Mikrogliasolut - aivojen puhdistajat ja puolustajat

Mikrogliasolut ovat tärkeä osa keskushermoston immuunipuolustusta ja kudostasapainon ylläpitoa. Perifeerisiä makrofageja sekä rakenteeltaan että toiminnaltaan muistuttavat mikrogliasolut tarkkailevat jatkuvasti ympäristöään. Mikrogliasolujen ympäristössä tapahtuvat muutokset vaikuttavat niiden toimintaan ja aktiivisuuteen. Normaaliolosuhteissa ne puhdistavat aivoja fagosytoimalla esimerkiksi vanhaa solujätettä. Niillä on kuitenkin myös tärkeä rooli aivojen tulehdusreaktion synnyssä ja säätelyssä, ja ne voivat joko lisätä tai hillitä tulehdusta. Kroonisissa neurodegeneratiivisissa sairauksissa mikrogliasolujen jääminen tulehdusta lisäävän aktivaation tilaan voi lisätä neuroaksonaalista vauriota. Mikrogliasolut vaikuttavatkin monen neurodegeneratiivisen sairauden patofysiologiaan. Mikrogliasolujen aktivoituessa niiden ilmentämissä proteiineissa, kuten TSPO:ssa (translocator protein), tapahtuu muutoksia. Aktivoituneita mikrogliasoluja voidaan paikantaa ja kvantifioida positroniemissiotomografia (PET) -kuvantamisella käyttämällä TSPO-molekyyliin sitoutuvia radioaktiivisesti leimattuja ligandeja.</p

Transthoracic echocardiography for imaging of the different coronary artery segments: a feasibility study

<p>Abstract</p> <p>Background</p> <p>Transthoracic echocardiography (TTE) may be used for direct inspection of various parts of the main coronary arteries for detection of coronary stenoses and occlusions. We aimed to assess the feasibility of TTE to visualise the complete segments of the left main (LM), left descending (LAD), circumflex (Cx) and right (RCA) coronary arteries.</p> <p>Methods</p> <p>One hundred and eleven patients scheduled for diagnostic coronary angiography because of chest pain or acute coronary syndrome had a TTE study to map the passage of the main coronary arteries. LAD, Cx and RCA were each divided into proximal, middle and distal segments. If any part of the individual segment of a coronary artery with antegrade blood flow was not visualised, the segment was labeled as not satisfactorily seen.</p> <p>Results</p> <p>Complete imaging of the LM was achieved in 98% of the patients. With antegrade directed coronary artery flow, the proximal, middle and distal segments of LAD were completely seen in 96%, 95% and 91% of patients, respectively. Adding the completely seen segments with antegrade coronary flow and segments with retrograde coronary flow, the proximal, middle and distal segments of LAD were adequately visualised in 96%, 96% and 93% of patients, respectively. With antegrade directed coronary artery flow, the proximal, middle and distal segments of Cx were completely seen in 88%, 61% and 3% and in RCA in 40%, 28% and 54% of patients. Retrograde coronary artery flow was correctly identified as verified by coronary angiography in seven coronary segments, mainly in the posterior descending artery (labeled as the distal segment of RCA) and distal LAD.</p> <p>Conclusions</p> <p>TTE is a feasible method for complete demonstration of coronary flow in the LM, the proximal Cx and the different segments of LAD, but less suitable for the RCA and mid and distal segments of the Cx. (ClinicalTrials.gov number NTC00281346.)</p

Natalizumab treatment leads to an increase in circulating CXCR3-expressing B cells

