16 research outputs found

    Addition of terlipressin to initial volume resuscitation in a pediatric model of hemorrhagic shock improves hemodynamics and cerebral perfusion

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    Hemorrhagic shock is one of the leading causes of mortality and morbidity in pediatric trauma. Current treatment based on volume resuscitation is associated to adverse effects, and it has been proposed that vasopressors may be used in the pharmacological management of trauma. Terlipressin has demonstrated its usefulness in other pediatric critical care scenarios and its long half-life allows its use as a bolus in an outpatient critical settings. The aim of this study was to analyze whether the addition of a dose of terlipressin to the initial volume expansion produces an improvement in hemodynamic and cerebral perfusion at early stages of hemorrhagic shock in an infant animal model. We conducted an experimental randomized animal study with 1-month old pigs. After 30 minutes of hypotension (mean arterial blood pressure [MAP]<45 mmHg) induced by the withdrawal of blood over 30 min, animals were randomized to receive either normal saline (NS) 30 mL/kg (n = 8) or a bolus of 20 mcg/kg of terlipressin plus 30 mL/kg of normal saline (TP) (n = 8). Global hemodynamic and cerebral monitoring parameters, brain damage markers and histology samples were compared. After controlled bleeding, significant decreases were observed in MAP, cardiac index (CI), central venous pressure, global end-diastolic volume index (GEDI), left cardiac output index, SvO(2), intracranial pressure, carotid blood flow, bispectral index (BIS), cerebral perfusion pressure (CPP) and increases in systemic vascular resistance index, heart rate and lactate. After treatment, MAP, GEDI, CI, CPP and BIS remained significantly higher in the TP group. The addition of a dose of terlipressin to initial fluid resuscitation was associated with hemodynamic improvement, intracranial pressure maintenance and better cerebral perfusion, which would mean protection from ischemic injury. Brain monitoring through BIS was able to detect changes caused by hemorrhagic shock and treatment.This work was partially supported by Basque Government Grant (GIU19/026) to VEM and Spanish Society of pediatric critical care (Ruza Grant 2017) to JG

    Neuronal hyperactivity disturbs ATP microgradients, impairs microglial motility, and reduces phagocytic receptor expression triggering apoptosis/microglial phagocytosis uncoupling

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    Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders

    Reactive Disruption of the Hippocampal Neurogenic Niche After Induction of Seizures by Injection of Kainic Acid in the Amygdala

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    Adult neurogenesis persists in the adult hippocampus due to the presence of multipotent neural stem cells (NSCs). Hippocampal neurogenesis is involved in a range of cognitive functions and is tightly regulated by neuronal activity. NSCs respond promptly to physiological and pathological stimuli altering their neurogenic and gliogenic potential. In a mouse model of mesial temporal lobe epilepsy (MTLE), seizures triggered by the intrahippocampal injection of the glutamate receptor agonist kainic acid (KA) induce NSCs to convert into reactive NSCs (React-NSCs) which stop producing new neurons and ultimately generate reactive astrocytes thus contributing to the development of hippocampal sclerosis and abolishing neurogenesis. We herein show how seizures triggered by the injection of KA in the amygdala, an alternative model of MTLE which allows parallel experimental manipulation in the dentate gyrus, also trigger the induction of React-NSCs and provoke the disruption of the neurogenic niche resulting in impaired neurogenesis. These results highlight the sensitivity of NSCs to the surrounding neuronal circuit activity and demonstrate that the induction of React-NSCs and the disruption of the neurogenic niche are not due to the direct effect of KA in the hippocampus. These results also suggest that neurogenesis might be lost in the hippocampus of patients with MTLE. Indeed we provide results from human MTLE samples absence of cell proliferation, of neural stem cell-like cells and of neurogenesis.This work was funded by the grants RyC-2012-11137 (MINECO) and SAF-2015-70866-R (MINECO with FEDER funds) to JE and PI_2016_0011 (Basque Government) to AS. This work was also supported by the Chilean Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) with grant Fondecyt regular 1141089, PIA Anillo en Investigacion en Ciencia y Tecnologia ACT 172121, and PIA Anillo ACT 1414

    Microglial phagocytic response during in vivo acute and chronic inflammatory challenge.

