Effect and mechanism of quercetin or quercetin-containing formulas against COVID-19: From bench to bedside.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global coronavirus disease 2019 (COVID-19) pandemic since 2019. Immunopathogenesis and thromboembolic events are central to its pathogenesis. Quercetin exhibits several beneficial activities against COVID-19, including antiviral, anti-inflammatory, immunomodulatory, antioxidative, and antithrombotic effects. Although several reviews have been published, these reviews are incomplete from the viewpoint of translational medicine. The authors comprehensively evaluated the evidence of quercetin against COVID-19, both basically and clinically, to apply quercetin and/or its derivatives in the future. The authors searched the PubMed, Embase, and the Cochrane Library databases without any restrictions. The search terms included COVID-19, SARS-CoV-2, quercetin, antiviral, anti-inflammatory, immunomodulatory, thrombosis, embolism, oxidative, and microbiota. The references of relevant articles were also reviewed. All authors independently screened and reviewed the quality of each included manuscript. The Cochrane Risk of Bias Tool, version 2 (RoB 2) was used to assess the quality of the included randomized controlled trials (RCTs). All selected studies were discussed monthly. The effectiveness of quercetin against COVID-19 is not solid due to methodological flaws in the clinical trials. High-quality studies are also required for quercetin-containing traditional Chinese medicines. The low bioavailability and highly variable pharmacokinetics of quercetin hinder its clinical applications. Its positive impact on immunomodulation through reverting dysbiosis of gut microbiota still lacks robust evidence. Quercetin against COVID-19 does not have tough clinical evidence. Strategies to improve its bioavailability and/or to develop its effective derivatives are needed. Well-designed RCTs are also crucial to confirm their effectiveness in the future.

Spine-like Joint Link Mechanism to Design Wearable Assistive Devices.

When we develop wearable assistive devices, comfort and support are two main issues that need to be considered. In conventional design approaches, the degree of freedom of the wearer's joint movements tends to be oversimplified. Accordingly, the wearer's motion becomes restrained and bone/ligament injuries might occur in case of an unexpected fall. To mitigate these issues, this paper proposes a novel joint link mechanism inspired by a human spine structure as well as functionalities. The key feature of the proposed spine-like joint link mechanism is that hemispherical blocks are concatenated via flexible synthetic fiber lines so that their concatenation stiffness can be adjusted according to a tensile force. This feature has a great potentiality for designing a wearable assistive device that can support aged people's sit-to-stand action or augment spinal motion by regulating the concatenation stiffness. In addition, the concatenated hemispherical blocks enable the wearer to move his/her joint with full freedom, which in turn increases the wearer's mobility and prevents joint misalignment. The experimental results with a testbed and a pilot wearer substantiated that the spine-like joint link mechanism can serve as a key component in the design of wearable assistive devices for better mobility.

Caregiving, care burden and awareness of caregivers and patients with dementia in Asian locations: a secondary analysis.

BACKGROUND: This study investigated the differences in caregiver activity, caregiver burden, and awareness of both caregivers and patients with Alzheimer's disease (AD) across different Asian locations. METHODS: This was a secondary analysis of a multi-national cohort study that aimed to assess caregiver activity and caregiver burden using the Caregiver Activity Scale (CAS) and Zarit Burden Interview (ZBI), respectively. Patients' awareness of their dementia diagnosis was assessed by asking the following yes/no question: "Do you have dementia?" Caregivers' awareness of the patient's dementia diagnosis was assessed by asking the following yes/no question: "Does your patient have dementia?" RESULTS: In total, 524 caregivers of patients with AD from China, Hong Kong, South Korea, the Philippines, Singapore, Thailand, and Taiwan participated. The CAS and ZBI score were significantly different across most locations (p < 0.001 and p = 0.033, respectively). Overall, 56.6% of caregivers and 37.5% of patients had awareness of the dementia diagnosis, and the proportion of patients and caregivers with awareness were also different between each location (all, p < 0.001). CONCLUSIONS: Caregiving, caregiver burden, and the awareness of caregivers and patients were different across many Asian locations. With understanding of cultural differences, further public education on dementia could help increase the awareness of patients and caregivers and reduce caregiver burden. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02262975 . Registered 13 October 2014.

