Assessment of the interplay between blood and skin vascular abnormalities in adult purpura fulminans

RATIONALE: Purpura fulminans in adults is a rare but devastating disease. Its pathophysiology is not well known. OBJECTIVES: To understand the pathophysiology of skin lesions in purpura fulminans, the interplay between circulating blood and vascular alterations was assessed. METHODS: Prospective multicenter study in four intensive care units. Patients with severe sepsis without skin lesions were recruited as control subjects. MEASUREMENTS AND MAIN RESULTS: Twenty patients with severe sepsis and purpura fulminans were recruited for blood sampling, and skin biopsy was performed in deceased patients. High severity of disease and mortality rates (80%) was observed. Skin biopsies in purpura fulminans lesions revealed thrombosis and extensive vascular damage: vascular congestion and dilation, endothelial necrosis, alteration of markers of endothelial integrity (CD31) and of the protein C pathway receptors (endothelial protein C receptor, thrombomodulin). Elevated plasminogen activating inhibitor-1 mRNA was also observed. Comparison with control patients showed that these lesions were specific to purpura fulminans. By contrast, no difference was observed for blood hemostasis parameters, including soluble thrombomodulin, activated protein C, and disseminated intravascular coagulation markers. Bacterial presence at the vascular wall was observed specifically in areas of vascular damage in eight of nine patients tested (including patients with Streptococcus pneumoniae, Neisseria meningitidis, Escherichia coli, and Pseudomonas aeruginosa infection). CONCLUSIONS: Thrombi and extensive vascular damage with multifaceted prothrombotic local imbalance are characteristics of purpura fulminans. A "vascular wall infection" hypothesis, responsible for endothelial damage and subsequent skin lesions, can be put forward

Mast Cells Granular Contents Are Crucial for Deep Vein Thrombosis in Mice

Rationale: Deep vein thrombosis (DVT) and its complication pulmonary embolism have high morbidity reducing quality of life and leading to death. Cellular mechanisms of DVT initiation remain poorly understood. Objective: We sought to determine the role of mast cells (MCs) in DVT initiation and validate MCs as a potential target for DVT prevention. Methods and Results: In a mouse model, DVT was induced by partial ligation (stenosis) of the inferior vena cava. We demonstrated that 2 strains of mice deficient for MCs were completely protected from DVT. Adoptive transfer of in vitro differentiated MCs restored thrombosis. MCs were present in the venous wall, and the number of granule-containing MCs decreased with thrombosis. Pharmacological depletion of MCs granules or prevention of MC degranulation also reduced DVT. Basal plasma levels of von Willebrand factor and recruitment of platelets to the inferior vena cava wall after DVT induction were reduced in MC-deficient mice. Stenosis application increased plasma levels of soluble P-selectin in wild-type but not in MC-deficient mice. MC releasate elevated ICAM-1 (intercellular adhesion molecule-1) expression on HUVEC (human umbilical vein endothelial cells) in vitro. Topical application of compound 48/80, an MC secretagogue, or histamine, a Weibel–Palade body secretagogue from MCs, potentiated DVT in wild-type mice, and histamine restored thrombosis in MC-deficient animals. Conclusions: MCs exacerbate DVT likely through endothelial activation and Weibel–Palade body release, which is, at least in part, mediated by histamine. Because MCs do not directly contribute to normal hemostasis, they can be considered potential targets for prevention of DVT in humans

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H2 receptor-mediated responses of aortic endothelial cells to histamine.

It is well known that umbilical vein endothelial cells express H1 receptors that mediate the various responses of these cells to histamine, including accumulation of inositol phosphates, rise of cytosolic Ca2+, increased permeability to macromolecules, and release of prostacyclin. In bovine aortic endothelial cells, histamine did not increase the level of inositol phosphates nor the release of prostacyclin. In contrast, it increased the adenosine 3',5'-cyclic monophosphate (cAMP) content of these cells. That response was obtained in the 1 to 100 microM range of concentrations and reached a maximum within 2 min of histamine addition. It was mimicked by the H2-specific agonist dimaprit, inhibited by the H2 antagonist ranitidine, and insensitive to the H1 antagonist mepyramine. Histamine reduced the permeability to albumin of bovine aortic endothelial cell monolayers; this paradoxical effect is likely to be mediated by the rise in cAMP, which is known to enhance the barrier property of the endothelium. In conclusion, bovine aortic endothelial cells are responsive to histamine, and this response is mediated by H2 and not H1 receptors.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Spatial Summation Processes in Visually Driven Neurons of Cat\u27s Pretectal Region

The spatial summation processes of single neurones of cat\u27s pretectal region were investigated with moving and stationary visual stimuli. The results indicate that the majority of the investigated neurones changed their responses essentially at the gradual increase of size of the applied stimuli (i.e. showed negative or positive summation). Particularly, direction non-sensitive neurones showed symmetrical changes of spatial summation curves in response to two opposite directions of movement. By contrast, in some direction sensitive neurones different characteristics of responses for the two opposite directions of movement were observed. Thus the number of discharges in the responses to the preferred direction could increase or decrease at the gradual increase of the moving stimulus size, while the responses to the null direction could remain stable or vice versa. The same was observed for the ON and OFF responses in the ON-OFF neurones. Thus, it appears that the pattern of responses of a given neurone to different directions of movement and to the on and off periods of stationary stimulation are shaped by independent mechanisms

Responses of Cat\u27s Dorsal Hippocampal Neurones to Moving Visual Stimuli

Response properties of visually driven neurones in the cat\u27s hippocampal region were investigated. Out of 688 single cells observed 181 (26%) were visually driven. Ocular dominance was determined for 147 of those cells, 90 of which were driven only by the contralateral eye, 20 were driven exclusively by ipsilateral eye and 37 neurones could be activated by both eyes. Receptive field boundaries were outlined for 157; 152 of those neurones were movement-sensitive, and 125 neurones were sensitive to stationary stimuli. A small group of neurones (13%) showed more pronounced reactions to the vertical direction of motion. Some neurones (22%) revealed sensitivity to the shape and size of the applied visual stimuli. These results confirmed earlier data indicating that visually driven neurones in hippocampal region possess complex properties. They are probably involved in a higher level of visual information processing