Management of pneumonia in intensive care

Pneumonia, an inflammatory infiltrate of the alveolar airspace, is commonly triggered by bacterial infection of the lungs, or less commonly by viral or fungal infection. It remains the commonest infective reason for admission to Intensive Care as well as being the most common secondary infection acquired whilst in the Intensive Care Unit. It presents a significant global burden of disease and is especially prevalent in low- and middle-income countries. The major categories of pneumonia encountered by the Intensive Care clinician are community-acquired, ventilator-acquired, non-ventilator hospital-acquired and pneumonia in the immunocompromised patient. An appreciation of the type of pneumonia a patient has developed is critical to its effective treatment. Pneumonia is the commonest precipitant of acute respiratory distress syndrome (ARDS) and clinicians should be mindful that the evidence-base surrounding ARDS will, in large part, apply to severe pneumonia. The causative organisms which lead to pneumonia vary depending on the site of acquisition (community or hospital-acquired), the immune status of the patient and the presence of intercurrent medications including antibiotics. Current standard microbiological testing is seldom able to give a rapid answer as to which microorganisms are present and causing infection. Therefore, empirical therapy guided by a knowledge of local microbial flora and resistance patterns is the recommended course of action. This approach risks the over-treatment of pneumonia with unnecessarily broad-spectrum agents which bring with them the problems of antibiotic-associated harm. Novel rapid diagnostic tests aimed at both the pathogen and the host response hold promise in the rationalisation and appropriate targeting of antimicrobial therapy. At present neither scoring systems nor diagnostic tests are able to accurately risk stratify a patient’s need for intensive care admission. Beyond antibiotic therapy, a number of adjuvant therapies have been trialled in pneumonia although none have yet made it into widespread clinical use. Corticosteroids are recommended in some cases of community-acquired pneumonia, but their role in the patient with severe community-acquired pneumonia in ICU remains uncertain whilst they are a risk factor for the development of hospital and ventilator-acquired pneumonia. Immuno-stimulation has not yet translated from small scale clinical trials into clinical use. Supportive management includes lung protective ventilation, and those interventions proven to improve outcomes in ARDS. This review will give an overview of the epidemiology of severe pneumonia, the microbiological causes and diagnostic strategies. It will then turn to management, including antimicrobial therapy, role of adjuvant therapies, respiratory support and prevention of complications

Operating theatre photography for orthopaedics and aesthetic surgery.

The aim of this paper is to examine the author's personal experience and practice in operating theatre photography. The ways of working are personal to the author but hopefully will help others in undertaking this type of work

AFM study of strawberry pectin nanostructure and its relevance on fruit texture

Atomic force microscopy (AFM) has been used to characterize the nanostructure of cell wall pectins during strawberry fruit growth and ripening, as well as in transgenic fruits with pectinase genes downregulated. This technique allows the imaging of individual polymers at high magnification with minimal sample preparation. AFM studies during fruit development show that pectin size, ramification and aggregation is reduced in ripe fruits. Additionally, transgenic lines with different pectinase genes downregulated (polygalacturonase, pectate lyase and B-galactosidase) also show a more complex pectin nanostructure, including longer chains, higher branching degree and larger presence of aggregates. In all those cases the higher pectin complexity at nanoscale correlates with a reduced softening in strawberry fruits at macroscale level. Globally, our results support the key role of pectins in fruit structure and highlights the use of AFM as a powerful tool to gain insights about the bases of textural fruit quality not only in strawberry, but also in other commercial crops.AGL2017-86531-C2-1-R, Ministerio de Economía, Industria y Competitividad of Spain and FEDER EU funds. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Basal protein phosphatase 2A activity restrains cytokine expression: Role for MAPKs and tristetraprolin

PP2A is a master controller of multiple inflammatory signaling pathways. It is a target in asthma; however the molecular mechanisms by which PP2A controls inflammation warrant further investigation. In A549 lung epithelial cells in vitro we show that inhibition of basal PP2A activity by okadaic acid (OA) releases restraint on MAPKs and thereby increases MAPK-mediated pro-asthmatic cytokines, including IL-6 and IL-8. Notably, PP2A inhibition also impacts on the anti-inflammatory protein - tristetraprolin (TTP), a destabilizing RNA binding protein regulated at multiple levels by p38 MAPK. Although PP2A inhibition increases TTP mRNA expression, resultant TTP protein builds up in the hyperphosphorylated inactive form. Thus, when PP2A activity is repressed, pro-inflammatory cytokines increase and anti-inflammatory proteins are rendered inactive. Importantly, these effects can be reversed by the PP2A activators FTY720 and AAL(s), or more specifically by overexpression of the PP2A catalytic subunit (PP2A-C). Moreover, PP2A plays an important role in cytokine expression in cells stimulated with TNFα; as inhibition of PP2A with OA or PP2A-C siRNA results in significant increases in cytokine production. Collectively, these data reveal the molecular mechanisms of PP2A regulation and highlight the potential of boosting the power of endogenous phosphatases as novel anti-inflammatory strategies to combat asthmatic inflammation

