Stem Cell Aging and Age-Related Cardiovascular Disease: Perspectives of Treatment by Ex-vivo Stem Cell Rejuvenation.

Aging affects endogenous stem cells in terms of functionality and numbers. In particular, during aging, the stemness property can decrease because of enhanced apoptotic cell death and senescence. In addition, aging and aging-related co-morbidities affect the paracrine activity of stem cells and the efficiency of their transplantation. Collectively, this leads to a reduction of the capacity of organs to repair themselves, possibly due to a reduced functional capability of stem cells. Therefore, major efforts have been invested to improve the repair capability of stem cells in aged individuals by overexpressing antisenescence and antiapoptotic genes. In this review, we describe critical genes and signaling pathways in stem cell aging and discuss ex vivo genetic modification approaches aimed at stem cell rejuvenation that are of interest for the cardiovascular system

Extracellular matrix formation after transplantation of human embryonic stem cell-derived cardiomyocytes

Transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CM) for cardiac regeneration is hampered by the formation of fibrotic tissue around the grafts, preventing electrophysiological coupling. Investigating this process, we found that: (1) beating hESC-CM in vitro are embedded in collagens, laminin and fibronectin, which they bind via appropriate integrins; (2) after transplantation into the mouse heart, hESC-CM continue to secrete collagen IV, XVIII and fibronectin; (3) integrin expression on hESC-CM largely matches the matrix type they encounter or secrete in vivo; (4) co-transplantation of hESC-derived endothelial cells and/or cardiac progenitors with hESC-CM results in the formation of functional capillaries; and (5) transplanted hESC-CM survive and mature in vivo for at least 24 weeks. These results form the basis of future developments aiming to reduce the adverse fibrotic reaction that currently complicates cell-based therapies for cardiac disease, and to provide an additional clue towards successful engraftment of cardiomyocytes by co-transplanting endothelial cells

Targeted encouragement of GP consultations for possible cancer symptoms: a randomised controlled trial

This is the final version. Available on open access from the Royal College of General Practitioners via the DOI in this recordBackground For some common cancers, survival is lower in the UK than in comparable high-income countries. Aim To assess the effectiveness of a targeted postal intervention (to promote awareness of cancer symptoms and earlier help seeking) on patient consultation rates. Design and setting A two-arm randomised controlled trial was carried out on patients aged 50-84 years registered at 23 general practices in rural and urban areas of Greater London, Greater Manchester, and the North East of England. Method Patients who had not had a consultation at their general practice in the previous 12 months and had at least two other risk factors for late presentation with cancer were randomised to intervention and control arms. The intervention consisted of a posted letter and leaflet. Primary outcome was the number of consultations at the practice with patients randomised to each arm in the 6 months subsequent to posting the intervention. All patients with outcome data were included in the intention-to-treat analyses. Results In total, 1513 patients were individually randomised to the intervention (n = 783) and control (n = 730) arms between Nov 2016 — May 2017; outcome data were available for 749 and 705 patients, respectively, with a statistically significantly higher rate of consultation in the intervention arm compared with the control arm: 436 versus 335 consultations (relative risk 1.40, 95% confidence interval = 1.11 to 1.77, P = 0.004). There was, however, no difference in the numbers of patients consulting. Conclusion Targeted interventions of this nature can change behaviour; there is a need to develop interventions that can be more effective at engaging patients with primary care. This study demonstrates that targeted interventions promoting both awareness of possible cancer symptoms and earlier health seeking, can change behaviour. There is a need to develop and test interventions that can be more effective at engaging the most at-risk patients.National Institute for Health Research (NIHR

Morphology of the first instar larva of obligatory traumatic myiasis agents (Diptera: Calliphoridae, Sarcophagidae)

