Changes in expression and activity of the secretory pathway Ca2+ATPase 1 (SPCA1) in A7r5 vascular smooth muscle cells cultured at different glucose concentrations

Diabetes mellitus-related vascular disease is often associated with both a dysregulation of Ca$^{2+}$ homoeostasis and enhanced secretory activity in VSMCs (vascular smooth muscle cells). Here, we employ a commonly used rat cell line for VSMCs (A7r5 cells) to investigate the effects of glucose on the expression and activity of the SPCA1 (secretory pathway Ca$^{2+}$-ATPase 1; also known as ATP2C1), which is a P-type Ca$^{2+}$ pump located in the Golgi apparatus that plays a key role in the secretory pathway. Our results show that mRNA expression levels of SPCA1 are significantly increased in A7r5 cells cultured in high glucose (25.0 mM)-supplemented medium compared with normal glucose (5.55 mM)-supplemented medium. SPCA1 protein expression levels and thapsigargin-insensitive Ca$^{2+}$-dependent ATPase activity were also consistent with a higher than normal expression level of SPCA1 in high-glucose-cultured A7r5 cells. Analysis of AVP (arginine-vasopressin)-induced cytosolic Ca$^{2+}$ transients in A7r5 cells (after pre-treatment with thapsigargin) showed faster rise and decay phases in cells grown in high glucose medium compared with cells grown in normal glucose medium, supporting the observation of increased SPCA expression/activity. The significant levels of both Ca$^{2+}$-ATPase activity and AVP-induced Ca$^{2+}$ transients, in the presence of thapsigargin, indicate that SPCA must play a significant role in Ca$^{2+}$ uptake within VSMCs. We therefore propose that, if such increases in SPCA expression and activity also occur in primary VSMCs, this may play a substantial role in the aetiology of diabetes mellitus-associated vascular disease, due to alterations in Ca$^{2+}$ homoeostasis within the Golgi apparatus

Anti-Crusoes, Alternative Crusoes: Revisions of the Island Story in the Twentieth Century

In lieu of an abstract, here are the chapter\u27s first two paragraphs: Everyone thinks they know the plot of Robinson Crusoe. The story of the man who is shipwrecked on an island alone is ubiquitous and feels deeply familiar, even for those who have not read it. Robinson Crusoe has been plagiarized, cannibalized, and serialized almost since the moment it hit the streets of London in 1719. Here is a passage from an Argentinean novel by Victoria Slavuski published in 1993 that captures the sense of familiarity and also the distance twentieth-century readers have in their relationship to Robinson Crusoe: “On days like these we promised each other that at long last we would take the time to read the copy of Robinson (Crusoe) that each household kept alongside the Bible and Twenty-five Ways to Prepare Lobster, written on Juan Fernandez by Amelita Riera. Nobody got past page fifteen of Robinson and almost nobody opened the Bible.”1 Literary critics often treat the multitude of twentieth-century versions of Crusoe as antagonistic to Defoe’s character. They tend to consider contemporary novels or films or poems as entities in competition with Robinson Crusoe’s fictional world. However, these modern renderings are never so neatly drawn. More often than not, writers use these alternative Crusoes to forge lines of affiliation and empathy, between the eighteenth century and our own time as well as between different regions and languages. Argentinean, Caribbean, and African Crusoes are in conversation with one another as much as they are in dialogue with the historic Defoe. Writers around the globe adapt and transform Crusoe and Defoe’s novel to establish a literary web of connection that has come to define our own global moment where fiction travels beyond national and linguistic borders. In this chapter I will move through a few observations on nineteenth-century Crusoes before delving into the twentieth-century map of literary islands crisscrossing the globe

Personalised service? Changing the role of the government librarian

Investigates the feasibility of personalised information service in a government department. A qualitative methodology explored stakeholder opinions on the remit, marketing, resourcing and measurement of the service. A questionnaire and interviews gathered experiences of personalised provision across the government sector. Potential users were similarly surveyed to discuss how the service could meet their needs. Data were analysed using coding techniques to identify emerging theory. Lessons learned from government librarians centred on clarifying requirements, balancing workloads and selective marketing. The user survey showed low usage and awareness of existing specialist services, but high levels of need and interest in services repackaged as a tailored offering. Fieldwork confirmed findings from the literature on the scope for adding value through information management advice, information skills training and substantive research assistance and the need to understand business processes and develop effective partnerships. Concluding recommendations focus on service definition, strategic marketing, resource utilisation and performance measurement

Implantable cardioverter defibrillators for the treatment of arrhythmias and cardiac resynchronisation therapy for the treatment of heart failure: systematic review and economic evaluation

