Aims/hypothesis We sought to establish the extent and basis for adaptive changes in beta cell numbers in human pregnancy. Methods Pancreas was obtained at autopsy from women who had died while ...pregnant (n = 18), post-partum (n = 6) or were not pregnant at or shortly before death (controls; n = 20). Pancreases were evaluated for fractional pancreatic beta cell area, islet size and islet fraction of beta cells, beta cell replication (Ki67) and apoptosis (TUNEL), and indirect markers of beta cell neogenesis (insulin-positive cells in ducts and scattered beta cells in pancreas). Results The pancreatic fractional beta cell area was increased by ∼1.4-fold in human pregnancy, with no change in mean beta cell size. In pregnancy there were more small islets rather than an increase in islet size or beta cells per islet. No increase in beta cell replication or change in beta cell apoptosis was detected, but duct cells positive for insulin and scattered beta cells were increased with pregnancy. Conclusions/interpretation The adaptive increase in beta cell numbers in human pregnancy is not as great as in most reports in rodents. This increase in humans is achieved by increased numbers of beta cells in apparently new small islets, rather than duplication of beta cells in existing islets, which is characteristic of pregnancy in rodents.
Organs recovered from donors after circulatory death (DCD) suffer warm ischemia before cold storage which may prejudice graft survival and result in a greater risk of complications after transplant. ...A period of normothermic regional perfusion (NRP) in the donor may reverse these effects and improve organ function. Twenty‐one NRP retrievals from Maastricht category III DCD donors were performed at three UK centers. NRP was established postasystole via aortic and caval cannulation and maintained for 2 h. Blood gases and biochemistry were monitored to assess organ function. Sixty‐three organs were recovered. Forty‐nine patients were transplanted. The median time from asystole to NRP was 16 min (range 10–23 min). Thirty‐two patients received a kidney transplant. The median cold ischemia time was 12 h 30 min (range 5 h 25 min–18 h 22 min). The median creatinine at 3 and 12 months was 107 µmol/L (range 72–222) and 121 µmol/L (range 63–157), respectively. Thirteen (40%) recipients had delayed graft function and four lost the grafts. Eleven patients received a liver transplant. The first week median peak ALT was 389 IU/L (range 58–3043). One patient had primary nonfunction. Two combined pancreas–kidney transplants, one islet transplant and three double lung transplants were performed with primary function. NRP in DCD donation facilitates organ recovery and may improve short‐term outcomes.
This study shows that the use of normothermic regional perfusion for organ recovery from controlled donation after circulatory death leads to an increased organ recovery rate and may improve short‐term transplant outcomes.
There is growing evidence that excessive microglial phagocytosis of neurons and synapses contributes to multiple brain pathologies. RNA‐seq and genome‐wide association (GWAS) studies have linked ...multiple phagocytic genes to neurodegenerative diseases, and knock‐out of phagocytic genes has been found to protect against neurodegeneration in animal models, suggesting that excessive microglial phagocytosis contributes to neurodegeneration. Here, we review recent evidence that microglial phagocytosis of live neurons and synapses causes neurodegeneration in animal models of Alzheimer's disease and other tauopathies, Parkinson's disease, frontotemporal dementias, multiple sclerosis, retinal degeneration and neurodegeneration induced by ischaemia, infection or ageing. We also review factors regulating microglial phagocytosis of neurons, including: nucleotides, frackalkine, phosphatidylserine, calreticulin, UDP, CD47, sialylation, complement, galectin‐3, Apolipoprotein E, phagocytic receptors, Siglec receptors, cytokines, microglial epigenetics and expression profile. Some of these factors may be potential treatment targets to prevent neurodegeneration mediated by excessive microglial phagocytosis of live neurons and synapses.
Microglia are the brain's main phagocytes and can phagocytose both live and dead neurons, as well as synapses, dendrites and axons. We review here how this microglial phagocytosis is regulated, and the evidence that microglial phagocytosis of live neurons and synapses may contribute to neurodegeneration. During neurodegenerative disease, neurons, dendrites or synapses may become stressed by aggregated proteins, neuroinflammation, oxidants, energy depletion or excitotoxicity, resulting in release of opsonins, find‐me and eat‐me signals, inducing their phagocytosis by activated microglia. Thus, blocking this signalling and phagocytosis may help prevent neurodegeneration.