Two-month breathing-based walking improves anxiety, depression, dyspnoea and quality of life in chronic obstructive pulmonary disease: A randomised controlled study.

AIMS AND OBJECTIVES: To examine the effects of the two-month breathing-based walking intervention and its follow-up on anxiety, depression, dyspnoea and quality of life in patients with chronic obstructive pulmonary disease. BACKGROUND: Mind-body-related exercises improve bio-psychological symptoms and quality of life in chronic diseases, but these improvements are not proven for chronic obstructive pulmonary disease. DESIGN: This was a randomised controlled study and applied the Consolidated Standards of Reporting Trials (CONSORT) statement. METHODS: Outpatients diagnosed with chronic obstructive pulmonary disease were recruited from a medical centre in Taiwan and randomly assigned to two groups. The walking group (n = 42) received breathing, meditation and walking for two months, and the control group (n = 42) did not. Data from the outcomes of anxiety, depression, dyspnoea and quality of life were collected at baseline and in Month 1, Month 2 and Month 3. Clinical trial registration was done (ClinicalTrials.gov.: NCT03388489). FINDINGS: The results showed significant changes in anxiety, depression, dyspnoea and quality of life in the walking group across three months, compared to those in the control group and at baseline. CONCLUSION: This breathing-based walking intervention is promising to achieve bio-psychological well-being for patients with chronic obstructive pulmonary disease. RELEVANCE TO CLINICAL PRACTICE: This breathing-based walking, as a mind-body exercise, could serve as an evidence-based nursing care that contributes to improving anxiety, depression, dyspnoea and quality of life in stable chronic obstructive pulmonary disease outpatients. The feasibility and acceptability of the breathing-based walking were met the requirement of the chronic obstructive pulmonary disease outpatients, which could be considered as home-based exercise.

Unraveling the Molecular Mechanism of Traditional Chinese Medicine: Formulas Against Acute Airway Viral Infections as Examples.

Herbal medicine, including traditional Chinese medicine (TCM), is widely used worldwide. Herbs and TCM formulas contain numerous active molecules. Basically, they are a kind of cocktail therapy. Herb-drug, herb-food, herb-herb, herb-microbiome, and herb-disease interactions are complex. There is potential for both benefit and harm, so only after understanding more of their mechanisms and clinical effects can herbal medicine and TCM be helpful to users. Many pharmacologic studies have been performed to unravel the molecular mechanisms; however, basic and clinical studies of good validity are still not enough to translate experimental results into clinical understanding and to provide tough evidence for better use of herbal medicines. There are still issues regarding the conflicting pharmacologic effects, pharmacokinetics, drug interactions, adverse and clinical effects of herbal medicine and TCM. Understanding study validation, pharmacologic effects, drug interactions, indications and clinical effects, adverse effects and limitations, can all help clinicians in providing adequate suggestions to patients. At present, it would be better to use herbs and TCM formulas according to their traditional indications matching the disease pathophysiology and their molecular mechanisms. To unravel the molecular mechanisms and understand the benefits and harms of herbal medicine and TCM, there is still much work to be done.

Development of the LYVE-1 gene with an acidic-amino-acid-rich (AAAR) domain in evolution is associated with acquisition of lymph nodes and efficient adaptive immunity.

CRSBP-1 (mammalian LYVE-1) is a membrane glycoprotein highly expressed in lymphatic endothelial cells (LECs). It has multiple ligands, including hyaluronic acid (HA) and growth factors/cytokines (e.g., PDGF-BB and VEGF-A) containing CRS motifs (clusters of basic amino-acid residues). The ligand binding activities are mediated by Link module and acidic-amino-acid-rich (AAAR) domains, respectively. These CRSBP-1/LYVE-1 ligands have been shown to induce opening of lymphatic intercellular junctions in LEC monolayers and in lymphatic vessels in wild-type mice. We hypothesize that CRSBP-1/LYVE-1 ligands, particularly CRS-containing growth factors/cytokines, are secreted by immune and cancer cells for lymphatic entry during adaptive immune responses and lymphatic metastasis. We have looked into the origin of the Link module and AAAR domain of LYVE-1 in evolution and its association with the development of lymph nodes and efficient adaptive immunity. Lymph nodes represent the only major recent innovation of the adaptive immune systems in evolution particularly to mammals and bird. Here we demonstrate that the development of the LYVE-1 gene with the AAAR domain in evolution is associated with acquisition of lymph nodes and adaptive immunity. LYVE-1 from other species, which have no lymph nodes, lack the AAAR domain and efficient adaptive immunity. Synthetic CRSBP-1 ligands PDGF and VEGF peptides, which contain the CRS motifs of PDGF-BB and VEGF-A, respectively, specifically bind to CRSBP-1 but do not interact with either PDGFßR or VEGFR2. These peptides function as adjuvants by enhancing adaptive immunity of pseudorabies virus (PRV) vaccine in pigs. These results support the notion that LYVE-1 is involved in adaptive immunity in mammals.

