Paracrine or virus-mediated induction of decorin expression by endothelial cells contributes to tube formation and prevention of apoptosis in collagen lattices

Resting endothelial cells express the small proteoglycan biglycan, whereas sprouting endothelial cells also synthesize decorin, a related proteoglycan. Here we show that decorin is expressed in endothelial cells in human granulomatous tissue. For in vitro investigations, the human endothelium-derived cell line, EA.hy 926, was cultured for 6 or more days in the presence of 1% fetal calf serum on top of or within floating collagen lattices which were also populated by a small number of rat fibroblasts. Endothelial cells aligned in cord-like structures and developed cavities that were surrounded by human decorin. About 14% and 20% of endothelial cells became apoptotic after 6 and 12 days of co-culture, respectively. In the absence of fibroblasts, however, the extent of apoptosis was about 60% after 12 days, and cord-like structures were not formed nor could decorin production be induced. This was also the case when lattices populated by EA.hy 926 cells were maintained under one of the following conditions: 1) 10% fetal calf serum; 2) fibroblast-conditioned media; 3) exogenous decorin; or 4) treatment with individual growth factors known to be involved in angiogenesis. The mechanism(s) by which fibroblasts induce an angiogenic phenotype in EA.hy 926 cells is (are) not known, but a causal relationship between decorin expression and endothelial cell phenotype was suggested by transducing human decorin cDNA into EA.hy 926 cells using a replication-deficient adenovirus. When the transduced cells were cultured in collagen lattices, there was no requirement of fibroblasts for the formation of capillary-like structures and apoptosis was reduced. Thus, decorin expression seems to be of special importance for the survival of EA.hy 926 cells as well as for cord and tube formation in this angiogenesis model.

Detection, treatment, and prevention of carbapenemase-producing Enterobacteriaceae : Recommendations from an International Working Group

The prevalence of carbapenemase-producing Enterobacteriaceae (CPE) has increased during the past 10 years. Its detection is frequently difficult, because they do not always show a minimum inhibitory concentration (MIC) value for carbapenems in the resistance range. Both broth microdilution and agar dilution methods are more sensitive than disk diffusion method, Etest and automated systems. Studies on antimicrobial treatment are based on a limited number of patients; therefore, the optimal treatment is not well established. Combination therapy with two active drugs appears to be more effective than monotherapy. Combination of a carbapenem with another active agent — preferentially an aminoglycoside or colistin — could lower mortality provided that the MIC is #4 mg/l and probably #8 mg/l, and is administered in a higher-dose/prolonged-infusion regimen. An aggressive infection control and prevention strategy is recommended, including reinforcement of hand hygiene, using contact precautions and early detection of CPE through use of targeted surveillance.

Heart rate is a prognostic risk factor for myocardial infarction: a post hoc analysis in the PERFORM (Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack) study population

BACKGROUND Elevated resting heart rate is known to be detrimental to morbidity and mortality in cardiovascular disease, though its effect in patients with ischemic stroke is unclear. We analyzed the effect of baseline resting heart rate on myocardial infarction (MI) in patients with a recent noncardioembolic cerebral ischemic event participating in PERFORM. METHODS We compared fatal or nonfatal MI using adjusted Cox proportional hazards models for PERFORM patients with baseline heart rate <70 bpm (n=8178) or ≥70 bpm (n=10,802). In addition, heart rate was analyzed as a continuous variable. Other cerebrovascular and cardiovascular outcomes were also explored. RESULTS Heart rate ≥70 bpm was associated with increased relative risk for fatal or nonfatal MI (HR 1.32, 95% CI 1.03-1.69, P=0.029). For every 5-bpm increase in heart rate, there was an increase in relative risk for fatal and nonfatal MI (11.3%, P=0.0002). Heart rate ≥70 bpm was also associated with increased relative risk for a composite of fatal or nonfatal ischemic stroke, fatal or nonfatal MI, or other vascular death (excluding hemorrhagic death) (P<0001); vascular death (P<0001); all-cause mortality (P<0001); and fatal or nonfatal stroke (P=0.04). For every 5-bpm increase in heart rate, there were increases in relative risk for fatal or nonfatal ischemic stroke, fatal or nonfatal MI, or other vascular death (4.7%, P<0.0001), vascular death (11.0%, P<0.0001), all-cause mortality (8.0%, P<0.0001), and fatal and nonfatal stroke (2.4%, P=0.057). CONCLUSION Elevated heart rate ≥70 bpm places patients with a noncardioembolic cerebral ischemic event at increased risk for MI.

