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"Dark, John"
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The nine pound hammer
Drawn by the lodestone his father gave him years before, twelve-year-old orphan Ray travels south, meeting along the way various characters from folklore who are battling against an evil industry baron known as the Gog.
Book
Annual Lipid Cycles in Hibernators: Integration of Physiology and Behavior
▪ Abstract Mammalian hibernation is a temporary suspension of euthermia allowing endotherms to undergo reversible hypothermia and generate a marked savings in energy expenditure. In most fat-storing hibernator species, seasonal changes in food intake, triacylglycerol deposition, metabolism, and reproductive development are controlled by a circannual clock. In ground-dwelling sciurid rodents (ground squirrels and marmots), for example, energy intake increases during a summer body mass gain phase, and toward the end of this phase metabolic rate also begins to decrease, resulting in a profound increase in lipid deposition as fat. Increased activity of lipogenic hormones and enzymes correspond with this increase. The hibernation mass loss phase begins after the body mass peak in the fall and ends in spring. During this phase, stored lipids are slowly utilized in a programmed manner by undergoing deep torpor or hibernation during which the hypothalamic setpoint for body temperature is typically reduced to just above 0°C. Throughout the hibernation season, bouts of deep torpor are punctuated by periodic arousals in which brown adipose tissue thermogenesis plays a critical role. Lipid oxidation nearly exclusively fuels deep torpor and most of the rewarming process. The fatty acid composition of stored lipids can affect the depth and duration of deep torpor, and saturated fatty acids may be preferentially used during hibernation, whereas polyunsaturated fatty acids may be preferentially retained. Female and underweight male hibernators terminate hibernation in spring when aboveground food becomes available; in contrast, heavier males with sufficient lipid reserves spontaneously terminate hibernation several weeks before females and independent of food availability. Mating occurs shortly after emergence from hibernation, and the lipid cycle begins again with the completion of reproduction. Lipid deposition and mobilization, temperature regulation, reproduction, and circannual timing are intimately interdependent. The unique manner in which they are controlled during the annual cycle, especially lipid reserves, makes hibernators valuable and promising models for research into the mechanisms underlying these processes in all mammals.
Journal Article
The Eagle has landed : 50 years of lunar science fiction
\"In celebration of the 50th anniversary of the Apollo 11 landing, the endlessly-mysterious moon is explored in this reprint short science fiction anthology from award-winning editor and anthologist Neil Clarke ... On July 20, 1969, mankind made what had only years earlier seemed like an impossible leap forward: when Apollo 11 became the first manned mission to land on the moon, and Neil Armstrong the first person to step foot on the lunar surface. While there have only been a handful of new missions since, the fascination with our planet's satellite continues, and generations of writers and artists have imagined the endless possibilities of lunar life. From adventures in the vast gulf of space between the earth and the moon, to journeys across the light face to the dark side, to the establishment of permanent residences on its surface, science fiction has for decades given readers bold and forward-thinking ideas about our nearest interstellar neighbor and what it might mean to humankind, both now and in our future. [This book] collects the best stories written in the fifty years since mankind first stepped foot on the lunar surface, serving as a shining reminder that the moon is and always has been our most visible and constant example of all the infinite possibility of the wider universe\"-- Provided by publisher.
BOOK
A human model of bilateral pulmonary vein sampling to assess the effects of one-lung ventilation on neutrophil function
Neutrophil activation drives lung complications after cardiopulmonary bypass (CPB). Evidence suggests the healthy, ventilated lung may beneficially re-condition pro-inflammatory neutrophils. However, evidence in humans is lacking, due to a paucity of good models. CPB with simultaneous central venous and bilateral pulmonary vein sampling provides an opportunity to model effects of one-lung ventilation. The study's primary objectives were to establish a model of intra-operative, bilateral pulmonary vein sampling and to determine whether neutrophil function differed after passing through inflated or deflated lungs.
Seventeen patients having \"on pump\" coronary artery bypass grafting (CABG) with one-lung ventilation (in two cohorts with tidal volume 2ml kg-1 and FiO2 0.21, or tidal volume 4 ml kg-1 and FiO2 0.5 respectively) were recruited. Cohort 1 consisted of 9 patients (7 male, median age 62.0 years) and Cohort 2 consisted of 8 male patients (median age 65.5 years). Recruitment was via prospective screening of scheduled elective and non-elective CABG procedures with cardiopulmonary bypass. Each patient had five blood samples taken-central venous blood pre-operatively; central venous blood pre-CPB; central venous blood post-CPB; pulmonary venous blood draining the ventilated lung post-CPB; and pulmonary venous blood draining the deflated lung post-CPB. Neutrophil phagocytosis and priming status were quantified. Plasma cytokines were measured.