Comparison of the montreal cognitive assessment and the mini-mental state examination as screening tests in hemodialysis patients without symptoms.

Cognitive impairment in end-stage renal disease patients is associated with an increased risk of mortality. We examined the cognitive function in hemodialysis (HD) patients and compared the Korean versions of the Montreal Cognitive Assessment (K-MoCA) and of the Mini-Mental State Examination (K-MMSE) to identify the better cognitive screening instrument in these patients. Thirty patients undergoing hemodialysis and 30 matched reference group of apparently healthy control were included. All subjects underwent the K-MoCA, K-MMSE and a neuropsychological test battery to measure attention, visuospatial function, language, memory and executive function. All cognitive data were converted to z-scores with appropriate age and education level prior to group comparisons. Cognitive performance 1.0 SD below the mean was defined as modest cognitve impairment while 1.5 below the mean was defined as severe cognitive impairment. Modest cognitive impairment in memory plus other cognitive domains was detected in 27 patients (90%) while severe cognitive impairment in memory plus other cognitive domains was detected in 23 (77%) patients. Total scores in the K-MoCA were significantly lower in HD patients than in the reference group. However, no significant group difference was found in the K-MMSE. The K-MMSE ROC AUC (95% confidence interval) was 0.72 (0.59-0.85) and K-MoCA ROC AUC was 0.77 (0.65-0.89). Cognitive impairment is common but under-diagnosed in this population. The K-MoCA seems to be more sensitive than the K-MMSE in HD patients.

7-Dehydrocholesterol (7-DHC), But Not Cholesterol, Causes Suppression of Canonical TGF-ß Signaling and Is Likely Involved in the Development of Atherosclerotic Cardiovascular Disease (ASCVD).

For several decades, cholesterol has been thought to cause ASCVD. Limiting dietary cholesterol intake has been recommended to reduce the risk of the disease. However, several recent epidemiological studies do not support a relationship between dietary cholesterol and/or blood cholesterol and ASCVD. Consequently, the role of cholesterol in atherogenesis is now uncertain. Much evidence indicates that TGF-ß, an anti-inflammatory cytokine, protects against ASCVD and that suppression of canonical TGF-ß signaling (Smad2-dependent) is involved in atherogenesis. We had hypothesized that cholesterol causes ASCVD by suppressing canonical TGF-ß signaling in vascular endothelium. To test this hypothesis, we determine the effects of cholesterol, 7-dehydrocholesterol (7-DHC; the biosynthetic precursor of cholesterol), and other sterols on canonical TGF-ß signaling. We use Mv1Lu cells (a model cell system for studying TGF-ß activity) stably expressing the Smad2-dependent luciferase reporter gene. We demonstrate that 7-DHC (but not cholesterol or other sterols) effectively suppresses the TGF-ß-stimulated luciferase activity. We also demonstrate that 7-DHC suppresses TGF-ß-stimulated luciferase activity by promoting lipid raft/caveolae formation and subsequently recruiting cell-surface TGF-ß receptors from non-lipid raft microdomains to lipid rafts/caveolae where TGF-ß receptors become inactive in transducing canonical signaling and undergo rapid degradation upon TGF-ß binding. We determine this by cell-surface 125 I-TGF-ß-cross-linking and sucrose density gradient ultracentrifugation. We further demonstrate that methyl-ß-cyclodextrin (MßCD), a sterol-chelating agent, reverses 7-DHC-induced suppression of TGF-ß-stimulated luciferase activity by extrusion of 7-DHC from resident lipid rafts/caveolae. These results suggest that 7-DHC, but not cholesterol, promotes lipid raft/caveolae formation, leading to suppression of canonical TGF-ß signaling and atherogenesis. J. Cell. Biochem. 118: 1387-1400, 2017. © 2016 Wiley Periodicals, Inc.

