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Glioblastoma (GBM) is the most common and lethal form of primary brain cancer. Microglia infiltration into the tumor microenvironment is associated with immunosuppression and poor prognosis. Improved physicochemical understanding of microglia activation and invasion may provide novel GBM therapeutic strategies essential for improving long-term treatment efficacy. Here, we combine microfluidic systems with 3-D collagen hydrogels to systematically investigate microglia activation, invasion, contractility and cytokine secretion in response of GBM-microglia crosstalk. GBM inflammatory biomolecules significantly promote activation and 3D invasion of microglia. Interestingly, microglia invasion is not significantly affected by inhibitors of MMP activity or cellular glycolysis. In contrast, ROCK-pathway inhibition significantly impedes microglia invasion. Infrared microscopy analyses show that GBM co-culture does not significantly alter microglia lipid content. Further, GBM conditioned media resulted in significantly increased collagen hydrogel contraction, suggesting the importance of microglia contractility to physically remodel the local extracellular matrix (ECM). We also identify a panel of soluble proteins that may contribute to microglia chemotaxis, such as TIMP-1 and CXCL12. Taken together, this study suggests that the presence of GBM cells can enhance microglia invasion via increased cellular contractility, independent of MMP activity and cellular glycolysis.

Background: Cognitive reserve (CR) involves an individual's ability to maintain cognitive vitality over their lifespan. Glucocerebrosidase (GBA) gene mutations contribute to additional effects on cognitive function in Parkinson's disease (PD) patients, but the interplay between GBA mutations and CR remains unclear. We investigated the interactions among CR, GBA, and diseases, aiming to examine whether the CR established at different stages interacts with specific genotypes to affect cognitive function., Methods: Three hundred and eighteen participants' CR indicators (i.e., education, occupation, and social function) and comprehensive neuropsychological function (i.e., tests for executive function, attention/working memory, visuospatial function, memory, and language) were evaluated., Results: We found that CR established in a specific life stage influences the individual's cognitive function, particularly in PD, based on their distinct GBA rs9628662 genotypes. Attention/working memory and memory performance are affected by occupational complexity in midlife in PD patients with the GG genotype (q < 0.0001; q < 0.0001) and healthy adults with the T genotype (q = 0.0440; q < 0.0001). Language is influenced by early education and occupation, and the effects of occupation are also observed in PD patients with the GG genotype (q = 0.0040) and in healthy adults carrying the T genotype (q = 0.0040)., Conclusions: CR, established at different life stages, can be influenced by the GBA rs9628662 genotype, impacting later-life cognition. Validating genotypes and incorporating genotype information when assessing cognitive reserve effects is crucial and can enhance targeted cognitive training., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

We study the change in the surface electromagnetic field provided by photoexcited silver nanoparticles as the field is disturbed by fluorescent carbon nanodots. Fluorescent carbon nanodots with an appropriate quantity and quality of surface functional groups are used to mediate the aggregation of silver nanoparticles of matching size and shape to form available nano-size conical structures. Carbon nanodots in the composite absorb and transfer additional photoenergy to the silver surface, resulting in energy aggregation within the cone structure and enhancement of the electromagnetic field in proximity to the silver surface. This elevated energy state is manifested in the strengthening of the SERS signal of the analytical probe 4-aminophenyl disulfide and the mechanism involved is elucidated by additional molecular spectroscopy studies.

In this paper, the performance of Cu-(In,Ga)-S 2 (CIGS 2 ) solar cells with adjusting composite [Cu]/([Ga] + [In]) (CGI)-ratio absorber was explored and compared through an improved three-stage co-evaporation technique. For co-evaporating CIGS 2 absorber as a less toxic alternative to Cd-containing film, we analyzed the effect of the CGI-ratio stoichiometry and crystallinity, and explored its opto-electric sensing characteristic of individual solar cell. The results of this research signified the potential of high-performance CIGS 2 -absorption solar cells for photovoltaic (PV)-module industrial applications. For the optimal CIGS 2 -absorption film (CGI = 0.95), the Raman main-phase signal (A1) falls at 291 cm -1 , which was excited by the 532 nm line of Ar + -laser. Using photo-luminescence (PL) spectroscopy, the corresponding main-peak bandgaps measured was 1.59 eV at the same CGI-ratio film. Meanwhile, the best conversion efficiency ( η = 3.212%) and the average external quantum efficiency (EQE = 51.1% in the visible-wavelength region) of photo-electric properties were achieved for the developed CIGS 2 -solar cells (CGI = 0.95). The discoveries of this CIGS 2 -absorption PV research provided a new scientific understanding of solar cells. Moreover, this research undeniably contributes to a major advancement towards practical PV-module applications and can help more to build an eco-friendly community.

Sprouting angiogenesis is orchestrated by an intricate balance of biochemical and mechanical cues in the local tissue microenvironment. Interstitial flow has been established as a potent regulator of angiogenesis. Similarly, extracellular matrix (ECM) physical properties, such as stiffness and microarchitecture, have also emerged as important mediators of angiogenesis. However, the interplay between interstitial flow and ECM physical properties in the initiation and control of angiogenesis is poorly understood. Using a three-dimensional (3D) microfluidic tissue analogue of angiogenic sprouting with defined interstitial flow superimposed over ECM with well-characterized physical properties, we found that the addition of hyaluronan (HA) to collagen-based matrices significantly enhances sprouting induced by interstitial flow compared to responses in collagen-only hydrogels. We confirmed that both the stiffness and matrix pore size of collagen-only hydrogels were increased by the addition of HA. Interestingly, interstitial flow-potentiated sprouting responses in collagen/HA matrices were not affected when functionally blocking the HA receptor CD44. In contrast, enzymatic depletion of HA in collagen/HA matrices with hyaluronidase (HAdase) resulted in decreased stiffness, pore size, and interstitial flow-mediated sprouting to the levels observed in collagen-only matrices. Taken together, these results suggest that HA enhances interstitial flow-mediated angiogenic sprouting through its alterations to collagen ECM stiffness and pore size.

Nivolumab belongs to immune checkpoint inhibitors (ICIs). ICIs-induced kidney injury is rare and acute interstitial nephritis (AIN) is the majority. A 58-year-old woman had gastric cancer treated with nivolumab. Her serum creatinine (Cr) increased to 5.94 mg/dL post 2 cycles of nivolumab and co-administered with acemetacin. A kidney biopsy showed acute tubular injury (ATI). Nivolumab rechallenge was done and Cr worsened again. The lymphocyte transformation test (LTT) indicated a strong positive for nivolumab. Although rare, ATI due to ICIs could not be ruled out, and LTT is a tool to identify the culprit., Competing Interests: All authors have no financial or other conflicts of interest., (© 2023 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: Traumatic brain injury (TBI) is a major cause of disability and mortality worldwide. People with TBI exhibit poor quality of life (QOL). Exercise is considered a possible intervention for improving cognitive function and mood, helping improve QOL in patients with TBI. According to our review of the relevant literature, meta-analyses have yet to explore the effect of exercise on QOL in patients with TBI., Objectives: To determine by meta-analysis of relevant studies whether physical exercise could promote QOL in patients with TBI., Methods: A systematic review and meta-analysis of intervention studies involving physical exercise for improving QOL outcomes in TBI populations were conducted according to the PRISMA guideline. Our inclusion criteria were as follows: being randomized or nonrandomized controlled trials with quantitative designs that included patients diagnosed with TBI., Results: Thus, six studies met the inclusion criteria. The interventions in four of the six studies had statistically significant effects on QOL improvement. Our meta-analysis revealed a moderate effect size of physical exercise on QOL promotion in patients with TBI., Conclusion: For TBI, exercise seems to improve QOL. More research with long-term follow-up should be conducted to assess the effect of exercise on patients with TBI.

