The Clinical Significance of Anaerobic Coverage in the Antibiotic Treatment of Aspiration Pneumonia: A Systematic Review and Meta-Analysis.

INTRODUCTION: Aspiration pneumonia is increasingly recognised as a common condition. While antibiotics covering anaerobes are thought to be necessary based on old studies reporting anaerobes as causative organisms, recent studies suggest that it may not necessarily benefit prognosis, or even be harmful. Clinical practice should be based on current data reflecting the shift in causative bacteria. The aim of this review was to investigate whether anaerobic coverage is recommended in the treatment of aspiration pneumonia. METHODS: A systematic review and meta-analysis of studies comparing antibiotics with and without anaerobic coverage in the treatment of aspiration pneumonia was performed. The main outcome studied was mortality. Additional outcomes were resolution of pneumonia, development of resistant bacteria, length of stay, recurrence, and adverse effects. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS: From an initial 2523 publications, one randomised control trial and two observational studies were selected. The studies did not show a clear benefit of anaerobic coverage. Upon meta-analysis, there was no benefit of anaerobic coverage in improving mortality (Odds ratio 1.23, 95% CI 0.67-2.25). Studies reporting resolution of pneumonia, length of hospital stay, recurrence of pneumonia, and adverse effects showed no benefit of anaerobic coverage. The development of resistant bacteria was not discussed in these studies. CONCLUSION: In the current review, there are insufficient data to assess the necessity of anaerobic coverage in the antibiotic treatment of aspiration pneumonia. Further studies are needed to determine which cases require anaerobic coverage, if any.

Long-interval Cytapheresis as a Novel Therapeutic Strategy Leading to Dosage Reduction and Discontinuation of Steroids in Steroid-dependent Ulcerative Colitis.

Objective This study was performed to confirm the efficacy of long-interval cytapheresis on steroid-dependent ulcerative colitis (UC). Methods To discontinue steroids in patients with steroid-dependent UC, we previously designed a novel regimen of cytapheresis (CAP), which we termed "long-interval cytapheresis (LI-CAP)", in which CAP was performed as one session every two or three weeks and continued during the whole period of tapering steroid dosage. In this study, we performed LI-CAP therapy 20 times (11 male and 9 female; mean age 41.8 years) between April 2010 and April 2015 for 14 patients with steroid-dependent UC. We evaluated the effectiveness of LI-CAP by examining the improvement in Lichtiger's clinical activity index (CAI), the rate of clinical remission, and the rate of steroid discontinuation. We further examined the rate of sustained steroid-free clinical remission at 6 and 12 months after LI-CAP in patients who successfully discontinued steroid-use after LI-CAP. The primary endpoint was the rate of discontinuation of steroids after LI-CAP. Results The mean CAI score before LI-CAP (7.550) significantly decreased to 1.65 after LI-CAP (p<0.0001). The rate of clinical remission after LI-CAP was 80%. The rate of steroid discontinuation after LI-CAP was 60.0%. The mean dose of daily prednisolone was significantly decreased after LI-CAP (2.30 mg) compared with that before therapy (17.30 mg) (p=0.0003). The rate of sustained steroid-free clinical remission after LI-CAP was 66.7% at 6 months and 66.7% at 12 months. Conclusion We confirmed that LI-CAP has therapeutic effects on reducing the dosage and discontinuing steroids in patients with steroid-dependent UC.

Endosomal Na+/H+ exchanger NHE5 influences MET recycling and cell migration.

Increased recycling and elevated cell surface expression of receptors serve as a mechanism for persistent receptor-mediated signaling. We show that the neuron-enriched Na(+)/H(+) exchanger NHE5 is abundantly expressed in C6 glioma cells and plays an important part in regulating cell surface expression of the receptor tyrosine kinases MET and EGF receptor. NHE5 is associated with transferrin receptor (TfR)- and Rab11-positive recycling endosomal membranes, and NHE5 knockdown by short hairpin RNA significantly elevates pH of TfR-positive recycling endosomes. We present evidence that NHE5 facilitates MET recycling to the plasma membrane, protects MET from degradation, and modulates HGF-induced phosphatidylinositol-3-kinase and mitogen-activated protein kinase signaling. Moreover, NHE5 depletion abrogates Rac1 and Cdc42 signaling and actin cytoskeletal remodeling. We further show that NHE5 knockdown impairs directed cell migration and causes loss of cell polarity. Our study highlights a possible role of recycling endosomal pH in regulating receptor-mediated signaling through vesicular trafficking.

