SorCS2 binds progranulin to regulate motor neuron development.

Motor neuron (MN) development and nerve regeneration requires orchestrated action of a vast number of molecules. Here, we identify SorCS2 as a progranulin (PGRN) receptor that is required for MN diversification and axon outgrowth in zebrafish and mice. In zebrafish, SorCS2 knockdown also affects neuromuscular junction morphology and fish motility. In mice, SorCS2 and PGRN are co-expressed by newborn MNs from embryonic day 9.5 until adulthood. Using cell-fate tracing and nerve segmentation, we find that SorCS2 deficiency perturbs cell-fate decisions of brachial MNs accompanied by innervation deficits of posterior nerves. Additionally, adult SorCS2 knockout mice display slower motor nerve regeneration. Interestingly, primitive macrophages express high levels of PGRN, and their interaction with SorCS2-positive motor axon is required during axon pathfinding. We further show that SorCS2 binds PGRN to control its secretion, signaling, and conversion into granulins. We propose that PGRN-SorCS2 signaling controls MN development and regeneration in vertebrates.

Heterocyclic [9]Helicenes Exhibiting Bright Circularly Polarized Luminescence.

We describe a concise synthetic strategy for the preparation of heterocyclic [9]helicenes and a simple preparative-scale protocol for the optical resolution of the resulting M- and P-enantiomers. The helicenes were characterized by single-crystal X-ray diffraction along with a range of spectroscopic and computational techniques. A fluorescence quantum yield of up to 65 % was observed, and the chiroptical properties of both M- and P-helicenes revealed large dissymmetry factors. The circularly polarized luminescence brightness reaches up to 17 M-1 cm-1 , as measured experimentally and verified computationally, which makes this the highest circularly polarized luminescence brightness among heterocyclic helicenes. We describe how chiroptical properties (both circular dichroism and circularly polarized luminescence) can be described and predicted using quantum chemical calculations. The synthetic approach also reveals by-products that originate from internal oxidation reactions, presumably mediated by the close proximity of the π-surfaces in the helicene structure.

Platelet Function in Acute Kidney Injury: A Systematic Review and a Cohort Study.

Acute kidney injury (AKI) patients have increased bleeding risk, which could be partially due to acquired platelet dysfunction. We conducted a systematic review and a cohort study to investigate platelet function and count in AKI and their association with AKI-related bleeding and mortality. Through a systematic literature search in PubMed and Embase, we identified 9 studies reporting platelet function and 56 studies reporting platelet count or platelet indices in AKI patients. Overall, platelet aggregation was reduced in AKI patients in nonintensive care unit (ICU) settings but not in ICU settings, except that reduced aggregation was associated with renal replacement therapy. Thrombocytopenia in AKI was frequent and often predictive of mortality. In our cohort study, we prospectively included 54 adult ICU patients who developed AKI within 24 hours of ICU admission and 33 non-AKI ICU controls. Platelet function was measured with light transmission aggregometry and flow cytometry. AKI patients bled more frequently than non-AKI patients (p = 0.04), and bleeding was associated with increased 30-day mortality in AKI (p = 0.02). However, platelet function was not different between AKI and non-AKI patients (aggregation: all p > 0.52; flow cytometry: all p > 0.07) and platelet function was not associated with bleeding in AKI. In conclusion, a reduced platelet count is frequent in AKI, but the literature on platelet function in AKI is sparse. In a cohort study, we demonstrated that patients with AKI within 24 hours of ICU admission exhibited increased bleeding tendency but this was not associated with reduced platelet function.

Patient Satisfaction of Propofol Versus Midazolam and Fentanyl Sedation During Colonoscopy in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Colonoscopy is essential for optimal management of inflammatory bowel disease. However, many patients opt out due to unpleasantness related to this procedure. We investigated if Nurse Administered Propofol Sedation (NAPS) would improve patient satisfaction and attitude towards future colonoscopies. METHODS: Randomized clinical trial of deep sedation with NAPS (n = 63) versus moderate midazolam and fentanyl sedation (n = 67). To assess the primary end point of patient satisfaction at discharge, we developed a Satisfaction Questionnaire comprising 13 items each rated by a 5-point Likert scale and with higher scores reflecting more positive outcomes (13-65 points). RESULTS: Fifty-six patients (43%) with ulcerative colitis, 48 (37%) with Crohn's disease, and 26 (20%) with high suspicion of inflammatory bowel disease were included. Most (88%) had previously had a colonoscopy and pre-procedure expectations were similar between groups. Patients receiving deep sedation had significantly higher satisfaction score (mean 60.1, SD 3.4) than those receiving moderate sedation (51.2, 8.4; P < .001). This was driven especially by less pain, more amnesia, sedation more to their liking, and better experience with the current than previous sedations. Importantly, these patients significantly more often preferred the same sedation for a future colonoscopy and were also inclined to accept more frequent colonoscopies. Assistance from another colonoscopist and disruption of the procedure due to pain occurred significantly more frequent in the moderate sedation group. There were no safety signals associated with NAPS. CONCLUSIONS: Patients with inflammatory bowel disease favor deep propofol sedation over moderate midazolam and fentanyl sedation. Availability of NAPS may facilitate patient adherence to endoscopy-based monitoring programs. Clinicaltrials.gov NCT01934088.