Post-stroke dementia - a comprehensive review.

Post-stroke dementia (PSD) or post-stroke cognitive impairment (PSCI) may affect up to one third of stroke survivors. Various definitions of PSCI and PSD have been described. We propose PSD as a label for any dementia following stroke in temporal relation. Various tools are available to screen and assess cognition, with few PSD-specific instruments. Choice will depend on purpose of assessment, with differing instruments needed for brief screening (e.g., Montreal Cognitive Assessment) or diagnostic formulation (e.g., NINDS VCI battery). A comprehensive evaluation should include assessment of pre-stroke cognition (e.g., using Informant Questionnaire for Cognitive Decline in the Elderly), mood (e.g., using Hospital Anxiety and Depression Scale), and functional consequences of cognitive impairments (e.g., using modified Rankin Scale). A large number of biomarkers for PSD, including indicators for genetic polymorphisms, biomarkers in the cerebrospinal fluid and in the serum, inflammatory mediators, and peripheral microRNA profiles have been proposed. Currently, no specific biomarkers have been proven to robustly discriminate vulnerable patients ('at risk brains') from those with better prognosis or to discriminate Alzheimer's disease dementia from PSD. Further, neuroimaging is an important diagnostic tool in PSD. The role of computerized tomography is limited to demonstrating type and location of the underlying primary lesion and indicating atrophy and severe white matter changes. Magnetic resonance imaging is the key neuroimaging modality and has high sensitivity and specificity for detecting pathological changes, including small vessel disease. Advanced multi-modal imaging includes diffusion tensor imaging for fiber tracking, by which changes in networks can be detected. Quantitative imaging of cerebral blood flow and metabolism by positron emission tomography can differentiate between vascular dementia and degenerative dementia and show the interaction between vascular and metabolic changes. Additionally, inflammatory changes after ischemia in the brain can be detected, which may play a role together with amyloid deposition in the development of PSD. Prevention of PSD can be achieved by prevention of stroke. As treatment strategies to inhibit the development and mitigate the course of PSD, lowering of blood pressure, statins, neuroprotective drugs, and anti-inflammatory agents have all been studied without convincing evidence of efficacy. Lifestyle interventions, physical activity, and cognitive training have been recently tested, but large controlled trials are still missing.

Prediction of post-stroke dementia using NINDS-CSN 5-minute neuropsychology protocol in acute stroke.

BACKGROUND: The National Institute of Neurological Disease and Stroke-Canadian Stroke Network (NINDS-CSN) 5-minute neuropsychology protocol consists of only verbal tasks, and is proposed as a brief screening method for vascular cognitive impairment. We evaluated its feasibility within two weeks after stroke and ability to predict the development of post-stroke dementia (PSD) at 3 months after stroke. METHOD: We prospectively enrolled subjects with ischemic stroke within seven days of symptom onset who were consecutively admitted to 12 university hospitals. Neuropsychological assessments using the NINDS-CSN 5-minute and 60-minute neuropsychology protocols were administered within two weeks and at 3 months after stroke onset, respectively. PSD was diagnosed with reference to the American Heart Association/American Stroke Association statement, requiring deficits in at least two cognitive domains. RESULTS: Of 620 patients, 512 (82.6%) were feasible for the NINDS-CSN 5-minute protocol within two weeks after stroke. The incidence of PSD was 16.2% in 308 subjects who had completed follow-up at 3 months after stroke onset. The total score of the NINDS-CSN 5-minute protocol differed significantly between those with and without PSD (4.0 ± 2.7, 7.4 ± 2.7, respectively; p < 0.01). A cut-off value of 6/7 showed reasonable discriminative power (sensitivity 0.82, specificity 0.67, AUC 0.74). The NINDS-CSN 5-minute protocol score was a significant predictor for PSD (adjusted odds ratio 6.32, 95% CI 2.65-15.05). DISCUSSION: The NINDS-CSN 5-minute protocol is feasible to evaluate cognitive functions in patients with acute ischemic stroke. It might be a useful screening method for early identification of high-risk groups for PSD.