There are only three fly species that are obligate agents of traumatic myiasis of humans and livestock: a single species of flesh fly, Wohlfahrtia magnifica (Sarcophagidae), and two species of blow flies, Chrysomya bezziana and Cochliomyia hominivorax (Calliphoridae). The morphology of their first instar larvae is thoroughly and consistently documented here with light microscopy photographs and scanning electron microscopy micrographs. The following morphological structures are documented: pseudocephalon, antennal complex, maxillary palpus, oral ridges, thoracic and abdominal spinulation, spiracular field, posterior spiracles and cephaloskeleton. New diagnostic features drawn from the cephaloskeleton and the spinulation of abdominal segments, including the anal pad, are discovered and extensively described. Earlier descriptions in the literature are revisited, and major discrepancies between these and the results of the current study are discussed. The present results allow clarification, correction and, especially, complementation of information provided by earlier authors. The relatively distant taxonomic position of all three species is evidence that obligatory myiasis has arisen independently, and the extensively similar morphology in the first instar larvae of Chrysomya bezziana, Cochliomyia hominivorax and W. magnifica in comparison to necrophagous species, especially the enhancement of the anterior part of the cephaloskeleton and the segmental spinulation, is therefore best interpreted as homoplasic adaptations to a life strategy as obligate vertebrate parasites. An identification key for first instar larvae of all obligatory traumatic myiasis agents of mammals is provided.Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited

Restored Agricultural Wetlands in central Iowa: Habitat Quality and Amphibian Response

Amphibians are declining throughout the United States and worldwide due, partly, to habitat loss. Conservation practices on the landscape restore wetlands to denitrify tile drainage effluent and restore ecosystem services. Understanding how water quality, hydroperiod, predation, and disease affect amphibians in restored wetlands is central to maintaining healthy amphibian populations in the region. We examined the quality of amphibian habitat in restored wetlands relative to reference wetlands by comparing species richness, developmental stress, and adult leopard frog (Lithobates pipiens) survival probabilities to a suite of environmental metrics. Although measured habitat variables differed between restored and reference wetlands, differences appeared to have sub-lethal rather than lethal effects on resident amphibian populations. There were few differences in amphibian species richness and no difference in estimated survival probabilities between wetland types. Restored wetlands had more nitrate and alkaline pH, longer hydroperiods, and were deeper, whereas reference wetlands had more amphibian chytrid fungus zoospores in water samples and resident amphibians exhibited increased developmental stress. Restored and reference wetlands are both important components of the landscape in central Iowa and maintaining a complex of fish-free wetlands with a variety of hydroperiods will likely contribute to the persistence of amphibians in this landscape

Backpack-mounted satellite transmitters do not affect reproductive performance in a migratory bustard

Backpack-mounted satellite transmitters (PTTs) are used extensively in the study of avian habitat use and of the movements and demography of medium- to large-bodied species, but can affect individuals’ performance and fitness. Transparent assessment of potential transmitter effects is important for both ethical accountability and confidence in, or adjustment to, life history parameter estimates. We assessed the influence of transmitters on seven reproductive parameters in Asian houbara Chlamydotis macqueenii, comparing 114 nests of 38 females carrying PTTs to 184 nests of untagged birds (non-PTT) over seven breeding seasons (2012‒2018) in Uzbekistan. There was no evidence of any influence of PTTs on: lay date (non-PTT x̅ = 91.7 Julian day ± 12.3 SD; PTT x̅ = 95.1 Julian day ± 15.7 SD); clutch size (non-PTT x̅ = 3.30 ± 0.68 SD; PTT x̅ = 3.25 ± 0.65 SD); mean egg weight at laying (non-PTT x̅ = 66.1g ± 5.4 SD; PTT x̅ = 66.4g ± 5.4 SD); nest success (non-PTT x̅ = 57.08% ± 4.3 SE; PTT x̅ = 58.24% ± 4.5 SE for nests started 2 April); egg hatchability (non-PTT x̅ = 88.3% ± 2.2 SE; PTT x̅ = 88.3% ± 2.6 SE); or chick survival to fledging from broods that had at least one surviving chick (non-PTT x̅ = 63.4% ± 4.2 SE; PTT x̅= 64.4% ± 4.7 SE). High nesting propensity (97.3% year-1 ± 1.9% SE) of tagged birds indicated minimal PTT effect on breeding probability. These findings show harness-mounted transmitters can give unbiased measures of demographic parameters of this species, and are relevant to other large-bodied, cursorial, ground-nesting birds of open habitats, particularly other bustards