A lifestyle intervention among elderly men on active surveillance for non-aggressive prostate cancer: a randomised feasibility study with whole-grain rye and exercise.

BACKGROUND: The prognosis for men with non-aggressive prostate cancer is good, and several studies have investigated the impact of lifestyle changes including physical activity and diet on the prognosis. Despite positive results in animal studies and a few human interventions with whole-grain rye on markers of prostate cancer progression, the feasibility of trials investigating such dietary changes in combination with physical activity remains largely unstudied. The primary aim was to investigate the feasibility of an intervention with high whole-grain rye intake and vigorous physical activity for 6 months in men diagnosed with prostate cancer. METHODS: In total, 26 men (53-72 years) recently diagnosed with non-aggressive prostate cancer and on active surveillance, were enrolled in 2011-2012 and randomly assigned to an intervention or a control group. The intervention included 170 g/day of whole-grain rye and 3 × 45 minutes/week of vigorous physical activity. The duration of the intervention was 6 months and end of follow-up 12 months after baseline. Clinic visits were scheduled at baseline and 3, 6 and 12 months after baseline. Compliance with the intervention was evaluated by diaries, food frequency questionnaires, biomarkers, and heart rate monitor data. The effect of the intervention was evaluated by linear multiple regression analysis. RESULTS: In the intervention group, the mean daily intake of whole-grain rye measured from diaries was 146 g (SD: 19) for the first 3 months and 125 g (SD: 40) for the last 3 months of the intervention. The median level (5th and 95th percentiles) of vigorous physical activity was 91 (17, 193) min/week for the first 3 months and 66 (13, 259) min/week for the last 3 months. No recordings of physical activity were done for the control group. Aerobic fitness (VO2 peak) increased in the intervention group compared to the control group after the intervention. No effects were found on other cardio-metabolic outcomes or prostate cancer progression. CONCLUSIONS: The lifestyle intervention appeared feasible for 6 months among Danish men and the results are encouraging for conducting full-scale studies, where the impact of whole-grain rye and vigorous physical activity on prostate cancer progression and metabolic parameters can be evaluated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01300104 . Registered on 18 February 2011.

Endozoicomonas Are Specific, Facultative Symbionts of Sea Squirts.

Ascidians are marine filter feeders and harbor diverse microbiota that can exhibit a high degree of host-specificity. Pharyngeal samples of Scandinavian and Mediterranean ascidians were screened for consistently associated bacteria by culture-dependent and -independent approaches. Representatives of the Endozoicomonas (Gammaproteobacteria, Hahellaceae) clade were detected in the ascidian species Ascidiella aspersa, Ascidiella scabra, Botryllus schlosseri, Ciona intestinalis, Styela clava, and multiple Ascidia/Ascidiella spp. In total, Endozoicomonas was detected in more than half of all specimens screened, and in 25-100% of the specimens for each species. The retrieved Endozoicomonas 16S rRNA gene sequences formed an ascidian-specific subclade, whose members were detected by fluorescence in situ hybridization (FISH) as extracellular microcolonies in the pharynx. Two strains of the ascidian-specific Endozoicomonas subclade were isolated in pure culture and characterized. Both strains are chemoorganoheterotrophs and grow on mucin (a mucus glycoprotein). The strains tested negative for cytotoxic or antibacterial activity. Based on these observations, we propose ascidian-associated Endozoicomonas to be commensals, living off the mucus continuously secreted into the pharynx. Members of the ascidian-specific Endozoicomonas subclade were also detected in seawater from the Scandinavian sampling site, which suggests acquisition of the symbionts by horizontal transmission. The combined results indicate a host-specific, yet facultative symbiosis between ascidians and Endozoicomonas.