Prediction and prevention of psychosis: current progress and future tasks

Prevention of psychoses has been intensively investigated within the past two decades, and particularly, prediction has been much advanced. Depending on the applied risk indicators, current criteria are associated with average, yet significantly heterogeneous transition rates of ≥30 % within 3 years, further increasing with longer follow-up periods. Risk stratification offers a promising approach to advance current prediction as it can help to reduce heterogeneity of transition rates and to identify subgroups with specific needs and response patterns, enabling a targeted intervention. It may also be suitable to improve risk enrichment. Current results suggest the future implementation of multi-step risk algorithms combining sensitive risk detection by cognitive basic symptoms (COGDIS) and ultra-high-risk (UHR) criteria with additional individual risk estimation by a prognostic index that relies on further predictors such as additional clinical indicators, functional impairment, neurocognitive deficits, and EEG and structural MRI abnormalities, but also considers resilience factors. Simply combining COGDIS and UHR criteria in a second step of risk stratification produced already a 4-year hazard rate of 0.66. With regard to prevention, two recent meta-analyses demonstrated that preventive measures enable a reduction in 12-month transition rates by 54-56 % with most favorable numbers needed to treat of 9-10. Unfortunately, psychosocial functioning, another important target of preventive efforts, did not improve. However, these results are based on a relatively small number of trials; and more methodologically sound studies and a stronger consideration of individual profiles of clinical needs by modular intervention programs are required

Combined effect of a fluoride-, stannous- and chitosan-containing toothpaste and stannous-containing rinse on the prevention of initial enamel erosion-abrasion.

OBJECTIVES The aim of this study was to assess the preventive effect of a fluoride-, stannous- and chitosan-containing (F/Sn/chitosan-) toothpaste (TP) on initial enamel erosion and abrasion. METHODS In total, 150 human premolar enamel specimens were ground, polished and divided into 5 toothpaste/rinse groups (n=30): (G1) placebo-TP/tap water, (G2) sodium fluoride (NaF-) TP/tap water, (G3) F/Sn/chitosan-TP/tap water, (G4) F/Sn/chitosan-TP/Sn-rinse, (G5) NaF-TP/NaF-rinse. The 8-day erosion-abrasion cyclic treatment (one cycle/day) consisted of incubating the samples in artificial saliva (30min), then submitting the samples to toothbrush abrasion (2min incubation in toothpaste slurry; brushing with 20 toothbrush strokes) and rinsing (2min; 10ml) with the respective solution: tap water (G1-G3), Sn-rinse (G4) or NaF-rinse (G5). Afterwards, the samples were submitted to erosion (2min; 30ml 1% citric acid, pH=3.6). Surface microhardness (SMH) was measured initially and after every abrasion and erosion treatment. Enamel substance loss was calculated after each abrasion. Non-parametric ANOVA followed by Wilcoxon rank tests were used for analysis. RESULTS G1 presented the greatest SMH decrease, while G4 presented the least SMH decrease (p<0.001). G3 had a similar SMH decrease to G2 and G5. Substance loss was significantly lower in G4 than all other groups (p<0.05), closely followed by G3. Both G2 and G5 showed similar calculated enamel substance loss to G1. CONCLUSION The treatment with F/Sn/chitosan-TP and tap water provided a similar SMH decrease to both NaF-TP groups, but significantly lower substance loss. F/Sn/Chitosan-TP and Sn-rinse showed a better preventive effect, which promoted less SMH decrease and reduced substance loss. CLINICAL SIGNIFICANCE The toothpaste containing fluoride, stannous and chitosan shows promising results in reducing substance loss from erosion and abrasion. The combination of this toothpaste with the stannous-containing rinse showed even better prevention against erosion-abrasion.

Antiplatelet therapy for secondary prevention of coronary artery disease.

The choice and duration of antiplatelet therapy for secondary prevention of coronary artery disease (CAD) is determined by the clinical context and treatment strategy. Oral antiplatelet agents for secondary prevention include the cyclo-oxygenase-1 inhibitor aspirin, and the ADP dependent P2Y12 inhibitors clopidogrel, prasugrel and ticagrelor. Aspirin constitutes the cornerstone in secondary prevention of CAD and is complemented by clopidogrel in patients with stable CAD undergoing percutaneous coronary intervention. Among patients with acute coronary syndrome, prasugrel and ticagrelor improve net clinical outcome by reducing ischaemic adverse events at the expense of an increased risk of bleeding as compared with clopidogrel. Prasugrel appears particularly effective among patients with ST elevation myocardial infarction to reduce the risk of stent thrombosis compared with clopidogrel, and offered a greater net clinical benefit among patients with diabetes compared with patients without diabetes. Ticagrelor is associated with reduced mortality without increasing the rate of coronary artery bypass graft (CABG)-related bleeding as compared with clopidogrel. Dual antiplatelet therapy should be continued for a minimum of 1 year among patients with acute coronary syndrome irrespective of stent type; among patients with stable CAD treated with new generation drug-eluting stents, available data suggest no benefit to prolong antiplatelet treatment beyond 6 months.

