Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation.

Eosinophil accumulation is a prominent feature of allergic inflammatory reactions, such as those occurring in the lung of the allergic asthmatic, but the endogenous chemoattractants involved have not been identified. We have investigated this in an established model of allergic inflammation, using in vivo systems both to generate and assay relevant activity. Bronchoalveolar lavage (BAL) fluid was taken from sensitized guinea pigs at intervals after aerosol challenge with ovalbumin. BAL fluid was injected intradermally in unsensitized assay guinea pigs and the accumulation of intravenously injected 111In-eosinophils was measured. Activity was detected at 30 min after allergen challenge, peaking from 3 to 6 h and declining to low levels by 24 h. 3-h BAL fluid was purified using high performance liquid chromatography techniques in conjunction with the skin assay. Microsequencing revealed a novel protein from the C-C branch of the platelet factor 4 superfamily of chemotactic cytokines. The protein, eotaxin, exhibits homology of 53% with human MCP-1, 44% with guinea pig MCP-1, 31% with human MIP-1α, and 26% with human RANTES. Laser desorption time of flight mass analysis gave four different signals (8.15, 8.38, 8.81, and 9.03 kD), probably reflecting differential O-glycosylation. Eotaxin was highly potent, inducing substantial 111In-eosinophil accumulation at a 1-2-pmol dose in the skin, but did not induce significant 111In-neutrophil accumulation. Eotaxin was a potent stimulator of both guinea pig and human eosinophils in vitro. Human recombinant RANTES, MIP-1α, and MCP-1 were all inactive in inducing 111In-eosinophil accumulation in guinea pig skin; however, evidence was obtained that eotaxin shares a binding site with RANTES on guinea pig eosinophils. This is the first description of a potent eosinophil chemoattractant cytokine generated in vivo and suggests the possibility that similar molecules may be important in the human asthmatic lung

Impact of enteral protein supplementation in premature infants

David M Barrus1, Joann Romano-Keeler2, Christopher Carr3, Kira Segebarth4, Betty Claxton2, William F Walsh2, Paul J Flakoll51Department of Neonatology, Saint Francis Hospital–Bartlett, Memphis, TN, 2Department of Pediatrics, Vanderbilt Medical Center, Nashville, TN, 3Department of Surgery, Naval Hospital Bremerton, Bremerton, WA, 4Pediatric and Diabetes Specialists, Carolinas Medical Center, Charlotte, NC, 5Department of Surgery, Vanderbilt Medical Center, Nashville, TN, USAObjective: The quantity of enteral protein supplementation required by premature infants to optimize growth has not been determined. This study compares the growth of premature infants fed the current standard intake of protein (3.5 g/kg/day) with the growth of those fed a higher amount (4.0 g/kg/day).Study design: Fifty-two infants <1500 g and <33 weeks gestational age participated in a blinded, single-center, prospective randomized control trial to compare growth between two groups of different protein-intake levels. Primary outcomes were average daily weight gain (g/kg/day), head-circumference (cm/kg/week) and linear growth velocity (cm/kg/week). Secondary outcomes were serum indices of protein tolerance and plasma amino acid concentrations.Results: Infants receiving higher amounts of protein had higher rates of growth for body weight (18.2 ± 0.7 versus 16.2 ± 1.0 g/kg/day; P < 0.05) and head circumference (0.87 ± 0.08 versus 0.62 ± 0.07 cm/kg/week; P < 0.05), with no differences in blood protein or plasma amino acid concentrations. Length of hospital stay was 14 days shorter for the higher-protein group (51.4 ± 4.0 versus 65.9 ± 6.3 days).Conclusion: Increasing premature infant enteral protein supplementation from a calculated intake of 3.5–4.0 g/kg/day improved growth in a safe manner.Keywords: human milk, human milk fortifier, growth, low birth weigh

Undergraduate medical textbooks do not provide adequate information on intravenous fluid therapy: a systematic survey and suggestions for improvement