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    <p>(<b>A</b>) Experimental design and apoptosis in the DG of c57BL/6 fms-EGFP 1-mo mice injected systemically with LPS (1mg/kg; <i>n</i> = 5) or vehicle (saline; <i>n</i> = 4) 8 h prior to sacrifice. Apoptotic cells were identified by pyknosis/karryorhexis. <b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.g002" target="_blank">Fig 2A</a></b> was generated from data that was originally published as part of [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.ref009" target="_blank">9</a>]. (<b>B</b>) Weighted Ph capacity of microglia (in parts per unit, ppu) in control and LPS mice. (<b>C</b>) Number of microglial cells in control and LPS mice. (<b>D</b>) Ph/A coupling in the 1-mo mouse hippocampus (in fold change) during acute inflammatory challenge. (<b>E</b>) Experimental design and representative confocal z-stacks of the DG of PND21 Swiss mice fed during gestation and lactation with a diet balanced (Ω3 bal; <i>n</i> = 7) or deficient (Ω3 def; <i>n</i> = 7) in the omega 3 polyunsaturated fatty acid, a diet that induces chronic inflammation in the hippocampus. Microglia were labeled with Iba1 (cyan) and apoptotic nuclei were detected by pyknosis/karyorrhexis (white, DAPI). Arrows point to apoptotic cells engulfed by microglia (M). Scale bars = 50 μm; z = 22.5μm. (<b>F</b>) Number of apoptotic (pyknotic/karyorrhectic) cells in mice fed with Ω3 balanced and deficient diets. (<b>G</b>) Ph index in the PND21 hippocampus (in % of apoptotic cells) in mice fed with Ω3 balanced and deficient diets. (<b>H</b>) Weighted Ph capacity of microglia (in ppu) in PND21 mice. (<b>I</b>) Histogram showing the Ph capacity distribution of microglia (in % of cells) in PND21 mice. (<b>J</b>) Total number of microglial cells (Iba1<sup>+</sup>) in PND21 mice. (<b>K</b>) Ph/A coupling in PND21 mice. Bars represent mean ± SEM. * indicates <i>p</i> < 0.05 and ** indicates <i>p</i> < 0.01 by one-tail Student´s <i>t</i> test. Underlying data is shown in <b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s001" target="_blank">S1 Data</a></b>.</p

    Microglial phagocytic impairment leads to delayed clearance of apoptotic cells at 1 dpi.