Closure of patent foramen ovale for secondary prevention of cerebrovascular events

Stroke is the most debilitating cardiovascular event. It has a variety of causes that may be present simultaneously. In young or otherwise healthy people a patent foramen ovale (PFO) is increasingly searched for. In stroke of the elderly atherosclerosis and atrial fibrillation are in the foreground but the PFO should not be ignored. The risk of a PFO related stroke over time is controversial and so is its prevention by PFO closure. Percutaneous PFO closure is a minimally invasive procedure which can be performed with high success and low morbidity. We review the rationale for PFO closure for secondary prevention of embolic events.

Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease

OBJECTIVE This EAS Consensus Panel critically appraised evidence relevant to the benefit to risk relationship of functional foods with added plant sterols and/or plant stanols, as components of a healthy lifestyle, to reduce plasma low-density lipoprotein-cholesterol (LDL-C) levels, and thereby lower cardiovascular risk. METHODS AND RESULTS Plant sterols/stanols (when taken at 2 g/day) cause significant inhibition of cholesterol absorption and lower LDL-C levels by between 8 and 10%. The relative proportions of cholesterol versus sterol/stanol levels are similar in both plasma and tissue, with levels of sterols/stanols being 500-/10,000-fold lower than those of cholesterol, suggesting they are handled similarly to cholesterol in most cells. Despite possible atherogenicity of marked elevations in circulating levels of plant sterols/stanols, protective effects have been observed in some animal models of atherosclerosis. Higher plasma levels of plant sterols/stanols associated with intakes of 2 g/day in man have not been linked to adverse effects on health in long-term human studies. Importantly, at this dose, plant sterol/stanol-mediated LDL-C lowering is additive to that of statins in dyslipidaemic subjects, equivalent to doubling the dose of statin. The reported 6-9% lowering of plasma triglyceride by 2 g/day in hypertriglyceridaemic patients warrants further evaluation. CONCLUSION Based on LDL-C lowering and the absence of adverse signals, this EAS Consensus Panel concludes that functional foods with plant sterols/stanols may be considered 1) in individuals with high cholesterol levels at intermediate or low global cardiovascular risk who do not qualify for pharmacotherapy, 2) as an adjunct to pharmacologic therapy in high and very high risk patients who fail to achieve LDL-C targets on statins or are statin- intolerant, 3) and in adults and children (>6 years) with familial hypercholesterolaemia, in line with current guidance. However, it must be acknowledged that there are no randomised, controlled clinical trial data with hard end-points to establish clinical benefit from the use of plant sterols or plant stanols.

Prevention of preterm delivery with vaginal progesterone in women with preterm labour (4P): randomised double-blind placebo-controlled trial.

OBJECTIVE To evaluate the effectiveness of 200 mg of daily vaginal natural progesterone to prevent preterm birth in women with preterm labour. DESIGN Multicentre, randomised, double-blind, placebo-controlled trial. SETTING Twenty-nine centres in Switzerland and Argentina. POPULATION A total of 385 women with preterm labour (24(0/7) to 33(6/7) weeks of gestation) treated with acute tocolysis. METHODS Participants were randomly allocated to either 200 mg daily of self-administered vaginal progesterone or placebo within 48 hours of starting acute tocolysis. MAIN OUTCOME MEASURES Primary outcome was delivery before 37 weeks of gestation. Secondary outcomes were delivery before 32 and 34 weeks, adverse effects, duration of tocolysis, re-admissions for preterm labour, length of hospital stay, and neonatal morbidity and mortality. The study was ended prematurely based on results of the intermediate analysis. RESULTS Preterm birth occurred in 42.5% of women in the progesterone group versus 35.5% in the placebo group (relative risk [RR] 1.2; 95% confidence interval [95% CI] 0.93-1.5). Delivery at <32 and <34 weeks did not differ between the two groups (12.9 versus 9.7%; [RR 1.3; 95% CI 0.7-2.5] and 19.7 versus 12.9% [RR 1.5; 95% CI 0.9-2.4], respectively). The duration of tocolysis, hospitalisation, and recurrence of preterm labour were comparable between groups. Neonatal morbidity occurred in 44 (22.8%) cases on progesterone versus 35 (18.8%) cases on placebo (RR: 1.2; 95% CI 0.82-1.8), whereas there were 4 (2%) neonatal deaths in each study group. CONCLUSION There is no evidence that the daily administration of 200 mg vaginal progesterone decreases preterm birth or improves neonatal outcome in women with preterm labour.