Development and validation of a theoretical test in non-anaesthesiologist-administered propofol sedation for gastrointestinal endoscopy.

OBJECTIVE: Safety with non-anaesthesiologist-administered propofol sedation (NAAP) during gastrointestinal (GI) endoscopy is related to theoretical knowledge. A summative testing of knowledge before attempting supervised nurse-administered propofol sedation (NAPS) in the clinic is advised. The aims of this study were to develop a theoretical test about propofol sedation, to gather validity evidence for the test and to measure the effect of a NAPS-specific training course. MATERIAL AND METHODS: A three-phased psychometric study on multiple choice questionnaire (MCQ) test development, gathering of validity evidence and evaluation of the effect of a specific NAAP course on the test result. A MCQ containing 86 questions was developed and administered 113 times to 91 participants representing novices, intermediates and experienced. RESULTS: Question difficulty analyses revealed 50 level I and II questions. The 50 MCQs showed mean (SD) intergroup differences (p = 0.001) between novices = 28.6 (4.82), intermediates = 36.8 (5.43) and experienced = 41.8 (4.65) and provided a pass score of 35.2. The course with pre-course test had significant effect on the knowledge of nurses (18% increase) and physicians (19% increase; p = 0.001 and 0.001, respectively). CONCLUSIONS: Data supported the validity of the developed MCQ test. The NAPS-specific course with pre-course testing adds theoretical knowledge to already well-prepared participants.

High efficacy with deep nurse-administered propofol sedation for advanced gastroenterologic endoscopic procedures.

BACKGROUND AND STUDY AIMS: Whereas data on moderate nurse-administered propofol sedation (NAPS) efficacy and safety for standard endoscopy is abundant, few reports on the use of deep sedation by endoscopy nurses during advanced endoscopy, such as Endoscopic Retrograde Cholangiopancreatography (ERCP) and Endoscopic Ultrasound (EUS) are available and potential benefits or hazards remain unclear. The aims of this study were to investigate the efficacy of intermittent deep sedation with propofol for a large cohort of advanced endoscopies and to provide data on the safety. PATIENTS AND METHODS: All available data from patients sedated with intermittent deep NAPS for ERCP, EUS or double balloon enteroscopy (DBE, since the method was implemented in May 2007 through December 2012 were included for evaluation in a retrospective case-control design. RESULTS: Data from 1899 patients undergoing 1899 procedures were included for evaluation. All but one procedure were completed with intermittent deep NAPS. The mean propofol dose was 397 mg (SD: 232.4) and the infusion rate was 23.9 mg/kg. The frequency of hypoxia was 4.3 % and 20 patients needed assisted ventilation (1.1 %). Anesthesiologic support was requested eight times (0.4 %). One patient was intubated due to suspected aspiration. CONCLUSIONS: Intermittent deep NAPS for advanced endoscopies in selected patients provided an almost 100 % success rate. However, the rate of hypoxia, hypotension and respiratory support was high compared with previously published data, but the method was still assessed as safe.

Moderate and deep nurse-administered propofol sedation is safe.

INTRODUCTION: Non-anaesthesiologist-administered propofol sedation (NAPS/NAAP) is increasingly used in many countries. Most regimens aim for light or moderate sedation. Little evidence on safety of deep NAPS sedation is available. The aim of this study was to explore the safety of intermittent deep sedation with NAPS in patients undergoing gastroenterologic endoscopic procedures. METHODS: This was a retrospective case-control study. All patients sedated with NAPS for colonoscopies, sigmoidoscopies and oesophagogastroduodenoscopies from May 2007 through December 2012 were included. Cases were defined as patients developing an adverse event (oxygen saturation < 92%, a drop in mean arterial pressure of > 30% or a drop in systolic blood pressure of > 50 mmHg). The remaining patients served as controls. RESULTS: A total of 6,840 consecutive patients undergoing 7,364 procedures were included. The mean propofol dose was 331.6 mg (standard deviation = 179.4 mg). The overall rate of hypoxia was 3.2%, and the rate of hypotension was 3.1%. Assisted ventilation was needed in 0.5%. Age (p < 0.001), American Society of Anesthesiologists (ASA) class 3 (p = 0.017) and total propofol dose (p = 0.001) were associated with a higher rate of adverse events. CONCLUSION: Safety during intermittent deep sedation with NAPS was good. Age, ASA class 3 and total propofol dose were correlated with a higher rate of adverse events. Patients aged 60 years or more needed more handling during adverse events. FUNDING: Arvid Nilsson's Foundation provided funding for this study. The founders did not have any influence on the design or the presentation of the study. TRIAL REGISTRATION: not relevant.