Introduction: We aim to explore the association between chronic kidney disease (CKD) and cataracts., Methods: A total of 121,380 participants with adequate information collected from 29 community-based recruitment centers since 2008 were analyzed. The association between CKD and self-reported diagnosed cataracts was examined in a cross-sectional cohort and was validated in a longitudinal cohort of 25,263 participants without cataracts at baseline., Results and Discussion: Of all participants, cataracts occurred in 503/1,947 (26%) and 10,464/119,433 (9%) subjects in the CKD and non-CKD groups, respectively. Multivariate logistic regression showed that CKD was significantly associated with a higher prevalence of self-reported diagnosed cataracts. In the validation cohort, a higher incidence of cataracts was also noted in the CKD group (65/317, 21%) compared to the non-CKD group (1,964/24,252, 8%) during a mean 47-month follow-up. After adjusting for confounders, subjects with CKD had a 1.498-fold higher risk of incident cataracts than those without CKD (95% confidence interval = 1.114 to 2.013, p value = 0.007). We found that CKD was associated with a higher prevalence of cataracts as well as incident cataracts, which suggests CKD patients and their primary physicians should be aware of this disease and can provide a clue for further exploration of the possible mechanisms and treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Lee, Chang, Liu, Huang, Chen and Geng.)

We aimed to investigate the association between habitual tea consumption and the risk of developing cataracts in a large community-based cohort study. We prospectively collected volunteers from 29 recruitment centers that were ≧ 55 years old with no history of cataracts at the beginning of the study. There were 12,080 participants with available information in our study and were divided into two groups according to habitual tea consumption; non-tea-drinking and tea-drinking groups. The mean age was 59 years. Compared to the non-tea-drinking group, the tea-drinking group had a significantly lower incidence of developing cataracts (15.5% vs 12.1%) during follow-up of 46 months. In multivariate Cox proportional hazards regression analysis, the relative risk (RR) of incident cataracts was lower in the tea-drinking group than the non-tea-drinking group (RR = 0.848; 95% confidence interval [CI] = 0.751 to 0.957). Participants with ≧ 2 cups per day were associated with almost 16% reduction in the risk of developing cataracts compared with the non-tea-drinking group (RR = 0.844; 95% CI = 0.741 to 0.961). Our study suggests that habitual tea consumption can reduce the incidence of cataracts and raises the possibility that the tea content may slow the progression of cataracts., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Cancer-associated fibroblasts (CAFs) play an active role in remodeling the local tumor stroma to support tumor initiation, growth, invasion, metastasis, and therapeutic resistance. The CAF-secreted chemokine, CXCL12, has been directly implicated in the tumorigenic progression of carcinomas, including breast cancer. Using a 3-D in vitro microfluidic-based microtissue model, we demonstrate that stromal CXCL12 secreted by CAFs has a potent effect on increasing the vascular permeability of local blood microvessel analogues through paracrine signaling. Moreover, genetic deletion of fibroblast-specific CXCL12 significantly reduced vessel permeability compared to CXCL12 secreting CAFs within the recapitulated tumor microenvironment (TME). We suspected that fibroblast-mediated extracellular matrix (ECM) remodeling and contraction indirectly accounted for this change in vessel permeability. To this end, we investigated the autocrine effects of CXCL12 on fibroblast contractility and determined that antagonistic blocking of CXCL12 did not have a substantial effect on ECM contraction. Our findings indicate that fibroblast-secreted CXCL12 has a significant role in promoting a leakier endothelium hospitable to angiogenesis and tumor cell intravasation; however, autocrine CXCL12 is not the primary upstream trigger of CAF contractility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Holter, Chang, Avendano, Garg, Verma, Charan, Ahirwar, Ganju and Song.)

Solid-state SERS sensors are desirable point-of-care tools due to their portability. However, the level of SERS sensitivity achieved in liquid phase is rarely duplicated in the solid phase. We report herein the fabrication of a SERS sensor using alumina beads as the solid support and demonstrate its high SERS sensitivity with the model analyte 4-aminophenyl disulfide (4-APDS). The key to sensitivity is a hydrophilic-hydrophobic surface gradient constructed by sequentially coating with the surfactant cetyltrimethylammonium bromide and fluorous 1H,1H,2H,2H-perfluorooctyltriethoxysilane. The surface gradient, together with chloride etching, allows the detection of 4-APDS at the low concentration of 10 -15 M. The practicality of the sensor beads is evidenced by successfully tracking the SERS fingerprints of five food colorant standards in the SERS spectra of a popular candy product. These SERS sensor beads are easy to prepare, convenient to use, and highly responsive as a SERS platform for the analysis of colorants., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A variety of enzyme-based colorimetric biosensors have been developed for clinical practice; however, these methods will only become cost-effective when they are able to process multiple samples with a high degree of sensitivity. In this study, a novel heat-stable enzyme, 2,3-dopa-dioxygenase from the thermophilic bacterium Streptomyces sclerotialus (SsDDO), was used in the development of a protein- and cell-based biosensor for the detection of L-DOPA for the first time. SsDDO catalyzes the oxidative cleavage of L-DOPA forms linear semialdehyde (AHMS) and cyclizes to a 3-carboxy-3-hydroxyallylidene-3,4-dihydropyrrole-2-carboxylic acid (CHAPCA). We next derivatized CHAPCA by reacting with 3-aminobenzoic acid (MABA) to yield a red-fluorescent pigment. Overall, the detection of L-DOPA via the red fluorescent signal can be completed in only 30 min. We also developed a sequential analysis method to detect the coexistence of dopamine and L-DOPA with a high degree of sensitivity using the dual-fluorescent signals to monitor the therapy of patients with Parkinson's disease treated with L-DOPA. The robustness and applicability of the system were further validated in serum. In addition, paper microfluidics modified with chitosan was applied for fast and cost-effective analysis of dopamine and L-DOPA in the mixed solutions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

A dynamic covalent system of the picolyl heterocyclic amino aminals has been studied. The aminals are characterized as a metastable species and easily switch to other forms via external stimuli. The solvent, temperature, acid-base and substituent effects have been examined to evaluate the dynamic covalent system. The results reveal that a more polar solvent, a lower temperature, basic conditions and an electron-withdrawing moiety contribute to the stabilities of aminals. The existence of the n → π* interaction between acetonitrile and the C[double bond, length as m-dash]N moiety makes the N -pyrimidyl imine (4c and 4d) yield higher in CD 3 CN. In a similar fashion, all aminals tend to convert to the corresponding hemiaminal ethers in a methanol environment. According to these findings, we successfully synthesized the following species: (a) N -2-picolylpyrimidin-2-amine 6c obtained by reduction using acetonitrile as the specific solvent; (b) a picolyl aromatic amino aminal 3e prepared from 2-pyridinecarboxaldehyde and the electron withdrawing 2-methoxy-5-nitroaniline., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Sequence variants in vacuolar protein sorting 35 ( VPS35 ) have been reported to be associated with Parkinson's disease (PD). To investigate if the genetic variants in VPS35 contribute to Taiwanese PD, VPS35 cDNA fragments from 62 patients with PD were sequenced. A cohort of PD ( n = 560) and ethnically matched controls ( n = 506) were further examined for the identified mutation. The effects of the mutation on cation-independent mannose-6-phosphate receptor (CI-MPR) sorting and mitochondrial morphology were further examined in 293T cells expressing the mutant VPS35 . Here, a novel heterozygous A320V in the VPS35 gene was identified in two late-onset PD (LOPD) patients, which was absent in 506 normal controls. Expression of the A320V mutant in 293T cells demonstrated increased colocalization of VPS35 with CI-MPR and decreased CI-MPR and lysosomal-associated membrane protein 2 (LAMP2) levels. Decreased CI-MPR manifested in missorting of cathepsin D and decreased proteolysis of α-synuclein. A320V mutation also increased mitochondrial E3 ubiquitin protein ligase 1 (MUL1) and thus led to mitofusin 2 (MFN2) degradation. The results suggest that the expression of VPS35 A320V leads to disrupted CI-MPR sorting and impaired mitochondrial morphology, which may partly explain its action in PD.

