Several clinical conditions, in particular those associated with a systemic inflammatory response, can cause some degree of activation of coagulation but when the procoagulant stimulus is ...sufficiently severe and overcomes the natural anticoagulant mechanisms of coagulation, disseminated intravascular coagulation (DIC) may occur. The clinical manifestations of DIC encompass multiorgan dysfunction caused by fibrin‐platelet clots in the microcirculation, and bleeding caused by consumption of platelets and coagulation factors. Molecular mechanisms that play a role in inflammation‐induced effects on coagulation have been recognized in much detail. Exposure of blood to tissue factor is the most common trigger, whereas the intravascular coagulation is propagated due to loss of function of physiological anticoagulants and impaired fibrinolysis. In patients with DIC, various abnormalities in routine coagulation parameters may be observed, including thrombocytopenia, prolonged global coagulation assays, or high levels of fibrin split products. In addition, more sophisticated tests for activation of individual factors or pathways of coagulation may point to specific involvement of these components in the pathogenesis of the disorder. A combination of readily available tests is usually sufficient in establishing the diagnosis of DIC, and for this purpose, several scoring algorithms have been developed. Some specific clinical situations may elicit coagulation responses that can be distinguished from DIC or may occur in combination with DIC, including dilutional coagulopathy, liver failure‐related coagulation derangement, and thrombotic microangiopathies.
Crowding, generally defined as the deleterious influence of nearby contours on visual discrimination, is ubiquitous in spatial vision. Crowding impairs the ability to recognize objects in clutter. It ...has been extensively studied over the last 80 years or so, and much of the renewed interest is the hope that studying crowding may lead to a better understanding of the processes involved in object recognition. Crowding also has important clinical implications for patients with macular degeneration, amblyopia and dyslexia.
There is no shortage of theories for crowding—from low-level receptive field models to high-level attention. The current picture is that crowding represents an essential bottleneck for object perception, impairing object perception in peripheral, amblyopic and possibly developing vision. Crowding is neither masking nor surround suppression. We can localize crowding to the cortex, perhaps as early as V1; however, there is a growing consensus for a two-stage model of crowding in which the first stage involves the detection of simple features (perhaps in V1), and a second stage is required for the integration or interpretation of the features as an object beyond V1. There is evidence for top-down effects in crowding, but the role of attention in this process remains unclear. The strong effect of learning in shrinking the spatial extent of crowding places strong constraints on possible models for crowding and for object recognition.
The goal of this review is to try to provide a broad, balanced and succinct review that organizes and summarizes the diverse and scattered studies of crowding, and also helps to explain it to the non-specialist. A full understanding of crowding may allow us to understand this bottleneck to object recognition and the rules that govern the integration of features into objects.
Enantioselective allylic substitution reactions comprise some of the most versatile methods for preparing enantiomerically enriched materials. These reactions form products that contain multiple ...functionalities by creating carbon−nitrogen, carbon−oxygen, carbon−carbon, and carbon−sulfur bonds. For many years, the development of catalysts for allylic substitution focused on palladium complexes. However, studies of complexes of other metals have revealed selectivities that often complement those of palladium systems. Most striking is the observation that reactions with unsymmetrical allylic electrophiles that typically occur with palladium catalysts at the less hindered site of an allylic electrophile occur at the more hindered site with catalysts based on other metals. In this Account, we describe the combination of an iridium precursor and a phosphoramidite ligand that catalyzes enantioselective allylic substitution reactions with a particularly broad scope of nucleophiles. The active form of this iridium catalyst is not generated by the simple binding of the phosphoramidite ligand to the metal precursor. Instead, the initial phosphoramidite and iridium precursor react in the presence of base to form a metallacyclic species that is the active catalyst. This species is generated either in situ or separately in isolated form by reactions with added base. The identification of the structure of the active catalyst led to the development of simplified catalysts as well as the most active form of the catalyst now available, which is stabilized by a loosely bound ethylene. Most recently, this structure was used to prepare intermediates containing allyl ligands, the structures of which provide a model for the enantioselectivities discussed here. Initial studies from our laboratory on the scope of iridium-catalyzed allylic substitution showed that reactions of primary and secondary amines, including alkylamines, benzylamines, and allylamines, and reactions of phenoxides and alkoxides occurred in high yields, with high branched-to-linear ratios and high enantioselectivities. Parallel mechanistic studies had revealed the metallacyclic structure of the active catalyst, and subsequent experiments with the purposefully formed metallacycle increased the reaction scope dramatically. Aromatic amines, azoles, ammonia, and amides and carbamates as ammonia equivalents all reacted with high selectivities and yields. Moreover, weakly basic enolates (such as silyl enol ethers) and enolate equivalents (such as enamines) also reacted, and other research groups have used this catalyst to conduct reactions of stabilized carbon nucleophiles in the absence of additional base. One hallmark of the reactions catalyzed by this iridium system is the invariably high enantioselectivity, which reflects a high stereoselectivity for formation of the allyl intermediate. Enantioselectivity typically exceeds 95%, regioselectivity for formation of branched over linear products is usually near 20:1, and yields generally exceed 75% and are often greater than 90%. Thus, the development of iridium catalysts for enantioselective allylic substitution shows how studies of reaction mechanism can lead to a particularly active and a remarkably general system for an enantioselective process. In this case, a readily accessible catalyst effects allylic substitution, with high enantioselectivity and regioselectivity complementary to that of the venerable palladium systems.
