Deciphering the influence of paraimmunobiotic bifidobacteria on the innate antiviral immune response of bovine intestinal epitheliocytes by transcriptomic analysis.

Previously, we reported that the non-viable immunomodulatory Bifidobacterium infantis MCC12 and Bifidobacterium breve MCC1274 strains (paraimmunobiotic bifidobacteria) were able to increase the protection against rotavirus infection in bovine intestinal epithelial (BIE) cells. In order to gain insight into the influence of paraimmunobiotic bifidobacteria on the innate antiviral immune response of BIE cells, their effect on the transcriptomic response triggered by Toll-like receptor 3 (TLR3) activation was investigated. By using microarray technology and qPCR analysis, we obtained a global overview of the immune genes involved in the innate antiviral immune response in BIE cells. Activation of TLR3 by poly(I:C) in BIE cells significantly increased the expression of interferon (IFN)-α and IFN-ß, several interferon-stimulated genes, cytokines, and chemokines. It was also observed that both paraimmunobiotic bifidobacteria differently modulated immune genes expression in poly(I:C)-challenged BIE cells. Most notable changes were found in genes involved in antiviral defence (IFN-ß, MX1, OAS1X, MDA5, TLR3, STAT2, STAT3), cytokines (interleukin (IL)-6), and chemokines (CCL2, CXCL2, CXCL6) that were significantly increased in bifidobacteria-treated BIE cells. B. infantis MCC12 and B. breve MCC1274 showed quantitative and qualitative differences in their capacities to modulate the innate antiviral immune response in BIE cells. B. breve MCC1274 was more efficient than the MCC12 strain to improve the production of type I IFNs and antiviral factors, an effect that could be related to its higher ability to protect against rotavirus replication in BIE cells. Interestingly, B. infantis MCC12 showed a remarkable anti-inflammatory effect. The MCC12 strain was more efficient to reduce the expression of inflammatory cytokines and chemokines (IL-16, IL-20, CX3CL1) when compared with B. breve MCC1274. These results provided valuable information for the deeper understanding of the antiviral immune response of intestinal epithelial cells as well as the host-paraimmunobiotic interaction in the bovine host.

Prediction of outliers in pain, analgesia requirement, and recovery of function after childbirth: a prospective observational cohort study.

BACKGROUND: Prediction models to identify parturients who experience protracted pain, prolonged opioid use, and delayed self-assessed functional recovery are currently inadequate. METHODS: For this study, 213 nulliparous women who planned vaginal delivery were enrolled and assessed daily until they completed three outcomes: (1) pain resolution; (2) opioid cessation; and (3) self-assessed functional recovery to predelivery level. The primary composite endpoint, 'pain and opioid-free functional recovery' was the time required to reach all three endpoints. The subjects were divided into two categories (the worst (longest time) 20% and remaining 80%) for reaching the primary composite endpoint, and each individual component. Prediction models for prolonged recovery were constructed using multivariate logistic regression with demographic, obstetric, psychological, and health-related quality of life characteristics as candidate predictors. RESULTS: Labour induction (vs spontaneous labour onset) predicted the worst 20% for the primary composite endpoint in the final multivariate model. Labour induction and higher postpartum day 1 numerical rating score for pain were predictors for being in the worst 20% for both functional recovery and pain burden. Labour type, delivery type, Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety score, RAND 36 Item Health Survey 1.0 (SF-36) physical health composite score, and postpartum breastfeeding success were predictive of delayed opioid cessation. CONCLUSIONS: Labour induction and elevated numerical rating score for pain are predictive of poor recovery after childbirth. Further research is necessary to determine whether modification would benefit mothers at risk for poor recovery.

Lactobacillus fermentum UCO-979C beneficially modulates the innate immune response triggered by Helicobacter pylori infection in vitro.

Helicobacter pylori infection is associated with important gastric pathologies. An aggressive proinflammatory immune response is generated in the gastric tissue infected with H. pylori, resulting in gastritis and a series of morphological changes that increase the susceptibility to cancer development. Probiotics could present an alternative solution to prevent or decrease H. pylori infection. Among them, the use of immunomodulatory lactic acid bacteria represents a promising option to reduce the severity of chronic inflammatory-mediated tissue damage and to improve protective immunity against H. pylori. We previously isolated Lactobacillus fermentum UCO-979C from human gastric tissue and demonstrated its capacity to reduce adhesion of H. pylori to human gastric epithelial cells (AGS cells). In this work, the ability of L. fermentum UCO-979C to modulate immune response in AGS cells and PMA phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 (human monocytic leukaemia) macrophages in response to H. pylori infection was evaluated. We demonstrated that the UCO-979C strain is able to differentially modulate the cytokine response of gastric epithelial cells and macrophages after H. pylori infection. Of note, L. fermentum UCO-979C was able to significantly reduce the production of inflammatory cytokines and chemokines in AGS and THP-1 cells as well as increase the levels of immunoregulatory cytokines, indicating a remarkable anti-inflammatory effect. These findings strongly support the probiotic potential of L. fermentum UCO-979C and provide evidence of its beneficial effects against the inflammatory damage induced by H. pylori infection. Although our findings should be proven in appropriate experiments in vivo, in both H. pylori infection animal models and human trials, the results of the present work provide a scientific rationale for the use of L. fermentum UCO-979C to prevent or reduce H. pylori-induced gastric inflammation in humans.