Background: Primary carnitine deficiency (PCD) is a rare but potentially life-threatening genetic disorder if left untreated. Although some patients remain asymptomatic lifelong, a few patients present with hepatic encephalopathy, hypoglycemia, cardiomyopathy, dysrhythmia, and even sudden death., Case Report: A 25-year-old woman with PCD collapsed suddenly while eating lunch. Bystander cardiopulmonary resuscitation (CPR) was performed for 8 min, with automated external defibrillation once before admission. Upon arrival at our emergency department (ED), she was unresponsive without a pulse or spontaneous breathing. The initial heart rhythm on the electrocardiogram monitor was ventricular fibrillation (VF). The medical staff continued CPR with defibrillation for sustained VF. Return of spontaneous circulation (ROSC) was achieved after a total resuscitation time of 14 min, with defibrillation twice after cardiac arrest. The heart rhythm after ROSC was atrial fibrillation, with a rapid ventricular rate initially and subsequent progression to sinus tachycardia with diffuse ST segment depression and a prolonged QT interval. Her low carnitine level was consistent with her underlying disease. Cardiac magnetic resonance imaging and sonography for detection of cardiomyopathy showed no significant findings. With carnitine supplementation for a few days, her plasma carnitine level returned to 30 μM, with no recurrence of ventricular dysrhythmia. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: PCD is rare but could be life-threatening, and compiling detailed histories may help emergency physicians to determine the cause of sudden cardiac death after resuscitation. This information may be used to correct potential underlying problems and prevent recurrence of the condition after treatment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Hemobilia refers to bleeding in the biliary tract, commonly due to iatrogenic, traumatic, and neoplastic causes. It is a rare source of upper gastrointestinal hemorrhage, but it can be severe and fatal. However, gallstones account for 5%-15% of hemobilia cases., Case Report: A 60-year-old woman with diabetes mellitus and chronic kidney disease visited the emergency department with complaints of epigastric pain and vomiting of coffee ground-like content for 2 days. Physical examination revealed epigastric tenderness and hyperactive bowel sounds. Laboratory tests showed anemia with a hemoglobin count of 10.7 mg/dL and elevated liver function tests with total and direct bilirubin levels of 3.6 mg/dL and 2.5 mg/dL, respectively. Panendoscopy showed oozing of coffee ground-like material at the orifice of the ampulla of Vater and second portion of the duodenum, leading to suspicion of hemobilia. After admission, endoscopic retrograde cholangiopancreatography revealed common bile duct (CBD) dilatation with choledocholithiasis, biliary sludge, and filling defect at the middle section of the CBD. Endoscopic sphincterotomy with balloon lithotripsy was performed. After biliary decompression and broad-spectrum antibiotic administration, abdominal pain was relieved, and liver enzyme and total bilirubin levels improved. Symptoms of hemobilia depend on the bleeding rate and presence of bile duct obstructions due to clots. Minor and slow bleeding tend to form clots and cause biliary obstruction. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although minor hemobilia may remain asymptomatic and tends to resolve spontaneously, the cause of hemobilia must be corrected to prevent recurrent bleeding or obstruction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Angiogenesis is associated with increased vessel sprouting and permeability. Important mediators of these angiogenic responses include local environment of signaling molecules and supporting extracellular matrix (ECM). However, dissecting the interplay of these instructive signals in vivo with multiple cells and extracellular molecules remains a central challenge. Here, microfluidic biomimicry is integrated with 3D ECM hydrogels that are well-characterized for molecular-binding and mechanical properties to reconstitute vessel-like analogues in vitro. This study focuses on three distinct isoforms of the pro-metastatic chemokine CXCL12. In collagen-only hydrogel, CXCL12-α is the most potent isoform in promoting sprouting and permeability, followed by CXCL12-β and CXCL12-γ. Strikingly, addition of hyaluronan (HA), a large and negatively charged glycosaminoglycan, with collagen matrices selectively increases vessel sprouting and permeability conferred by CXCL12-γ. This outcome is supported by the measured binding affinities to collagen/HA ECM, suggesting that negatively charged HA increases the binding of CXCL12-γ to augment its angiogenic potency. Moreover, it is shown that addition of HA to collagen matrices on its own decreases vessel sprouting and permeability, and these responses are nullified by blocking the HA receptor CD44. Collectively, these results demonstrate that differences in binding to extracellular HA help underlie CXCL12 isoform-specific responses toward directing angiogenesis., (© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease, and α-synuclein plays a critical role in the pathogenesis of PD. Studies have revealed controversial results regarding the correlation between motor severity and α-synuclein levels in peripheral blood from patients with PD. Objective: We examined α-synuclein levels in plasma or serum in patients with PD and investigated the relationship between plasma or serum α-synuclein level and motor symptom severity. Methods: We recruited 88 participants (48 patients with PD and 40 healthy controls). Clinical information was collected, and venous blood was drawn from each participant to be processed to obtain plasma or serum. The plasma or serum α-synuclein level was detected using monoclonal antibodies with magnetic nanoparticles, and was measured through immunomagnetic reduction. Plasma or serum α-synuclein levels were quantitatively detected. Results: In patients with PD, the means of plasma and serum α-synuclein level were 3.60 ± 2.53 and 0.03 ± 0.04 pg/mL, respectively. The areas under the receiver operating characteristic curve of plasma and serum α-synuclein for distinguishing patients with PD from healthy controls were 0.992 and 0.917, respectively. The serum α-synuclein level also showed a significant correlation with patients in H-Y stages 1-3 ( r = 0.40, p = 0.025), implying that the serum α-synuclein level may be a potential marker of motor symptom severity in patients with early PD. Conclusions: Our data suggest that the α-synuclein level in serum or plasma can differentiate between healthy controls and patients with PD. Serum α-synuclein levels moderately correlate with motor severity in patients with early PD., (Copyright © 2020 Chang, Yang, Yang, Chang and Wu.)

Immense progress in microscale engineering technologies has significantly expanded the capabilities of in vitro cell culture systems for reconstituting physiological microenvironments that are mediated by biomolecular gradients, fluid transport, and mechanical forces. Here, we examine the innovative approaches based on microfabricated vessels for studying lymphatic biology. To help understand the necessary design requirements for microfluidic models, we first summarize lymphatic vessel structure and function. Next, we provide an overview of the molecular and biomechanical mediators of lymphatic vessel function. Then we discuss the past achievements and new opportunities for microfluidic culture models to a broad range of applications pertaining to lymphatic vessel physiology. We emphasize the unique attributes of microfluidic systems that enable the recapitulation of multiple physicochemical cues in vitro for studying lymphatic pathophysiology. Current challenges and future outlooks of microscale technology for studying lymphatics are also discussed. Collectively, we make the assertion that further progress in the development of microscale models will continue to enrich our mechanistic understanding of lymphatic biology and physiology to help realize the promise of the lymphatic vasculature as a therapeutic target for a broad spectrum of diseases., (© 2019 John Wiley & Sons Ltd.)

