Vascular Dementia and Crosstalk Between the Complement and Coagulation Systems

Vascular Dementia (VaD) is a neurocognitive disorder caused by reduced blood flow to the brain tissue, resulting in infarction, and is the second most common type of dementia. The complement and coagulation systems are evolutionary host defence mechanisms activated by acute tissue injury to induce inflammation, clot formation and lysis; recent studies have revealed that these systems are closely interlinked. Overactivation of these systems has been recognised to play a key role in the pathogenesis of neurological disorders such as Alzheimer's disease and multiple sclerosis, however their role in VaD has not yet been extensively reviewed. This review aims to bridge the gap in knowledge by collating current understanding of VaD to enable identification of complement and coagulation components involved in the pathogenesis of this disorder that may have their effects amplified or supressed by crosstalk. Exploration of these mechanisms may unveil novel therapeutic targets or biomarkers that would improve current treatment strategies for VaD.

Stoking the Fire: How Dying Cells Propagate Inflammatory Signalling through Extracellular Vesicle Trafficking

Communication between dying cells and their environment is a critical process that promotes tissue homeostasis during normal cellular turnover, whilst during disease settings, it can contribute to inflammation through the release of intracellular factors. Extracellular vesicles (EVs) are a heterogeneous class of membrane-bound cell-derived structures that can engage in intercellular communication via the trafficking of bioactive molecules between cells and tissues. In addition to the well-described functions of EVs derived from living cells, the ability of dying cells to release EVs capable of mediating functions on target cells or tissues is also of significant interest. In particular, during inflammatory settings such as acute tissue injury, infection and autoimmunity, the EV-mediated transfer of proinflammatory cargo from dying cells is an important process that can elicit profound proinflammatory effects in recipient cells and tissues. Furthermore, the biogenesis of EVs via unique cell-death-associated pathways has also been recently described, highlighting an emerging niche in EV biology. This review outlines the mechanisms and functions of dying-cell-derived EVs and their ability to drive inflammation during various modes of cell death, whilst reflecting on the challenges and knowledge gaps in investigating this subgenre of extracellular vesicles research.

Selective Apheresis of C-Reactive Protein for Treatment of Indications with Elevated CRP Concentrations

Almost every kind of inflammation in the human body is accompanied by rising C-reactive protein (CRP) concentrations. This can include bacterial and viral infection, chronic inflammation and so-called sterile inflammation triggered by (internal) acute tissue injury. CRP is part of the ancient humoral immune response and secreted into the circulation by the liver upon respective stimuli. Its main immunological functions are the opsonization of biological particles (bacteria and dead or dying cells) for their clearance by macrophages and the activation of the classical complement pathway. This not only helps to eliminate pathogens and dead cells, which is very useful in any case, but unfortunately also to remove only slightly damaged or inactive human cells that may potentially regenerate with more CRP-free time. CRP action severely aggravates the extent of tissue damage during the acute phase response after an acute injury and therefore negatively affects clinical outcome. CRP is therefore a promising therapeutic target to rescue energy-deprived tissue either caused by ischemic injury (e.g., myocardial infarction and stroke) or by an overcompensating immune reaction occurring in acute inflammation (e.g., pancreatitis) or systemic inflammatory response syndrome (SIRS; e.g., after transplantation or surgery). Selective CRP apheresis can remove circulating CRP safely and efficiently. We explain the pathophysiological reasoning behind therapeutic CRP apheresis and summarize the broad span of indications in which its application could be beneficial with a focus on ischemic stroke as well as the results of this therapeutic approach after myocardial infarction.

Mesenchymal stromal cell therapeutic potency is dependent upon viability, route of delivery, and immune match

Culture-adapted bone marrow mesenchymal stromal cells (MSCs) deploy paracrine anti-inflammatory and tissue regenerative functionalities that can be harnessed as a living cell pharmaceutical product. Independent of clinical indication, a near majority of human clinical trials administer MSC IV, often with an allogeneic MSC cell product immediately after thawing from cryostorage. Despite hundreds of studies in a wide assortment of inflammatory, degenerative, and acute tissue injury syndromes, human clinical outcomes often fail to mirror promising rigorously conducted preclinical animal studies. Using a mouse model of toxic colitis, we demonstrate that replication fit MSCs harvested in log phase of growth have substantial impact on colitis clinical and pathologic endpoints when delivered subcutaneously or intraperitoneally, whereas the maximum tolerated IV bolus dosing failed to do so. We also demonstrate that heat-inactivated MSCs lose all therapeutic utility and the observation is mirrored by use of viable MSC administered immediately postthaw from cryostorage. Using luciferase transgenic MSC as donor cells, we demonstrate that transient in vivo engraftment is severely compromised when MSCs are dead or thawed and further demonstrate that MSC redosing is feasible in relapsing colitis, but only syngeneic MSCs lead to sustained improvement of clinical endpoints. These data support the notion that pharmaceutical potency of MSC requires viability and functional fitness. Reciprocally, IV administration of thawed MSC products may be biased against positive clinical outcomes for treatment of colitis and that extravascular administration of syngeneic, fit MSCs allows for effect in a recurrent therapy model.

Proteases and tissue repair: peri operative role of chymotrypsin: trypsin in surgical patients

Background: Proteolytic enzymes have been used to facilitate tissue repair ever since ancient times. Trypsin: Chymotrypsin, proteolytic enzyme oral preparation which has been in clinical use ever since 1960s, provides a better resolution of inflammatory symptoms and promotes speedier recovery of acute tissue injury by minimising the fibrinolytic shut down. This paper revisits the role and clinical utility of chymotrypsin: trypsin oral combination in tissue repair, in surgical patients. The aim of the present study was to determine the efficacy of chymotrypsin n trypsin in reducing post-operative oedema and haematoma formation and its role in surgical prophylaxis and scar formation.Methods: A prospective study was done on 50 electively posted surgical patients during a period of 6months comparing placebo with chymotrypsin and trypsin oral combination.Results: Statistically significant reduction in post-operative oedema, seroma and haematoma formation and reduction in pain and incidence of suture site infection, better cosmetic appearance of the scar and decline in need for secondary suturing was noted.Conclusions: From the current study, it is thus concluded that trypsin: chymotrypsin prophylaxis pre-operatively and post-operative treatment in surgical patients hastens the healing process and significantly reduces the recovery time.

Role of cardiovascular magnetic resonance in the evaluation of cardiomyopathy

Cardiovascular magnetic resonance imaging plays a central role in the assessment and monitoring of patients with cardiomyopathy. It offers a comprehensive assessment during a single scan setting, with information on ventricular volumes, function and mass as well as tissue characterisation, fibrosis, flow, viability and perfusion. Acute tissue injury (oedema and necrosis) can be distinguished from fibrosis, infiltration and iron overload. It provides information on the cause and prognosis of the cardiomyopathy, and its high measurement accuracy makes it ideal for monitoring disease progression and effects of therapy. The present review highlights the main features of commonly encountered cardiomyopathies in imaging practice.