Astrocyte-specific knockout of YKL-40/Chi3l1 reduces Aß burden and restores memory functions in 5xFAD mice.

Glial cell-mediated neuroinflammation and neuronal attrition are highly correlated with cognitive impairment in Alzheimer's disease. YKL-40 is a secreted astrocytic glycoprotein that serves as a diagnostic biomarker of Alzheimer's disease. High levels of YKL-40 are associated with either advanced Alzheimer's disease or the normal aging process. However, the functional role of YKL-40 in Alzheimer's disease development has not been firmly established. In a 5xFAD mouse model of Alzheimer's disease, we observed increased YKL-40 expression in the cerebrospinal fluid of 7-month-old mice and was correlated with activated astrocytes. In primary astrocytes, Aß1-42 upregulated YKL-40 in a dose-dependent manner and was correlated with PI3-K signaling pathway activation. Furthermore, primary neurons treated with YKL-40 and/or Aß1-42 resulted in significant synaptic degeneration, reduced dendritic complexity, and impaired electrical parameters. More importantly, astrocyte-specific knockout of YKL-40 over a period of 7 days in symptomatic 5xFAD mice could effectively reduce amyloid plaque deposition in multiple brain regions. This was also associated with attenuated glial activation, reduced neuronal attrition, and restored memory function. These biological phenotypes could be explained by enhanced uptake of Aß1-42 peptides, increased rate of Aß1-42 degradation and acidification of lysosomal compartment in YKL-40 knockout astrocytes. Our results provide new insights into the role of YKL-40 in Alzheimer's disease pathogenesis and demonstrate the potential of targeting this soluble biomarker to alleviate cognitive defects in symptomatic Alzheimer's disease patients.

Factors affecting nursing students' intention to use a 3D game to learn field triage skills: a structural equation modelling analysis.

BACKGROUND: As mass casualty incidents are low-probability events, students often do not have the chance to practise field triage skills during their clinical placement. This study used a 3D game to engage participants in experiential learning in a realistic virtual environment. The purpose of the study was to explore factors affecting nursing students' intention to use a 3D game to learn field triage skills. METHODS: This was a cross-sectional survey study. The technology acceptance model augmented by computer self-efficacy was used as a research model and a questionnaire was used to evaluate students' intention to use the 3D game to learn field triage. Data was collected from nursing students of a degree-awarding higher education institution in Hong Kong. RESULTS: A total of 177 valid questionnaires were returned, and structural equation modeling was used to test the research model and hypotheses. Consistent with the technology acceptance model, perceived usefulness (0.21, p < 0.05) and perceived ease of use (0.91, p < 0.001) had a positive effect on the behavioral intention to use the 3D game. Computer self-efficacy positively influenced both perceived usefulness (0.66, p < 0.001) and perceived ease of use (0.73, p < 0.001). The research model explained 42 percent of the variance in the behavioral intention to use the 3D game. CONCLUSION: Students believed that using the 3D game would enhance their field triage skills and found the game easy to use. Using 3D games to facilitate learning is a worthwhile educational approach for preparing healthcare professionals to handle low-probability clinical tasks, such as field triage in mass casualty incidents. Insights provided by findings of this study included the best way to design and promote interactive education programmes in a virtual environment.

Evaluation of multiplex tandem PCR (MT-PCR) assays for the detection of bacterial resistance genes among Enterobacteriaceae in clinical urines.

Background: Increasing resistance drives empirical use of less potent and previously reserved antibiotics, including for urinary tract infections (UTIs). Molecular profiling, without culture, might better guide early therapy. Objectives: To explore the potential of AusDiagnostics multiplex tandem (MT) PCR UTI assays. Methods: Two MT-PCR assays were developed successively, seeking 8 or 16 resistance genes. Amplification was tracked in real time, with melting temperatures used to confirm product identity. Assays were variously performed on: (i) extracted DNA; (ii) cultured bacteria; (iii) urine spiked with reference strains; and (iv) bacteria harvested from clinical urines. Results were compared with those from sequencing, real-time SybrGreen PCR or phenotypic susceptibility. Results: Performance was similar irrespective of whether DNA, cultures or urines were used, with >90% sensitivity and specificity with respect to common ß-lactamases, dfr genes and aminoglycoside resistance determinants except aadA1/A2/A3, for which carriage correlated poorly with streptomycin resistance. Fluoroquinolone-susceptible and -resistant Escherichia coli (but not other species) were distinguished by the melting temperatures of their gyrA PCR products. The time from urine to results was <3 h. Conclusions: The MT-PCR assays rapidly identified resistance genes from Gram-negative bacteria in urines as well as from cultivated bacteria. Used directly on urines, this assay has the potential to guide early therapy.

