17 research outputs found
Denser brain capillary network with preserved pericytes in Alzheimer's disease
Pericytes are vascular mural cells that surround capillaries of the central nervous system (CNS). They are crucial for brain development and contribute to CNS homeostasis by regulating blood-brain barrier function and cerebral blood flow. It has been suggested that pericytes are lost in Alzheimer's disease (AD), implicating this cell type in disease pathology. Here, we have employed state-of-the-art stereological morphometry techniques as well as tissue clearing and two-photon imaging to assess the distribution of pericytes in two independent cohorts of AD (n = 16 and 13) and non-demented controls (n = 16 and 4). Stereological quantification revealed increased capillary density with a normal pericyte population in the frontal cortex of AD brains, a region with early amyloid beta deposition. Two-photon analysis of cleared frontal cortex tissue confirmed the preservation of pericytes in AD cases. These results suggest that pericyte demise is not a general hallmark of AD pathology
Origin and pathways of the mineral dust transport to two Spanish EARLINET sites: Effect on the observed columnar and range-resolved dust optical properties
In this paper, is presented a method for estimation of the effect of the transport process to aerosol optical properties. Aerosol optical data retrieved by lidars and sun-photometer measurements, are applied to Saharan dust events observed simultaneously at the two EARLINET/AERONET sites of Barcelona and Granada during the periods of June–September of 2012 and 2013. For this purpose, elastic lidar profiles and sun-photometer columnar retrievals are analyzed together with satellite observations and dust forecast models. Granada presents more than twice Saharan dust outbreaks compared to Barcelona. The scenarios favoring the Saharan dust outbreaks are identified in both places. The mineral dust originating in the Sahara region and arriving at both stations is usually transport wither over the Atlas Mountains or through an Atlantic pathway. Analyses of dust events affecting both stations reveal how differences in the transport process lead to differences in the aerosol optical properties measured at each station. Mean dust related Ångström exponent is 1.8 times higher in Barcelona than in Granada. This difference is a result of the additional contribution of anthropogenic aerosol, mainly in the aerosol fine mode, during the transport of the mineral dust plume over the Iberian Peninsula.Andalusia Regional Government through the project P12-RNM-2409Spanish Ministry of Economy and Competitiveness through the project CGL2013-45410-
Sarcoma classification by DNA methylation profiling
Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications
Role of pericytes in the modulation of capillary blood flow in the cerebral cortex of the mouse
Einleitung: Perizyten sind murale Zellen in den Kapillaren, die im zentralen
Nervensystem die Endothelzellen umfassen und die zunehmend als wichtige
zelluläre Bestandteile der neurovaskulären Funktionseinheit anerkannt werden.
Sie sind an der Bildung und Regulation der Bluthirnschranke beteiligt.
Perizyten sind kontraktile Zellen, und reagieren in organotypischen
Hirnpräparaten auf Neurotransmitter mit Konstriktionen und Dilatationen. Somit
sind diese Zellen grundsätzlich in der Lage, die stete Kopplung des zerebralen
Blutflusses an die neuronale Aktivität zu bewirken. Diese Funktion der
Perizyten ist jedoch noch nicht eindeutig in vivo geklärt worden. Es ist
ebenfalls weitgehend unbekannt, wie diese Zellen im Rahmen von pathologischen
Veränderungen im zentralen Nervensystem reagieren. Methoden: Wir haben mittels
eines transgenen Tiermodells (die β-actin eGFP Maus) und intravitaler Zwei-
Photonen Mikroskopie die kontraktilen Eigenschaften der Perizyten im
zerebralen Kortex untersucht. Um einen weiteren Einblick in die Rolle von
Perizyten in pathologischen Szenarien zu gewinnen, haben wir in einem
Schlaganfallmodell und in humanem post-mortem Gewebe aus Patienten mit der
neuropathologischen Diagnose eines Schlaganfalls die Reaktion von Perizyten
histologisch charakterisiert. Ergebnisse: Perizyten in Kapillaren der β-actin
eGFP Maus zeigten im Präparat des akuten Hirnschnitts oder in vivo kontraktile
Fähigkeiten und modulierten in vivo wirksam den Blutfluss in einzelnen
Kapillaren. Jedoch konnten wir in einem Modell von funktioneller Hyperämie
keine Durchmesserveränderungen durch kapilläre Perizyten detektieren. Im
experimentellen Schlaganfallmodell wie auch im humanen Schlaganfall konnten
wir zeigen, dass kapilläre Perizyten im Kern des Infarktes akut dezimiert
werden, während Zellen um große Gefäße im Kern des Infarktes proliferieren und
mit der Ablagerung von fibrotischer extrazellulärer Matrix assoziiert sind.
Schlussfolgerung: Unsere Arbeit suggeriert, dass Perizyten in Kapillaren nicht
Mediatoren der funktionellen Hyperämie während neuronaler Aktivierung sind.
