Effects of An Acute Increase in Atrial Pressure on Atrial Refractoriness in Humans

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73199/1/j.1540-8159.1992.tb02954.x.pd

Belowground DNA-based techniques: untangling the network of plant root interactions

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Neutrophil elastase reduces secretion of secretory leukoproteinase inhibitor (SLPI) by lung epithelial cells: role of charge of the proteinase-inhibitor complex

<p>Abstract</p> <p>Background</p> <p>Secretory leukoproteinase inhibitor (SLPI) is an important inhibitor of neutrophil elastase (NE), a proteinase implicated in the pathogenesis of lung diseases such as COPD. SLPI also has antimicrobial and anti-inflammatory properties, but the concentration of SLPI in lung secretions in COPD varies inversely with infection and the concentration of NE. A fall in SLPI concentration is also seen in culture supernatants of respiratory cells exposed to NE, for unknown reasons. We investigated the hypothesis that SLPI complexed with NE associates with cell membranes <it>in vitro</it>.</p> <p>Methods</p> <p>Respiratory epithelial cells were cultured in the presence of SLPI, varying doses of proteinases over time, and in different experimental conditions. The likely predicted charge of the complex between SLPI and proteinases was assessed by theoretical molecular modelling.</p> <p>Results</p> <p>We observed a rapid, linear decrease in SLPI concentration in culture supernatants with increasing concentration of NE and cathepsin G, but not with other serine proteinases. The effect of NE was inhibited fully by a synthetic NE inhibitor only when added at the same time as NE. Direct contact between NE and SLPI was required for a fall in SLPI concentration. Passive binding to cell culture plate materials was able to remove a substantial amount of SLPI both with and without NE. Theoretical molecular modelling of the structure of SLPI in complex with various proteinases showed a greater positive charge for the complex with NE and cathepsin G than for other proteinases, such as trypsin and mast cell tryptase, that also bind SLPI but without reducing its concentration.</p> <p>Conclusion</p> <p>These data suggest that NE-mediated decrease in SLPI is a passive, charge-dependent phenomenon <it>in vitro</it>, which may correlate with changes observed <it>in vivo</it>.</p

Cardiorespiratory effects of venous lipid micro embolization in an experimental model of mediastinal shed blood reinfusion

<p>Abstract</p> <p>Background</p> <p>Retransfusion of the patient's own blood during surgery is used to reduce the need for allogenic blood transfusion. It has however been found that this blood contains lipid particles, which form emboli in different organs if the blood is retransfused on the arterial side. In this study, we tested whether retransfusion of blood containing lipid micro-particles on the venous side in a porcine model will give hemodynamic effects.</p> <p>Methods</p> <p>Seven adult pigs were used. A shed blood surrogate containing 400 ml diluted blood and 5 ml radioactive triolein was produced to generate a lipid embolic load. The shed blood surrogate was rapidly (<2 minutes) retransfused from a transfusion bag to the right atrium under general anesthesia. The animals' arterial, pulmonary, right and left atrial pressure were monitored, together with cardiac output and deadspace. At the end of the experiment, an increase in cardiac output and pulmonary pressure was pharmacologically induced to try to flush out lipid particles from the lungs.</p> <p>Results</p> <p>A more than 30-fold increase in pulmonary vascular resistance was observed, with subsequent increase in pulmonary artery pressure, and decrease in cardiac output and arterial pressure. This response was transient, but was followed by a smaller, persistent increase in pulmonary vascular resistance. Only a small portion of the infused triolein passed the lungs, and only a small fraction could be recirculated by increasing cardiac output and pulmonary pressure.</p> <p>Conclusion</p> <p>Infusion of blood containing lipid micro-emboli on the venous side leads to acute, severe hemodynamic responses that can be life threatening. Lipid particles will be trapped in the lungs, leading to persistent effects on the pulmonary vascular resistance.</p

Prior outpatient antibiotic use as predictor for microbial aetiology of community-acquired pneumonia: hospital-based study