Chick Embryo Partial Ischemia Model: A New Approach to Study Ischemia Ex Vivo

Background: Ischemia is a pathophysiological condition due to blockade in blood supply to a specific tissue thus damaging the physiological activity of the tissue. Different in vivo models are presently available to study ischemia in heart and other tissues. However, no ex vivo ischemia model has been available to date for routine ischemia research and for faster screening of anti-ischemia drugs. In the present study, we took the opportunity to develop an ex vivo model of partial ischemia using the vascular bed of 4th day incubated chick embryo. Methodology/Principal Findings: Ischemia was created in chick embryo by ligating the right vitelline artery using sterile surgical suture. Hypoxia inducible factor- 1 alpha (HIF-1a), creatine phospho kinase-MB and reactive oxygen species in animal tissues and cells were measured to confirm ischemia in chick embryo. Additionally, ranolazine, N-acetyl cysteine and trimetazidine were administered as an anti-ischemic drug to validate the present model. Results from the present study depicted that blocking blood flow elevates HIF-1a, lipid peroxidation, peroxynitrite level in ischemic vessels while ranolazine administration partially attenuates ischemia driven HIF-1a expression. Endothelial cell incubated on ischemic blood vessels elucidated a higher level of HIF-1a expression with time while ranolazine treatment reduced HIF-1a in ischemic cells. Incubation of caprine heart strip on chick embryo ischemia model depicted an elevated creatine phospho kinase-MB activity under ischemic condition while histology of the treated heart sections evoked edema and disruption of myofibril structures. Conclusions/Significance: The present study concluded that chick embryo partial ischemia model can be used as a novel ex vivo model of ischemia. Therefore, the present model can be used parallel with the known in vivo ischemia models in understanding the mechanistic insight of ischemia development and in evaluating the activity of anti-ischemic drug.status: publishe

Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database

Background: Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). Methods: An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. Results: Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78-1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54-1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93-1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. Conclusions: In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS. Trial registration: NCT02010073. Registered on 12 December 2013

Spontaneous Breathing in Early Acute Respiratory Distress Syndrome: Insights From the Large Observational Study to UNderstand the Global Impact of Severe Acute Respiratory FailurE Study

OBJECTIVES: To describe the characteristics and outcomes of patients with acute respiratory distress syndrome with or without spontaneous breathing and to investigate whether the effects of spontaneous breathing on outcome depend on acute respiratory distress syndrome severity. DESIGN: Planned secondary analysis of a prospective, observational, multicentre cohort study. SETTING: International sample of 459 ICUs from 50 countries. PATIENTS: Patients with acute respiratory distress syndrome and at least 2 days of invasive mechanical ventilation and available data for the mode of mechanical ventilation and respiratory rate for the 2 first days. INTERVENTIONS: Analysis of patients with and without spontaneous breathing, defined by the mode of mechanical ventilation and by actual respiratory rate compared with set respiratory rate during the first 48 hours of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Spontaneous breathing was present in 67% of patients with mild acute respiratory distress syndrome, 58% of patients with moderate acute respiratory distress syndrome, and 46% of patients with severe acute respiratory distress syndrome. Patients with spontaneous breathing were older and had lower acute respiratory distress syndrome severity, Sequential Organ Failure Assessment scores, ICU and hospital mortality, and were less likely to be diagnosed with acute respiratory distress syndrome by clinicians. In adjusted analysis, spontaneous breathing during the first 2 days was not associated with an effect on ICU or hospital mortality (33% vs 37%; odds ratio, 1.18 [0.92-1.51]; p = 0.19 and 37% vs 41%; odds ratio, 1.18 [0.93-1.50]; p = 0.196, respectively ). Spontaneous breathing was associated with increased ventilator-free days (13 [0-22] vs 8 [0-20]; p = 0.014) and shorter duration of ICU stay (11 [6-20] vs 12 [7-22]; p = 0.04). CONCLUSIONS: Spontaneous breathing is common in patients with acute respiratory distress syndrome during the first 48 hours of mechanical ventilation. Spontaneous breathing is not associated with worse outcomes and may hasten liberation from the ventilator and from ICU. Although these results support the use of spontaneous breathing in patients with acute respiratory distress syndrome independent of acute respiratory distress syndrome severity, the use of controlled ventilation indicates a bias toward use in patients with higher disease severity. In addition, because the lack of reliable data on inspiratory effort in our study, prospective studies incorporating the magnitude of inspiratory effort and adjusting for all potential severity confounders are required