Jedoch sind sie in der Lage, den Blutfluss in Kapillaren durch Kontraktion zu
beeinflussen, was während pathologischer Zustände des zentralen Nervensystems
von Bedeutung sein könnte. Perizyten werden in Rahmen von Ischämie beschädigt
und sterben im Kern des Infarktes akut ab. Murale Zellen in großen Gefäßen,
die auch Perizytenmarker exprimieren, generieren im ischämischen Parenchym
eine bisher unbekannte Population von stromalen Zellen, die zur Transformation
des ischämischen Kerns in fibrotisches Narbengewebe beitragen. Das stromale
Narbengewebe unterscheidet sich von der klassischen astroglialen Narbe und
bietet möglicherweise einen neuen therapeutischen Angriffspunkt, um das
Regenerationspotential vom ischämischen Gewebe zu verbessern.Introduction: Pericytes, the mural cells of capillaries, are most abundant in
the central nervous system, where they regulate the blood-brain barrier. They
are contractile in vitro and respond to neurotransmitters in organ
preparations. Therefore, it has been proposed that they may mediate the
coupling of blood flow to neuronal activity, and further provoke impairment to
blood flow after ischemic lesions to the central nervous system. However,
their ability to modulate blood flow in the brain in vivo has not been
demonstrated and it is largely unknown how lesions to the neural tissue may
affect pericytes over time. Methods: We used two-photon microscopy to study
pericytes and the dynamic changes of capillary diameter and blood flow in the
cortex of anesthetized β-actin eGFP mice in real time, as well as in brain
slices. In order to determine the reaction of pericytes at different time
points after cerebral ischemia, we have used histological samples obtained
from an experimental stroke model or from human post-mortem stroke tissue.
Results: Pericytes caused localized decreases in capillary diameter in acute
brain slices and in the brain of anaesthetized mice, where they effected
changes in capillary red blood cell flow. In contrast, during brief bursts of
neuronal activity, capillary red blood cell flow increased without pericyte-
induced capillary diameter changes. The analysis of immunohistological stains
of murine or human ischemic tissue demonstrated an acute loss of capillary
pericytes. At the same time, cells in larger vessels, sharing common cell
markers with pericytes, proliferate and give rise to a stromal cell population
associated to the deposition of fibrous extracellular matrix. Conclusions: Our
data suggest that mural cells in precapillary and penetrating arterioles,
rather than pericytes in capillaries, are responsible for the blood flow
increase induced by neural activity. However, we also show that pericytes can
modulate capillary blood flow in the brain in vivo, which may be important
under pathological conditions. In an experimental stroke model as well as in
humans, the immunohistological analysis suggests that capillary pericytes are
affected and succumb largely after brain ischemia. Vascular cells of large
vessels expressing pericyte markers participate in the generation of
previously unrecognized stromal scar tissue, which is distinct from the
classic astroglial scar. The stromal scar tissue represents a novel potential
target for therapies aimed at increasing the regenerative potential of brain
tissue after stroke
Targeting myeloid cells to the brain using non-myeloablative conditioning.
Bone marrow-derived cells (BMDCs) are able to colonize the central nervous system (CNS) at sites of damage. This ability makes BMDCs an ideal cellular vehicle for transferring therapeutic genes/molecules to the CNS. However, conditioning is required for bone marrow-derived myeloid cells to engraft in the brain, which so far has been achieved by total body irradiation (TBI) and by chemotherapy (e.g. busulfan treatment). Unfortunately, both regimens massively disturb the host's hematopoietic compartment. Here, we established a conditioning protocol to target myeloid cells to sites of brain damage in mice using non-myeloablative focal head irradiation (HI). This treatment was associated with comparatively low inflammatory responses in the CNS despite cranial radiation doses which are identical to TBI, as revealed by gene expression analysis of cytokines/chemokines such as CCL2, CXCL10, TNF-α and CCL5. HI prior to bone marrow transplantation resulted in much lower levels of blood chimerism defined as the percentage of donor-derived cells in peripheral blood (< 5%) compared with TBI (> 95%) or busulfan treatment (> 50%). Nevertheless, HI effectively recruited myeloid cells to the area of motoneuron degeneration in the brainstem within 7 days after facial nerve axotomy. In contrast, no donor-derived cells were detected in the lesioned facial nucleus of busulfan-treated animals up to 2 weeks after transplantation. Our findings suggest that myeloid cells can be targeted to sites of brain damage even in the presence of very low levels of peripheral blood chimerism. We established a novel non-myeloablative conditioning protocol with minimal disturbance of the host's hematopoietic system for targeting BMDCs specifically to areas of pathology in the brain
Selective engraftment of donor-derived myeloid cells in the lesioned facial nucleus after HI.