Secretory Carrier Membrane Protein (SCAMP) deficiency influences behavior of adult flies.

Secretory Carrier Membrane Proteins (SCAMPs) are a group of tetraspanning integral membrane proteins evolutionarily conserved from insects to mammals and plants. Mammalian genomes contain five SCAMP genes SCAMP1-SCAMP5 that regulate membrane dynamics, most prominently membrane-depolarization and Ca(2+)-induced regulated secretion, a key mechanism for neuronal and neuroendocrine signaling. However, the biological role of SCAMPs has remained poorly understood primarily owing to the lack of appropriate model organisms and behavior assays. Here we generate Drosophila Scamp null mutants and show that they exhibit reduced lifespan and behavioral abnormalities including impaired climbing, deficiency in odor associated long-term memory, and a susceptibility to heat-induced seizures. Neuron-specific restoration of Drosophila Scamp rescues all Scamp null behavioral phenotypes, indicating that the phenotypes are due to loss of neuronal Scamp. Remarkably, neuronal expression of human SCAMP genes rescues selected behavioral phenotypes of the mutants, suggesting the conserved function of SCAMPs across species. The newly developed Drosophila mutants present the first evidence that genetic depletion of SCAMP at the organismal level leads to varied behavioral abnormalities, and the obtained results indicate the importance of membrane dynamics in neuronal functions in vivo.

Endosomal acidification by Na+/H+ exchanger NHE5 regulates TrkA cell-surface targeting and NGF-induced PI3K signaling.

To facilitate polarized vesicular trafficking and signal transduction, neuronal endosomes have evolved sophisticated mechanisms for pH homeostasis. NHE5 is a member of the Na(+)/H(+) exchanger family and is abundantly expressed in neurons and associates with recycling endosomes. Here we show that NHE5 potently acidifies recycling endosomes in PC12 cells. NHE5 depletion by plasmid-based short hairpin RNA significantly reduces cell surface abundance of TrkA, an effect similar to that observed after treatment with the V-ATPase inhibitor bafilomycin. A series of cell-surface biotinylation experiments suggests that anterograde trafficking of TrkA from recycling endosomes to plasma membrane is the likeliest target affected by NHE5 depletion. NHE5 knockdown reduces phosphorylation of Akt and Erk1/2 and impairs neurite outgrowth in response to nerve growth factor (NGF) treatment. Of interest, although both phosphoinositide 3-kinase-Akt and Erk signaling are activated by NGF-TrkA, NGF-induced Akt-phosphorylation appears to be more sensitively affected by perturbed endosomal pH. Furthermore, NHE5 depletion in rat cortical neurons in primary culture also inhibits neurite formation. These results collectively suggest that endosomal pH modulates trafficking of Trk-family receptor tyrosine kinases, neurotrophin signaling, and possibly neuronal differentiation.

Organellar (Na+, K+)/H+ exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells.

Na+/H+ exchangers (NHEs) are a group of secondary active antiporters that regulate cellular pH, cell volume and ion homeostasis. In humans, nine isoforms (NHE1-NHE9) were identified and characterized as functional NHEs. While a growing body of evidence indicates that NHE1 generates an acidic tumor environment and thereby contributes to tumor invasion, little is known about the role of other NHE isoforms in tumor progression. NHE7 is a unique member of the NHE gene family that dynamically shuttles between the trans-Golgi network, endosomes and the plasma membrane, and regulates the luminal pH of these organelles. Here we show that NHE7-overexpression in breast cancer MDA-MB-231 cells enhances cell overlay, cell-cell adhesion, invasion, anchorage-independent tumor growth and tumor formation in vivo. In contrast, NHE1-overexpression enhances tumor invasion, but it has little effect on cell adhesion or anchorage-independent tumor growth. Pathological examinations of the tumor samples derived from NHE7-overexpressing cells showed a similar appearance to aggressive tumors. Together, these results suggest that NHE7 enhances tumor progression. This is the first report to show the involvement of an organellar NHE in oncogenic processes.