<b>Background</b><p></p> Inappropriate prescribing of intravenous (IV) fluid, particularly 0.9% sodium chloride, causes post-operative complications. Fluid prescription is often left to junior medical staff and is frequently poorly managed. One reason for poor intravenous fluid prescribing practices could be inadequate coverage of this topic in the textbooks that are used.<p></p> <b>Methods</b><p></p> We formulated a comprehensive set of topics, related to important common clinical situations involving IV fluid therapy, (routine fluid replacement, fluid loss, fluids overload) to assess the adequacy of textbooks in common use. We assessed 29 medical textbooks widely available to students in the UK, scoring the presence of information provided by each book on each of the topics. The scores indicated how fully the topics were considered: not at all, partly, and adequately. No attempt was made to judge the quality of the information, because there is no consensus on these topics.<p></p> <b>Results</b><p></p> The maximum score that a book could achieve was 52. Three of the topics we chose were not considered by any of the books. Discounting these topics as “too esoteric”, the maximum possible score became 46. One textbook gained a score of 45, but the general score was poor (median 11, quartiles 4, 21). In particular, coverage of routine postoperative management was inadequate.<p></p> <b>Conclusions</b><p></p> Textbooks for undergraduates cover the topic of intravenous therapy badly, which may partly explain the poor knowledge and performance of junior doctors in this important field. Systematic revision of current textbooks might improve knowledge and practice by junior doctors. Careful definition of the remit and content of textbooks should be applied more widely to ensure quality and “fitness for purpose”, and avoid omission of vital knowledge

Synchrotron analysis of toughness anomalies in nanostructured bainite

High-resolution synchrotron X-ray diffraction has been used to characterise the notch root regions of Charpy impact test specimens of a superbainitic steel, both before and after loading. The changes in the volume fraction of austenite induced by the application of a three-point-bending load were quantified. Analysis of diffraction peak shifts revealed the extent of residual tensile and compressive strains present due to both machining and an applied load. The results lend support to the hypothesis that the comparatively low energies absorbed during Charpy impact testing of superbainitic steels, < 7 J, are due to the formation of stress-induced martensite at the notch root, prior to crack initiation.The authors are grateful to Prakash Srirangam Venkata and Bernard Ennis for their valuable contribution to the synchrotron work; to Diamond Light Source (Oxford) for access to the synchrotron facilities (under experiment EE8564); to Tata Steel UK and the Engineering and Physical Sciences Research Council of the UK for financial support (under EP/H500375/1 and EP/I02249X/1).This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.actamat.2015.11.02

Pharmacological profiling of the hemodynamic effects of cannabinoid ligands: a combined in vitro and in vivo approach

The receptors mediating the hemodynamic responses to cannabinoids are not clearly defined due to the multifarious pharmacology of many commonly used cannabinoid ligands. While both CB1 and TRPV1 receptors are implicated, G protein-coupled receptor 55 (GPR55) may also mediate some of the hemodynamic effects of several atypical cannabinoid ligands. The present studies attempted to unravel the pharmacology underlying the in vivo hemodynamic responses to ACEA (CB1 agonist), O-1602 (GPR55 agonist), AM251 (CB1 antagonist), and cannabidiol (CBD; GPR55 antagonist). Agonist and antagonist profiles of each ligand were determined by ligand-induced GTPγS binding in membrane preparations expressing rat and mouse CB1 and GPR55 receptors. Blood pressure responses to ACEA and O-1602 were recorded in anesthetized and conscious mice (wild type, CB1−/− and GPR55−/−) and rats in the absence and presence of AM251 and CBD. ACEA demonstrated GTPγS activation at both receptors, while O-1602 only activated GPR55. AM251 exhibited antagonist activity at CB1 and agonist activity at GPR55, while CBD demonstrated selective antagonist activity at GPR55. The depressor response to ACEA was blocked by AM251 and attenuated by CBD, while O-1602 did not induce a depressor response. AM251 caused a depressor response that was absent in GPR55−/− mice but enhanced by CBD, while CBD caused a small vasodepressor response that persisted in GPR55−/− mice. Our findings show that assessment of the pharmacological profile of receptor activation by cannabinoid ligands in in vitro studies alongside in vivo functional studies is essential to understand the role of cannabinoids in hemodynamic control