Activating protein phosphatase 2A (PP2A) enhances tristetraprolin (TTP) anti-inflammatory function in A549 lung epithelial cells

© 2016. Chronic respiratory diseases are driven by inflammation, but some clinical conditions (severe asthma, COPD) are refractory to conventional anti-inflammatory therapies. Thus, novel anti-inflammatory strategies are necessary. The mRNA destabilizing protein, tristetraprolin (TTP), is an anti-inflammatory molecule that functions to induce mRNA decay of cytokines that drive pathogenesis of respiratory disorders. TTP is regulated by phosphorylation and protein phosphatase 2A (PP2A) is responsible for dephosphorylating (and hence activating) TTP, amongst other targets. PP2A is activated by small molecules, FTY720 and AAL(S), and in this study we examine whether these compounds repress cytokine production in a cellular model of airway inflammation using A549 lung epithelial cells stimulated with tumor necrosis factor α (TNFα) in vitro. PP2A activators significantly increase TNFα-induced PP2A activity and inhibit mRNA expression and protein secretion of interleukin 8 (IL-8) and IL-6; two key pro-inflammatory cytokines implicated in respiratory disease and TTP targets. The effect of PP2A activators is not via an increase in TNFα-induced TTP mRNA expression; instead we demonstrate a link between PP2A activation and TTP anti-inflammatory function by showing that specific knockdown of TTP with siRNA reversed the repression of TNFα-induced IL-8 and IL-6 mRNA expression and protein secretion by FTY720. Therefore we propose that PP2A activators affect the dynamic equilibrium regulating TTP; shifting the equilibrium from phosphorylated (inactive) towards unphosphorylated (active) but unstable TTP. PP2A activators boost the anti-inflammatory function of TTP and have implications for future pharmacotherapeutic strategies to combat inflammation in respiratory disease

Fifty years of spellchecking

A short history of spellchecking from the late 1950s to the present day, describing its development through dictionary lookup, affix stripping, correction, confusion sets, and edit distance to the use of gigantic databases

Glutamate spill-over in substantia nigra pars compacta

N-Methyl-D-aspartate glutamate receptors (NMDARs) contribute to neural development, plasticity and survival, but they are also linked with neurodegeneration. NMDARs at synapses are activated by coincident glutamate release and depolarization. NMDARs distal to synapses can sometimes be recruited by 'spill-over' of glutamate during high-frequency synaptic stimulation or when glutamate uptake is compromised, and this influences the shape of NMDAR-mediated postsynaptic responses. In substantia nigra dopamine neurons, activation of NMDARs beyond the synapse during different frequencies of presynaptic stimulation has not been explored, even though excitatory afferents from the subthalamic nucleus show a range of firing frequencies, and these frequencies change in human and experimental Parkinson's disease. This study reports that high-frequency stimulation (80 Hz/200 ms) evoked NMDAR-excitatory postsynaptic currents (EPSCs) that were larger and longer lasting than those evoked by single stimuli at low frequency (0.1 Hz). MK-801, which irreversibly blocked NMDAR-EPSCs activated during 0.1-Hz stimulation, left a proportion of NMDAR-EPSCs that could be activated by 80-Hz stimulation and that may represent activity of NMDARs distal to synapses. TBOA, which blocks glutamate transporters, significantly increased NMDAR-EPSCs in response to 80-Hz stimulation, particularly when metabotropic glutamate receptors (mGluRs) were also blocked, indicating that recruitment of NMDARs distal to synapses is regulated by glutamate transporters and mGluRs. These regulatory mechanisms may be essential in the substantia nigra for restricting glutamate diffusion from synaptic sites and keeping NMDAR-EPSCs in dopamine neurons relatively small and fast. Failure of glutamate transporters may contribute to the declining health of dopamine neurons during pathological conditions.Funding from The Wellcome Trust (092611/B/10/Z), The Isaac Newton Trust, and a BBSRC-DTP Studentship to PGM.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/ejn.1307

Erratum to: Estimation of country-specific and global prevalence of male circumcision.

[This corrects the article DOI: 10.1186/s12963-016-0073-5.]

TOp TEn resistant Microorganisms at intensive care unit: a 2018 global expert survey (TOTEM study protocol)

Background: This global survey will provide global expert ranking of the most urgent multidrug bacteria present at the intensive care units (ICU) that have become a threat in daily clinical practice. We believe efforts on education, investigation, funding and development of new antimicrobials or new antimicrobial approach should be directed in near future. The 2018 study protocol is reported here in. Methods: A global survey will be performed using an electronic platform (SurveyMonkey®). The survey will compile data on key aspects of the actual threat of antimicrobial-resistant bacteria globally in the ICU