Steroid administration after anaesthetic induction with etomidate does not reduce in-hospital mortality or cardiovascular morbidity after non-cardiac surgery.

BACKGROUND: We tested the primary hypothesis that corticosteroid administration after etomidate exposure reduces a composite of in-hospital mortality and cardiovascular morbidity after non-cardiac surgery. METHODS: We evaluated ASA physical status III and IV patients who had non-cardiac surgery with general anaesthesia at the Cleveland Clinic. Amongst 4275 patients in whom anaesthesia was induced with etomidate, 804 were also given steroid intraoperatively, mostly dexamethasone at a median dose of 6 mg. We successfully matched 582 steroid patients with 1023 non-steroid patients. The matched groups were compared on composite of in-hospital mortality and cardiovascular morbidity using a generalized-estimating-equation model. Secondly, the matched groups were compared on length of hospital stay using a Cox proportional hazard model, and were descriptively compared on intraoperative blood pressures using a standardized difference. RESULTS: There was no significant association between intraoperative steroid administration after anaesthetic induction with etomidate and the composite of in-hospital mortality or cardiovascular morbidity; the estimated common odds ratio across the two components of the composite was 0.86 [95% confidence interval (CI): 0.64, 1.16] for steroid vs non-steroid, P=0.33. The duration of postoperative hospitalisation was significantly shorter amongst steroid patients [median (Q1, Q3): 6 (3, 10) days] than non-steroid patients [7 (4, 11) days], with an estimated hazard ratio of 0.89 (0.80, 0.98) for steroid vs non-steroid, P=0.01. Intraoperative blood pressures were similar in steroid and non-steroid patients. CONCLUSIONS: Steroid administration after induction of anaesthesia with etomidate did not reduce mortality or cardiovascular morbidity.

Dissecting the structural basis for the intracellular delivery of OSW-1 by fluorescent probes.

The structural basis for the intracellular delivery of OSW-1 is investigated using fluorescent derivatives of OSW-1 and its closely related congeners. Despite the large differences in activity, all the fluorescent probes are found to translocate across the plasma membrane to the ER and Golgi apparatus. This observation suggests that the glycosylated cholestane moiety plays an important role in the cell internalization and intracellular localization property of OSW-1.

Synthesis of a fluorescent photoaffinity probe of OSW-1 by site-selective acylation of an inactive congener and biological evaluation.

A novel fluorescent photoaffinity probe of OSW-1 was prepared in two steps from a naturally occurring inactive congener by a sequential site-selective acylation strategy using Me2SnCl2. It displayed highly potent anticancer activity and a similar intracellular localization property to that of a fluorescently-tagged OSW-1, thereby demonstrating its potential utility in live cell studies.

Correction: Synthesis of a fluorescent photoaffinity probe of OSW-1 by site-selective acylation of an inactive congener and biological evaluation.

Correction for 'Synthesis of a fluorescent photoaffinity probe of OSW-1 by site-selective acylation of an inactive congener and biological evaluation' by K. Sakurai et al., Chem. Commun., 2017, DOI: .

IFPA Meeting 2012 Workshop Report II: epigenetics and imprinting in the placenta, growth factors and villous trophoblast differentiation, role of the placenta in regulating fetal exposure to xenobiotics during pregnancy, infection and the placenta.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2012 there were twelve themed workshops, four of which are summarized in this report. These workshops related to various aspects of placental biology: 1) epigenetics and imprinting in the placenta; 2) growth factors and villous trophoblast differentiation; 3) role of the placenta in regulating fetal exposure to xenobiotics during pregnancy; 4) infection and the placenta.

Increased expression and plasma levels of myeloperoxidase are closely related to the presence of angiographically-detected complex lesion morphology in unstable angina.

