venous Outflow Disturbance-Related Neurological Symptoms.

Cerebral venous outflow disturbance (CVOD) has begun to garner the attention of researches owing to a series of clinical symptoms that impose a significant impact on people's quality of life. Herein, we aimed to investigate whether normobaric oxygen (NBO) can ameliorate CVOD-induced neurological symptoms. This was one part of the prospective trial registered in ClinicalTrials.gov (NCT03373292). A total of 37 CVOD patients were divided into the NBO group (5-8 L/min of oxygen inhalation, 1 h per time, 3 times daily, n = 19) and the control group (without oxygen inhalation, n = 18) randomly. The assessments were performed at admission, 1-week hospitalization, and 6-month follow-up. Quantitative electroencephalogram (qEEG) data were recorded prior to and post 1 h of NBO in some patients. R software was used for data analysis. No NBO-related adverse events were observed during the whole NBO intervention process. The 1-week Patient Global Impression of Change (PGIC) scale showed that the symptom improvement occurred in nine patients in the NBO group (47.4%) while none in the control group (p = 0.001). NBO could improve headache evaluated with visual analog scale (pre-NBO vs. post-NBO: 4.70 ± 2.16 vs. 2.90 ± 2.03, p = 0.024) and Headache Impact Test-6 (53.40 ± 12.15 vs. 50.30 ± 13.04, p = 0.041). As for 6-month PGIC follow-up, eight out of 14 cases (57.1%) in the NBO group reported improvement, while only one out of 12 patients in the control group replied mild improvement (p = 0.014). The qEEG revealed that NBO reduced the ratio of theta to alpha power (0.65 ± 0.38 vs. 0.56 ± 0.35, p = 0.030) over the fronto-central electrodes. To sum up, NBO may be a safe and effective approach to attenuate CVOD-related symptoms (especially for headache) by brain functional improvement resulting from increasing oxygen supply to the brain tissues.

Clinical characteristics and neuroimaging findings in eagle syndrome induced internal jugular vein stenosis.

BACKGROUND: Eagle syndrome is a condition that causes pharyngeal pain, facial pain, swallowing difficulties, and symptoms of arterial impingement due to the elongated styloid process. However, few reports were about eagle syndrome with venous compression up to now. This study aimed to identify the clinical profiles of the internal jugular vein stenosis (IJVS) related eagle syndrome comprehensively. METHODS: A total of 27 patients, who were diagnosed as IJVS induced by styloid process compression were enrolled. The clinical manifestations and imaging features were analyzed. RESULTS: Styloid process compression was presented in all of the 27 IJVS patients, in which, the top three symptoms included insomnia (81.5%), tinnitus (63.0%) and head noises (63.0%). The most vulnerable segment of internal jugular vein (IJV) was J3 segment (96.3%). The average styloid process length in our study was 3.7 cm. Hearing impairment was more common in bilateral IJVS (68.8% vs. 18.2%, P=0.018). One patient reported significant relief of symptoms at 1 year follow-up after underwent styloidectomy combined with stenting. CONCLUSIONS: Neurological symptoms of eagle syndrome induced IJVS were various, including either arterial or venous issues. Better understanding of this disease entity may be helpful for clinical diagnosis and treatment.

Probable risk factors of internal jugular vein stenosis in Chinese patients-A real-world cohort study.

OBJECTIVES: Extracranial venous anomalies, especially internal jugular vein stenosis (IJVS), have recently received increasing attention, however, its etiologies are uncertain. This study aimed to explore the probable risk factors of IJVS in Chinese PATIENTS AND METHODS: Eligible patients with IJVS confirmed by contrast-enhanced magnetic resonance venography (CE-MRV) were enrolled from October 2017 through October 2018. Probable risk factors were analyzed, including the conditions that may result in IJV wall damage, extraluminal compression, gender and age. RESULTS: A total of 133 patients enrolled in the final analysis, including 73 females and 60 males, the mean age were 54.83 ±â€¯15.25 years. In this IJVS cohort, the top two risks were previous hepatitis B virus (HBV) infection (48.9 %) and osseous compression (41.4 %). The IJVS cohort was divided into two subsets: extraluminal compression and non-compression. In the former, osseous compression (80.9 %) was the top risk factor, other risks including arterial (22.1 %) and lymph node compression (2.9 %). While, in the latter subset, the most common risk factor was previous HBV infection (46.2 %). In addition, cerebral venous sinus thrombosis (CVST) in non-compression subset was more common than that in extraluminal compression subset (21.5 % VS. 2.9 %, p = 0.001). When considered the gender (Male vs. Female), the ratios were 28.3 % vs. 0 % of smoking, p < 0.001, 16.67 % vs. 1.37 % of hyperhomocysteinemia, p = 0.002, and 11.67 % vs. 1.37 % of hyperuricemia, p = 0.023. In the subset with age less than 45 years, the top three risks included CVST (56.25 %), immunological diseases (55.56 %), and hyperhomocysteinemia (50.00 %), while, in the subset with the ages over 60 years, type-2 diabetes (66.66 %), carotid artery compression (53.33 %), previous HBV infection (52.31 %), and osseous compression (49.09 %) were more common than others. CONCLUSION: This study illustrates the probable risks of IJVS may be diverse, in which osseous compression and previous HBV infection may be the top two probable risks of IJVS in Chinese. This is the biggest difference from previous reports based on Caucasian.