Nurses' preparedness for infectious disease outbreaks: A literature review and narrative synthesis of qualitative evidence.

AIMS AND OBJECTIVES: To explore the core components that constitute nurses' preparedness in an epidemic event. BACKGROUND: Healthcare service providers have worked to augment efforts to protect the public from the impact of epidemic events. While constituting the major healthcare taskforce, nurses are frequently tasked with fronting the response to an infectious disease outbreak. Given the crucial role of nurses in the management of prevailing epidemics, the constituents of their preparedness in epidemic events should be identified. DESIGN: A systematic search was undertaken to identify eligible studies from the literature. A narrative synthesis approach was employed to extract and synthesise findings of the reviewed qualitative studies. METHODS: Seven qualitative studies on nurses' experience and perceptions of epidemic events were examined for scientific quality using the Critical Appraisal Skills Programme Qualitative Checklist. Findings of these studies were synthesised adopting a narrative synthesis approach. RESULTS: Three interplaying themes were identified as follows: (i) personal resources, (ii) workplace resources and (iii) situational influences. The findings suggest that an effective epidemic outbreak response would require further effort to reinforce the interplay between individual nurses, healthcare institutions and the governments. CONCLUSIONS: The practical interplay among individual nurses, healthcare institutions and the governments is crucial in establishing an effective epidemic response. Further research on the understanding of the dynamic process of preparedness development is recommended to set future directions in research. RELEVANCE TO CLINICAL PRACTICE: This study offers important insights for devising future strategies in enhancing nurses' preparedness and response to an epidemic event. These include recommendations on providing education and training to nurses regarding infectious diseases, fostering institutional assistance and support in an outbreak and revising government policies and planning.

Neuropathological signatures revealed by transcriptomic and proteomic analysis in Pten-deficient mouse models.

PTEN hamartoma tumour syndrome is characterised by mutations in the human PTEN gene. We performed transcriptomic and proteomic analyses of neural tissues and primary cultures from heterozygous and homozygous Pten-knockout mice. The somatosensory cortex of heterozygous Pten-knockout mice was enriched in immune response and oligodendrocyte development Gene Ontology (GO) terms. Parallel proteomic analysis revealed differentially expressed proteins (DEPs) related to dendritic spine development, keratinisation and hamartoma signatures. However, primary astrocytes (ASTs) from heterozygous Pten-knockout mice were enriched in the extracellular matrix GO term, while primary cortical neurons (PCNs) were enriched in immediate-early genes. In ASTs from homozygous Pten-knockout mice, cilium-related activity was enriched, while PCNs exhibited downregulation of forebrain neuron generation and differentiation, implying an altered excitatory/inhibitory balance. By integrating DEPs with pre-filtered differentially expressed genes, we identified the enrichment of traits of intelligence, cognitive function and schizophrenia, while DEPs in ASTs were significantly associated with intelligence and depression.

Production of 2-aminophenoxazin-3-one by Staphylococcus aureus causes false-positive results in ß-galactosidase assays.

Staphylococcus aureus can be distinguished from similar coagulase-positive staphylococci by its absence of ß-galactosidase activity. This is commonly tested using o-nitrophenyl-ß-D-galactopyranoside (ONPG) as the substrate. Unexpectedly, 111 and 58 of 123 isolates displayed apparent ß-galactosidase activity in the ONPG assay and on the Vitek 2 system, respectively. Compositional analysis showed that the yellow coloration of the positive ONPG assay resulted from production of 2-aminophenoxazin-3-one. Alternative ß-galactosidase substrates like X-Gal (5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside) should be used for testing staphylococci.

Long-term efficacy of cardiac pacemakers and implantable cardioverter/defibrillators.

Cardiac pacemakers and implantable cardioverter/defibrillators are becoming more common due to expanded indications and increasing patient survival. In addition, these device systems are being implanted in younger patients, which increases their necessity for long-term durability. Device adverse events can be seen early, during or following implantation (perforation, lead dislodgement, infection), or late (lead fraction, insulation failure or device system infection). These adverse events can, at least in part, be attributed to intrinsic device system structure. Since the initial pacemakers and implantable cardioverter/defibrillators, many modifications in both device system hardware and software have been made to enhance both their durability and function. The current era of devices appear to have made adjustments for previous inadequacies and promise to be reliable and to function well. Despite this, however, it is necessary for clinicians to be aware of possible malfunctions, their warning signs, and the appropriate course of action should these malfunctions be encountered. In this review we describe the common device system malfunctions and device system insertion complications.