Ethanol Enhances TGF-ß Activity by Recruiting TGF-ß Receptors From Intracellular Vesicles/Lipid Rafts/Caveolae to Non-Lipid Raft Microdomains.

Regular consumption of moderate amounts of ethanol has important health benefits on atherosclerotic cardiovascular disease (ASCVD). Overindulgence can cause many diseases, particularly alcoholic liver disease (ALD). The mechanisms by which ethanol causes both beneficial and harmful effects on human health are poorly understood. Here we demonstrate that ethanol enhances TGF-ß-stimulated luciferase activity with a maximum of 0.5-1% (v/v) in Mv1Lu cells stably expressing a luciferase reporter gene containing Smad2-dependent elements. In Mv1Lu cells, 0.5% ethanol increases the level of P-Smad2, a canonical TGF-ß signaling sensor, by ∼ 2-3-fold. Ethanol (0.5%) increases cell-surface expression of the type II TGF-ß receptor (TßR-II) by ∼ 2-3-fold from its intracellular pool, as determined by I(125) -TGF-ß-cross-linking/Western blot analysis. Sucrose density gradient ultracentrifugation and indirect immunofluorescence staining analyses reveal that ethanol (0.5% and 1%) also displaces cell-surface TßR-I and TßR-II from lipid rafts/caveolae and facilitates translocation of these receptors to non-lipid raft microdomains where canonical signaling occurs. These results suggest that ethanol enhances canonical TGF-ß signaling by increasing non-lipid raft microdomain localization of the TGF-ß receptors. Since TGF-ß plays a protective role in ASCVD but can also cause ALD, the TGF-ß enhancer activity of ethanol at low and high doses appears to be responsible for both beneficial and harmful effects. Ethanol also disrupts the location of lipid raft/caveolae of other membrane proteins (e.g., neurotransmitter, growth factor/cytokine, and G protein-coupled receptors) which utilize lipid rafts/caveolae as signaling platforms. Displacement of these membrane proteins induced by ethanol may result in a variety of pathologies in nerve, heart and other tissues.

DMSO Enhances TGF-ß Activity by Recruiting the Type II TGF-ß Receptor From Intracellular Vesicles to the Plasma Membrane.

Dimethyl sulfoxide (DMSO) is used to treat many diseases/symptoms. The molecular basis of the pharmacological actions of DMSO has been unclear. We hypothesized that DMSO exerts some of these actions by enhancing TGF-ß activity. Here we show that DMSO enhances TGF-ß activity by ∼3-4-fold in Mv1Lu and NMuMG cells expressing Smad-dependent luciferase reporters. In Mv1Lu cells, DMSO enhances TGF-ß-stimulated expression of P-Smad2 and PAI-1. It increases cell-surface expression of TGF-ß receptors (TßR-I and/or TßR-II) by ∼3-4-fold without altering their cellular levels as determined by (125) I-labeled TGF-ß-cross-linking/Western blot analysis, suggesting the presence of large intracellular pools in these cells. Sucrose density gradient ultracentrifugation/Western blot analysis reveals that DMSO induces recruitment of TßR-II (but not TßR-I) from its intracellular pool to plasma-membrane microdomains. It induces more recruitment of TßR-II to non-lipid raft microdomains than to lipid rafts/caveolae. Mv1Lu cells transiently transfected with TßR-II-HA plasmid were treated with DMSO and analyzed by indirect immunofluoresence staining using anti-HA antibody. In these cells, TßR-II-HA is present as a vesicle-like network in the cytoplasm as well as in the plasma membrane. DMSO causes depletion of TßR-II-HA-containing vesicles from the cytoplasm and co-localization of TßR-II-HA and cveolin-1 at the plasma membrane. These results suggest that DMSO, a fusogenic substance, enhances TGF-ß activity presumably by inducing fusion of cytoplasmic vesicles (containing TßR-II) and the plasma membrane, resulting in increased localization of TßR-II to non-lipid raft microdomains where canonical signaling occurs. Fusogenic activity of DMSO may play a pivotal role in its pharmacological actions involving membrane proteins with large cytoplasmic pools. J. Cell. Biochem. 117: 1568-1579, 2016. © 2015 Wiley Periodicals, Inc.

