Perivascular spaces and the two steps to neuroinflammation

Immune cells enter the central nervous system (CNS) from the circulation under normal conditions for immunosurveillance and in inflammatory neurologic diseases. This review describes the distinct anatomic features of the CNS vasculature that permit it to maintain parenchymal homeostasis and which necessitate specific mechanisms for neuroinflammation to occur. We review the historical evolution of the concept of the blood-brain barrier and discuss distinctions between diffusion/transport of solutes and migration of cells from the blood to CNS parenchyma. The former is regulated at the level of capillaries, whereas the latter takes place in postcapillary venules. We summarize evidence that entry of immune cells into the CNS parenchyma in inflammatory conditions involves 2 differently regulated steps: transmigration of the vascular wall into the perivascular space and progression across the glia limitans into the parenchyma.

Biomarker-guided personalised emergency medicine for all - hope for another hype?

Polymorbid patients, diverse diagnostic and therapeutic options, more complex hospital structures, financial incentives, benchmarking, as well as perceptional and societal changes put pressure on medical doctors, specifically if medical errors surface. This is particularly true for the emergency department setting, where patients face delayed or erroneous initial diagnostic or therapeutic measures and costly hospital stays due to sub-optimal triage. A "biomarker" is any laboratory tool with the potential better to detect and characterise diseases, to simplify complex clinical algorithms and to improve clinical problem solving in routine care. They must be embedded in clinical algorithms to complement and not replace basic medical skills. Unselected ordering of laboratory tests and shortcomings in test performance and interpretation contribute to diagnostic errors. Test results may be ambiguous with false positive or false negative results and generate unnecessary harm and costs. Laboratory tests should only be ordered, if results have clinical consequences. In studies, we must move beyond the observational reporting and meta-analysing of diagnostic accuracies for biomarkers. Instead, specific cut-off ranges should be proposed and intervention studies conducted to prove outcome relevant impacts on patient care. The focus of this review is to exemplify the appropriate use of selected laboratory tests in the emergency setting for which randomised-controlled intervention studies have proven clinical benefit. Herein, we focus on initial patient triage and allocation of treatment opportunities in patients with cardiorespiratory diseases in the emergency department. The following five biomarkers will be discussed: proadrenomedullin for prognostic triage assessment and site-of-care decisions, cardiac troponin for acute myocardial infarction, natriuretic peptides for acute heart failure, D-dimers for venous thromboembolism, C-reactive protein as a marker of inflammation, and procalcitonin for antibiotic stewardship in infections of the respiratory tract and sepsis. For these markers we provide an overview on physiopathology, historical evolution of evidence, strengths and limitations for a rational implementation into clinical algorithms. We critically discuss results from key intervention trials that led to their use in clinical routine and potential future indications. The rational for the use of all these biomarkers, first, tackle diagnostic ambiguity and consecutive defensive medicine, second, delayed and sub-optimal therapeutic decisions, and third, prognostic uncertainty with misguided triage and site-of-care decisions all contributing to the waste of our limited health care resources. A multifaceted approach for a more targeted management of medical patients from emergency admission to discharge including biomarkers, will translate into better resource use, shorter length of hospital stay, reduced overall costs, improved patients satisfaction and outcomes in terms of mortality and re-hospitalisation. Hopefully, the concepts outlined in this review will help the reader to improve their diagnostic skills and become more parsimonious laboratory test requesters.

The Evolution of Totalitarianism: From Stalin to Putin

The Soviet Union is commonly cited as "totalitarian." But just how totalitarian was the Soviet Union? The modern Russian Federation? There is an ongoing debate in Georgia about the Soviet past, the role of Stalin in Georgian history, an importance of Soviet legacies in shaping the nationalist discourse after independence and etc. Various roundtables and conferences reflecting on the historical, political and sociological contexts of the Soviet occupation are held in Georgian academic institutions and universities. On a discursive level, it is taken as a given that the „Evil Empire‟ was indeed totalitarian – brutally repressive, all-encompassing, and terrorizing. The term "totalitarian" embodies a multitude of concepts which we will try to discuss in a historical perspective, testing the extent of applicability and relevance of this term to modern-day Russia.

Endovascular Treatment of Acute Stroke: Evolution and Selection of Techniques and Instruments Based on Thrombus Imaging.

Mechanical thrombectomy provides higher recanalization rates than intravenous or intra-arterial thrombolysis. Finally this has been shown to translate into improved clinical outcome in six multicentric randomized controlled trials. However, within cohorts the clinical outcomes may vary, depending on the endovascular techniques applied. Systems aiming mainly for thrombus fragmentation and lacking a protection against distal embolization have shown disappointing results when compared to recent stent-retriever studies or even to historical data on local arterial fibrinolysis. Procedure-related embolic events are usually graded as adverse events in interventional neuroradiology. In stroke, however, the clinical consequences of secondary emboli have so far mostly been neglected and attributed to progression of the stroke itself. We summarize the evolution of instruments and techniques for endovascular, image-guided, microneurosurgical recanalization in acute stroke, and discuss how to avoid procedure-related embolic complications.

Referential hierarchies: A new look at some historical and typological patterns

This paper proposes a diachronic typology for the various patterns that have been referred to as Hierarchical Alignment or Inverse Alignment. Previous typological studies have tried to explain such patterns as grammatical reflections of a universal Referential Hierarchy, in which first person outranks second person outranks third person and humans outrank other animates outrank inanimates. However, our study shows that most of the formal properties of hierarchy-sensitive constructions are essentially predictable from their historical sources. We have identified three sources for hierarchical person marking, three for direction marking, two for obviative case marking, and one for hierarchical constituent ordering. These sources suggest that there is more than one explanation for hierarchical alignment: one is consistent with Givón’s claim that hierarchical patterns are a grammaticalization of generic topicality; another is consistent with DeLancey’s claim that hierarchies reflect the deictic distinction between present (1/2) and distant (3) participants; another is simply a new manifestation of a common asymmetrical pattern, the use of zero marking for third persons. More importantly, the evolution of hierarchical grammatical patterns does not reflect a consistent universal ranking of participants – at least in those cases where we can see (or infer) historical stages in the evolution of these properties, different historical stages appear to reflect different hierarchical rankings of participants, especially first and second person. This leads us to conclude that the diversity of hierarchical patterns is an artifact of grammatical change, and that in general, the presence of hierarchical patterns in synchronic grammars is not somehow conditioned by some more general universal hierarchy.