Improving the practice environment: a pilot project in a critical care unit.

The objective of this pilot project was to determine whether engaging critical care unit staff in designing and implementing enhancements to the practice environment would positively impact the clinical environment and staff outcomes. The project used a one-group pre-post test design and a participatory action process. Significant changes in the practice environment were observed in the priority areas identified by the unit staff. Results indicated that team collaboration and respectful work relationships improved following interventions.

Nurse staffing levels and hospital mortality in critical care settings: literature review and meta-analysis.

AIM: This paper reports a review of the literature on the association between critical care nurse staffing levels and patient mortality. BACKGROUND: Statistically significant inverse associations between levels of nurse staffing and hospital mortality have not been consistently found in the literature. Critical care settings are ideal to address this relationship due to high patient acuity and mortality, high intensity of the nursing care required, and availability of individual risk adjustment methods. METHODS: Major electronic databases were searched, including MEDLINE, EMBASE, and the Cumulative Index of Nursing and Allied Health Literature. The search terms included critical/intensive care, quality of health care, mortality/hospital mortality, personnel staffing and scheduling, and nursing staff (hospital). Only papers published in English were included. The original search was conducted in 2002 and updated in 2005. RESULTS: Nine studies were selected from 251 references screened. All nine were observational. Six were conducted in the United States of America, one in Austria, one in Brazil, and one in Scotland. The unadjusted risk ratio of nurse staffing (high vs. low) on hospital mortality were combined meta-analytically (five studies). The pooled estimate was 0.65 (95% confidence interval 0.47-0.91). However, after adjusting for various covariates within each study, the individually reported associations between high nurse staffing and low hospital mortality became non-significant in all but one study. CONCLUSION: The impact of nurse staffing levels on patients' hospital mortality in critical care settings was not evident in the reviewed studies. Methodological challenges that might have impeded correct assessment of the association include measurement problems in exposure status and confounding factors, often uncontrolled. The lack of association also indicates that hospital mortality may not be sensitive enough to detect the consequences of low nurse staffing levels in critical care settings.

Teaching time for metered-dose inhalers in the emergency setting.

OBJECTIVES: In some acute-care settings, practitioners are reluctant to institute bronchodilator therapy with metered-dose inhalers (MDIs) as standard management. Such therapy requires that personnel ensure optimal use of these devices. We prospectively evaluated the time required to teach patients correct inhaler use for the emergency treatment of asthma and COPD, and patient factors associated with duration of teaching. DESIGN: MDI arm within a single-center randomized clinical trial comparing bronchodilator administration by MDI with a delivery enhancement device (MDI/DED) vs delivery by wet nebulizer. SETTING: All subjects were treated for asthma or COPD exacerbations at the respiratory acute-care day hospital of the Montreal Chest Institute, immediately after presentation to our emergency department. Inhaler-use education was provided according to a predetermined protocol. MEASUREMENTS: Subjects' baseline characteristics were obtained from medical charts, spirometry, and questionnaires; satisfaction was evaluated by questionnaire. All inhaler-use education was observed and timed. RESULTS: Sixty-one patients with asthma (median age, 46 years) and 32 patients with COPD (median age, 68.5 years) were randomized to treatment by MDI/DED. Mean FEV1 (percent predicted) was 63.5% for patients with asthma and 39.5% for patients with COPD. Five patients could not complete MDI teaching and therefore received subsequent treatment by wet nebulization. For the 88 other patients, the median teaching time was 6.5 min. Shorter teaching-time requirements were independently associated with higher initial arterial oxygen saturation, home DED use after previous MDI instruction, and a single initial bronchodilator treatment by wet nebulization. Most subjects expressed satisfaction with MDI/DED teaching and treatment. CONCLUSIONS: Successful MDI/DED teaching followed by self-medication is feasible in the emergency setting, based on a simple protocol. A single bronchodilator dose administered by wet nebulization may facilitate subsequent MDI teaching.