Endoscopy nurse-administered propofol sedation performance. Development of an assessment tool and a reliability testing model.

OBJECTIVE: A gold standard of skills required for nurse-administered propofol sedation (NAPS) for gastroenterological endoscopic procedures has been proposed but not established. Due to the potentially hazardous nature of NAPS, an assessment tool is needed to objectively judge the adequacy of training and for future certification. The aim of this study was to develop an assessment tool for measuring competency in propofol sedation and to explore the reliability and validity of the tool. MATERIAL AND METHODS: The nurse-administered propofol assessment tool (NAPSAT) was developed in a Delphi-like fashion. Consensus was achieved on 17 items. Validity evidence was gathered in a case-control study in a full-scale simulation setting. Six experienced nurses and six novice nurses were filmed in two scenarios for assessment according to the assessment tool by three content expert raters. RESULTS: A total of 72 NAPSAT assessment forms were analyzed. Inter-rater reliability, Cronbach's α = 0.54 and generalizability coefficient = 0.68. The experienced nurses scored higher than the novices, 52.8 versus 62.7, p = 0.009. The provided pass/borderline/fail assessment showed significant difference, p = < 0.001, Cronbach's α = 0.80, with the novices being more likely to fail and the experienced more likely to pass. CONCLUSION: Assessing sedation skills in a simulator is possible. Video assessment requires expert knowledge of the procedure and the rating matrix. Overall, NAPSAT showed fair inter-rater reliability and good construct validity. This makes NAPSAT fit for formative assessment and proficiency feedback; however, high stakes and summative assessment cannot be advised.

Nurse administered propofol sedation for pulmonary endoscopies requires a specific protocol.

INTRODUCTION: This study provides an evaluation and risk analysis of propofol sedation for endoscopic pulmonary procedures according to our unit's "gastroenterologic nurse-administered propofol sedation (NAPS) guideline". MATERIAL AND METHODS: The present study is a prospective descriptive study performed at the Endoscopy Unit, Gentofte Hospital, Copenhagen, from May to July 2009. The study comprised at total of 51 consecutive patients who underwent 77 endoscopic procedures. Only patients above the age of 16 years were eligible for treatment. The exclusion criteria were as follows: American Society of Anesthesiologists (ASA) class > 3, history of sedation-related complications, severe chronic obstructive pulmonary disease. Excluded were patients with a potentially difficult airway and ventricular retention. Data on the number and type of procedure, baseline characteristics, sedation time, propofol dose administered and adverse events were obtained from medical histories. RESULTS: A total of 23 cases of adverse events were recorded, including one event of hypotension and 22 events of hypoxaemia. Five patients needed assisted ventilation. The frequency of hypoxaemia in sessions involving bronchoscopy was 17 of 26 (65%) compared with transoesophageal endoscopic ultrasound (EUS) (17 of 45, 35%) and endoscopic bronchial ultrasound (EBUS) (three of six, 50%). Endoscopist assessment of working conditions was good and patient assessment of discomfort was low. No patients required endotracheal intubation and there was no mortality. CONCLUSION: This study supports the conclusion that propofol administered by nurses provides for good working conditions and satisfied patients. But our "NAPS for endoscopic gastroenterologic procedures" guideline was unsuited for endoscopic pulmonary procedures including EUS. FUNDING: This work was supported by the START research foundation at Gentofte Hospital. TRIAL REGISTRATION: not relevant.

Glycosylation of the self-recognizing Escherichia coli Ag43 autotransporter protein.

Glycosylation is a common modulation of protein function in eukaryotes and is biologically important. However, in bacteria protein glycosylation is rare, and relatively few bacterial glycoproteins are known. In Escherichia coli only two glycoproteins have been described to date. Here we introduce a novel member to this exclusive group, namely, antigen 43 (Ag43), a self-recognizing autotransporter protein. By mass spectrometry Ag43 was demonstrated to be glycosylated by addition of heptose residues at several positions in the passenger domain. Glycosylation of Ag43 by the action of the Aah and TibC glycosyltransferases was observed in laboratory strains. Importantly, Ag43 was also found to be glycosylated in a wild-type strain, suggesting that Ag43-glycosylation may be a widespread phenomenon. Glycosylation of Ag43 does not seem to interfere with its self-associating properties. However, the glycosylated form of Ag43 enhances bacterial binding to human cell lines, whereas the nonglycosylated version of Ag43 does not to confer this property.