OBJECTIVE: To study the effects of natalizumab treatment on subgroups of circulating peripheral blood B cell populations.METHODS: We studied the proportions and absolute numbers of CD19+CD20+, CD10+, and CD5+ B cell populations, and determined very late activation antigen-4 and chemokine receptor CXCR3, CCR5, and CCR6 expression on B cells in the peripheral blood of 14 natalizumab-treated patients with relapsing-remitting multiple sclerosis. Five blood samples per patient were obtained longitudinally before and during the first year of treatment. Blood samples were analyzed by 6-color flow cytometry.RESULTS: Proportions of B cells and CD10+ pre-B cells were significantly increased, and very late activation antigen-4 expression on the B cell surface was significantly decreased already after 1 week of natalizumab treatment. Natalizumab-induced sustained increase in the proportion and absolute number of CXCR3-expressing B cells was statistically significant after 1 month of treatment. There were no changes in the proportions of CCR5- or CCR6-expressing B cells.CONCLUSIONS: The rapid and persistent increase in circulating CXCR3-expressing B cells in response to natalizumab treatment possibly reflects the relevance of this chemokine receptor in controlling migration of B cells into the CNS in humans in vivo.</p

Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

IMPORTANCE: Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies. OBJECTIVE: To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. INTERVENTIONS: Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group). MAIN OUTCOMES AND MEASURES: The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months. RESULTS: Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053). CONCLUSIONS AND RELEVANCE: Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00879892

Time-course of left ventricle function during mild therapeutic hypothermia in out-of-hospital cardiac arrest patients

Peer reviewe

Direct visualization of a significant stenosis of the right coronary artery by transthoracic echocardiography. A case report

Non-invasive imaging of coronary arteries by transthoracic echocardiography is an emerging diagnostic tool to study the left main (LM), left descending artery (LAD), circumflex (Cx) and right coronary artery (RCA). Impaired coronary circulation can be assessed by measuring coronary velocity flow reserve (CVFR) by transthoracic Doppler echocardiography. Coronary artery stenoses can be identified as localized colour aliasing and accelerated flow velocities. We report a case with an acute coronary syndrome (ACS) of a 46-year-old man. With non-invasive imaging of coronary arteries by transthoracic echocardiography (TTE), we identified a segment of the mid right coronary artery (RCA) suggestive of stenosis with localized colour aliasing and accelerated flow velocity. We found a high ratio between the stenotic peak velocity and the prestenotic peak velocity, and a pathologic coronary flow velocity reserve (CFVR) distal to the stenosis in the posterior interventricular descending branch (RDP). Subsequent coronary angiography demonstrated one vessel disease with a stenosis in segment 3 of RCA, which was successfully treated with percutaneos coronary intervention PCI. Two weeks following the PCI procedure he was readmitted to hospital with chest pain. A subacute stent thrombosis was questioned, and repeated echocardiography was preformed. The mid portion of RCA showed normal and laminar flow. The CVFR of RCA measured in the RDP showed normal vasodilatory response, confirming an open RCA without any flow limitation. A repeated coronary angiogram demonstrated only a mild in stent intimal hyperplasia. This case illustrates the value of transthoracic echocardiography as a tool both in the diagnosis and the follow-up of chest pain disorders and coronary flow problems. Transthoracic echocardiography allows both direct visualization of the various coronary segments and assessment of the CVFR

Circulating N-terminal brain natriuretic peptide and cardiac function in response to acute systemic hypoxia in healthy humans

Background: As it remains unclear whether hypoxia of cardiomyocytes could trigger the release of brain natriuretic peptide (BNP) in humans, we investigated whether breathing normobaric hypoxic gas mixture increases the circulating NT-proBNP in healthy male subjects.Methods: Ten healthy young men (age 29 ± 5 yrs, BMI 24.7 ± 2.8 kg/m2) breathed normobaric hypoxic gas mixture (11% O2/89% N2) for one hour. Venous blood samples were obtained immediately before, during, and 2 and 24 hours after hypoxic exposure. Cardiac function and flow velocity profile in the middle left anterior descending coronary artery (LAD) were measured by Doppler echocardiography.Results: Arterial oxygen saturation decreased steadily from baseline value of 99 ± 1% after the initiation hypoxia challenge and reached steady-state level of 73 ± 6% within 20-30 minutes. Cardiac output increased from 6.0 ± 1.2 to 8.1 ± 1.6 L/min and ejection fraction from 67 ± 4% to 75 ± 6% (both p < 0.001). Peak diastolic flow velocity in the LAD increased from 0.16 ± 0.04 to 0.28 ± 0.07 m/s, while its diameter remained unchanged. In the whole study group, NT-proBNP was similar to baseline (60 ± 32 pmol/ml) at all time points. However, at 24 h, concentration of NT-proBNP was higher (34 ± 18%) in five subjects and lower (17 ± 17%), p = 0.002 between the groups) in f