Background This assessment updates and expands on two previous technology assessments that evaluated implantable cardioverter defibrillators (ICDs) for arrhythmias and cardiac resynchronisation therapy (CRT) for heart failure (HF). Objectives To assess the clinical effectiveness and cost-effectiveness of ICDs in addition to optimal pharmacological therapy (OPT) for people at increased risk of sudden cardiac death (SCD) as a result of ventricular arrhythmias despite receiving OPT; to assess CRT with or without a defibrillator (CRT-D or CRT-P) in addition to OPT for people with HF as a result of left ventricular systolic dysfunction (LVSD) and cardiac dyssynchrony despite receiving OPT; and to assess CRT-D in addition to OPT for people with both conditions. Data sources Electronic resources including MEDLINE, EMBASE and The Cochrane Library were searched from inception to November 2012. Additional studies were sought from reference lists, clinical experts and manufacturers’ submissions to the National Institute for Health and Care Excellence. Review methods Inclusion criteria were applied by two reviewers independently. Data extraction and quality assessment were undertaken by one reviewer and checked by a second. Data were synthesised through narrative review and meta-analyses. For the three populations above, randomised controlled trials (RCTs) comparing (1) ICD with standard therapy, (2) CRT-P or CRT-D with each other or with OPT and (3) CRT-D with OPT, CRT-P or ICD were eligible. Outcomes included mortality, adverse events and quality of life. A previously developed Markov model was adapted to estimate the cost-effectiveness of OPT, ICDs, CRT-P and CRT-D in the three populations by simulating disease progression calculated at 4-weekly cycles over a lifetime horizon. Results A total of 4556 references were identified, of which 26 RCTs were included in the review: 13 compared ICD with medical therapy, four compared CRT-P/CRT-D with OPT and nine compared CRT-D with ICD. ICDs reduced all-cause mortality in people at increased risk of SCD, defined in trials as those with previous ventricular arrhythmias/cardiac arrest, myocardial infarction (MI) > 3 weeks previously, non-ischaemic cardiomyopathy (depending on data included) or ischaemic/non-ischaemic HF and left ventricular ejection fraction ≤ 35%. There was no benefit in people scheduled for coronary artery bypass graft. A reduction in SCD but not all-cause mortality was found in people with recent MI. Incremental cost-effectiveness ratios (ICERs) ranged from £14,231 per quality-adjusted life-year (QALY) to £29,756 per QALY for the scenarios modelled. CRT-P and CRT-D reduced mortality and HF hospitalisations, and improved other outcomes, in people with HF as a result of LVSD and cardiac dyssynchrony when compared with OPT. The rate of SCD was lower with CRT-D than with CRT-P but other outcomes were similar. CRT-P and CRT-D compared with OPT produced ICERs of £27,584 per QALY and £27,899 per QALY respectively. The ICER for CRT-D compared with CRT-P was £28,420 per QALY. In people with both conditions, CRT-D reduced the risk of all-cause mortality and HF hospitalisation, and improved other outcomes, compared with ICDs. Complications were more common with CRT-D. Initial management with OPT alone was most cost-effective (ICER £2824 per QALY compared with ICD) when health-related quality of life was kept constant over time. Costs and QALYs for CRT-D and CRT-P were similar. The ICER for CRT-D compared with ICD was £27,195 per QALY and that for CRT-D compared with OPT was £35,193 per QALY. Limitations Limitations of the model include the structural assumptions made about disease progression and treatment provision, the extrapolation of trial survival estimates over time and the assumptions made around parameter values when evidence was not available for specific patient groups. Conclusions In people at risk of SCD as a result of ventricular arrhythmias and in those with HF as a result of LVSD and cardiac dyssynchrony, the interventions modelled produced ICERs of < £30,000 per QALY gained. In people with both conditions, the ICER for CRT-D compared with ICD, but not CRT-D compared with OPT, was < £30,000 per QALY, and the costs and QALYs for CRT-D and CRT-P were similar. A RCT comparing CRT-D and CRT-P in people with HF as a result of LVSD and cardiac dyssynchrony is required, for both those with and those without an ICD indication. A RCT is also needed into the benefits of ICD in non-ischaemic cardiomyopathy in the absence of dyssynchrony. Study registration This study is registered as PROSPERO number CRD42012002062. Funding The National Institute for Health Research Health Technology Assessment programme

Impact of age at type 2 diabetes mellitus diagnosis on mortality and vascular complications: systematic review and meta-analyses