Antecedents and Contextual Factors Affecting Occupational Turnover among Registered Nurses in Public Hospitals in Hong Kong: A Qualitative Descriptive Study.

Global increases in both population size and ageing have led to a drastic expansion in the demand for healthcare services. The shortage of nursing workforce capacity continues, posing immense challenges for the global healthcare system. We aimed to identify the antecedents and contextual factors that contribute to the decisions of occupational turnover from the clinical duties of registered nurses in public hospitals in Hong Kong. A qualitative descriptive design was used in this study. A total of 18 registered nurses who had resigned from public hospitals in Hong Kong and changed their occupations were recruited via convenience and snowball sampling methods. Data were collected through individual, semi-structured, and face-to-face interviews and were analyzed according to the content analysis approach. The antecedents and contextual factors that contributed to the registered nurses' decisions regarding occupational turnover were identified from the collected data. These factors were classified into three overarching categories: (1) job dissatisfaction due to a tense work environment, (2) low motivation due to limited career opportunities, and (3) inadequate communication due to ineffective leadership. The identification of these antecedents and contextual factors could help healthcare service providers to develop strategies to enhance nurses' commitment and engagement in their positions and eventually improve their retention. Based on these factors, healthcare sector policy makers could consider incorporating appropriate strategies into healthcare system policy.

Nursing students' experiences and perceptions of learner-centred education in a disaster nursing course: A qualitative study.

Learner-centred education has been shown to be an effective teaching method in the healthcare disciplines that integrate practical skills and theoretical knowledge. However, the elements of learner-centred education that influence students' motivation and engagement in learning remain unclear. In this descriptive qualitative research study, 43 nursing students in a baccalaureate nursing programme in Hong Kong who enrolled in a disaster and trauma nursing course were recruited through purposive sampling. Data were collected through semi-structured, face-to-face, focus group interviews. The transcribed interviews were interpreted through the use of qualitative analysis. This study revealed that adopting learner-centred education techniques in a disaster nursing course could cater to the hedonic nature and practical nature of learning disaster nursing, which consequently strengthens student's motivation and engagement in learning. The findings also suggested that learner-centred education could improve nursing students' learning experience and promote their transformation from passive and receptive students into proactive learners. The present study provides a greater and more focused understanding of the elements of learner-centred education that promote motivation and engagement in learning among nursing students. This study could offer insights into the development and evaluation of disaster nursing courses and other subjects in the undergraduate nursing curriculum.

Investigating the Strategies Adopted by Emergency Nurses to Address Uncertainty and Change in the Event of Emerging Infectious Diseases: A Grounded Theory Study.

Emergency nurses frequently encounter uncertainty and changes during the management of emerging infectious diseases, which challenge their capability to perform their duties in a well-planned and systematic manner. To date, little is known about the coping strategies adopted by emergency nurses in addressing uncertainty and changes during an epidemic event. The present study explored emergency nurses' behaviours and strategies in handling uncertainty and practice changes during an epidemic event. A qualitative study based on the Straussian grounded theory approach was established. Semi-structured, face-to-face, individual interviews were conducted with 26 emergency nurses for data collection. Adapting protocol to the evolving context of practice was revealed as the core category. Four interplaying subcategories were identified: (1) Completing a comprehensive assessment, (2) continuing education for emerging infectious disease management, (3) incorporating guideline updates and (4) navigating new duties and competencies. The nurses demonstrated the prudence to orientate themselves to an ambiguous work situation and displayed the ability to adapt and embrace changes in their practice and duties. These findings offer insights into the need for education and training schemes that allow emergency nurses to acquire and develop the necessary decision-making and problem-solving skills to handle a public health emergency.

TGN38/41: a molecule on the move.

TGN38/41 is a heterodimeric integral membrane protein that cycles between the trans Golgi network and the cell surface. A tyrosine-containing tetrapeptide motif within its cytoplasmic tail is necessary and sufficient for determining its steady-state location in the TGN. Recent results have shown that TGN38/41 plays an essential role in the formation of exocytic vesicles at the TGN by serving as a receptor for complexes of a cytoplasmic protein known as p62, and one of four small GTP-binding proteins, including rab6. For budding to occur, this complex must bind to the cytoplasmic domain of TGN38/41. We propose here that TGN38/41 may couple the segregation of secretory proteins to the budding of exocytic vesicles at the TGN.

A qualitative descriptive study of the contextual factors influencing the practice of emergency nurses in managing emerging infectious diseases.