Summary
The interaction between platelets and the vessel wall is mediated by various receptors and adhesive proteins, of which von Willebrand factor (VWF) is the most prominent. The multimeric size ...of VWF is an important determinant of a more intense platelet–vessel wall interaction, and is regulated by the VWF‐cleaving protease ADAMTS‐13. A deficiency in ADAMTS‐13 leads to higher concentrations of ultralarge VWF multimers and pathological platelet–vessel wall interactions, in its most typical and extreme form leading to thrombocytopenic thrombotic purpura, a thrombotic microangiopathy characterized by thrombocytopenia, non‐immune hemolysis, and organ dysfunction. Thrombotic microangiopathy associated with low levels of ADAMTS‐13 may be a component of the coagulopathy observed in patients with sepsis. Here, we review the potential role of ADAMTS‐13 deficiency and ultralarge VWF multimers in sepsis, and their relationship with sepsis severity and prognosis. In addition, we discuss the possible benefit of restoring ADAMTS‐13 levels or reducing the effect of ultralarge VWF as an adjunctive treatment in patients with sepsis.
Summary
Disseminated intravascular coagulation (DIC) is a condition in which systemic activation of coagulation without a specific localization occurs, resulting in extensive formation of ...intravascular fibrin, particularly in small and midsize vessels. Disseminated intravascular coagulation may lead to several altered coagulation parameters, including a low platelet count, abnormal global clotting assays, low levels of physiological anticoagulant proteases, or increased fibrin degradation products. Also, more complex assays for activation of coagulation factors or pathways may indicate involvement of these molecules in DIC. None of these tests alone, however, can accurately ascertain or rebuff a diagnosis of DIC. Nonetheless, a combination of readily available routine assays may be instrumental in establishing a diagnosis of DIC and can also be useful to point to a subset of patients with DIC that may need definite, often costly, interventions in the hemostatic system. Current insights on relevant etiological pathways that may contribute to the occurrence of DIC have led to innovative therapeutic and adjunctive approaches to patient with DIC. Management options directed at the amelioration of hemostatic activation may tentatively be indicated and were found to be advantageous in experimental and clinical investigations. These treatments encompass elimination of tissue factor‐mediated thrombin generation or restitution of normal anticoagulant function.
Summary
Laboratory medicine has evolved tremendously but not so much to the individual patient's benefit as far as the volume of blood samples is concerned. It can be calculated that with the current ...collection methods and the small amounts of blood or serum required by modern laboratory analyzers in the Western world alone each 25 million liter of patients’ blood is thrown into waste containers. That is four times more than the total volume of blood that is transfused each year. And this is not a trivial issue, as studies show that many patients develop ‘hospital acquired anemia’ due to blood collection and this is associated with an adverse outcome. It is time that collection methods for blood samples are adapted to the much smaller volumes that are required by new generation laboratory analyzers, in particular for vulnerable groups, such as hematology or oncology patients, critically ill patients, or children.
The recently developed modified Donnan (mD) model provides a simple and useful description of the electrical double layer in microporous carbon electrodes, suitable for incorporation in porous ...electrode theory. By postulating an attractive excess chemical potential for each ion in the micropores that is inversely proportional to the total ion concentration, we show that experimental data for capacitive deionization (CDI) can be accurately predicted over a wide range of applied voltages and salt concentrations. Since the ion spacing and Bjerrum length are each comparable to the micropore size (few nanometers), we postulate that the attraction results from fluctuating bare Coulomb interactions between individual ions and the metallic pore surfaces (image forces) that are not captured by mean-field theories, such as the Poisson-Boltzmann-Stern model or its mathematical limit for overlapping double layers, the Donnan model. Using reasonable estimates of the micropore permittivity and mean size (and no other fitting parameters), we propose a simple theory that predicts the attractive chemical potential inferred from experiments. As additional evidence for attractive forces, we present data for salt adsorption in uncharged microporous carbons, also predicted by the theory.
Summary
Derangement of the coagulation system is a common phenomenon in critically ill patients, who may present with severe bleeding and/or conditions associated with a prothrombotic state. ...Monitoring of this coagulopathy can be performed with conventional coagulation assays; however, point‐of‐care tests have become increasingly attractive, because not only do they yield a more rapid result than clinical laboratory testing, but they may also provide a more complete picture of the condition of the hemostatic system. There are many potential areas of study and applications of point‐of‐care hemostatic testing in critical care, including patients who present with massive blood loss, patients with a hypercoagulable state (such as in disseminated intravascular coagulation), and monitoring of antiplatelet treatment for acute arterial thrombosis, mostly acute coronary syndromes. However, the limitations of near‐patient hemostatic testing has not been fully appreciated, and are discussed here. The currently available evidence indicates that point‐of‐care tests may be applied to guide appropriate blood product transfusion and the use of hemostatic agents to correct the hemostatic defect or to ameliorate antithrombotic treatment. Disappointingly, however, only in cardiac surgery is there adequate evidence to show that application of near‐patient thromboelastography leads to an improvement in clinically relevant outcomes, such as reductions in bleeding‐related morbidity and mortality, and cost‐effectiveness. More research is required to validate the utility and cost‐effectiveness of near‐patient hemostatic testing in other areas, especially in traumatic bleeding and postpartum hemorrhage.