Cerebral cavernous malformation (CCM) is a vascular malformation characterized by clustered enlarged capillary-like channels in the central nervous system. The genes harboring variants in patients with CCM include CCM1/Krev interaction trapped-1, CCM2/MGC4607, and CCM3/programmed cell death protein 10. We aimed to identify pathogenic variants in an ethnic Chinese population in Taiwan. We recruited 95 patients with multiple CCMs or a single lesion with a relevant family history. Sanger sequencing was performed for 41 patients. Variants were identified using sequence alignment tools, and the clinical significance of these variants was determined using American College of Medical Genetics and Genomics standards and guidelines. Several pathogenic variants were found in six patients, including three unrelated patients and three affected members of one family. Two novel pathogenic variants leading to early truncation comprised a deletion variant in exon 18 of CCM1 (c.1846delA; p.Glu617LysfsTer44) and an insertion variant in exon 4 of CCM2 (c.401&#95;402insGCCC; p.Ile136AlafsTer4). One novel pathogenic splice site variant was c.485 + 1G > C at the beginning of intron 8 of CCM1. In this study, we identified novel variants related to CCM in an ethnically Chinese population in Taiwan.

Background: Mutations in the GRN (granulin precursor) are a frequent cause of frontotemporal dementia (FTD) and other atypical parkinsonian disorders. However, the frequency of GRN mutations in Asian patients with atypical parkinsonian disorders is still uncertain., Methods: We screened GRN mutations by sequencing cDNA from 98 patients with FTD or atypical parkinsonian disorders. The functional properties of the identified mutation were evaluated by overexpression in human embryonic kidney (HEK)-293 cells., Results: We identified a new missense (GRN p.T487I) mutation in a female patient with undefined atypical parkinsonism. The overexpression experiment further demonstrated that p.T487I mutation reduced the progranulin protein level and stability in HEK-293 cells., Conclusion: GRN p.T487I mutation, which decreases the stability of progranulin protein, could be a new causative mutation in patients with atypical parkinsonian disorders., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Catechol-O-methyltransferase (COMT), an enzyme that catalyzes the degradation of dopamine, is necessary for both motor and cognitive functions. Few studies have examined the association between COMT variants and cognition in patients with Parkinson's disease (PD)., Methods: We assessed a cohort of 409 PD patients without dementia who were regularly followed for two years. The Unified Parkinson's Disease Rating Scale (UPDRS) and Mini-Mental State Examination (MMSE) were administered at baseline and during the follow-up. The genetic variants and haplotypes of COMT, including rs6267, rs6269, rs4633, rs4818, and rs4680, were examined., Results: No association was observed between COMT genotypes and baseline cognitive function. After a mean follow-up period of 647.3 days, MMSE scores deteriorated with age. Cognitive decline correlated with age (P < 0.05) but not with the motor severity defined using UPDRS part III scores (P = 0.21). Kaplan-Meier survival analyses showed that PD patients carrying the G allele of the rs6269 variant and COMT haplotypes constituting the G allele of rs6269 showed a significantly more rapid decline in the MMSE scores over the follow-up period (log-rank test, P < 0.01). Cox proportional regression analysis adjusted for covariates revealed that among patients with PD, those carrying the high-COMT activity haplotype (G&#95;C&#95;C&#95;G for rs6269, rs4633, rs4818, and rs4680) showed a high risk of cognitive decline (hazard ratio = 3.24; P = 0.02)., Conclusion: Our findings suggest that the high-COMT activity haplotype is associated with cognitive decline in patients with PD., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Genomic studies have revealed that multiple genes are mutated at varying frequency in endometrial cancer (EC); however, the relevance of many of these mutations is poorly understood. An EC-specific recurrent mutation in the MAX transcription factor p.His28Arg was recently discovered. We sought to assess the functional consequences of this hotspot mutation and determine its association with cancer-relevant phenotypes., Methods: MAX was sequenced in 509 endometrioid ECs, and associations between mutation status and clinicopathologic features were assessed. EC cell lines stably expressing MAXH28R were established and used for functional experiments. DNA binding was examined using electrophoretic mobility shift assays and chromatin immunoprecipitation. Transcriptional profiling was performed with microarrays. Murine flank (six to 11 mice per group) and intraperitoneal tumor models were used for in vivo studies. Vascularity of xenografts was assessed by MECA-32 immunohistochemistry. The paracrine pro-angiogenic nature of MAXH28R-expressing EC cells was tested using microfluidic HUVEC sprouting assays and VEGFA enzyme-linked immunosorbent assays. All statistical tests were two-sided., Results: Twenty-two of 509 tumors harbored mutations in MAX, including 12 tumors with the p.His28Arg mutation. Patients with a MAX mutation had statistically significantly reduced recurrence-free survival (hazard ratio = 4.00, 95% confidence interval = 1.15 to 13.91, P = .03). MAXH28R increased affinity for canonical E-box sequences, and MAXH28R-expressing EC cells dramatically altered transcriptional profiles. MAXH28R-derived xenografts statistically significantly increased vascular area compared with MAXWT and empty vector tumors (P = .003 and P = .008, respectively). MAXH28R-expressing EC cells secreted nearly double the levels of VEGFA compared with MAXWT cells (P = .03, .005, and .005 at 24, 48, and 72 hours, respectively), and conditioned media from MAXH28R cells increased sprouting when applied to HUVECs., Conclusion: These data highlight the importance of MAX mutations in EC and point to increased vascularity as one mechanism contributing to clinical aggressiveness of EC.

Rationale: Cheiro-Oral syndrome (COS) is a pure sensory deficit confined to the perioral area and ipsilateral distal fingers or hand. Owing to relatively minor clinical findings and various presentations in different cases, the insidious and severe illness it implies may be overlooked at acute settings., Patient Concerns: A 70-year-old man with history of hypertension and type II diabetes mellitus under regular medication control came to our emergency department with chief complaint of sudden onset of right perioral region and right upper limb numbness. General physical and neurological examinations were normal except for subtle hypoesthesia to light touch, and pinprick in the right corner of mouth and right forearm to distal fingers., Diagnoses: Routine blood analysis was all in normal range including white blood cell count, hemocrit platelet, renal and liver function, and electrolytes such as sodium and potassium. Noncontrast brain computed tomography showed abnormal high-attenuation collection in the left thalamus., Intervention: Follow-up computed tomography showed absorption of the hemorrhage after strict control of his blood pressure., Outcomes: The patient was discharged 7 days later from our hospital with stable condition., Lessons: We demonstrated type I COS associated with thalamic hemorrhage to highlight the neurological implication of COS. It is crucial for emergency clinicians to recognize the symptoms and promptly order a neuroimaging study to exclude large infarction/hemorrhage, which would deeply affect the disposition and following treatment of the patient., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

The increasing death rate caused by drug overdose points to an urgent demand for the development of novel detoxification therapy. In an attempt to detoxify tricyclic antidepressant overdose, we prepared a lipid nanoemulsion, called squarticles, as the nanoantidote. Squalene was the major lipid matrix of the squarticles. Here, we present the animal study to investigate both the pharmacokinetic and pharmacodynamic effects of squarticles on amitriptyline intoxication. The anionic and cationic squarticles had average diameters of 97 and 122 nm, respectively. Through the entrapment study, squarticles could intercept 40%-50% of the amitriptyline during 2 h with low leakage after loading into the nanoparticles. The results of isothermal titration calorimetry demonstrated greater interaction of amitriptyline with the surface of anionic squarticles ( K a =28,700) than with cationic ones ( K a =5,010). Real-time imaging showed that intravenous administration of anionic squarticles resulted in a prolonged retention in the circulation. In a rat model of amitriptyline poisoning, anionic squarticles increased the plasma drug concentration by 2.5-fold. The drug uptake in the highly perfused organs was diminished after squarticle infusion, indicating the lipid sink effect of bringing the entrapped overdosed drug in the tissues back into circulation. In addition, the anionic nanosystems restored the mean arterial pressure to near normal after amitriptyline injection. The survival rate of overdosed amitriptyline increased from 25% to 75% by treatment with squarticles. Our results show that the adverse effects of amitriptyline intoxication could be mitigated by administering anionic squarticles. This lipid nanoemulsion is a potent antidote to extract amitriptyline and eliminate it., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