Purpose: Emergency nurses are engaged in the management of epidemic events that unfold along with the evolution of diseases. The goal of this study was to explore the contextual factors that inhibited the ability of emergency nurses to perform their duties in response to an outbreak. Methods: A qualitative descriptive design was used to explore the experiences and perceptions of emergency nurses. Participants were purposively recruited from 12 emergency departments in Hong Kong. Semi-structured face-to-face individual interviews were conducted with 26 emergency nurses. The audio-recorded interviews were transcribed verbatim and interpreted with a thematic analysis approach. Results: Four intertwined themes emerged from the analysis: resource constraints, threats of infection, ubiquitous changes and lingering uncertainties. These themes portrayed the constraints and challenges surrounding the work environment of emergency nurses. Conclusion: This study described the instabilities and vulnerabilities of the circumstances in which the emergency nurses were situated in during epidemic events. The findings shed light on the importance of hospitals and emergency departments in addressing both the technical problems and adaptive challenges that face emergency nurses during epidemic events.

Effects of Resveratrol and Morin on Insoluble Tau in Tau Transgenic Mice.

Tauopathies are neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD), in which tau protein aggregates within neurons. An effective treatment is lacking and is urgently needed. We evaluated two structurally similar natural compounds, morin and resveratrol, for treating tauopathy in JNPL3 P301L mutant human tau overexpressing mice. Rotarod tests were performed to determine effects on motor function. After treatment from age 11 to 14 months, brains of 26 mice were collected to quantify aggregated hyperphosphorylated tau by Thioflavin T and immunohistochemistry (IHC) and to quantify total tau (HT7 antibody) and hyperphosphorylated tau (AT8 antibody) in homogenates and a fraction enriched for paired helical filaments. Resveratrol reduced the level of total hyperphosphorylated tau in IHC sections (p=0.036), and morin exhibited a tendency to do so (p=0.29), while the two drugs tended to increase the proportion of solubilizable tau that was hyperphosphorylated, as detected in blots. Neither resveratrol nor morin affected motor function. One explanation of these results is that the drugs might interrupt a late stage in tau aggregation, after small aggregates have formed but before further aggregation has occurred. Further animal studies would be informative to explore the possible efficacy of morin or resveratrol for treating tauopathies.

Evaluating the efficacy of an integrated curriculum on adolescent health and development for pre-service nursing education in Hong Kong.

BACKGROUND: An integrated adolescent curriculum on health and development (ADH) was implemented in a pre-service nursing programme in a university. AIM: This study examined the efficacy of an ADH curricular framework in improving the competency variables of student nurses in delivering ADH services. METHOD: The design of the study was quasi-experimental with the systematically designed ADH training curriculum as an intervention. Pre- and post-tests incorporating an experimental group and a control group for a sample of 101 student nurses were used. FINDINGS: Reports from 50 student nurses in the experimental group indicated that there was a significant increase from the pre-test to the post-test phase in the total score for the variables in the ADH Competency Checklist (Z=-5.71, p<0.001) and its four subscales: the professional development subscale (Z=-5.37, p<0.001), the psychosocial and physical well-being subscale (Z=-5.66, p<0.001), the health behaviours and lifestyles subscale (Z=-5.07, p<0.001), and the identity and reproductive health subscale (Z=-4.86, p<0.001). Significant changes were detected in the ADH competency variables for the control group in the post-test phase. CONCLUSION: The findings reveal that the systematic integration of ADH in the nursing curriculum had the positive impact of increasing the competency of student nurses for the examined variables.

The Arrhenius plot behaviour of rat liver 5'-nucleotidase in different lipid environments.

The plasma membrane enzyme 5'-nucleotidase (EC 3.1.3.5) was prepared from rat liver as a complex with sphingomyelin or in detergent-solubilized forms. Each preparation exhibited a Km and Arrhenius break temperature indistinguishable from that of 5'-nucleotidase in plasma membranes. Measurement of fatty acid profiles, cholesterol and phospholipid content however showed a very wide variation between these preparations. We conclude that the biphasic nature of the Arrhenius plot of 5'-nucleotidase may be a property of the enzyme rather than its lipid environment.

Estrogen-stimulated transcytosis of desialylated ligands and alpha2 macroglobulin in rat liver.