BACKGROUND: Myeloperoxidase (MPO) is a leucocyte enzyme that catalyses the formation of a number of reactive oxidant species. OBJECTIVE: The purpose of this study is to evaluate the relationship between angiographic coronary plaque morphology in patients with unstable angina pectoris (UAP) or stable angina pectoris (SAP) and MPO levels. PATIENTS AND DESIGN: Plasma MPO levels on admission were measured in 236 patients with UAP, 146 with SAP and 85 control subjects using an ELISA kit. The angiographic morphology of the culprit lesion was classified into two types, simple or complex, based on the Ambrose classification. In addition, 61 atherectomy specimens obtained from a different cohort of patients with UAP and SAP were studied immunohistochemically for MPO. RESULTS: Median (IQR) plasma MPO levels in patients with UAP with a complex lesion were significantly higher than in patients with a simple lesion (41.9 (21.7­73.7) ng/ml vs 20.5 (15.9­27.9) ng/ml, p<0.0001), but there was no significant difference between the two groups in patients with SAP. On multivariate analysis, raised plasma MPO levels and Braunwald class III were independent factors for angiographically-detected complex lesions (adjusted OR 12.49, 95% CI 3.24 to 48.17, p=0.0002). In the atherectomy specimens the number of MPO-positive cells in patients with UAP with complex lesions was significantly higher (p<0.0005) than in patients with simple lesions. Moreover, in this cohort, plasma MPO levels were positively correlated with the number of MPO-positive cells in atherectomy specimens (R=0.42, p=0.024). CONCLUSIONS: This study shows that increased expression and plasma MPO levels are closely related to the presence of angiographically-detected complex lesion morphology in patients with UAP.

Factors influencing performance of Global Fund-supported tuberculosis grants.

OBJECTIVE: To explore grant and country characteristics associated with the performance of tuberculosis (TB) grants supported by the Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund), which uses performance-based funding of grants. METHODS: We used Global Fund grant data to compute the average programmatic performance of 108 TB grants in 88 countries. Using stepwise regression models, we examined the correlation of grant performance with a range of grant and country characteristics. RESULTS: Funding duration and funding per estimated smear-positive TB case were positively correlated with grant performance (partial correlations of 0.386-0.416 for the former, 0.200 for the latter). Successful completion of an evaluation of a grant during the second year of funding was linked to higher performance (0.357). Performance was further influenced by the independent organisation hired by the Global Fund to provide ongoing monitoring of the grants (0.197-0.243). Two country-specific factors were significantly correlated with performance: political stability (0.197-0.234) and disease burden (-0.211). DISCUSSION: Successful evaluation that leads to continued funding predicts higher performance of TB grants, even in challenging settings such as weak health services. However, other contextual factors affect grant performance and should be considered when assessing grants to ensure that countries that have a high disease burden and are politically unstable are not penalized.

A comparison of the Airway Scope and McCoy laryngoscope in patients with simulated restricted neck mobility.

We compared the efficacy of the Airway Scope and McCoy laryngoscope as intubation tools with the neck stabilised by a rigid cervical collar. After induction of anaesthesia and neck stabilisation, 100 patients were randomly assigned to tracheal intubation with an Airway Scope or McCoy laryngoscope. Overall intubation success rate, time required for intubation, number of intubation attempts required for successful intubation, and airway complications related to intubation were recorded. Overall intubation success rates were 100% with both devices and a similar number of intubation attempts were required. However, the mean (SD) time required for successful intubation was shorter with the Airway Scope (30 (7) s) than with the McCoy laryngoscope (40 (14) s; p < 0.0001). The incidences of intubation complications were similar, but oesophageal intubation (in six cases) occurred only with McCoy laryngoscope.

Effect of nasal cannula oxygen administration on oxygen concentration at facial and adjacent landmarks.

An oxygen-enriched atmosphere enhances the potential for operating-room fires. We thus determined oxygen concentrations at various facial landmarks during oxygen administration via nasal cannulae. Thirteen supine volunteers were draped similarly to patients undergoing a cervical-node biopsy. Oxygen was delivered in random order through nasal cannulae at rates of 2, 4, and 6 l x min(-1). Oxygen concentration was measured at pre-determined facial landmarks and also distal to the drape at non-facial sites. At a flow of 2 l x min(-1), oxygen concentrations exceeded 23% only within a few centimetres of the nasal cannula. Concentration increased as a function of flow, but rarely exceeded 26%. At all flow rates, concentrations distal to the drape were < 24%. To reduce combustion risk, ignition sources should be kept at least 10 cm from the oxygen outlet when using nasal cannula at a flow rate > or = 4 l x min(-1).

Airway scope and gum elastic bougie with Macintosh laryngoscope for tracheal intubation in patients with simulated restricted neck mobility.