Clinical and neuroimaging correlates among cohorts of cerebral arteriostenosis, venostenosis and arterio-venous stenosis.

The purpose of this study was to discriminate the clinical and imaging correlates of cerebral arterial stenosis (CAS), venous stenosis (CVS) and arterio-venous stenosis (CAVS) in the clinical setting. Patients were classified into three groups: CAS (n = 75), CVS (n=74) and CAVS (n=67). Focal neurological deficits were the prominent presenting symptoms in CAS group, while venous turbulence related symptoms were common in both CVS and CAVS group. Risk factor analysis showed the OR (95%CI) for diabetes, male gender and age in CAS vs. CVS group were 13.67(2.71, 68.85), 6.69(2.39, 18.67) and 1.07(1.03, 1.12) respectively. Male gender, diabetes and age in CAVS vs. CAS groups were 0.27(0.11, 0.63), 0.26(0.10, 0.67) and 1.09(1.04, 1.14) respectively, while age in CAVS vs. CVS group was 1.11(1.07, 1.15). The white matter lesions (WMLs) in CAS group varied in size, with clear boundaries asymmetrically distributed in bilateral hemispheres. CVS-induced WMLs revealed a bilaterally symmetric, cloudy-like appearance. The cerebral perfusion was asymmetrically reduced in CAS but symmetrically reduced in CVS group. The clinical characteristics and neuroimaging presentations were different among patients with CAS, CVS and CAVS. We recommended for aged patients, both arterial and venous imaging should be considered in diagnosis of cerebral stenotic vascular disorders.

Efficacy of remote ischemic conditioning on improving WMHs and cognition in very elderly patients with intracranial atherosclerotic stenosis.

Our previous study revealed that remote ischemic conditioning (RIC) reduced the incidence of stroke or TIA in octo- and nonagenarians with intracranial atherosclerotic stenosis (ICAS). Herein, we aimed to investigate whether RIC would influence the progression of white matter hyperintensities (WMHs) and cognitive impairment in the same group of patients. Fifty-eight patients with ICAS were randomly assigned in a 1:1 ratio to receive standard medical treatment with RIC (n=30) versus sham-RIC (n=28). The RIC protocol consisted of 5 cycles of alternating 5-min ischemia and 5-min reperfusion applied in the bilateral upper arms twice daily for 300 days. The efficacy outcomes included WMHs change on T2 FLAIR sequences, estimated by the Fazekas scale and Scheltens scale, cognitive change as assessed by the MMSE and MoCA, and some clinical symptoms within 300-day follow-up. Compared with the baseline, RIC treatment significantly reduced Fazekas and Scheltens scores at both 180-day (both p<0.05) and 300-day (both p<0.01) follow-ups, whereas no such reduction was observed in the control group. In the RIC group, Fazekas scores were significantly lower at 300-day follow-up (p<0.001) while Scheltens scores were significantly lower at both 180-day and 300-day follow-ups (both p<0.001), as compared with the control group. There were statistically significant between-group differences in the overall MMSE or MoCA scores, favoring RIC at 180-day and 300-day follow-ups (all p<0.05). RIC may serve as a promising adjunctive to standard medical therapy for preventing the progression of WMHs and ameliorating cognitive impairment in very elderly patients with ICAS.

Batroxobin in combination with anticoagulation may promote venous sinus recanalization in cerebral venous thrombosis: A real-world experience.