Previous studies have shown that treatment of rats with 17 alpha-ethynylestradiol (EE) causes the appearance in bile of intravenously injected, desialylated ligands, including asialofetuin and low density lipoprotein (LDL). Here we show that activated alpha2-macroglobulin (alpha2-M*), but not insulin, transferrin or acetylated LDL, shows the same phenomenon. Alpha2-M* appearance in bile in EE-treated rats was inhibited by receptor associated protein, but not unlabelled asialofetuin, strongly implicating the alpha2-macroglobulin receptor (alpha2MR/LRP) receptor in this process. Asialofetuin, apolipoprotein B (ApoB) of LDL and alpha2-M* appeared undegraded in the bile of EE-treated but not control rats. When LDL was injected, not only was intact apolipoprotein B detected in bile, but the profile of cholesterol esters appearing in bile was characteristic of the injected human LDL rather than rat lipoproteins. After floatation of the bile on KBr gradients, intact Apo B and cholesterol esters characteristic of human LDL were found at the normal density of LDL suggesting that the majority of the lipoprotein particle remains intact. Stimulation of transcytosis was specific to estrogens, and was highest with 17alpha-ethynylestradiol. After subcutaneous injection of 0.05 mg/kg body weight of ethynylestradiol, sufficient to give a measurable increase in transcytosis, the plasma concentration of ethynylestradiol rose to 2.2 nM. Thus estrogen-stimulated transcytosis of desialylated ligands and alpha2-M* would be expected at physiological estrogen concentrations.

The 5'-flanking region of the alpha 2MR/LRP gene contains an enhancer-like cluster of Sp1 binding sites.

We have sequenced a genomic DNA fragment containing the promoter and 5'-flanking region of the alpha 2MR/LRP. A cluster of five Sp1 sites situated over 600 base pairs away from the putative transcription start site doubles the activity of the promoter. A similar increase in activity was observed when this region was replaced by the SV40 enhancer, but the presence of both the cluster of Sp1 sites and SV40 enhancer gave no more transcription than either region alone. Within the previously described promoter region we have shown that only the most proximal Sp1 binding site influences transcription in CHO cells. The Sp 1 site situated 346 bp upstream of the putative transcription start site and previously described DNAse protection footprints had no effect on promoter activity in CHO cells. We also describe an NRF-1 binding site situated 143 bp upstream of the putative transcription start site. Deletion of the central 4 bp of this site caused a 60% decrease in transcription. No sterol regulatory (SRE-1) sites, used in the LDL receptor promoter for control of expression by cholesterol, were found in the alpha 2MR/LRP 5'-flanking region. However, one SRE-1 site was identified in the 5'-untranslated region of alpha 2MR/LRP.

Structure of the low-density lipoprotein receptor-related protein (LRP) promoter.

The low-density Lipoprotein receptor-related protein (LRP) is a 4544-amino-acid membrane protein which closely resembles the LDL receptor in its arrangement of cysteine-rich motifs. Binding studies have suggested that one function of the molecule is as a receptor for ligands containing apolipoprotein E. We present here the sequence and structure of the promoter region of the LRP. These data show that the LRP contains no sterol regulatory element, and is not down-regulated by sterols like the LDL receptor. This lends further support to the identity of the LRP as a chylomicron remnant receptor.

Loading with oxidised low density lipoprotein alters endocytic and secretory activities of murine macrophages.

Lipid-loaded macrophages were produced in vitro by incubation with acetylated or copper-oxidized LDL. In order to establish whether cellular membrane traffic is generally perturbed by such loading, we assessed endocytosis of fluid; cell surface binding, internalisation and degradation of a soluble ligand and of a particulate preparation; and exocytosis of lysosmal enzymes. Fluid-phase pinocytosis of sucrose was unaffected by either form of loading. Binding, uptake and degradation of soluble (mannosylated-BSA) and particulate (zymosan) ligands by these lipid-loaded and by non-loaded cells were compared. Loading with oxidized LDL decreased the processing of both ligands, while loading with acetylated LDL had little effect. Loading with oxidized LDL (Ox-LDL) also decreased zymosan binding at 4 degrees C; and the internalisation and degradation of ligands in Ox-LDL loaded and non-loaded cells reflected the extent of surface binding. Changes in binding and uptake of mannosylated-BSA and zymosan were not due to changes in viability or cell number. Zymosan stimulated release of lysosomal beta-N-acetyl-D-glucosaminidase from the cells. Loading with Ox- but not Ac-LDL decreased beta-N-acetyl-D-glucosaminidase secretion. After incubation with zymosan, intracellular levels of the enzyme were increased in the Ox-LDL loaded cells. Zymosan uptake and beta-N-acetyl-D-glucosaminidase secretion were correlated, but enzyme activity per culture rose more in the absence than in the presence of zymosan. We conclude that membrane traffic is perturbed in model foam cells, particularly those loaded with Ox-LDL.