This paper proposes new algorithms based on the fuzzy c-regressing model algorithm for Takagi-Sugeno (T-S) fuzzy modeling of the complex nonlinear systems. A fuzzy c-regression state model (FCRSM) algorithm is a T-S fuzzy model in which the functional antecedent and the state-space-model-type consequent are considered with the available input-output data. The antecedent and consequent forms of the proposed FCRSM consists mainly of two advantages: one is that the FCRSM has low computation load due to only one input variable is considered in the antecedent part; another is that the unknown system can be modeled to not only the polynomial form but also the state-space form. Moreover, the FCRSM can be extended to FCRSM-ND and FCRSM-Free algorithms. An algorithm FCRSM-ND is presented to find the T-S fuzzy state-space model of the nonlinear system when the input-output data cannot be precollected and an assumed effective controller is available. In the practical applications, the mathematical model of controller may be hard to be obtained. In this case, an online tuning algorithm, FCRSM-FREE, is designed such that the parameters of a T-S fuzzy controller and the T-S fuzzy state model of an unknown system can be online tuned simultaneously. Four numerical simulations are given to demonstrate the effectiveness of the proposed approach.

Pain is a distressing symptom of Parkinson disease (PD). We aim to determine whether the genetic variants of chronic pain-related genes contribute to pain in PD patients. We included 418 PD patients and evaluated pain severity on King's PD pain scale. We genotyped rs6267, rs6269, rs4633, rs4818 and rs4680 of COMT, rs6746030 of SCN9A, and rs1799971 of OPRM1. In total, 193 participants (46.2%) experienced pain. Compared to pain-free PD patients, PD patients with pain had an earlier age of onset, longer disease duration, and higher depression and motor severity (P < 0.01). The frequencies of COMT rs4680 "A" allele were higher in PD patients with pain than those without pain (46.1% vs. 31.1%, P < 0.01). Pain severity was significantly associated with disease duration (P = 0.02), and COMT rs6267 T allele (P < 0.01). We stratified PD by status of depression and the association between COMT rs6267 "GT" genotype and pain severity remained significant (P < 0.01). Furthermore, pain severity was significantly higher in participants having COMT rs4680 "GG" and "GA" genpotypes than those having "AA" genotype (P = 0.04). We concluded that depression and COMT rs4680 "GG" and "GA" genotypes and COMT rs6267 "GT" genotype contribute to pain in PD patients.

Background/purpose: Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Although idiopathic PD accounts for most of the cases, several genetic mutations have been found to cause PD. Mutations in the eukaryotic translation initiation factor 4-γ, 1 (EIF4G1) gene have been identified since 2011, which were reported to be associated with PD among Caucasians in subsequent research. However, this observation was not consistent. The contribution to other ethnic groups remains limited, with < 1% of sporadic cases. We conducted a case-control study to analyze if EIF4G1 is a risk factor for PD patients in Taiwan., Methods: There were 595 PD patients and 600 controls without neurological diseases enrolled in this study. Four reported mutations-A502V (c.1505C>T), G686C (c.2056 G>T), R1197W (c.3589C>T), and R1205H (c.3614G>A)-were analyzed., Results: There were no mutations found in either PD patients or controls., Conclusion: This study indicates that the EIF4G1 mutation is rare in Taiwan, which is consistent with other reports from Asia. Ethnicity could have a great influence on EIF4G1 in PD. Further large scale studies are warranted to evaluate the association of PD and EIF4G1 gene., (Copyright © 2015. Published by Elsevier B.V.)

Tricyclic antidepressants (TCAs) are found to have an analgesic action for relieving cutaneous pain associated with neuropathies. The aim of this study was to assess cutaneous absorption and analgesia of topically applied TCAs. Percutaneous delivery was investigated using nude mouse and pig skin models at both infinite and saturated doses. We evaluated the cutaneous analgesia in nude mice using the pinprick scores. Among five antidepressants tested in the in vitro experiment, mesoridazine, promazine and doxepin showed a superior total absorption percentage. The drug with the lowest total absorption percentage was found to be fluphenazine (<7%) either at an infinite dose or at saturated solubility. The follicular pathway was important for mesoridazine and promazine delivery. Mesoridazine showed stronger skin analgesia than the other TCAs although the in vivo skin absorption of mesoridazine (0.34nmol/mg) was less than that of promazine (0.80nmol/mg) and doxepin (0.74nmol/mg). Mesoridazine had a prolonged duration of pain relief (165min) compared to promazine (83min) and doxepin (17min). The skin irritation test demonstrated an evident barrier function deterioration and cutaneous erythema by promazine and doxepin treatment, whereas mesoridazine caused no obvious adverse effect by topical application for up to 7days., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aiming at reducing the smoking population, the Taiwan government adopted a successful smoking cessation quitline model from California Smokers' Helpline, commissioned a private non-profit organization-Teacher Chang Foundation, which was well-known for its quality telephone counseling service-to set up Asia's first quitline, Taiwan Smokers' Helpline (TSH) in 2003. The establishment of the quitline constituted significant progress for tobacco control in Taiwan, as it built up a cooperative model with smoking cessation clinics to increase the quit rate through assisting smokers to overcome their psychological obstacles encountered while attempting to quit smoking.

This paper reports a polydimethylsiloxane (PDMS) SlipChip for in vitro cell culture applications, multiple-treatment assays, cell co-cultures, and cytokine detection assays. The PDMS SlipChip is composed of two PDMS layers with microfluidic channels on each surface that are separated by a thin silicone fluid (Si-fluid) layer. The integration of Si-fluid enables the two PDMS layers to be slid to different positions; therefore, the channel patterns can be re-arranged for various applications. The SlipChip design significantly reduces the complexity of sample handling, transportation, and treatment processes. To apply the developed SlipChip for cell culture applications, human lung adenocarcinoma epithelial cells (A549) and lung fibroblasts (MRC-5) were cultured to examine the biocompatibility of the developed PDMS SlipChip. Moreover, embryonic pluripotent stem cells (ES-D3) were also cultured in the device to evaluate the retention of their stemness in the device. The experimental results show that cell morphology, viability and proliferation are not affected when the cells are cultured in the SlipChip, indicating that the device is highly compatible with mammalian cell culture. In addition, the stemness of the ES-D3 cells was highly retained after they were cultured in the device, suggesting the feasibility of using the SlipChip for stem cell research. Various cell experiments, such as simultaneous triple staining of cells and co-culture of MRC-5 with A549 cells, were also performed to demonstrate the functionalities of the PDMS SlipChip. Furthermore, we used a cytokine detection assay to evaluate the effect of endotoxin (lipopolysaccharides, LPS) treatment on the cytokine secretion of A549 cells using the SlipChip. The developed PDMS SlipChip provides a straightforward and effective platform for various on-chip in vitro cell cultures and consequent analysis, which is promising for a number of cell biology studies and biomedical applications.