Phagocytosis and priming were not significantly different in neutrophils returning from the ventilated lung as compared to the non-ventilated lung. Plasma IL-6, IL-8 and IL-10 were significantly elevated by CPB.
The intra-operative, bilateral pulmonary vein sampling model provides unique opportunities to assess biological effects of interventions to one lung, with the other lung acting as an internal control. Single-lung ventilation during CPB had no significant effects on neutrophil function.
Journal Article
Effect of donor smoking on survival after lung transplantation: a cohort study of a prospective registry
The risk that a positive smoking history in lung donors could adversely affect survival of transplant recipients causes concern. Conversely, reduction of the donor pool by exclusion of donors with positive smoking histories could compromise survival of patients waiting to receive a transplant. We examined the consequences of donor smoking on post-transplantation survival, and the potential effect of not transplanting lungs from such donors.
We analysed the effect of donor smoking on 3 year survival after first adult lung transplantation from brain-dead donors done between July 1, 1999, and Dec 31, 2010, by Cox regression modelling of data from the UK Transplant Registry. We estimated the effect of acceptance of lungs from donors with positive smoking histories on survival and compared it with the effect of remaining on the waiting list for a potential transplant from a donor with a negative smoking history donor, by analysing all waiting-list registrations during the same period with a risk-adjusted sequentially stratified Cox regression model.
Of 1295 lung transplantations, 510 (39%) used lungs from donors with positive smoking histories. Recipients of such lungs had worse 3 year survival after transplantation than did those who received lungs from donors with negative smoking histories (unadjusted hazard ratio [HR] 1·46, 95% CI 1·20–1·78; adjusted HR 1·36, 1·11–1·67). Independent factors affecting survival were recipient's age, donor–recipient cytomegalovirus matching, donor–recipient height difference, donor's sex, and total ischaemic time. Of 2181 patients registered on the waiting list, 802 (37%) died or were removed from the list without receiving a transplant. Patients receiving lungs from donors with positive smoking histories had a lower unadjusted hazard of death after registration than did those who remained on the waiting list (0·79, 95% CI 0·70–0·91). Patients with septic or fibrotic lung disease registered in 1999–2003 had risk-adjusted hazards of 0·60 (95% CI 0·42–0·87) and 0·39 (0·28–0·55), respectively.
In the UK, an organ selection policy that uses lungs from donors with positive smoking histories improves overall survival of patients registered for lung transplantation, and should be continued. Although lungs from such donors are associated with worse outcomes, the individual probability of survival is greater if they are accepted than if they are declined and the patient chooses to wait for a potential transplant from a donor with a negative smoking history. This situation should be fully explained to and discussed with patients who are accepted for lung transplantation.
National Health Service Blood and Transplant.
Journal Article
Ex vivo repair of human donor lungs for transplantation
Injured human donor lungs deemed unsuitable for immediate transplantation may be successfully recovered by connection into the circulation of a porcine host with perfusion and ventilation ex vivo for 24 hours.
Journal Article
Heart Transplantation and Donation After Circulatory Death in Children. A Review of the Technological, Logistical and Ethical Framework
Heart transplant for adults following Donation after Circulatory Death (DCD) is well established in many parts of the world, including the United Kingdom (UK). Small child DCD hearts have now been recovered in the UK and internationally utilising novel technologies. Despite these recent advances, extension of this practice to pediatric cardiac transplantation has been slow and difficult despite the severe shortage of donors for children leading to a high number of deaths annually of children waiting for heart transplant. This is in direct contrast with the thriving UK programme of adult DCD heart transplant and pediatric DCD donation for non-cardiac organs. There has been insufficient action in addressing this inequality thus far. Barriers to development of a pediatric cardiac DCD programme are multifaceted: ethical concerns, technological paucity, financial and logistical hurdles. We describe the background, live issues, current developments and how we are driving resources toward a sustainable DCD programme for small children in the UK to provide valuable insights to other countries of the elements and principles at play. This is a call to responsible bodies to take urgent and achievable actions to establish an equitable paediatric DCD cardiac programme for donors, recipients and their families.