Objective: The causative micro-organism in community-acquired pneumonia (CAP) is often difficult to predict. Different studies have examined chronic morbidity and clinical symptoms as predictors for microbial aetiology of pneumonia. The aim of our study was to assess whether prior outpatient antimicrobial treatment is predictive for determining the microbial aetiology of CAP. Methods: This was a hospital-based prospective observational study including all patients admitted with CAP between 1 October 2004 and 1 August 2006. Microbial investigations included sputum, blood culture, sputum PCR, antigen testing and serology. Exposure to antimicrobial drugs prior to hospital admission was ascertained through community pharmacy dispensing records. Multivariate logistic regression analysis was conducted to assess whether prior outpatient antimicrobial treatment is a predictor of microbial aetiology. Patient demographics, co-morbidities and pneumonia severity were considered to be other potential predictors. Results: Overall, 201 patients were included in the study. The microbial aetiology was determined in 64% of the patients. The five most prevalent pathogens were Streptococcus pneumoniae, Heamophilus influenzae, Legionella spp., Mycoplasma pneumoniae and Influenza virus A+B. Forty-seven of the patients (23%) had received initial antimicrobial treatment as outpatients. Multivariate analyses revealed that initial outpatient beta-lactam treatment was associated with a threefold increased chance of finding atypical pathogens and a threefold decreased probability of pneumococcal infection; the corresponding odds ratios were 3.51 (95% CI 1.25-9.99) and 0.30 (95% CI 0.10-0.90), respectively. Patients who received macrolides prior to hospitalisation had an increased probability of viral pneumonia. Conclusion: Prior outpatient antimicrobial therapy has a predictive value in the diagnostic workup aimed at identifying the causative pathogen and planning corresponding antimicrobial treatment in patients hospitalised for pneumonia

An intervention to support stroke survivors and their carers in the longer term (LoTS2Care): study protocol for a cluster randomised controlled feasibility trial

Background Despite the evidence that many stroke survivors report longer term unmet needs, the provision of longer term care is limited. To address this, we are conducting a programme of research to develop an evidence-based and replicable longer term care strategy. The developed complex intervention (named New Start), which includes needs identification, exploration of social networks and components of problem solving and self-management, was designed to improve quality of life by addressing unmet needs and increasing participation. Methods/Design A multicentre, cluster randomised controlled feasibility trial designed to inform the design of a possible future definitive cluster randomised controlled trial (cRCT) and explore the potential clinical and cost-effectiveness of New Start. Ten stroke services across the UK will be randomised on a 1:1 basis either to implement New Start or continue with usual care only. New Start will be delivered by trained facilitators and will be offered to all stroke survivors within the services allocated to the intervention arm. Stroke survivors will be eligible for the trial if they are 4–6 months post-stroke and residing in the community. Carers (if available) will also be invited to take part. Invitation to participate will be initiated by post and outcome measures will be collected via postal questionnaires at 3, 6 and 9 months after recruitment. Outcome data relating to perceived health and disability, wellbeing and quality of life as well as unmet needs will be collected. A ‘study within a trial’ (SWAT) is planned to determine the most acceptable format in which to provide the postal questionnaires. Details of health and social care service usage will also be collected to inform the economic evaluation. The feasibility of recruiting services and stroke survivors to the trial and of collecting postal outcomes will be assessed and the potential for effectiveness will be investigated. An embedded process evaluation (reported separately) will assess implementation fidelity and explore and clarify causal assumptions regarding implementation. Discussion This feasibility trial with embedded process evaluation will allow us to gather important and detailed data regarding methodological and implementation issues to inform the design of a possible future definitive cRCT of this complex intervention. Trial Registration ISRCTN38920246. Registered 22 June 2016

Highly Unsaturated Fatty Acid Synthesis in Atlantic Salmon: Characterization of ELOVL5- and ELOVL2-like Elongases