The MEEKC separation and on-line preconcentration of nonsteroidal anti-inflammatory drugs (NSAIDs) were investigated. In this work, two microemulsion (ME) systems were employed. Complete separation could be achieved at a pH of 5.5 with octane as the oil phase (ME I). The LODs for the determination of flurbiprofen, fenoprofen, naproxen, ketoprofen, suprofen, and indoprofen were 0.45, 0.32, 0.10, 0.48, 0.77, and 0.29 mg/L, respectively. To enhance the sensitivity, anion selective exhaustive injection-sweeping (ASEI-sweeping) and stacking with reverse migrating pseudostationary phase (SRMP) were compared. For having a simple process without polarity switching and shorter analysis time, a suppressed EOF and di-n-butyl-L-tartrate as the oil phase (ME II) were used for the simultaneous determination of NSAIDs. The sensitivity for ASEI-sweeping was enhanced approximately 280-fold. However, there was much background noise, and some of the analytes were co-eluted. When SRMP was used, all of the analytes could be detected simultaneously, and baseline separation could be achieved. The sensitivities of all of the analytes, except for indoprofen, were enhanced approximately 170-fold compared with the normal MEEKC, and the LODs were 2-45 μg/L. Herein, we propose a simple method for the direct determination of NSAIDs at therapeutic and toxic levels in urine throughout a wide concentration range., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aim: This study examines how trust and monetary reward influence nurses' job satisfaction and strengthen organisational commitment., Background: Hospitals with high nurse retention rates typically have fewer medical errors and better quality care for patients. Therefore, health care administrators should provide a trustworthy workplace and a satisfactory reward system to retain experienced and skilled nurses., Method: This study adopts the partial least squares method for parameter estimates and hypotheses based on 797 valid questionnaires from registered nurses in a Taiwan medical centre., Result: All hypotheses were supported. The results show that the perceived trust of and rewards for registered nurses significantly influence their job satisfaction and organisational commitment. Although the impact of rewards is slightly stronger than that of trust among nurses on job satisfaction, the influence of trust among nurses is significantly higher than that of reward on organisational commitment., Conclusion: The results show that administrators should enhance trust among nurses, establish a fair and attractive reward system, and increase nurse job satisfaction to elevate their commitment to the organisation., Implications for Nursing Management: To build a high level of organisational commitment, developing trust among nurses and increasing job satisfaction are more critical than compensating with monetary incentives alone., (© 2013 John Wiley & Sons Ltd.)

This paper reports a polydimethylsiloxane-polycarbonate (PDMS-PC) hybrid microfluidic device capable of performing cell culture under combinations of chemical and oxygen gradients. The microfluidic device is constructed of two PDMS layers with microfluidic channel patterns separated by a thin PDMS membrane. The top layer contains an embedded PC film and a serpentine channel for a spatially confined oxygen scavenging chemical reaction to generate an oxygen gradient in the bottom layer for cell culture. Using the chemical reaction method, the device can be operated with a small amount of chemicals, without bulky gas cylinders and sophisticated flow control schemes. Furthermore, it can be directly used in conventional incubators with syringe pumps to simplify the system setup. The bottom layer contains arrangements of serpentine channels for chemical gradient generation and a cell culture chamber in the downstream. The generated chemical and oxygen gradients are experimentally characterized using a fluorescein solution and an oxygen-sensitive fluorescent dye, respectively. For demonstration, a 48 hour cell-based drug test and a cell migration assay using human lung adenocarcinoma epithelial cells (A549) are conducted under various combinations of the chemical and oxygen gradients in the experiments. The drug testing results show an increase in A549 cell apoptosis due to the hypoxia-activated cytotoxicity of tirapazamine (TPZ) and also suggest great cell compatibility and gradient controllability of the device. In addition, the A549 cell migration assay results demonstrate an aerotactic behavior of the A549 cells and suggest that the oxygen gradient plays an essential role in guiding cell migration. The migration results, under combinations of chemokine and oxygen gradients, cannot be simply superposed with single gradient results. The device is promising to advance the control of in vitro microenvironments, to better study cellular responses under various physiological conditions for biomedical applications.

A typical oil-in-water microemulsion (ME) was applied for the capillary electrophoretic separation of nonsteroidal anti-inflammatory drugs (NSAIDs). As the high-pH ME was introduced into the capillary and a voltage was applied, we observed an unusual phenomenon during the preconditioning process: a sharp inflection point occurred at 56.2 min ( ± 4.8%) (N = 15). Both before (region A) and after (region B) that point, a steady state was observed. Highly reproducible results were obtained for this event. Two different absorbance patterns were observed for the hydrostatic injection of either freshly prepared ME or ME collected from the outlet of the capillary column during the steady state of region B. The latter had an inflection point at approximately 9 min, whereas the former had a constant absorbance over the entire range. To further characterize this property, regions A and B were used for the separation of NSAIDs. The results showed that both the detection limit and the reproducibility of the separation were superior in region B. For deep insight into the stability of the ME in an electric field, the effects of the oil, cosurfactant, pH, and voltage were systematically investigated in the neat ME. From our findings, it can be concluded that the inflection time might be the migration time of the ME in an electric field, and it might actually be the result of equilibration. Moreover, the existence of many unexpected phenomena seems to be the result of a change in the properties of ME droplet in an electric field., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A surface enhanced Raman spectroscopy (SERS) substrate made of gold nanoparticles-embedded mesoporous silica (AuNPs@mesoSiO2) varying with size and gold concentrations was applied for SERS applications. In this study, the AuNPs@mesoSiO2 substrate produced notable intensity and more distinguishable peaks when compared with the spectra collected directly from an Au/Cr-coated substrate with regard to the detection of a lower concentration of chemicals or environmental contamination. Both aqueous and dried coffee rings of 5-5'-Dithio-bis (2-nitrobenzoic acid) (DTNB) solutions were examined. SERS spectra obtained from the substrate showed more fingerprint peaks with significant enhancement on the spectra signals. The correlation between the SERS signal and the DTNB concentration was found to be linear within a range of 10(-2) to 10(-12) M. SERS enhancement between 25 and 8 times greater can be achieved for DTNB detection using AuNPs@mesoSiO2 compared with the normal Raman spectra obtained from the aqueous solution and the contact line of the dried coffee ring, respectively., (© 2013 Elsevier B.V. All rights reserved.)

Essential tremor (ET), which is one of the most common movement disorders, may lead to severe interference in quality of life. The first genome-wide association study (GWAS) has identified an association of the LINGO1 variant (rs9652490) with ET in Americans and Europeans. Recently, a second GWAS that was performed in a European population has discovered a new variant (rs3794087) of the main glial glutamate transporter (SLC1A2) that increases the risk of ET with an odds ratio of about 1.4. SLC1A2 encodes for the major glial high-affinity glutamate reuptake transporter in the brain and is a potential ET susceptibility gene. Because replication in a different ethnic population is important for validating a finding, we conducted a case-control study to investigate the SLC1A2 variant in an Asian cohort with ET in Taiwan. A total of 542 subjects (273 ET patients and 269 controls) were included. The results showed that rs3794087 was associated with ET among the Taiwanese. The odds ratio was 1.37. Our results were similar to those of the second GWAS of ET in Europeans, and this confirms that SLC1A2 may be a good functional candidate gene for ET. A replication study in another independent population is of importance to validate this association.

Objective: A nonsense mutation in the amyotrophic lateral sclerosis gene FUS has been found to segregate in a large family with essential tremor (ET). Coding variants in this gene have not been comprehensively evaluated in ET. We conducted a genetic analysis of FUS for pathogenic and novel coding variants in 2 case-control cohorts among ethnic Chinese., Methods: In a study that involved 7,548 subjects, we first sequenced all the exon and exon-intronic boundaries of FUS in 84 ET samples. Potential causative variants that were identified were then genotyped in 2 separate case-control cohorts involving 263 additional ET samples and 5,919 controls (set 1) and 250 ET cases and 250 controls (set 2), and 782 diseased controls of Chinese ethnicity from 2 different Asian countries., Results: We identified a novel variant, Met392Ile, in exon 12 of the FUS gene. This variant was associated with ET in set 1 (odds ratio = 4.72 [95% confidence interval = 1.90-11.71], p = 0.0037). The association was subsequently validated in set 2 (joint analysis odds ratio = 3.92 [95% confidence interval = 1.57-9.82], p = 8.6 × 10(-4)). No association was observed in another neurologic cohort of patients with Parkinson disease, and no other potential pathogenic mutations were identified., Conclusion: We identified a novel risk variant, Met392Ile, in the FUS gene that increases susceptibility of ET among ethnic Chinese. Further studies in other ethnic populations are needed to determine whether this is an ethnic-specific risk factor.