The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study: protocol for an international multicentre randomised controlled trial

INTRODUCTION Postoperative delirium is one of the most common complications of major surgery, affecting 10-70% of surgical patients 60 years and older. Delirium is an acute change in cognition that manifests as poor attention and illogical thinking and is associated with longer intensive care unit (ICU) and hospital stay, long-lasting cognitive deterioration and increased mortality. Ketamine has been used as an anaesthetic drug for over 50 years and has an established safety record. Recent research suggests that, in addition to preventing acute postoperative pain, a subanaesthetic dose of intraoperative ketamine could decrease the incidence of postoperative delirium as well as other neurological and psychiatric outcomes. However, these proposed benefits of ketamine have not been tested in a large clinical trial. METHODS The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study is an international, multicentre, randomised controlled trial. 600 cardiac and major non-cardiac surgery patients will be randomised to receive ketamine (0.5 or 1 mg/kg) or placebo following anaesthetic induction and prior to surgical incision. For the primary outcome, blinded observers will assess delirium on the day of surgery (postoperative day 0) and twice daily from postoperative days 1-3 using the Confusion Assessment Method or the Confusion Assessment Method for the ICU. For the secondary outcomes, blinded observers will estimate pain using the Behavioral Pain Scale or the Behavioral Pain Scale for Non-Intubated Patients and patient self-report. ETHICS AND DISSEMINATION The PODCAST trial has been approved by the ethics boards of five participating institutions; approval is ongoing at other sites. Recruitment began in February 2014 and will continue until the end of 2016. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement and popular media. REGISTRATION DETAILS The study is registered at clinicaltrials.gov, NCT01690988 (last updated March 2014). The PODCAST trial is being conducted under the auspices of the Neurological Outcomes Network for Surgery (NEURONS). TRIAL REGISTRATION NUMBER NCT01690988 (last updated December 2013).

Prevention of increased abnormal fundus autofluorescence with blue light-filtering intraocular lenses

PURPOSE To observe changes in fundus autofluorescence 2 years after implantation of blue light-filtering (yellow-tinted) and ultraviolet light-filtering (colorless) intraocular lenses (IOLs). SETTING Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, and the Department of Ophthalmology, University of Bern, Bern, Switzerland. DESIGN Prospective comparative observational study. METHODS Patients were enrolled who had cataract surgery with implantation of a yellow-tinted or colorless IOL and for whom images were obtained on which the fundus autofluorescence was measurable using the Heidelberg Retina Angiogram 2 postoperatively. The fundus autofluorescence in the images was classified into 8 abnormal patterns based on the classification of the International Fundus Autofluorescence Classification Group, The presence of normal fundus autofluorescence, geographic atrophy, and wet age-related macular degeneration (AMD) also was recorded. The fundus findings at baseline and 2 years postoperatively were compared. RESULTS Fifty-two eyes with a yellow-tinted IOL and 79 eyes with a colorless IOL were included. Abnormal fundus autofluorescence did not develop or increase in the yellow-tinted IOL group; however, progressive abnormal fundus autofluorescence developed or increased in 12 eyes (15.2%) in the colorless IOL group (P = .0016). New drusen, geographic atrophy, and choroidal neovascularization were observed mainly in the colorless IOL group. The incidence of AMD was statistically significantly higher in the colorless IOL group (P = .042). CONCLUSIONS Two years after cataract surgery, significant differences were seen in the progression of abnormal fundus autofluorescence between the 2 groups. The incidence of AMD was lower in eyes with a yellow-tinted IOL. FINANCIAL DISCLOSURE No author has a financial or proprietary interest in any material or method mentioned.

Prophylactic antibiotics or G(M)-CSF for the prevention of infections and improvement of survival in cancer patients receiving myelotoxic chemotherapy.

BACKGROUND Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment-related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The two main types of prophylactic regimens are granulocyte (macrophage) colony-stimulating factors (G(M)-CSF) and antibiotics, frequently quinolones or cotrimoxazole. Current guidelines recommend the use of colony-stimulating factors when the risk of febrile neutropenia is above 20%, but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken. OBJECTIVES To compare the efficacy and safety of G(M)-CSF compared to antibiotics in cancer patients receiving myelotoxic chemotherapy. SEARCH METHODS We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to December 2015). We planned to include both full-text and abstract publications. Two review authors independently screened search results. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing prophylaxis with G(M)-CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimes and other supportive care. We included full-text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. We excluded cross-over trials, quasi-randomised trials and post-hoc retrospective trials. DATA COLLECTION AND ANALYSIS Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard Cochrane methods. We did final interpretation together with an experienced clinician. MAIN RESULTS In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high-dose chemotherapy and G-CSF compared to antibiotics, a second one evaluating 155 patients with small-cell lung cancer receiving GM-CSF or antibiotics.We judge the overall risk of bias as high in the G-CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM-CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias.For the trial comparing G-CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection-related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection-related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias.There was no evidence of a difference in terms of median survival time in the trial comparing GM-CSF and antibiotics. Two-year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM-CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM-CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM-CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non-haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM-CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection-related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial. AUTHORS' CONCLUSIONS As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.