Association of prescribed Chinese herbal medicine use with risk of end-stage renal disease in patients with chronic kidney disease.

The evidence on whether Chinese herbal medicines affect outcome in patients with chronic kidney disease (CKD) is limited. Here we retrospectively explored the association of prescribed Chinese herbal medicine use and the risk of end-stage renal disease (ESRD) in patients with CKD. Patients with newly diagnosed CKD in the Taiwan National Health Insurance Research Database from 2000 to 2005 were categorized into new use or nonuse of prescribed Chinese herbal medicine groups. These patients were followed until death, dialysis initiation, or till the end of 2008. Among the 24,971 study patients, 11,351 were new users of prescribed Chinese herbal medicine after CKD diagnosis. Overall, after adjustment for confounding variables, the use group exhibited a significant 60% reduced ESRD risk (cause-specific hazard ratio 0.41, 95% confidence interval 0.37-0.46) compared with the nonuse group. The change was significantly large among patients using wind dampness-dispelling formulas (0.63, 0.51-0.77) or harmonizing formulas (0.59, 0.46-0.74), suggesting an independent association between specific Chinese herbal medicines and reduced ESRD risk. The findings were confirmed using propensity score matching, stratified analyses, and three weighting methods. However, dampness-dispelling and purgative formulas were associated with increased ESRD risk. Thus, specific Chinese herbal medicines are associated with reduced or enhanced ESRD risk in patients with CKD.

Role of Atypical Pathogens and the Antibiotic Prescription Pattern in Acute Bronchitis: A Multicenter Study in Korea.

The role of atypical bacteria and the effect of antibiotic treatments in acute bronchitis are still not clear. This study was conducted at 22 hospitals (17 primary care clinics and 5 university hospitals) in Korea. Outpatients (aged ≥ 18 yr) who had an acute illness with a new cough and sputum (≤ 30 days) were enrolled in 2013. Multiplex real-time polymerase chain reaction (RT-PCR) was used to detect five atypical bacteria. A total of 435 patients were diagnosed as having acute bronchitis (vs. probable pneumonia, n = 75), and 1.8% (n = 8) were positive for atypical pathogens (Bordetella pertussis, n = 3; B. parapertussis, n = 0; Mycoplasma pneumoniae, n = 1; Chlamydophila pneumoniae, n = 3; Legionella pneumophila, n = 1). Among clinical symptoms and signs, only post-tussive vomiting was more frequent in patients with atypical pathogens than those without (P = 0.024). In all, 72.2% of the enrolled patients received antibiotic treatment at their first visits, and ß-lactams (29.4%) and quinolones (20.5%) were the most commonly prescribed agents. In conclusion, our study demonstrates that the incidence of atypical pathogens is low in patients with acute bronchitis, and the rate of antibiotic prescriptions is high.

Post-stroke memory impairment among patients with vascular mild cognitive impairment.

BACKGROUND: The American Stroke Association/American Heart Association recommended the criteria for diagnosis of vascular cognitive impairment and memory impairment (MI) is a feature in the classification of vascular mild cognitive impairment (VaMCI). VaMCI patients with MI may differ in terms of infarct location or demographic features, so we evaluated the clinical characteristics associated with MI in patients with VaMCI. METHODS: A prospective multicenter study enrolled 353 acute ischemic stroke patients who underwent evaluation using the Korean Vascular Cognitive Impairment Harmonization Standard Neuropsychological Protocol at three months after onset. The association between MI and demographic features, stroke risk factors, and infarct location was assessed. RESULTS: VaMCI was diagnosed in 141 patients, and 58 (41.1%) exhibited MI. Proportions of men and of left side infarcts were higher in VaMCI with MI than those without (75.9 vs. 57.8%, P = 0.03, 66.7 vs. 47%, P = 0.02). Multiple logistic analyses revealed that male sex (odds ratio [OR] 3.07, 95% confidence interval [95% CI] 1.12-8.42), left-side infarcts (OR 3.14, 95% CI 1.37-7.20), and basal ganglia/internal capsule infarcts (OR 4.53, 95% CI 1.55-13.22) were associated with MI after adjusting other demographic variables, vascular risk factors, and subtypes of stroke. CONCLUSIONS: MI is associated with sex and infarct location in VaMCI patients.