<p><b>A</b>) Identification of GFP<sup>+</sup> myeloid cells in the lesioned facial nucleus of HI chimeras at 7 and 14 days after BMT. Note the increase in F4/80 immunoreactivity at day 14 compared with day 7, indicating increased inflammation. The contralateral unlesioned facial nucleus is devoid of donor-derived GFP<sup>+</sup> cells and shows minimal F4/80 immunoreactivity. Laser confocal microscopic images of areas of interest (white squares) are shown at increasing magnifications (scale bars: 100 µm – 25 µm). Seven days after BMT, amoeboid GFP<sup>+</sup>F4/80<sup>+</sup> and GFP<sup>+</sup>Iba-1<sup>+</sup> cells were detected in the lesioned facial nucleus. At 14 days after BMT, GFP<sup>+</sup>F4/80<sup>+</sup> and GFP<sup>+</sup>Iba-1<sup>+</sup> cells in the lesioned facial nucleus were highly ramified. All donor-derived GFP<sup>+</sup> cells expressed the macrophage markers, F4/80 and Iba-1. Nuclei were counterstained with DAPI. <b>B</b>) Quantification of myeloid cell engraftment in the lesioned facial nucleus at 7 and 14 days after BMT in FNA, HI, HI + FNA and busulfan + FNA animals. Note that donor-derived GFP<sup>+</sup> cells were only detected in HI + FNA mice. Data are means + SEM from 3-5 animals per group. n.d. = none detected. <b>C</b>) Quantitative real-time PCR of CXCL10 and CCL2 mRNA expression in the facial nucleus of animals with FNA (white bars), HI (grey bars) and HI + FNA (black bars) at 14 days after BMT. The mRNA expression levels were normalized to GAPDH mRNA and compared to naïve mice (fold induction). Increased chemokine mRNA levels were observed in the facial nucleus of HI + FNA mice compared to HI animals. Data are means + SEM from 3-5 animals per group. Statistical significance is indicated by asterisks (*p<0.05).</p
Gene expression profiles of cytokines and chemokines in the brain after HI and TBI.
<p><b>A</b>) Overview of the experimental protocol. <i>HI</i>, <i>TBI</i> and <i>Tx</i> denote focal head irradiation, total body irradiation and bone marrow transplantation, respectively. <b>B</b>) Quantitative real-time PCR of CCL2, CXCL10, CCL5 and TNF-α mRNA expression in brains of HI (grey columns) and TBI (white columns) animals at 1, 2, 4 and 16 weeks after irradiation and BMT. The mRNA expression levels were normalized to GAPDH mRNA and compared to naïve mice (fold induction). Reduced cytokine/chemokine mRNA levels were observed in HI brains compared to the TBI paradigm. Data are means + SEM from 3-5 animals per group. Statistical significance is indicated by asterisks (*p<0.05; **p<0.01; ***p<0.001).</p
Blood chimerism in HI- and busulfan-conditioned mice with FNA.
<p><b>A</b>) Overview of the experimental protocol. <i>HI</i>, <i>FNA</i> and <i>Tx</i> denote focal head irradiation, facial nerve axotomy and bone marrow transplantation, respectively. <b>B</b>) Flow cytometry of GFP expression in peripheral blood CD45<sup>+</sup> cells at 2 weeks after BMT. The level of chimerism was significantly higher in the busulfan + FNA group compared with the HI + FNA group. FNA had no impact on blood chimerism. Data are means + SEM from 3-5 animals per group. Statistical significance is indicated by asterisks (****p<0.0001). <b>C</b>) Flow cytometric characterization of GFP-expressing cells in peripheral blood at 2 weeks after BMT. The vast majority of GFP<sup>+</sup>CD45<sup>+</sup> cells express CD11b (>90%). Gating of this cell population reveals predominantly CD115<sup>+</sup>Ly6C<sup>hi</sup>Ly6G<sup>-</sup> monocytes and CD115<sup>-</sup>Ly6C<sup>+</sup>Ly6G<sup>+</sup> neutrophils. Data are means + SEM from 3-5 animals per group. n.d. = none detected. No statistical differences were observed between the groups.</p
The Influence of Emotional and Cognitive Factors on Limb Laterality Discrimination in Women with Fibromyalgia Syndrome: A Cross-Sectional Study Secondary Analysis
Previous scientific evidence has shown that patients with fibromyalgia syndrome (FMS) have alterations in the body schema. There have also been findings regarding the influence of psychological factors on pain, as well as evidence that patients with FMS have difficulty performing laterality discrimination tasks. The main objective of this study was to evaluate whether emotional and cognitive factors influence the limb laterality discrimination task in women with FMS. Seventeen of the participants were healthy female controls, and the other seventeen were women diagnosed with FMS. The main outcome measures were laterality discrimination, anxiety symptoms, depression symptoms, pain catastrophizing, and fear-related movement. The main analysis showed that patients with FMS had longer reaction times for laterality discrimination in hands (hand 20 images, p p p p p p < 0.0001)) disorders compared with healthy subjects. There was no correlation between limb laterality discrimination and psychological variables. In conclusion, patients with FMS showed impaired laterality discrimination, but psychological variables were not influenced. This could be due to the implicit nature of the task