Journal Article
A Split-Lung Ex Vivo Perfusion Model for Time- and Cost-Effective Evaluation of Therapeutic Interventions to the Human Donor Lung
With the ongoing shortage of donor lungs, ex vivo lung perfusion (EVLP) offers the opportunity for objective assessment and potential therapeutic repair of marginal organs. There is a need for robust research on EVLP interventions to increase the number of transplantable organs. The use of human lungs, which have been declined for transplant, for these studies is preferable to animal organs and is indeed essential if clinical translation is to be achieved. However, experimental human EVLP is time-consuming and expensive, limiting the rate at which promising interventions can be assessed. A split-lung EVLP model, which allows stable perfusion and ventilation of two single lungs from the same donor, offers advantages scientifically, financially and in time to yield results. Identical parallel circuits allow one to receive an intervention and the other to act as a control, removing inter-donor variation between study groups. Continuous hemodynamic and airway parameters are recorded and blood gas, perfusate, and tissue sampling are facilitated. Pulmonary edema is assessed directly using ultrasound, and indirectly using the lung tissue wet:dry ratio. Evans blue dye leaks into the tissue and can quantify vascular endothelial permeability. The split-lung ex vivo perfusion model offers a cost-effective, reliable platform for testing therapeutic interventions with relatively small sample sizes.
Journal Article
Azithromycin Reverses Airflow Obstruction in Established Bronchiolitis Obliterans Syndrome
A recent pilot study noted clinical benefit of macrolide therapy in the management of six lung transplant recipients with bronchiolitis obliterans syndrome (BOS), a condition previously regarded as irreversible.
To examine the effect of low-dose macrolides on lung function in lung allograft recipients with established BOS and to assess whether this benefit is sustained.
We retrospectively evaluated the effect of azithromycin (250 mg alternate days) on clinical status and lung function in 20 allograft recipients with established BOS, confirmed by decline in FEV(1) or FEF(25-75); consistent high-resolution computed tomography findings; and exclusion of acute rejection, infection, or anastomatic complications. Azithromycin was introduced at mean 82 months after transplantation. BOS staging at initiation of treatment was BOS 3 (10), BOS 2 (2), BOS 1 (6), and BOS0-p (2). All patients were on maintenance immunosuppression comprising cell-cycle inhibitor, oral corticosteroids, and calcineurin inhibitor.
There was a significant increase in FEV(1) of median 110 ml (range, -70 to 730 ml) between baseline and 3 months of azithromycin therapy (p = 0.002). This improvement was sustained beyond 3 months in the majority of patients, who had initially benefited from azithromycin (up to 11 months follow up).
This case series confirms the benefit of azithromycin in not only halting, but reversing the declining lung function seen in patients with BOS. This benefit appears to be maintained over time. Low-dose macrolides offer a new and exciting therapeutic strategy for the treatment of progressive BOS, and further clinical and translational mechanistic studies are required.
Journal Article
SIGNET: protocol for a multicentre, single-blind prospective, group sequential, randomised controlled trial to evaluate the benefits of a single dose of simvastatin given to potential organ donors declared dead by neurological criteria on outcomes in organ recipients
IntroductionSuccessful organ transplantation in patients with end-stage organ failure improves long-term survival, improves quality of life and reduces costs to the NHS. Despite an increase in the number of deceased organ donors over the last decade, there remains a considerable shortfall of suitable organs available for transplantation. Over half of UK donors are certified dead by neurological criteria following brain stem compression, which leads to severe physiological stress in the donor, combined with a hyperinflammatory state. Brain stem death-related dysfunction is an important reason for poor organ function and hence utilisation. For example, more than 30% of donation after brain stem death cardiac transplant recipients need short-term mechanical cardiac support, reflecting donor heart dysfunction.A small, randomised study previously showed improved outcomes for cardiac transplant recipients if the donor was given simvastatin. SIGNET takes inspiration from that study and hypothesises a potential reduction in damage to the heart and other organs during the period after diagnosis of death and prior to organ retrieval in donors that receive simvastatin.Methods and analysisSIGNET is a multicentre, single-blind, prospective, group sequential, randomised controlled trial to evaluate the benefits of a single high dose of simvastatin given to potential organ donors diagnosed dead by neurological criteria on outcomes in all organ recipients. The trial will run across a minimum of 89 UK sites with a recruitment target of 2600 donors over 4 years.Ethics and disseminationSIGNET received a favourable opinion from the London, Queen Square Research Ethics Committee (Ref: 21/LO/0412) and following approval of substantial amendment 1 in January 2023, the current protocol is version 2 (7 December 2022). Substantial amendment 1 clarified consent procedures and added additional sites and prescribers. Findings from the study will be publicly available and disseminated locally and internationally through manuscript publications in peer-reviewed journals and conference presentations at national and international platforms.Trial registration numberISRCTN11440354
Journal Article