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    <p>(<b>A</b>) Experimental design used to analyze the survival of 3 do cells after the injection of saline (<i>n</i> = 7) or KA (<i>n</i> = 8) in mice. (<b>B</b>) Representative confocal z-stacks of the DG of control and KA-injected mice (1 dpi). The damage induced by KA was evidenced by the presence of cells with abnormal nuclear morphology (DAPI, white), and the altered morphology of microglia (fms-EGFP<sup>+</sup>, cyan). (<b>C</b>) Representative confocal images of 3 do apoptotic (pyknotic, DAPI, white) cells labeled with BrdU (red; arrows) in the SGZ of the hippocampus of saline and KA-injected mice at 1 dpi. In the saline mouse, the BrdU<sup>+</sup> apoptotic cell, next to a cluster of BrdU<sup>+</sup> cells, was phagocytosed by a terminal branch of a nearby microglia (fms-EGFP, cyan), whose nucleus was also positive for BrdU. In the KA mouse, the apoptotic BrdU<sup>+</sup> cell was not phagocytosed by microglia. A nearby apoptotic cell (BrdU<sup>-</sup>; arrowhead) was partially engulfed by microglia. (<b>D</b>) Total number of live 3 do BrdU<sup>+</sup> cells (nonapoptotic) in the septal hippocampus after treatment with KA. The total number of 3 do and 8 do BrdU<sup>+</sup> cells by a single BrdU injection in saline and KA-injected mice is shown in <b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s026" target="_blank">S13A and S13B Fig</a></b>. (<b>E</b>) Total number of apoptotic 3 do BrdU<sup>+</sup> cells in the septal hippocampus after treatment with KA. (<b>F</b>) Percentage of 3 do BrdU<sup>+</sup> cells that re-enter cell cycle, assessed by their colabeling with the proliferation marker Ki67 after treatment with KA. Representative confocal z-stacks of BrdU/Ki67 cells are found in <b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s026" target="_blank">S13C Fig</a></b>. (<b>G</b>) Percentage of apoptotic BrdU<sup>+</sup> cells over total apoptotic cells in the septal hippocampus. (<b>H</b>) Estimated clearance of apoptotic cells in the septal hippocampus. The total number of apoptotic BrdU<sup>+</sup> (from E) present in the tissue was added to the number of estimated apoptotic BrdU<sup>+</sup> cells that had been cleared. In saline mice, this number was calculated using the clearance time formula shown in Methods with a clearance time of 1.5 h [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.ref009" target="_blank">9</a>]. As the total number of cells should be identical in saline and KA mice, the number of cleared apoptotic cells in KA mice was calculated as the difference between the total (in saline) and the number of present apoptotic cells (in KA). From here, we calculated a new clearance time using the same formula as in saline mice, of 6.3 h. (<b>I</b>) Linear regression analysis of the relationship between apoptosis and phagocytosis (Ph index) in saline and KA-injected mice (6 hpi and 1 dpi). (<b>J</b>) Experimental design used to compare SGZ apoptosis induced by KA at 1 dpi in young (2 mo) and mature (6 mo) mice. (<b>K</b>) Representative epifluorescent tiling image of the hippocampus and surrounding cortex of 2 and 6 mo mice injected with KA at 1 dpi stained with the neuronal activation marker c-fos. The same pattern of expression was found in young and mature mice throughout the DG, CA2, CA1 and the above cortex. (<b>L</b>) Representative confocal z-stacks of the apoptotic (pyknotic, white; act-casp3<sup>+</sup>, red) cells in the SGZ of the hippocampus of 2 mo and 6 mo mice injected with KA (1 dpi). The microglial phagocytosis impairment was similar in the two age groups (<b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s026" target="_blank">S13D Fig</a></b>). (<b>M</b>) Total number of apoptotic cells in the SGZ of 2 and 6 mo mice treated with saline or KA (1 dpi; <i>n</i> = 4–5 per group). Bars show mean ± SEM. * indicates <i>p</i> < 0.05, ** <i>p</i> < 0.01, and *** <i>p</i> < 0.001 by Student´s <i>t</i> test (E, G) or by Holm-Sidak posthoc test after one-way ANOVA (M) was significant at <i>p</i> < 0.05. Scale bars = 50 μm (B), 20 μm (C), 500 μm (K), 25 μm (L). z = 14 μm (B), 12.6 μm (C, sal), 15.4 μm (C, KA), 25 μm (L). Underlying data is shown in <b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s001" target="_blank">S1 Data</a></b>.</p

    ATP impairs microglial phagocytosis in vivo.

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    <p>(<b>A</b>) Representative confocal z-stacks of saline, 100 mM ATP and 100 mM ATPγS (2 hpi) DG labeled with DAPI (nuclear morphology, white), activated caspase 3 (act-casp3<sup>+</sup>, red, for apoptotic cells), and fms-EGFP (cyan, microglia). Arrow points to a phagocytosed apoptotic cell, whereas arrowheads point to nonphagocytosed apoptotic cells. Activated-caspase 3 puncta within microglia are labeled with a round-ended arrow. (<b>B, H</b>) Experimental designs (<b>B</b>, 100 mM of ATP and ATPγS, 2 h; <b>H</b>, 10 and 100 mM ATP, 4 h; <i>n</i> = 3–4 per group) and number of apoptotic (pyknotic/karyorrhectic and act-casp3<sup>+</sup>) in the septal DG (<i>n</i> = 3–4 per group). No changes in the volume of the DG were found in either experiment (<b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s024" target="_blank">S11C Fig</a></b>). (<b>C, I</b>) Ph index in the septal DG (in % of apoptotic cells). (<b>D, J</b>) Weighted Ph capacity of hippocampal microglia (in ppu). (<b>E, K</b>) Histogram showing the Ph capacity distribution of microglia (in % of cells) in the septal DG. (<b>F, L</b>) Total number of microglial cells (fms-EGFP<sup>+</sup>) in the septal DG. (<b>G, M</b>) Ph/A coupling (in fold change) in the septal DG. Bars represent mean ± SEM, * indicates <i>p</i> < 0.05, ** indicates <i>p</i> < 0.01, and *** indicates <i>p</i> < 0.001 by Holm-Sidak posthoc test after one-way ANOVA were significant at <i>p</i> < 0.05. Scale bars = 50 μm, z = 11.9 μm (control, ATP), 9.8 μm (ATPγs). Inserts are single plane images of the corresponding confocal z-stacks. Underlying data is shown in <b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s001" target="_blank">S1 Data</a></b>.</p

    Microglial phagocytosis impairment is unrelated to monocytes.