AIMS: The objective of this study was to evaluate cerebral venous recanalization with magnetic resonance black-blood thrombus imaging (MRBTI) in patients with cerebral venous thrombosis (CVT) who underwent batroxobin treatment in combination with anticoagulation. METHODS: A total of 31 CVT patients were enrolled in this real-world registry study. The patients were divided into batroxobin (n = 21) and control groups (n = 10). In addition to the same standard anticoagulation as in the control group, patients in the batroxobin group underwent intravenous batroxobin for a total of three times. RESULTS: In the batroxobin group compared with the control group, we found better odds of recanalization degree [adjusted OR (95%CI) of 8.10 (1.61-40.7)] and segment-stenosis attenuation [adjusted OR (95%CI) of 4.48 (1.69-11.9)] with batroxobin treatment. We further noted a higher ratio of patients with the attenuation of stenosis [adjusted OR (95%CI) of 26.4 (1.10-635)]; as well as a higher ratio of segments with stenosis reversion [adjusted OR (95%CI) of 4.52 (1.48-13.8)]. However, neurological deficits between the two groups showed no statistical difference at 90-day follow-up (P > 0.05). CONCLUSIONS: Batroxobin may promote venous sinus recanalization and attenuate CVT-induced stenosis. Further randomized study of this promising drug may be warranted to better delineate the amount of benefit.

Probable factors affecting clinical outcomes of internal jugular vein stenosis.

BACKGROUND: Internal jugular vein stenosis (IJVS) has recently aroused increasing interests, whereas, the factors affecting its clinical outcomes are not clear. This study aims to explore the probable factors affected clinical prognosis by evaluating the IJVS with different etiologies and strategies. METHODS: Patients with IJVS confirmed by contrast-enhanced magnetic resonance venography (CE-MRV) were enrolled from October 2017 through October 2018. One-year clinical outcomes of the IJVS cases enrolled in this study were assessed by outpatient and telephone follow-up using the Patient Global Impression of Change (PGIC) scores. According to the etiologies, patients were divided into thrombotic IJVS and non-thrombotic IJVS groups. And further, non-thrombotic IJVS group was divided into external compression and non-external compression subgroups. Outcomes of IJVS with different etiologies and strategies were compared and the probable prognostic factors were analyzed. RESULTS: A total of 118 eligible patients enrolled in this study, including 76 females and 42 males, mean aged 55.07±14.61 years. The average follow-up duration after discharge was 13.22±3.80 months. According to the PGIC scores, we categorized patients as good outcome and poor outcome groups. For thrombotic IJVS, patients underwent standard anticoagulant obtained remarkable PGIC improvement (100.0% vs. 33.3%, P=0.038). For non-thrombotic IJVS, stenting showed benefit in non-external compression subgroup (26.9% vs. 3.3%, P=0.019) but not in external compression subgroup. In addition, we found that in this Chinese IJVS cohort, poor outcomes involved old age (P=0.004), type 2 diabetes mellitus (P=0.036), previous hepatitis B virus (HBV) infection (P=0.027), and head noises (P=0.002). Multivariate logistic regression analysis indicated that continuous head noises [P=0.045, odds ratio (OR): 2.412, 95% confidence interval (CI): 1.019-5.711], as a unique symptom of IJVS may be significantly related to poor outcomes. CONCLUSIONS: In this Chinese cohort, elderly degenerative bone compression, type 2 diabetes mellitus, and previous HBV infection are the top-three probable etiologies of non-thrombotic IJVS and may involve poor outcome. Long-term head noises may predict IJVS and with poor outcome. Thrombosis-induced IJVS may get benefit from standard anticoagulation. Non-external compression IJVS can be corrected by stenting.

Hemorrhagic Moyamoya Disease Treatment: A Network Meta-Analysis.

BACKGROUND: Therapeutic strategies for managing hemorrhagic moyamoya disease (MMD) remain controversial. In this study, we investigated the optimal therapy for hemorrhagic MMD. METHODS: In accordance with the PRISMA statement, we searched through relevant articles and references from PubMed, Embase, and Cochrane database, and performed a network meta-analysis using R version 3.4.4 software. RESULTS: A total of 9 articles (including 1050 patients) were included in our analysis. Of these 1050 patients, 557 underwent surgical revascularization (including direct and indirect bypass), and the remaining 493 patients were managed with a conservative treatment regimen. A pooled analysis revealed that surgical revascularization was superior to the conservative treatment regimen in decreasing the rate of recurrent stroke events (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.24-0.65), including ischemic stroke recurrence (OR, 0.31; 95% CI, 0.12-0.79) and hemorrhage recurrence (OR, 0.45; 95% CI, 0.26-0.79), but not in reducing mortality (OR, 0.53; 95% CI, 0.24-1.17). Moreover, the incidence of recurrent stroke in the direct bypass cohort was lower than that for either the conservative treatment cohort (OR, 0.30; 95% CI, 0.15-0.58) or the indirect bypass cohort (OR, 0.39; 95% CI, 0.18-0.87). However, the ratios showed no statistically significant difference between the latter 2 cohorts (OR, 0.75; 95% CI, 0.33-1.68). CONCLUSIONS: Surgical revascularization, especially a direct bypass regimen, may be the optimal strategy for treating hemorrhagic MMD.