Highly variable blood pressure as a predictor of poor cognitive outcome in patients with acute lacunar infarction.

OBJECTIVE AND BACKGROUND: Many patients develop cognitive impairment after an acute stroke. It is not clear whether blood pressure variability is a prognostic factor for cognitive impairment. We aimed to determine the association between blood pressure variability on hospital admission and cognitive outcome in patients with acute lacunar infarction. METHODS: We performed a retrospective analysis on 22 men and 14 women (mean age, 61.8 years) who had completed a cognitive evaluation 3 months after onset of an acute lacunar infarction. The patients had no previous functional disability or dementia, stenosis in major cerebral arteries, cardiac embolic sources, or infarct in strategic territories for cognition. We used standard deviation and coefficient of variance as parameters of blood pressure variability, and each cognitive function test z score as an outcome parameter. We performed linear regression analysis to assess the relationship between blood pressure variability and cognition, adjusted for vascular risk factors, severity of neurologic deficits, and mean blood pressure. RESULTS: High variability of both systolic and diastolic blood pressure was significantly associated with low z scores on the Controlled Oral Word Association Test and the Digit Symbol Coding test (P<0.01). High variability of diastolic blood pressure was significantly associated with low z scores on the Korean Mini-Mental State Examination and Seoul Verbal Learning Test delayed recall (P<0.01). CONCLUSIONS: Highly variable blood pressure on admission for acute lacunar infarction may predict poor cognitive outcomes, especially frontal lobe dysfunction.

Cognitive impairment evaluated with Vascular Cognitive Impairment Harmonization Standards in a multicenter prospective stroke cohort in Korea.

BACKGROUND AND PURPOSE: Since the Vascular Cognitive Impairment Harmonization Standards (VCIHS) neuropsychological test protocol was proposed by the National Institute of Neurological Disorders and Stroke and Canadian Stroke Network, no studies have applied this neuropsychological protocol to poststroke survivors in a large-scale, multicenter stroke cohort. We determined the frequency of vascular cognitive impairment (VCI) and investigated the feasibility of using the Korean version of the VCIHS neuropsychological protocol in a multicenter, hospital-based stroke cohort in Korea. METHODS: We prospectively enrolled 620 subjects with ischemic stroke within 7 days of symptom onset among 899 patients who were consecutively admitted to 12 university hospitals in Korea. Neuropsychological assessments using the 60-minute Korean VCIHS neuropsychological protocol were administered at 3 months after stroke. RESULTS: Of the 620 patients, 506 were followed up at 3 months after stroke. Of these, 353 (69.8%) were evaluated for cognitive function using the 60-minute Korean VCIHS neuropsychological protocol. The frequency of VCI at 3 months was 62.6%: VCI with no dementia in 49.9% and vascular dementia in 12.7%. Old age (P=0.014), poor functional outcomes at 3 months (P=0.029), and stroke subtypes other than small vessel disease (P=0.004) were independent risk factors of VCI. CONCLUSIONS: VCI, evaluated using the Korean VCIHS neuropsychological protocol, is substantial at 3 months after ischemic stroke in Korea. The use of the 60-minute Korean VCIHS neuropsychological protocol was feasible in large-scale multicenter studies.

CRSBP-1/LYVE-1 ligands disrupt lymphatic intercellular adhesion by inducing tyrosine phosphorylation and internalization of VE-cadherin.