AIMS/HYPOTHESIS: Few studies examine the association between age at diagnosis and subsequent complications from type 2 diabetes. This paper aims to summarise the risk of mortality, macrovascular complications and microvascular complications associated with age at diagnosis of type 2 diabetes. METHODS: Data were sourced from MEDLINE and All EBM (Evidence Based Medicine) databases from inception to July 2018. Observational studies, investigating the effect of age at diabetes diagnosis on macrovascular and microvascular diabetes complications in adults with type 2 diabetes were selected according to pre-specified criteria. Two investigators independently extracted data and evaluated all studies. If data were not reported in a comparable format, data were obtained from authors, presented as minimally adjusted ORs (and 95% CIs) per 1 year increase in age at diabetes diagnosis, adjusted for current age for each outcome of interest. The study protocol was recorded with PROSPERO International Prospective Register of Systematic Reviews (CRD42016043593). RESULTS: Data from 26 observational studies comprising 1,325,493 individuals from 30 countries were included. Random-effects meta-analyses with inverse variance weighting were used to obtain the pooled ORs. Age at diabetes diagnosis was inversely associated with risk of all-cause mortality and macrovascular and microvascular disease (all p < 0.001). Each 1 year increase in age at diabetes diagnosis was associated with a 4%, 3% and 5% decreased risk of all-cause mortality, macrovascular disease and microvascular disease, respectively, adjusted for current age. The effects were consistent for the individual components of the composite outcomes (all p < 0.001). CONCLUSIONS/INTERPRETATION: Younger, rather than older, age at diabetes diagnosis was associated with higher risk of mortality and vascular disease. Early and sustained interventions to delay type 2 diabetes onset and improve blood glucose levels and cardiovascular risk profiles of those already diagnosed are essential to reduce morbidity and mortality. Graphical abstract

Unnecessary use of fluoroquinolone antibiotics in hospitalized patients

<p>Abstract</p> <p>Background</p> <p>Fluoroquinolones are among the most commonly prescribed antimicrobials and are an important risk factor for colonization and infection with fluoroquinolone-resistant gram-negative bacilli and for <it>Clostridium difficile </it>infection (CDI). In this study, our aim was to determine current patterns of inappropriate fluoroquinolone prescribing among hospitalized patients, and to test the hypothesis that longer than necessary treatment durations account for a significant proportion of unnecessary fluoroquinolone use.</p> <p>Methods</p> <p>We conducted a 6-week prospective, observational study to determine the frequency of, reasons for, and adverse effects associated with unnecessary fluoroquinolone use in a tertiary-care academic medical center. For randomly-selected adult inpatients receiving fluoroquinolones, therapy was determined to be necessary or unnecessary based on published guidelines or standard principles of infectious diseases. Adverse effects were determined based on chart review 6 weeks after completion of therapy.</p> <p>Results</p> <p>Of 1,773 days of fluoroquinolone therapy, 690 (39%) were deemed unnecessary. The most common reasons for unnecessary therapy included administration of antimicrobials for non-infectious or non-bacterial syndromes (292 days-of-therapy) and administration of antimicrobials for longer than necessary durations (234 days-of-therapy). The most common syndrome associated with unnecessary therapy was urinary tract infection or asymptomatic bacteriuria (30% of all unnecessary days-of-therapy). Twenty-seven percent (60/227) of regimens were associated with adverse effects possibly attributable to therapy, including gastrointestinal adverse effects (14% of regimens), colonization by resistant pathogens (8% of regimens), and CDI (4% of regimens).</p> <p>Conclusions</p> <p>In our institution, 39% of all days of fluoroquinolone therapy were unnecessary. Interventions that focus on improving adherence with current guidelines for duration of antimicrobial therapy and for management of urinary syndromes could significantly reduce overuse of fluoroquinolones.</p

Subacute ruminal acidosis reduces sperm quality in beef bulls

Breeding bulls are commonly fed high-energy diets, which may induce subacute ruminal acidosis (SARA). In this experiment, 8 Santa Gertrudis bulls (age 20 ± 6 mo) were used to evaluate the extent and duration of effects of SARA on semen quality and the associated changes in circulating hormones and metabolites. The bulls were relocated and fed in yards with unrestricted access to hay and daily individual concentrate feeding for 125 d before SARA challenge. Semen was collected and assessed at 14-d intervals before the challenge to ensure acclimatization and the attainment of a stable spermiogram. The challenge treatments consisted of either a single oral dose of oligofructose (OFF; 6.5 g/kg BW) or an equivalent sham dose of water (Control). Locomotion, behavior, respiratory rate, and cardiovascular and gastrointestinal function were intensively monitored during the 24-h challenge period. Rumen fluid samples were retained for VFA, ammonia, and lactate analysis. After the challenge, semen was then collected every third day for a period of 7 wk and then once weekly until 12 wk, with associated blood collection for FSH, testosterone, inhibin, and cortisol assay. Percent normal sperm decreased in bulls dosed with OFF after the challenge period (P < 0.05) and continued to remain lower on completion of the study at 88 d after challenge. There was a corresponding increase in sperm defects commencing from 16 d after challenge. These included proximal cytoplasmic droplets (P < 0.001), distal reflex midpieces (P = 0.01), and vacuole and teratoid heads (P < 0.001). Changes in semen quality after challenge were associated with lower serum testosterone (P < 0.001) and FSH (P < 0.05). Serum cortisol in OFF bulls tended to be greater (P = 0.07) at 7 d after challenge. This study shows that SARA challenge causes a reduction in sperm quality sufficient to preclude bulls from sale as single sire breeding animals 3 mo after the event occurred