Phagocytes release inflammatory mediators to defense harmful stimuli upon bacterial invasion, however, excessive inflammatory reaction leads to tissue damage and manifestation of pathological states. Therefore, targeting on uncontrolled inflammation seems feasible to control numerous inflammation-associated diseases. Under the drug screening process of synthetic diphenylpyrazole derivatives, we discovered compound yuwen02f1 possesses anti-inflammatory effects in decreasing the release of pro-inflammatory cytokines including TNFα and IL-6, nitric oxide, reactive oxygen species (ROS) as well as inhibiting migration of LPS-stimulated phagocytes. In addition, we observed that the molecular mechanism of yuwen02f1-mediated anti-inflammation is associated with decreasing phosphorylation of MAPK molecules including ERK1/2, JNK and p38, and attenuating translocation of p47(phox) and p67(phox) to the cell membrane. Yuwen02f1 also reverses IκBα degradation and attenuates the expression of NFκB-related downstream inducible enzymes like iNOS and COX-2. Furthermore, we found that yuwen02f1 attenuates some pathological syndromes of LPS-induced sepsis and adjuvant-induced arthritis in mice, as evidenced by decreasing the cytokine production, reversing thrombocytopenic syndrome, protecting the mice from tissue injury in septic mice, and attenuating paw edema in arthritic mice as well. These results suggest that yuwen02f1 is a potential anti-inflammatory agent for alleviating syndromes of acute and chronic inflammatory diseases as evidenced by attenuating the generation of cytokines and down-regulating the expression of iNOS and COX-2 through the blockade of ROS generation and NADPH oxidase, NFκB and MAPK activation pathways in LPS-stimulated phagocytes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aims: This article is a report on a study that empirically examines the influence of social capital on knowledge sharing and the impact of knowledge sharing on patient safety., Background: Knowledge sharing is linked to many desirable managerial outcomes, including learning and problem-solving, which are essential for patient safety. Rather than studying the tangible effects of rewards, this study examines whether social capital (including social interaction, trust and shared vision) directly supports individual knowledge sharing in an organization., Methods: This cross-sectional study analysed data collected through a questionnaire survey of nurses from a major medical centre in northern Taiwan. The data were collected over a 9-month period from 2008 to 2009. The data analysis was conducted using the Partial Least Squares Graph v3.0 program to evaluate the measurement properties and the structural relationships specified in the research model., Findings: Based on a large-scale survey, empirical results indicate that Registered Nurses' perceptions of trust and shared vision have statistically significant and direct effects on knowledge sharing. In addition, knowledge sharing is significantly and positively associated with patient safety., Conclusion: The findings suggest that hospital administrators should foster group trust and initiate a common vision among Registered Nurses. In addition, administrators and chief knowledge officers of hospitals should encourage positive intentions towards knowledge sharing., (© 2011 The Authors. Journal of Advanced Nursing © 2011 Blackwell Publishing Ltd.)

Dried flowers of Daphne genkwa Sieb. et Zucc. (Thymelaeaceae) are a Chinese herbal medicine used as an abortifacient with purgative, diuretic and anti-inflammatory activities. However, the activity of this medicine against enteroviral infections has not been investigated. The water-extract of dried buds of D. genkwa Sieb. et Zucc. (DGFW) was examined against various strains of enterovirus 71 (EV71) by neutralization assay, and its initial mode of action was characterized by time-of-addition assay followed by attachment and penetration assays. Pretreatment of DGFW with virus abolished viral replication, indicating that DGFW inhibits EV71 by targeting the virus. GFW exerts its anti-EV71 effects by inhibiting viral entry without producing cytotoxic side effects and thus provides a potential agent for antiviral chemotherapeutics.

This paper mainly addresses the decentralized formation problems for multiple robots, where a fuzzy sliding-mode formation controller (FSMFC) is proposed. The directed networks of dynamic agents with external disturbances and system uncertainties are discussed in consensus problems. To perform a formation control and to guarantee system robustness, a novel formation algorithm combining the concepts of graph theory and fuzzy sliding-model control is presented. According to the communication topology, formation stability conditions can be determined so that an FSMFC can be derived. By Lyapunov stability theorem, not only the system stability can be guaranteed, but the desired formation pattern of a multirobot system can be also achieved. Simulation results are provided to demonstrate the effectiveness of the provided control scheme. Finally, an experimental setup for the e-puck multirobot system is built. Compared to first-order formation algorithm and fuzzy neural network formation algorithm, it shows that real-time experimental results empirically support the promising performance of desire.

In this paper, the interval type-2 fuzzy controllers (FC(IT2)s) are approximated using the fuzzy ratio switching type-1 FCs to avoid the complex type-reduction process required for the interval type-2 FCs. The fuzzy ratio switching type-1 FCs (FC(FRST1)s) are designed to be a fuzzy combination of the possible-leftmost and possible-rightmost type-1 FCs. The fuzzy ratio switching type-1 fuzzy control technique is applied with the sliding control technique to realize the hybrid fuzzy ratio switching type-1 fuzzy sliding controllers (HFSC(FRST1)s) for the double-pendulum-and-cart system. The simulation results and comparisons with other approaches are provided to demonstrate the effectiveness of the proposed HFSC(FRST1)s.

Aims: This study examines the perceptions of registered nurses of social capital, organisational commitment and customer-oriented prosocial behaviour. Additionally, this study also addresses a conceptual model for testing how registered nurses' perceptions of three types of social capital influence their organisational commitment, in turn intensifying customer-oriented prosocial behaviour, including role-prescribed customer service and extra-role customer service., Background: Customer-oriented prosocial behaviour explains differences in job satisfaction and job performance. However, the critical role of customer orientation in the hospital setting has yet to be explored., Design: Survey., Methods: The survey was conducted to obtain data from registered nurses working for a large Taiwanese medical centre, yielding 797 usable responses and a satisfactory response rate of 86.7%. The partial least squares method was adopted to obtain parameter estimates and test proposed hypotheses., Results: The study measurements display satisfactory reliability, as well as both convergent and discriminant validities. All hypotheses were supported. Empirical results indicate that registered nurses' perceptions of social capital were significantly impacted the extent of organisational commitment, which in turn significantly influenced customer-oriented prosocial behaviour., Conclusion: By stimulating nursing staff commitment, health care providers can urge them to pursue organisational goals and provide high quality customer service. To enhance organisational commitment, health care managers should endeavour to create interpersonal interaction platforms in addition to simply offering material rewards., Relevance to Clinical Practice: Nurses act as contact employees for their patient customers in the hospital, and they are required to provide patient safety and service quality. This study shows that nurses with high organisational commitment are willing to provide customer-oriented prosocial activities, which in turn enhances patient satisfaction., (© 2011 Blackwell Publishing Ltd.)