Live Imaging at the Onset of Cortical Neurogenesis Reveals Differential Appearance of the Neuronal Phenotype in Apical versus Basal Progenitor Progeny

The neurons of the mammalian brain are generated by progenitors dividing either at the apical surface of the ventricular zone (neuroepithelial and radial glial cells, collectively referred to as apical progenitors) or at its basal side (basal progenitors, also called intermediate progenitors). For apical progenitors, the orientation of the cleavage plane relative to their apical-basal axis is thought to be of critical importance for the fate of the daughter cells. For basal progenitors, the relationship between cell polarity, cleavage plane orientation and the fate of daughter cells is unknown. Here, we have investigated these issues at the very onset of cortical neurogenesis. To directly observe the generation of neurons from apical and basal progenitors, we established a novel transgenic mouse line in which membrane GFP is expressed from the beta-III-tubulin promoter, an early pan-neuronal marker, and crossed this line with a previously described knock-in line in which nuclear GFP is expressed from the Tis21 promoter, a pan-neurogenic progenitor marker. Mitotic Tis21-positive basal progenitors nearly always divided symmetrically, generating two neurons, but, in contrast to symmetrically dividing apical progenitors, lacked apical-basal polarity and showed a nearly randomized cleavage plane orientation. Moreover, the appearance of beta-III-tubulin–driven GFP fluorescence in basal progenitor-derived neurons, in contrast to that in apical progenitor-derived neurons, was so rapid that it suggested the initiation of the neuronal phenotype already in the progenitor. Our observations imply that (i) the loss of apical-basal polarity restricts neuronal progenitors to the symmetric mode of cell division, and that (ii) basal progenitors initiate the expression of neuronal phenotype already before mitosis, in contrast to apical progenitors

Multimodality imaging: Bird’s eye view from the European Society of Cardiology Congress 2019 Paris, August 31st–September 4th, 2019

At the European Society of Cardiology (ESC) congress of this year 2019, held in Paris from August 31st to September 4th, 4509 abstracts were presented. Of those, 414 (9%) belonged to an imaging category. Experts in echocardiography (VD), nuclear imaging (AS), cardiac computed tomography (CT) (MD) and cardiovascular magnetic resonance (CMR) (CBD), have selected the abstracts in their areas of expertise that were of most interest to them and are summarized in this bird’s eye view from this ESC meeting. These abstracts were integrated by one of the Editors of the Journal (JB).</p

Phosfinder: a web server for the identification of phosphate-binding sites on protein structures

Phosfinder is a web server for the identification of phosphate binding sites in protein structures. Phosfinder uses a structural comparison algorithm to scan a query structure against a set of known 3D phosphate binding motifs. Whenever a structural similarity between the query protein and a phosphate binding motif is detected, the phosphate bound by the known motif is added to the protein structure thus representing a putative phosphate binding site. Predicted binding sites are then evaluated according to (i) their position with respect to the query protein solvent-excluded surface and (ii) the conservation of the binding residues in the protein family. The server accepts as input either the PDB code of the protein to be analyzed or a user-submitted structure in PDB format. All the search parameters are user modifiable. Phosfinder outputs a list of predicted binding sites with detailed information about their structural similarity with known phosphate binding motifs, and the conservation of the residues involved. A graphical applet allows the user to visualize the predicted binding sites on the query protein structure. The results on a set of 52 apo/holo structure pairs show that the performance of our method is largely unaffected by ligand-induced conformational changes. Phosfinder is available at http://phosfinder.bio.uniroma2.it