A randomised controlled trial of extended brief intervention for alcohol dependent patients in an acute hospital setting (ADPAC)

<p>Abstract</p> <p>Background</p> <p>Alcohol dependence affects approximately 3% of the English population, and accounts for significant medical and psychiatric morbidity. Only 5.6% of alcohol-dependent individuals ever access specialist treatment and only a small percentage ever seek treatment. As people who are alcohol dependent are more likely to have experienced health problems leading to frequent attendance at acute hospitals it would seem both sensible and practical to ensure that this setting is utilised as a major access point for treatment, and to test the effectiveness of these treatments.</p> <p>Methods/Design</p> <p>This is a randomised controlled trial with a primary hypothesis that extended brief interventions (EBI) delivered to alcohol-dependent patients in a hospital setting by an Alcohol Specialist Nurse (ASN) will be effective when compared to usual care in reducing overall alcohol consumption and improving on the standard measures of alcohol dependence. Consecutive patients will be screened for alcohol misuse in the Emergency Department (ED) of a district general hospital. On identification of an alcohol-related problem, following informed written consent, we aim to randomize 130 patients per group. The ASN will discharge to usual clinical care all control group patients, and plan a programme of EBI for treatment group patients. Follow-up interview will be undertaken by a researcher blinded to the intervention at 12 and 24 weeks. The primary outcome measure is level of alcohol dependence as determined by the Severity of Alcohol Dependence Questionnaire (SADQ) score. Secondary outcome measures include; Alcohol Use Disorders Identification Test (AUDIT) score, quantity and frequency of alcohol consumption, health-related quality of life measures, service utilisation, and patient experience. The trial will also allow an assessment of the cost-effectiveness of EBI in an acute hospital setting. In addition, patient experience will be assessed using qualitative methods.</p> <p>Discussion</p> <p>This paper presents a protocol for a RCT of EBI delivered to alcohol dependent patients by an ASN within an ED. Importantly; the trial will also seek to understand patients' perceptions and experiences of being part of a RCT and of receiving this form of intervention.</p> <p>Trial registration number</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN78062794">ISRCTN78062794</a></p

Modes of Action of Microbially-Produced Phytotoxins

Some of the most potent phytotoxins are synthesized by microbes. A few of these share molecular target sites with some synthetic herbicides, but many microbial toxins have unique target sites with potential for exploitation by the herbicide industry. Compounds from both non-pathogenic and pathogenic microbes are discussed. Microbial phytotoxins with modes of action the same as those of commercial herbicides and those with novel modes of action of action are covered. Examples of the compounds discussed are tentoxin, AAL-toxin, auscaulitoxin aglycone, hydantocidin, thaxtomin, and tabtoxin

The effectiveness of e-Learning on biosecurity practice to slow the spread of invasive alien species

Online e-Learning is increasingly being used to provide environmental training. Prevention measures including biosecurity are essential to reducing the introduction and spread of invasive alien species (IAS) and are central to international and national IAS policy. This paper is the first to evaluate the effectiveness of e-Learning as a tool to increase awareness, risk perception and biosecurity behaviour in relation to IAS among individuals conducting work activities or research (fieldwork) in the field. We surveyed participants (a mixture of students and professionals) before, and 6 months after undertaking an e-Learning course on IAS and biosecurity practices. Awareness of IAS and self-reported biosecurity behaviour increased after e-Learning among students and professionals. Students had a lower awareness of IAS than professionals before training (20% of students vs 60% of professionals), but after training students showed a greater increase in awareness which led to similar levels of awareness post-training (81%). Prior to training, risk perception was also lower amongst students than professionals (33% of students and 59% of professionals were aware of the risk that their activities posed to the accidental spread of IAS). There was no change in risk perception amongst professionals after training, however training led to a doubling of risk perception in students. E-Learning also led to an increase in reported biosecurity behaviour and cleaning practices and there were higher levels of biosecurity cleaning amongst professionals. The higher awareness and better biosecurity amongst professionals is likely to reflect their familiarity with the issues of IAS and day-to-day activities in the field. Our results suggest that e-Learning is an effective tool to raise awareness and encourage behaviour change among field workers and researchers in an attempt to reduce the risk of accidental introduction and spread of IAS