Aims of the Study: Ko-Ken Tang (KKT, aka kakkon-to), a conventional Chinese herbal medicine, has been used for the treatment of the common cold, fever and influenza virus infection. However, the underlying mechanism of its activity against influenza virus infection remains elusive. In this study, the antiviral effect and its underlying mechanism was evaluated, including the investigation of anti-influenza virus activity of KKT on MDCK cells and corresponding mechanism related to phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and its consecutive viral RNP nuclear export., Materials and Methods: The antiviral activity of non-toxic concentration of KKT was examined against various strains of influenza virus and enterovirus 71 by neutralization assay. PI3K/Akt signaling activated by influenza virus was inspected in A549 cells by western blot. Inhibition of influenza polymerase activity by KKT was measured with plasmid-based reverse genetics using primer extension assay and luciferase reporter assay. Inhibition of viral vRNP nuclear export was demonstrated by laser confocal microscopy and interspecies heterokaryon assay., Results: KKT inhibits influenza virus replication but not entry, and it exhibits a broad spectrum inhibitory activity against human influenza A viruses and enterovirus 71. KKT does not inhibit viral polymerase activity but directly blocks the virus-induced phosphatidylinositol 3-kinase/Akt signaling pathway, which in turns causes retention of viral nucleoprotein in the nucleus, thereby interfering with virus propagation. The inhibition by KKT of the nuclear export of viral protein was further confirmed by heterokaryon assay., Conclusions: The results obtained in this study give scientific support to KKT for the treatment of influenza virus infection. KKT could be of potential use in the management of seasonal pandemic influenza virus infection in addition to other clinically available drugs., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

We identify integrin α(v)β(3) and Fas as receptors for the streptococcal pyrogenic exotoxin B (SPE B), and G308S (SPE B mutant, glycine at residue 308 is changed to serine), which interacts with Fas only, in our previous study. Here, we explore the signal pathways that regulate proapoptotic protein expression after SPE B stimulation. We find that both SPE B and G308S can stimulate the serine phosphorylation of p53, and p53 phosphorylation is inhibited by the anti-Fas antibody but not by anti-α(V)β(3) antibody. p38 inhibitor and siRNA decrease the activation and translocation of p53 into the nucleus, which executes its transcription activity. These results indicate that after SPE B treatment, p53 is activated and p38 is the upstream of p53. p38 siRNA also decreases the binding of p53 to the bax promoter and interferes with the association of p53 and STAT1. p53, p38, and STAT1 siRNAs downregulate SPE B-induced Bax expression. This shows that SPE B activates the bax promoter via p38/p53 signal pathways through the Fas receptor, and that STAT1 acts as a coactivator of p53. In addition, p38 and p53 siRNAs inhibit SPE B-induced apoptosis. This is consistent with the findings that SPE B upregulates Bax expression through p38/p53 signal pathways that enhance cell apoptosis.

Aim: One of the most discernable differences between keratinized and non-keratinized oral mucosas is the quantity of elastin they contain in the connective tissues. Whether elastin modulates the keratin expression of oral epithelial cells is unknown., Methods: Four specimens containing both keratinized and non-keratinized mucosas were processed for immunohistochemical (IHC) stainings for elastin and four keratins. Six keratinized and non-keratinized portions of oral mucosas were dissected and cultured on an organ culture system. Purified elastin and elastase were added separately to the media. After 14 days, the mucosas were examined for four keratin expressions. Cell cultures of keratinized and non-keratinized gingival fibroblasts were established and tested for elastin expression. Oral mucosa equivalents were then engineered and tested for keratin expression., Results: Keratinized epithelium exclusively expressed keratin-1 and -10 (K1/10), while non-keratinized epithelium expressed keratin-4 and -13 (K4/13). Only non-keratinized fibroblasts expressed elastin in cell culture. Both the native and the engineered keratinized gingiva changed phenotypes and expressed K4/13 when treated with exogenous elastin. On the contrary, the native non-keratinized mucosa started to express K1/10 when elastase eradicated inherent elastin., Conclusions: Our study demonstrated that the elastin in the oral connective tissue is important for the non-keratinized phenotypes of overlaying epithelium.

We have previously identified integrin alpha(v)beta(3) and Fas as receptors for the streptococcal pyrogenic exotoxin B (SPE B), and G308S, a mutant of SPE B that binds to Fas only. In the current study we found that after binding to alpha(v)beta(3), SPE B stimulated the tyrosine phosphorylation of JAK2 and STAT1. STAT1 tyrosine phosphorylation was inhibited by a JAK2 inhibitor, AG490, short interfering RNA (siRNA) silencing of JAK2, and anti-alpha(V)beta(3) antibody. AG490 also decreased the binding of tyrosine-phosphorylated STAT1 to the procaspase 8 promoter, decreasing procaspase 8 expression, suggesting that SPE B up-regulates procaspase 8 expression via the JAK2/STAT1 pathway. Alternatively, both SPE B and G308S increased STAT1 phosphorylation at serine 727, which was inhibited by anti-Fas antibody, a p38 inhibitor, SB203580, and siRNA silencing of p38. In addition, SPE B and G308S increased binding of serine-phosphorylated STAT1 to the Bax promoter and Bax expression, which was decreased by SB203580. SPE B and G308S-stimulated Bax expression was also inhibited by anti-Fas antibody. These findings suggest that Fas mediate SPE B-induced Bax expression through p38. Silencing of JAK2 or p38 by siRNA blocked procaspase 8 expression, whereas only p38 siRNA decreased Bax expression. Furthermore, JAK2 inhibition and p38 inhibition reduced SPE B-induced apoptosis, but only p38 inhibition blocked G308S-induced apoptosis.

We have previously identified alpha(v)beta(3) and Fas as receptors for the streptococcal pyrogenic exotoxin B (SPE B), and G308S, a mutant of SPE B with RSD motif, which interacts with Fas only. This study aims to evaluate how SPE B interacts with cells to induce the production of IL-8. Our results showed that following exposure to SPE B or G308S, the levels of IL-8 protein and mRNA were increased and the increase was inhibited by the addition of anti-Fas antibody, suggesting that the increased production of IL-8 by SPE B is mediated through Fas receptor. In the presence of G308S, the association of FADD and procaspase 8, and activation of NF-kappaB were also detected. The application of siRNA of FADD and of procaspase 8 could inhibit the NF-kappaB activity. The proteolytic activity of caspase 8 was required for the NF-kappaB activity. Further studies showed that G308S could increase the phosphorylation of ERK and the translocation of NF-kappaB into the nucleus, and the inhibition of ERK phosphorylation decreased the IL-8 production, mRNA expression and activation of NF-kappaB. In addition, siRNA of procaspase 8 could inhibit the G308S-induced cleavage of MEKK1, binding of MEKK1 to caspase 8, activation of ERK and the NF-kappaB activity. Taken together, the production of IL-8 by SPE B in A549 cells is mediated by Fas, and followed by the activation of FADD, caspase 8, MEKK1, ERK and NF-kappaB.

Our previous work suggested that streptococcal pyrogenic exotoxin (SPE) B-induced apoptosis is mediated through a receptor-like mechanism. In this study, we have identified alpha(v)beta(3) and Fas as the SPE B receptors for this function. The SPE B fragment without the RGD motif and G308S, a SPE B mutant with the RSD motif, induced less apoptosis than did native SPE B, suggesting that the RGD motif is critical for SPE B-induced apoptosis. Fluorescein isothiocyanate-SPE B binding assays and immunoprecipitation analysis showed that SPE B specifically interacted with alpha(v)beta(3). Anti-alpha(v)beta(3) antibody partially inhibited SPE B-induced apoptosis but had no effect on G308S-induced apoptosis. In addition, Fas binding to SPE B was verified in an affinity column and an immunoprecipitation analysis. Anti-Fas antibody inhibited SPE B- and G308S-induced apoptosis in a dose-dependent manner, suggesting that Fas-mediated SPE B-induced apoptosis also occurs RGD independently. Both anti-alpha(v)beta(3) and anti-Fas antibodies synergistically inhibited SPE B-induced apoptosis. The apoptotic cascades were activated by SPE B and G308S, with a little delay by the latter. After SPE B binding, the cell surface level of alpha(v)beta(3), but not of Fas, was decreased. The decreased alpha(v)beta(3) level was restored by treatment with the proteasome inhibitor MG132, suggesting a SPE B-mediated endocytosis of integrin alpha(v)beta(3) via the ubiquitin-proteasome system. Taken together, our results demonstrate that SPE B-induced apoptosis is mediated through alpha(v)beta(3) integrin and Fas in a synergistic manner.