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    <p>(<b>A</b>) CD45 staining in saline- and KA-injected mice at 3 dpi. Cell nuclei are shown in white (DAPI), microglia in cyan (fms-EGFP), and CD45 in red. In control mice, the expression of CD45 was dim, showing diffuse cytoplasmic inclusions within microglia. A CD45<sup>+</sup> cell is shown engulfing an apoptotic cell (arrow, enlarged). In KA mice, CD45 had a higher and more widespread expression in all microglial cells, including a dividing cell (arrowhead, enlarged). A clear distinction between CD45<sup>high</sup> and CD45<sup>low</sup> cells was not evident. (<b>B</b>) Flow cytometry analysis of the expression of CD45 in fms-EGFP<sup>+</sup> hippocampal cells from control and KA-treated mice. Gates for CD45<sup>low</sup> (cyan) and CD45<sup>high</sup> (red) were defined based on the distribution of the fms-EGFP<sup>+</sup> cells in control (not injected) mice. 3 dpi after the KA injection, more cells were found in the CD45<sup>high</sup> gate, although the fms-EGFP<sup>+</sup> cells were in fact distributed along a continuum of CD45 expression, all of them with higher expression than control mice. At 7 dpi, the expression of CD45 returned to basal levels. The gating strategy is shown in <b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s017" target="_blank">S4B Fig</a></b>. (<b>C</b>) Percentage of fms-EGFP<sup>+</sup> cells that expressed low or high levels of CD45 in control or KA-treated mice determined by flow cytometry (<i>n</i> = 4 per group). (<b>D</b>) Experimental design and representative confocal z-stacks of the hippocampus of CCR2<sup>-/-</sup> (CCR2 KO) mice and control WTs (C57BL/6) injected with KA (3 dpi). No obvious differences in the status epilepticus, neuronal damage, microglial morphology, nor in the DG volume (<b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s017" target="_blank">S4C Fig</a></b>), or neutrophil infiltration were found (<b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s017" target="_blank">S4D and S4E Fig</a></b>). (<b>E</b>) Number of apoptotic (pyknotic/karyorrhectic) in the septal DG in WT and CCR2 KO mice 3 dpi after KA (<i>n</i> = 4 per group). (<b>F</b>) Ph index in the septal DG (in % of apoptotic cells) in WT and CCR2<sup>-/-</sup> mice 3 dpi after KA. (<b>G</b>) Multinuclearity in WT and CCR2<sup>-/-</sup> mice. (<b>H</b>) Size of multinucleated cells in WT and CCR2<sup>-/-</sup> mice. (<b>I</b>) Weighted Ph capacity in WT and CCR2<sup>-/-</sup> mice. Note that the Ph capacity is higher than in our previous time course (<b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.g004" target="_blank">Fig 4H</a></b>), reflecting an increased number of apoptotic cells in this experiment compared to the previous one, possibly because it was performed in different animal facilities. (<b>J</b>) Weighted PhP (phagoptosis) capacity in the septal DG in WT and CCR2<sup>-/-</sup> mice. Data are shown as mean ± SEM. * indicates <i>p</i> < 0.05, ** indicates <i>p</i> < 0.01, and *** indicates <i>p</i> < 0.001 by Holm-Sidak posthoc test, after one-way ANOVA was significant at <i>p</i> < 0.05; only significant interactions are shown. Scale bars = 20 μm (A), 50 μm (D); z = 14.7 μm (A), 12.6 μm (D). Underlying data is shown in <b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s001" target="_blank">S1 Data</a></b>.</p

    Long-term impairment of microglial phagocytosis in mouse and human MTLE.