BACKGROUND: /st> Airway Scope is a new videolaryngoscope which requires less cervical movement during intubation than direct laryngoscopy. Thus, in patients wearing a rigid cervical collar, we compared the efficacy of the Airway Scope and the gum elastic bougie with Macintosh laryngoscope during tracheal intubation. METHODS: /st> Anaesthesia was induced with propofol, fentanyl, and rocuronium. A rigid cervical collar was applied, and patients were randomly assigned to tracheal intubation with an Airway Scope (n=48) or multiple-use gum elastic bougie with Macintosh laryngoscope (n=48). Measurements included intubation time, gum elastic bougie insertion time, intubation success rate, and insertion and intubation attempts. Airway complications were also recorded. RESULTS: /st> The time required for successful intubation was significantly shorter with the Airway Scope compared with the gum elastic bougie with Macintosh laryngoscope [mean (sd) 34 (13) vs 49 (27) s, P=0.001], although the overall success rate of the Airway Scope (100%) compared with the gum elastic bougie with Macintosh laryngoscope (90%) did not reach the statistical significance (P=0.056). Oesophageal intubation (n=8) occurred only with the gum elastic bougie with Macintosh laryngoscope. Incidence of mucosal trauma and lip injury was similar with each device. No dental injury or hypoxia occurred with either device. CONCLUSIONS: /st> The Airway Scope shortens intubation time, is less likely to result in oesophageal intubation, and may offer a marginally higher intubation success rate in patients with simulated restricted neck mobility.

Estimating the number of HIV infections averted: an approach and its issues.

OBJECTIVE: To propose a methodology to estimate the number of new HIV infections averted. Knowledge of HIV infection has increased tremendously and modelling tools to project current epidemics into the future have greatly improved. Different types of models can be used to estimate HIV infections averted, although the number of new HIV infections averted cannot be measured directly. METHOD: Using cohort-component population projections, a disease modelling-based approach was used to compare the observed epidemiology of a disease after programme initiation with an expected epidemiology from past trends before programme initiation. The concept of modelling infections averted in a disease modelling-based approach involves a comparison between an "expected" or baseline epidemic with an "estimated" one. A hypothetical example was featured in order to demonstrate the proposed methodology. Using both the Estimation and Projection Package (EPP) and the Spectrum demographic modelling program, the underlying annual incidence levels implied by both the baseline and estimated epidemics were examined. RESULTS: The difference between baseline and estimated incidence levels is interpreted as "infections averted". Strengths and limitations of the approach are discussed. CONCLUSIONS: In this study an expected epidemiological approach was compared to one based on observation. Once sufficient data become available, the validation of various country data including HIV prevalence, mortality, and behaviour must be done. Additional information related to behaviour change may be critical to further support arguments for a change in disease trend. It is therefore important to use all available data, consequently strengthening findings from a disease modelling-based approach on HIV infections averted.

Remifentanil for general anaesthesia: a systematic review.

We performed a quantitative systematic review of randomised, controlled trials that compared remifentanil to short-acting opioids (fentanyl, alfentanil, or sufentanil) for general anaesthesia. Eighty-five trials were identified and these included a total of 13 057 patients. Intra-operatively, remifentanil was associated with clinical signs of deeper analgesia and anaesthesia, such as fewer responses to noxious stimuli (relative risk 0.65, 95% CI 0.48-0.87), more frequent episodes of bradycardia (1.46, 1.04-2.05), more hypotension (1.68, 1.36-2.07) and less hypertension (0.60, 0.46-0.78). Postoperatively, remifentanil was associated with faster recovery (difference in extubation time of -2.03, 9.5% CI, -2.92 to -1.14 min), more frequent postoperative analgesic requirements (1.36, 1.21-1.53) and fewer respiratory events requiring naloxone (0.25, 0.14-0.47). Remifentanil had no overall impact on postoperative nausea (1.03, 0.97-1.09) or vomiting (1.06, 0.96-1.17), but was associated with twice as much shivering (2.15, 1.73-2.69). Remifentanil does not seem to offer any advantage for lengthy, major interventions, but may be useful for selected patients, e.g. when postoperative respiratory depression is a concern.

Neopterin is associated with plaque inflammation and destabilisation in human coronary atherosclerotic lesions.

