The Brainbox—a tool to facilitate correlation of brain magnetic resonance imaging features to histopathology

Magnetic resonance imaging (MRI) has limitations in identifying underlying tissue pathology, which is relevant for neurological diseases such as multiple sclerosis, stroke or brain tumours. However, there are no standardized methods for correlating MRI features with histopathology. Thus, here we aimed to develop and validate a tool that can facilitate the correlation of brain MRI features to corresponding histopathology. For this, we designed the Brainbox, a waterproof and MRI-compatible 3D printed container with an integrated 3D coordinate system. We used the Brainbox to acquire post-mortem ex vivo MRI of eight human brains, fresh and formalin-fixed, and correlated focal imaging features to histopathology using the built-in 3D coordinate system. With its built-in 3D coordinate system, the Brainbox allowed correlation of MRI features to corresponding tissue substrates. The Brainbox was used to correlate different MR image features of interest to the respective tissue substrate, including normal anatomical structures such as the hippocampus or perivascular spaces, as well as a lacunar stroke. Brain volume decreased upon fixation by 7% (P = 0.01). The Brainbox enabled degassing of specimens before scanning, reducing susceptibility artefacts and minimizing bulk motion during scanning. In conclusion, our proof-of-principle experiments demonstrate the usability of the Brainbox, which can contribute to improving the specificity of MRI and the standardization of the correlation between post-mortem ex vivo human brain MRI and histopathology. Brainboxes are available upon request from our institution

NECAB2 is an endosomal protein important for striatal function

Synaptic signaling depends on ATP generated by mitochondria. Dysfunctional mitochondria shift the redox balance towards a more oxidative environment. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction. We found that neuronal calcium-binding protein 2 (NECAB2) plays a role in striatal function and mitochondrial homeostasis. NECAB2 is a predominantly endosomal striatal protein which partially colocalizes with mitochondria. This colocalization is enhanced by mild oxidative stress. Global knockout of Necab2 in the mouse results in increased superoxide levels, increased DNA oxidation and reduced levels of the antioxidant glutathione which correlates with an altered mitochondrial shape and function. Striatal mitochondria from Necab2 knockout mice are more abundant and smaller and characterized by a reduced spare capacity suggestive of intrinsic uncoupling respectively mitochondrial dysfunction. In line with this, we also found an altered stress-induced interaction of endosomes with mitochondria in Necab2 knockout striatal cultures. The predominance of dysfunctional mitochondria and the pro-oxidative redox milieu correlates with a loss of striatal synapses and behavioral changes characteristic of striatal dysfunction like reduced motivation and altered sensory gating. Together this suggests an involvement of NECAB2 in an endosomal pathway of mitochondrial stress response important for striatal functio

Memory B cells activate brain-homing, autoreactive CD4(+) T cells in multiple sclerosis

Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as “autoproliferation” of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells. Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells. These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies

Intra‐operative analgesia with remifentanil vs. dexmedetomidine: a systematic review and meta‐analysis with trial sequential analysis

Intra-operative remifentanil is associated with increased postoperative analgesic requirements and opioid consumption. Dexmedetomidine has characteristics suggesting it may substitute for intra-operative remifentanil during general anaesthesia, but existing literature has reported conflicting results. We undertook this meta-analysis to investigate whether general anaesthesia including dexmedetomidine would result in less postoperative pain than general anaesthesia including remifentanil. The MEDLINE and PubMed electronic databases were searched up to October 2018. Only randomised trials including patients receiving general anaesthesia and comparing dexmedetomidine with remifentanil administration were included. Meta-analyses were performed mostly employing a random effects model. The primary outcome was pain score at rest (visual analogue scale, 0-10) at two postoperative hours. The secondary outcomes included: pain score at rest at 24 postoperative hours; opioid consumption at 2 and 24 postoperative hours; and rates of hypotension, bradycardia, shivering and postoperative nausea and vomiting. Twenty-one randomised trials, including 1309 patients, were identified. Pain scores at rest at two postoperative hours were lower in the dexmedetomidine group, with a mean difference (95%CI) of -0.7 (-1.2 to -0.2), I <sup>2</sup>  = 85%, p = 0.004, and a moderate quality of evidence. Secondary pain outcomes were also significantly better in the dexmedetomidine group. Rates of hypotension, shivering and postoperative nausea and vomiting were at least twice as frequent in patients who received remifentanil. Time to analgesia request was longer, and use of postoperative morphine and rescue analgesia were less, with dexmedetomidine, whereas episodes of bradycardia were similar between groups. There is moderate evidence that intra-operative dexmedetomidine during general anaesthesia improves pain outcomes during the first 24 postoperative hours, when compared with remifentanil, with fewer side effects

Neurological Impairment in Experimental Antiphospholipid Syndrome is Associated with increased Ligand Binding to Serotonergic 5-HT1A Receptors

Coneley's Gallopers - G109 - pulling down circa 1957

Lung injury does not aggravate mechanical ventilation-induced early cerebral inflammation or apoptosis in an animal model.

INTRODUCTION:The acute respiratory distress syndrome is not only associated with a high mortality, but also goes along with cognitive impairment in survivors. The cause for this cognitive impairment is still not clear. One possible mechanism could be cerebral inflammation as result of a "lung-brain-crosstalk". Even mechanical ventilation itself can induce cerebral inflammation. We hypothesized, that an acute lung injury aggravates the cerebral inflammation induced by mechanical ventilation itself and leads to neuronal damage. METHODS:After approval of the institutional and state animal care committee 20 pigs were randomized to one of three groups: lung injury by central venous injection of oleic acid (n = 8), lung injury by bronchoalveolar lavage in combination with one hour of injurious ventilation (n = 8) or control (n = 6). Brain tissue of four native animals from a different study served as native group. For six hours all animals were ventilated with a tidal volume of 7 ml kg-1 and a scheme for positive end-expiratory pressure and inspired oxygen fraction, which was adapted from the ARDS network tables. Afterwards the animals were killed and the brains were harvested for histological (number of neurons and microglia) and molecular biologic (TNFalpha, IL-1beta, and IL-6) examinations. RESULTS:There was no difference in the number of neurons or microglia cells between the groups. TNFalpha was significantly higher in all groups compared to native (p < 0.05), IL-6 was only increased in the lavage group compared to native (p < 0.05), IL-1beta showed no difference between the groups. DISCUSSION:With our data we can confirm earlier results, that mechanical ventilation itself seems to trigger cerebral inflammation. This is not aggravated by acute lung injury, at least not within the first 6 hours after onset. Nevertheless, it seems too early to dismiss the idea of lung-injury induced cerebral inflammation, as 6 hours might be just not enough time to see any profound effect