Monomeric C-reactive protein (mCRP) is now accepted as having a key role in modulating inflammation and in particular, has been strongly associated with atherosclerotic arterial plaque progression and instability and neuroinflammation after stroke where a build-up of the mCRP protein within the brain parenchyma appears to be connected to vascular damage, neurodegenerative pathophysiology and possibly Alzheimer's Disease (AD) and dementia. Here, using immunohistochemical analysis, we wanted to confirm mCRP localization and overall distribution within a cohort of AD patients showing evidence of previous infarction and then focus on its co-localization with inflammatory active regions in order to provide further evidence of its functional and direct impact. We showed that mCRP was particularly seen in large amounts within brain vessels of all sizes and that the immediate micro-environment surrounding these had become laden with mCRP positive cells and extra cellular matrix. This suggested possible leakage and transport into the local tissue. The mCRP-positive regions were almost always associated with neurodegenerative, damaged tissue as hallmarked by co-positivity with pTau and β-amyloid staining. Where this occurred, cells with the morphology of neurons, macrophages and glia, as well as smaller microvessels became mCRP-positive in regions staining for the inflammatory markers CD68 (macrophage), interleukin-1 beta (IL-1β) and nuclear factor kappa B (NFκB), showing evidence of a perpetuation of inflammation. Positive staining for mCRP was seen even in distant hypothalamic regions. In conclusion, brain injury or inflammatory neurodegenerative processes are strongly associated with mCRP localization within the tissue and given our knowledge of its biological properties, it is likely that this protein plays a direct role in promoting tissue damage and supporting progression of AD after injury.

Background: Combining transcranial direct current stimulation (tDCS) with other therapies is reported to produce promising results in patients with stroke. The purpose of the study was to determine the effect of combining tDCS with motor imagery (MI) and upper-limb functional training for upper-limb rehabilitation among patients with chronic stroke. Methods: A single-center, prospective, randomized controlled trial was conducted among 64 patients with chronic stroke. The control group received sham tDCS with MI, while the experimental group received real tDCS with MI. Both groups performed five different upper-limb functional training exercises coupled with tDCS for 30 min, five times per week for two weeks. Fugl-Meyer’s scale (FMA) and the Action Research Arm Test (ARAT) were used to measure the outcome measures at baseline and after the completion of the 10th session. Results: Analysis of covariance showed significant improvements in the post-test mean scores for FMA (F (414.4) = 35.79, p < 0.001; η² = 0.37) and ARAT (F (440.09) = 37.46, p < 0.001; η² = 0.38) in the experimental group compared to the control group while controlling for baseline scores. Conclusions: Anodal tDCS stimulation over the affected primary motor cortex coupled with MI and upper-limb functional training reduces impairment and disability of the upper limbs among patients with chronic stroke.

The human population is currently facing the third and possibly the worst pandemic caused by human coronaviruses (CoVs). The virus was first reported in Wuhan, China, on 31 December 2019 and spread within a short time to almost all countries of the world. Genome analysis of the early virus isolates has revealed high similarity with SARS-CoV and hence the new virus was officially named SARS-CoV-2. Since CoVs have the largest genome among all RNA viruses, they can adapt to many point mutation and recombination events; particularly in the spike gene, which enable these viruses to rapidly change and evolve in nature. CoVs are known to cross the species boundaries by using different cellular receptors. Both animal reservoir and intermediate host for SARS-CoV-2 are still unresolved and necessitate further investigation. In the current review, different aspects of SARS-CoV-2 biology and pathogenicity are discussed, including virus genetics and evolution, spike protein and its role in evolution and adaptation to novel hosts, and virus transmission and persistence in nature. In addition, the immune response developed during SARS-CoV-2 infection is demonstrated with special reference to the interplay between immune cells and their role in disease progression. We believe that the SARS-CoV-2 outbreak will not be the last and spillover of CoVs from bats will continue. Therefore, establishing intervention approaches to reduce the likelihood of future CoVs spillover from natural reservoirs is a priority.

Objectives: In this study, we examined the possibility of using targeted antibodies and the potential of small molecular therapeutics (acetylcholine, nicotine and tacrine) to block the pro-inflammatory and adhesion-related properties of monomeric C-reactive protein (mCRP). Methods: We used three established models (platelet aggregation assay, endothelial leucocyte binding assay and monocyte inflammation via ELISA and Western blotting) to assess the potential of these therapeutics. Results: The results of this study showed that monocyte induced inflammation (raised tumor necrosis factor-alpha-TNF-α) induced by mCRP was significantly blocked in the presence of acetylcholine and nicotine, whilst tacrine and targeted antibodies (clones 8C10 and 3H12) had less of or no significant effects. Western blotting confirmed the ability of acetylcholine to inhibit mCRP-induced cell signaling phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), p38 and nuclear factor-kappa B (NF-κB). There was no evidence of direct binding between small molecules and mCRP. mCRP also induced endothelial cell-monocyte adhesion in a dose dependent fashion, however, both acetylcholine and nicotine as well as targeting antibodies notably inhibited adhesion. Finally, we investigated their effects on mCRP-induced platelet aggregation. All three small molecules significantly attenuated platelet aggregation as did the antibody 8C10, although 3H12 had a weaker effect. Discussion: Acetylcholine and to a lesser extent nicotine show potential for therapeutic inhibition of mCRP-induced inflammation and cell and platelet adhesion. These results highlight the potential of targeted antibodies and small molecule therapeutics to inhibit the binding of mCRP by prevention of membrane interaction and subsequent activation of cellular cascade systems, which produce the pro-inflammatory effects associated with mCRP.

Background: We previously identified increased tissue localization of monomeric C-reactive protein (mCRP) in the infarcted cortical brain tissue of patients following ischaemic stroke. Here, we investigated the relationship of mCRP expression in haemorrhagic stroke, and additionally examined the capacity of mCRP to travel to or appear at other locations within the brain that might account for later chronic neuroinflammatory or neurodegenerative effects. Methods: Immunohistochemistry was performed on Formalin-fixed, paraffin-embedded archived brain tissue blocks obtained at autopsy from stroke patients and age-matched controls. We modelled mCRP migration into the brain after haemorrhagic stroke by infusing mCRP (3.5 µg) into the hippocampus of mice and localized mCRP with histological and immunohistochemistry methods. Results: On human tissue in the early stages of haemorrhage, there was no staining of mCRP. However, with increasing post-stroke survival time, mCRP immunostaining was associated with some parenchymal brain cells, some stroke-affected neurons in the surrounding areas and the lumen of large blood vessels as well as brain capillaries. Further from the peri-haematoma region, however, mCRP was detected in the lumen of micro-vessels expressing aquaporin 4 (AQP4). In the hypothalamus, we detected clusters of neurons loaded with mCRP along with scattered lipofuscin-like deposits. In the peri-haematoma region of patients, mCRP was abundantly seen adjacent to AQP4 immunoreactivity. When we stereotactically injected mCRP into the hippocampus of mice, we also observed strong expression in distant neurones of the hypothalamus as well as cortical capillaries. Conclusions: mCRP is abundantly expressed in the brain after haemorrhagic stroke, directly impacting the pathophysiological development of the haematoma. In addition, it may have indirect effects, where the microcirculatory system appears to be able to carry it throughout the cortex as far as the hypothalamus, allowing for long-distance effects and damage through its capacity to induce inflammation and degenerate neuronal perivascular compartments.