Cell-surface retention sequence (CRS) binding protein (CRSBP-1) is a membrane glycoprotein identified by its ability to bind PDGF-BB and VEGF-A via their CRS motifs (clusters of basic amino acid residues). CRSBP-1 is identical to LYVE-1 and exhibits dual ligand (CRS-containing proteins and hyaluronic acid) binding activity, suggesting the importance of CRSBP-1 ligands in lymphatic function. Here, we show that CRSBP-1 ligands induce disruption of VE-cadherin-mediated intercellular adhesion and opening of intercellular junctions in lymphatic endothelial cell (LEC) monolayers as determined by immunofluorescence microscopy and Transwell permeability assay. This occurs by interaction with CRSBP-1 in the CRSBP-1-PDGFßR-ß-catenin complex, resulting in tyrosine phosphorylation of the complex, dissociation of ß-catenin and p120-catenin from VE-cadherin, and internalization of VE-cadherin. Pretreatment of LECs with a PDGFßR kinase inhibitor abolishes ligand-stimulated tyrosine phosphorylation of VE-cadherin, halts the ligand-induced disruption of VE-cadherin intercellular adhesion and blocks the ligand-induced opening of intercellular junctions. These CRSBP-1 ligands also induce opening of lymphatic intercellular junctions that respond to PDGFßR kinase inhibitor in wild-type mice (but not in Crsbp1-null mice) as evidenced by increased transit of injected FITC-dextran and induced edema fluid from the interstitial space into lymphatic vessels. These results disclose a novel mechanism involved in the opening of lymphatic intercellular junctions.

Proton pump inhibitors reduce the survival of advanced lung cancer patients with therapy of gefitinib or erlotinib.

Gefitinib and erlotinib are the first-line tyrosine kinase inhibitors (TKI) for advanced non-small-cell lung cancer. However, co-administration of either drug with proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2RA) may reduce TKI's bioavailability. Therefore, we aimed to investigate the effects of these drug-drug interactions. We surveyed nationwide population-based databases between Jan 1, 2010, and Dec 30, 2018. Newly diagnosed patients with advanced lung adenocarcinoma who received first-line gefitinib or erlotinib were identified. Effects on overall survival (OS) and time to next treatment (TTNT) association between PPIs or H2RAs and co-administrated gefitinib or erlotinib were evaluated. PPIs or H2RAs users were defined if the period overlapped with TKIs by ≥ 20%. A total of 4340 gefitinib and 1635 erlotinib users were included. PPI group had the shortest median OS and TTNT compared to the H2RA and non-user groups (in gefitinib cohort: OS: 14.35 vs. 17.67 vs. 21.87 months; P < 0.0001, TTNT: 8.47 vs. 10.78 vs. 10.33 months; P < 0.0001); (in erlotinib cohort: OS: 16.97 vs. 20.07 vs. 23.92 months; P < 0.0001, TTNT: 9.06 vs. 11.85 vs. 10.90 months; P = 0.0808). Compared with the non-user group, the adjusted hazard ratio (aHR) of the PPI group in the gefitinib was 1.58 on OS (95% CI 1.42-1.76), 1.37 on TTNT (95% CI 1.24-1.52); in the erlotinib was 1.54 on OS (95% CI 1.30-1.82) and 1.19 on TTNT (95% CI 1.01-1.39). Concurrent use of PPIs with first-line gefitinib or erlotinib therapy was associated with a worse OS and TTNT in patients with lung adenocarcinoma harboring EGFR mutations.

Structure of a major antigenic site on the respiratory syncytial virus fusion glycoprotein in complex with neutralizing antibody 101F.

Respiratory syncytial virus (RSV) is a major cause of pneumonia and bronchiolitis in infants and elderly people. Currently there is no effective vaccine against RSV, but passive prophylaxis with neutralizing antibodies reduces hospitalizations. To investigate the mechanism of antibody-mediated RSV neutralization, we undertook structure-function studies of monoclonal antibody 101F, which binds a linear epitope in the RSV fusion glycoprotein. Crystal structures of the 101F antigen-binding fragment in complex with peptides from the fusion glycoprotein defined both the extent of the linear epitope and the interactions of residues that are mutated in antibody escape variants. The structure allowed for modeling of 101F in complex with trimers of the fusion glycoprotein, and the resulting models suggested that 101F may contact additional surfaces located outside the linear epitope. This hypothesis was supported by surface plasmon resonance experiments that demonstrated 101F bound the peptide epitope ∼16,000-fold more weakly than the fusion glycoprotein. The modeling also showed no substantial clashes between 101F and the fusion glycoprotein in either the pre- or postfusion state, and cell-based assays indicated that 101F neutralization was not associated with blocking virus attachment. Collectively, these results provide a structural basis for RSV neutralization by antibodies that target a major antigenic site on the fusion glycoprotein.