BACKGROUND: Previous studies have shown that recent activation of the inflammatory response in coronary atherosclerotic lesions contributes to rapid progressive plaque destabilisation. Neopterin, a by-product of the guanosine triphosphate pathway, is produced by activated macrophages and serves as an activation marker for monocytes/macrophages. OBJECTIVE: To elucidate the role of neopterin in coronary plaque destabilisation by immunohistochemical study of the presence of neopterin in coronary atherectomy specimens obtained from patients with stable angina pectoris (SAP) and unstable angina pectoris (UAP). PATIENTS AND METHODS: All patients underwent atherectomy of the primary atherosclerotic lesions responsible for SAP (n = 25) and UAP (n = 25). Frozen samples were studied with antibodies against smooth muscle cells, macrophages, T cells, neutrophils and neopterin. RESULTS: In 22/25 patients with UAP, abundant neopterin-positive macrophages were found at the sites of coronary culprit lesions. However, in 25 lesions from patients with SAP, only 11 lesions showed neopterin positivity. Quantitatively, the neopterin-positive macrophage score was significantly higher (p<0.001) in patients with UAP than in patients with SAP. Moreover, the neopterin-positive macrophage score showed a significant positive correlation with the number of neutrophils or T cells, respectively (neutrophils, r = 0.55, p<0.001; T cells, r = 0.70, p<0.001). CONCLUSIONS: Neopterin can be considered as one of the significant factors in the process of plaque inflammation and destabilisation in human coronary atherosclerotic lesions. Its exact role in the process needs to be investigated further.

Ultrasound quantification of anterior soft tissue thickness fails to predict difficult laryngoscopy in obese patients.

Morbid obesity is associated with difficult laryngoscopy and intubation. In the general population, bedside indices for predicting difficult intubation (i.e. Mallampati classification, thyromental distance, sternomental distance, mouth-opening and Wilson risk score) have poor-to-moderate sensitivity (20-62%) and moderate-to-fair specificity (82-97%). In the obese population, although the risk of difficult intubation after a positive Mallampati test is 34%, it is still not sufficient to be used as a single predictive test. An abundance of pretracheal soft tissue anterior to the vocal cords, as quantified by ultrasound, was a better predictor of difficult laryngoscopy than body mass index (BMI) in Israeli patients. Obesity is a growing problem in the United States: therefore we sought to confirm this finding in the obese population in the United States. We used ultrasound to quantify the neck soft tissue, from the skin to the anterior aspect of the trachea at the vocal cords, in 64 obese patients (BMI > 35). We assessed thyromental distance, mouth-opening, jaw movement, limited neck mobility, modified Mallampati score, abnormal upper teeth, neck circumference, confirmed obstructive sleep apnoea, BMI, age, race and gender as predictors. Twenty patients were classified as difficult laryngoscopy; they were older (47 +/- 9 vs 42 +/- 1 years; P = 0.048; mean +/- SD) and had less soft pretracheal tissue (20.4 +/- 3.0 vs 22.3 +/- 3.8 mm; P = 0.049) than did easy laryngoscopy patients. Multivariate regression indicated that none of the factors was an independent predictor of difficult laryngoscopy. We conclude that the thickness of pretracheal soft tissue at the level of the vocal cords is not a good predictor of difficult laryngoscopy in obese patients in the United States.

Ondansetron does not reduce the shivering threshold in healthy volunteers.

BACKGROUND: Ondansetron, a serotonin-3 receptor antagonist, reduces postoperative shivering. Drugs that reduce shivering usually impair central thermoregulatory control, and may thus be useful for preventing shivering during induction of therapeutic hypothermia. We determined, therefore, whether ondansetron reduces the major autonomic thermoregulatory response thresholds (triggering core temperatures) in humans. METHODS: Control (placebo) and ondansetron infusions at the target plasma concentration of 250 ng ml(-1) were studied in healthy volunteers on two different days. Each day, skin and core temperatures were increased to provoke sweating; then reduced to elicit peripheral vasoconstriction and shivering. We determined the core-temperature sweating, vasoconstriction and shivering thresholds after compensating for changes in mean-skin temperature. Data were analysed using t-tests and presented as means (sds); P<0.05 was taken as significant. RESULTS: Ondensetron plasma concentrations were 278 (57), 234 (55) and 243 (58) ng ml(-1) at the sweating, vasoconstriction and shivering thresholds, respectively; these corresponded to approximately 50 mg of ondansetron which is approximately 10 times the dose used for postoperative nausea and vomiting. Ondansetron did not change the sweating (control 37.4 (0.4) degrees C, ondansetron 37.6 (0.3) degrees C, P=0.16), vasoconstriction (37.0 (0.5) degrees C vs 37.1 (0.3) degrees C; P=0.70), or shivering threshold (36.3 (0.5) degrees C vs 36.3 (0.6) degrees C; P=0.76). No sedation was observed on either study day. CONCLUSIONS: /b>. Ondansetron appears to have little potential for facilitating induction of therapeutic hypothermia.