Fish species vary in their capacity to biosynthesize the n-3 long-chain polyunsaturated fatty acids (LC-PUFA) eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids that are crucial to the health of higher vertebrates. The synthesis of LC-PUFA involves enzyme-mediated fatty acyl desaturation and elongation. Previously, a cDNA for an elongase, now termed elovl5a, had been cloned from Atlantic salmon. Here we report on the cloning of two new elongase cDNAs: a second elovl5b elongase, corresponding to a 294 aa protein, and an elovl2-like elongase, coding for a 287 aa protein, characterized for the first time in a non-mammalian vertebrate. Heterologous expression in yeast showed that the salmon Elovl5b elongated C18 and C20 PUFA, with low activity towards C22, while Elovl2 elongated C20 and C22 PUFA with lower activity towards C18 PUFA. All three transcripts showed predominant expression in the intestine and liver, followed by the brain. Elongase expression showed differential nutritional regulation. Levels of elovl5b and particularly of elovl2, but not of elovl5a, transcripts were significantly increased in liver of salmon fed vegetable oils (VO) compared to fish fed fish oil (FO). Intestinal expression showed a similar pattern. Phylogenetic comparisons indicate that, in contrast to salmon and zebrafish, Acanthopterygian fish species lack elovl2 which is consistent with their neglible ability to biosynthesise LC-PUFA and to adapt to VO dietary inclusion, compared to predominantly freshwater salmonids. Thus the presence of elovl2 in salmon explains the ability of this species to biosynthesise LC-HUFA and may provide a biotechnological tool to produce enhanced levels of LC-PUFA, particularly DHA, in transgenic organisms

Response to Mechanical Stress Is Mediated by the TRPA Channel Painless in the Drosophila Heart

Mechanotransduction modulates cellular functions as diverse as migration, proliferation, differentiation, and apoptosis. It is crucial for organ development and homeostasis and leads to pathologies when defective. However, despite considerable efforts made in the past, the molecular basis of mechanotransduction remains poorly understood. Here, we have investigated the genetic basis of mechanotransduction in Drosophila. We show that the fly heart senses and responds to mechanical forces by regulating cardiac activity. In particular, pauses in heart activity are observed under acute mechanical constraints in vivo. We further confirm by a variety of in situ tests that these cardiac arrests constitute the biological force-induced response. In order to identify molecular components of the mechanotransduction pathway, we carried out a genetic screen based on the dependence of cardiac activity upon mechanical constraints and identified Painless, a TRPA channel. We observe a clear absence of in vivo cardiac arrest following inactivation of painless and further demonstrate that painless is autonomously required in the heart to mediate the response to mechanical stress. Furthermore, direct activation of Painless is sufficient to produce pauses in heartbeat, mimicking the pressure-induced response. Painless thus constitutes part of a mechanosensitive pathway that adjusts cardiac muscle activity to mechanical constraints. This constitutes the first in vivo demonstration that a TRPA channel can mediate cardiac mechanotransduction. Furthermore, by establishing a high-throughput system to identify the molecular players involved in mechanotransduction in the cardiovascular system, our study paves the way for understanding the mechanisms underlying a mechanotransduction pathway

Equivalence and noninferiority trials – are they viable alternatives for registration of new drugs? (III)

The scientific community's reliance on active-controlled trials is steadily increasing, as widespread agreement emerges concerning the role of these trials as viable alternatives to placebo trials. These trials present substantial challenges with regard to design and interpretation as their complexity increases, and the potential need for larger sample sizes impacts the cost and time variables of the drug development process. The potential efficacy and safety benefits derived from these trials may never be demonstrated by other methods. Active-controlled trials can develop valuable data to inform both prescribers and patients about the dose- and time-dependent actions of any new drug and can contribute to the management and communication of risks associated with the relevant therapeutic products

Antimicrobial proteins and polypeptides in pulmonary innate defence

Inspired air contains a myriad of potential pathogens, pollutants and inflammatory stimuli. In the normal lung, these pathogens are rarely problematic. This is because the epithelial lining fluid in the lung is rich in many innate immunity proteins and peptides that provide a powerful anti-microbial screen. These defensive proteins have anti-bacterial, anti- viral and in some cases, even anti-fungal properties. Their antimicrobial effects are as diverse as inhibition of biofilm formation and prevention of viral replication. The innate immunity proteins and peptides also play key immunomodulatory roles. They are involved in many key processes such as opsonisation facilitating phagocytosis of bacteria and viruses by macrophages and monocytes. They act as important mediators in inflammatory pathways and are capable of binding bacterial endotoxins and CPG motifs. They can also influence expression of adhesion molecules as well as acting as powerful anti-oxidants and anti-proteases. Exciting new antimicrobial and immunomodulatory functions are being elucidated for existing proteins that were previously thought to be of lesser importance. The potential therapeutic applications of these proteins and peptides in combating infection and preventing inflammation are the subject of ongoing research that holds much promise for the future