AGE-RELATED EFFECTS OF INCREASING POSTURAL CHALLENGE ON EYE MOVEMENT ONSET LATENCIES TO VISUAL TARGETS

When a single light cue is given in the visual field, our eyes orient towards it with an average latency of 200 ms. If a second cue is presented at or around the time of the response to the first, a secondary eye movement occurs that represents a re-orientation to the new target. While studies have shown that eye movement latencies to ‘single-step’ targets may or may not be lengthened with age, secondary eye-movements (during ‘double-step’ displacements) are significantly delayed with increasing age. The aim of this study was to investigate if the postural challenge posed simply by standing (as opposed to sitting) results in significantly longer eye movement latencies in older adults compared to the young. Ten young (65 years) participated in the study. They were required to fixate upon a central target and move their eyes in response to 2 types of stimuli: 1) a single-step perturbation of target position either 15º to the right or left, and 2) a double-step target displacement incorporating an initial target jump to the right or left by 15º, followed after 200 ms, by a shift of target position to the opposite side (e.g., +15º then -15º). All target displacement conditions were executed in sit and stand positions with the participant at the same distance from the targets. Eye movements were recorded using electro-oculography. Older adults did not show significantly longer eye movement latencies than the younger adults for single-step target displacements, and postural configuration (stand compared to sit) had no effect upon latencies for either group. We categorised double-step trials into those during which the second light changed after or before the onset of the eye shift to the first light. For the former category, young participants showed faster secondary eye shifts to the second light in the standing position, while the older adults did not. For the latter category of double-step trial, young participants showed no significant difference between sit and stand secondary eye movement latencies, but older adults were significantly longer standing compared to sitting. The older adults were significantly longer than the younger adults across both postural conditions, regardless of when the second light change occurred during the eye shift to the first light. We suggest that older adults require greater time and perhaps attentional processes to execute eye movements to unexpected changes of target position when faced with the need to maintain standing balance. Keywords: Balance, Ageing, Gaze, Electro-oculography, Target perturbations

Human helminth therapy to treat inflammatory disorders - where do we stand?

Parasitic helminths have evolved together with the mammalian immune system over many millennia and as such they have become remarkably efficient modulators in order to promote their own survival. Their ability to alter and/or suppress immune responses could be beneficial to the host by helping control excessive inflammatory responses and animal models and pre-clinical trials have all suggested a beneficial effect of helminth infections on inflammatory bowel conditions, MS, asthma and atopy. Thus, helminth therapy has been suggested as a possible treatment method for autoimmune and other inflammatory disorders in humans

Symptoms associated with victimization in patients with schizophrenia and related disorders

Background: Patients with psychoses have an increased risk of becoming victims of violence. Previous studies have suggested that higher symptom levels are associated with a raised risk of becoming a victim of physical violence. There has been, however, no evidence on the type of symptoms that are linked with an increased risk of recent victimization. Methods: Data was taken from two studies on involuntarily admitted patients, one national study in England and an international one in six other European countries. In the week following admission, trained interviewers asked patients whether they had been victims of physical violence in the year prior to admission, and assessed symptoms on the Brief Psychiatric Rating Scale (BPRS). Only patients with a diagnosis of schizophrenia or related disorders (ICD-10 F20–29) were included in the analysis which was conducted separately for the two samples. Symptom levels assessed on the BPRS subscales were tested as predictors of victimization. Univariable and multivariable logistic regression models were fitted to estimate adjusted odds ratios. Results: Data from 383 patients in the English sample and 543 patients in the European sample was analysed. Rates of victimization were 37.8% and 28.0% respectively. In multivariable models, the BPRS manic subscale was significantly associated with victimization in both samples. Conclusions: Higher levels of manic symptoms indicate a raised risk of being a victim of violence in involuntary patients with schizophrenia and related disorders. This might be explained by higher activity levels, impaired judgement or poorer self-control in patients with manic symptoms. Such symptoms should be specifically considered in risk assessments

Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease.

Mycobacterium ulcerans infection causes a neglected tropical disease known as Buruli ulcer that is now found in poor rural areas of West Africa in numbers that sometimes exceed those reported for another significant mycobacterial disease, leprosy, caused by M. leprae. Unique among mycobacterial diseases, M. ulcerans produces a plasmid-encoded toxin called mycolactone (ML), which is the principal virulence factor and destroys fat cells in subcutaneous tissue. Disease is typically first manifested by the appearance of a nodule that eventually ulcerates and the lesions may continue to spread over limbs or occasionally the trunk. The current standard treatment is 8 weeks of daily rifampin and injections of streptomycin (RS). The treatment kills bacilli and wounds gradually heal. Whether RS treatment actually stops mycolactone production before killing bacilli has been suggested by histopathological analyses of patient lesions. Using a mouse footpad model of M. ulcerans infection where the time of infection and development of lesions can be followed in a controlled manner before and after antibiotic treatment, we have evaluated the progress of infection by assessing bacterial numbers, mycolactone production, the immune response, and lesion histopathology at regular intervals after infection and after antibiotic therapy. We found that RS treatment rapidly reduced gross lesions, bacterial numbers, and ML production as assessed by cytotoxicity assays and mass spectrometric analysis. Histopathological analysis revealed that RS treatment maintained the association of the bacilli with (or within) host cells where they were destroyed whereas lack of treatment resulted in extracellular infection, destruction of host cells, and ultimately lesion ulceration. We propose that RS treatment promotes healing in the host by blocking mycolactone production, which favors the survival of host cells, and by killing M. ulcerans bacilli