The sound of a tropical forest Burivalova, Zuzana; Game, Edward T; Butler, Rhett A
Science (American Association for the Advancement of Science),
01/2019, Volume:
363, Issue:
6422
Journal Article
Genome-wide methylation arrays are powerful tools for assessing cell composition of complex mixtures. We compare three approaches to select reference libraries for deconvoluting neutrophil, monocyte, ...B-lymphocyte, natural killer, and CD4+ and CD8+ T-cell fractions based on blood-derived DNA methylation signatures assayed using the Illumina HumanMethylationEPIC array. The IDOL algorithm identifies a library of 450 CpGs, resulting in an average R
= 99.2 across cell types when applied to EPIC methylation data collected on artificial mixtures constructed from the above cell types. Of the 450 CpGs, 69% are unique to EPIC. This library has the potential to reduce unintended technical differences across array platforms.
Biologists employ phylogenetic comparative methods to study adaptive evolution. However, none of the popular methods model selection directly. We explain and develop a method based on the ...Ornstein‐Uhlenbeck (OU) process, first proposed by Hansen. Ornstein‐Uhlenbeck models incorporate both selection and drift and are thus qualitatively different from, and more general than, pure drift models based on Brownian motion. Most importantly, OU models possess selective optima that formalize the notion of adaptive zone. In this article, we develop the method for one quantitative character, discuss interpretations of its parameters, and provide code implementing the method. Our approach allows us to translate hypotheses regarding adaptation in different selective regimes into explicit models, to test the models against data using maximum‐likelihood‐based model selection techniques, and to infer details of the evolutionary process. We illustrate the method using two worked examples. Relative to existing approaches, the direct modeling approach we demonstrate allows one to explore more detailed hypotheses and to utilize more of the information content of comparative data sets than existing methods. Moreover, the use of a model selection framework to simultaneously compare a variety of hypotheses advances our ability to assess alternative evolutionary explanations.
DNA methylation microarrays can be employed to interrogate cell-type composition in complex tissues. Here, we expand reference-based deconvolution of blood DNA methylation to include 12 leukocyte ...subtypes (neutrophils, eosinophils, basophils, monocytes, naïve and memory B cells, naïve and memory CD4 + and CD8 + T cells, natural killer, and T regulatory cells). Including derived variables, our method provides 56 immune profile variables. The IDOL (IDentifying Optimal Libraries) algorithm was used to identify libraries for deconvolution of DNA methylation data for current and previous platforms. The accuracy of deconvolution estimates obtained using our enhanced libraries was validated using artificial mixtures and whole-blood DNA methylation with known cellular composition from flow cytometry. We applied our libraries to deconvolve cancer, aging, and autoimmune disease datasets. In conclusion, these libraries enable a detailed representation of immune-cell profiles in blood using only DNA and facilitate a standardized, thorough investigation of immune profiles in human health and disease.
Abstract
Difficulties with tracheal intubation commonly arise and impact patient safety. This systematic review evaluates whether videolaryngoscopes reduce intubation failure and complications ...compared with direct laryngoscopy in adults. We searched CENTRAL, MEDLINE, Embase and clinicaltrials.gov up to February 2015, and conducted forward and backward citation tracking. We included randomized controlled trials that compared adult patients undergoing laryngoscopy with videolaryngoscopy or Macintosh laryngoscopy. We did not primarily intend to compare individual videolaryngoscopes. Sixty-four studies (7044 participants) were included. Moderate quality evidence showed that videolaryngoscopy reduced failed intubations (Odds Ratio (OR) 0.35, 95% Confidence Interval (CI) 0.19-0.65) including in participants with anticipated difficult airways (OR 0.28, 95% CI 0.15-0.55). There was no evidence of reduction in hypoxia or mortality, but few studies reported these outcomes. Videolaryngoscopes reduced laryngeal/airway trauma (OR 0.68, 95% CI 0.48-0.96) and hoarseness (OR 0.57, 95% CI 0.36-0.88). Videolaryngoscopy increased easy laryngeal views (OR 6.77, 95% CI 4.17-10.98) and reduced difficult views (OR 0.18, 95% CI 0.13-0.27) and intubation difficulty, typically using an 'intubation difficulty score' (OR 7.13, 95% CI 3.12-16.31). Failed intubations were reduced with experienced operators (OR 0.32, 95% CI 0.13-0.75) but not with inexperienced users. We identified no difference in number of first attempts and incidence of sore throat. Heterogeneity around time for intubation data prevented meta-analysis. We found evidence of differential performance between different videolaryngoscope designs. Lack of data prevented analysis of impact of obesity or clinical location on failed intubation rates. Videolaryngoscopes may reduce the number of failed intubations, particularly among patients presenting with a difficult airway. They improve the glottic view and may reduce laryngeal/airway trauma. Currently, no evidence indicates that use of a videolaryngoscope reduces the number of intubation attempts or the incidence of hypoxia or respiratory complications, and no evidence indicates that use of a videolaryngoscope affects time required for intubation.
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