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    <p>(<b>A</b>) Representative confocal images of the DG of saline- and KA-injected mice at 4 mpi showing the nuclei (with DAPI, in white) and microglia (Iba1<sup>+</sup>, in cyan). Note the gross dispersion of the DG in KA injected mice (<b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s017" target="_blank">S4F Fig</a></b>). The number of apoptotic cells in control and KA-treated mice at 4 mpi is shown in <b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s017" target="_blank">S4G Fig</a></b>. (<b>B</b>) Upper panel: representative confocal z-stack of an apoptotic cell (pyknotic, with DAPI, in white; arrowhead) located nearby a hypertrophic reactive astrocyte (rA; visualized with nestin-GFP<sup>+</sup>, in green) and a microglial cell (M; Iba1<sup>+</sup>, in cyan) at 4 mpi after KA. Lower panel: representative confocal z-stack of an apoptotic cell phagocytosed by microglia at 4 mpi after KA. A representative image of phagocytosis by a reactive astrocyte at 4 mpi after KA is shown in <b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s017" target="_blank">S4H Fig</a></b>. (<b>C</b>) Ph index in the DG (% of apoptotic cells engulfed). (<b>D</b>) Histogram showing the distribution of the distance (in μm) of apoptotic cells to microglia at 4 mpi after KA (in %). (<b>E</b>) Density of microglial cells (in cells/mm<sup>3</sup>). (<b>F</b>) Microglial volume (in % of volume of DG occupied). (<b>G</b>) Representative confocal tiled image of a slice of the human hippocampus from an MTLE patient showing cell nuclei (with DAPI, white), neuronal nuclei (NeuN<sup>+</sup>, magenta), and microglia (Iba1<sup>+</sup>, cyan). (<b>H</b>) Representative confocal image of a nonphagocytosed apoptotic cell (pyknotic, with DAPI) adjacent to a microglial process (Iba1<sup>+</sup>) in the hippocampus of an MTLE patient. (<b>I</b>) Representative confocal image of phagocytosis by a ball-and-chain mechanism in the hippocampus from an individual with MTLE. The apoptotic cell (pyknotic, with DAPI in white; arrow) was engulfed by a terminal branch of a nearby microglia (Iba1<sup>+</sup>, cyan). The right panel shows an orthogonal projection of the same cell, where the 3-D engulfment is evident. (<b>J</b>) Representative confocal z-stack of phagocytosis by an aster mechanism in the hippocampus from an individual with MTLE. The apoptotic cell (pyknotic, with DAPI in white; arrow) was engulfed by a mesh of processes from many surrounding microglia (Iba1<sup>+</sup>, cyan; M). The right panel shows an orthogonal projection of the same cell. (<b>K</b>) Representative confocal z-stack of a granule neuron in the DG (NeuN<sup>+</sup>, magenta; arrow) targeted by the processes of several surrounding microglia (Iba1<sup>+</sup>). Nuclei are shown in white (DAPI). The right panel shows an orthogonal projection of the same neuron directly targeted the processes of up to three microglia (M). Another example is shown in <b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s021" target="_blank">S8A Fig</a></b> and further data in <b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s029" target="_blank">S1 Table</a></b>. (<b>L</b>) Ph index in the human DG (% of apoptotic cells engulfed). (<b>M</b>) Density of microglial cells (in cells/mm<sup>3</sup>) in the DG of three hippocampal samples from human MTLE patients. (<b>N</b>) Histogram showing the distribution of the distance of apoptotic cells (in %) to Iba1<sup>+</sup> microglial processes in the DG of MTLE patients (<i>n</i> = 21 cells from 3 patients). (<b>O</b>) Microglial volume (in % of volume of DG occupied) in the three hippocampal samples from individuals with MTLE. Bars represent mean ± SEM (C, E, F), the individual values of all the pooled cells for each patient (L), the average values for measures in different z-stacks for each patient (M, O), or the sum of cells in each distance slot (D, N). ** represents <i>p</i> < 0.01 by Student´s <i>t</i> test (C, E, F). Scale bars = 50μm (A, K), 10 μm (B, H, I), 1 mm (G), 20 μm (J). <i>z</i> = 25 μm (A), 6.6 μm (B, upper panel), 12.7 μm (B, lower panel), 2.8 μm (H), 2.6 μm (I), 5.2 μm (J), 12 μm (K). Underlying data is shown in <b><a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002466#pbio.1002466.s001" target="_blank">S1 Data</a></b>.</p
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