Neutrophil Extracellular Trap-Driven Occlusive Diseases.

The enlightenment of the formation of neutrophil extracellular traps (NETs) as a part of the innate immune system shed new insights into the pathologies of various diseases. The initial idea that NETs are a pivotal defense structure was gradually amended due to several deleterious effects in consecutive investigations. NETs formation is now considered a double-edged sword. The harmful effects are not limited to the induction of inflammation by NETs remnants but also include occlusions caused by aggregated NETs (aggNETs). The latter carries the risk of occluding tubular structures like vessels or ducts and appear to be associated with the pathologies of various diseases. In addition to life-threatening vascular clogging, other occlusions include painful stone formation in the biliary system, the kidneys, the prostate, and the appendix. AggNETs are also prone to occlude the ductal system of exocrine glands, as seen in ocular glands, salivary glands, and others. Last, but not least, they also clog the pancreatic ducts in a murine model of neutrophilia. In this regard, elucidating the mechanism of NETs-dependent occlusions is of crucial importance for the development of new therapeutic approaches. Therefore, the purpose of this review is to address the putative mechanisms of NETs-associated occlusions in the pathogenesis of disease, as well as prospective treatment modalities.

Key Immune Events of the Pathomechanisms of Early Cardioembolic Stroke: Multi-Database Mining and Systems Biology Approach.

While inflammation has generally been regarded as a negative factor in stroke recovery, this viewpoint has recently been challenged by demonstrating that inflammation is a necessary and sufficient factor for regeneration in the zebrafish brain injury model. This close relationship with inflammation suggests that a re-examination of the immune system's role in strokes is necessary. We used a systems biology approach to investigate the role of immune-related functions via their interactions with other molecular functions in early cardioembolic stroke. Based on protein interaction models and on microarray data from the blood of stroke subjects and healthy controls, networks were constructed to delineate molecular interactions at four early stages (pre-stroke, 3 h, 5 h and 24 h after stroke onset) of cardioembolic stroke. A comparative analysis of functional networks identified interactions of immune-related functions with other molecular functions, including growth factors, neuro/hormone and housekeeping functions. These provide a potential pathomechanism for early stroke pathophysiology. In addition, several potential targets of miRNA and methylation regulations were derived based on basal level changes observed in the core networks and literature. The results provide a more comprehensive understanding of stroke progression mechanisms from an immune perspective and shed light on acute stroke treatments.

Cardioembolic and small vessel disease stroke show differences in associations between systemic C3 levels and outcome.

BACKGROUND: Activation of the complement system has been proposed to play a role in the pathophysiology of stroke. As the specific involvement of the complement proteins may be influenced by stroke etiology, we compared plasma C3 and C3a levels in patients with cardioembolic (CE) and small vessel disease (SVD) subtypes of ischemic stroke and control subjects and evaluated their association to outcome at three months and two years. METHODOLOGY/PRINCIPAL FINDINGS: Plasma C3 and C3a levels in 79 CE and 79 SVD stroke patients, sampled within 10 days and at three months after stroke, and age- and sex-matched control subjects from The Sahlgrenska Academy Study on Ischemic Stroke were measured by ELISA. Functional outcome was assesed with modified Rankin Scale. In the CE group, plasma C3 levels were elevated only in the acute phase, whereas C3a was elevated at both time points. The follow-up phase plasma C3 levels in the upper third were associated with an increased risk of unfavorable outcome at three months (OR 7.12, CI 1.72-29.46, P = 0.007) as well as after two years (OR 8.25, CI 1.61-42.28, P = 0.011) after stroke. These associations withstand adjustment for age and sex. Conversely, three-month follow-up plasma C3a/C3 level ratios in the middle third were associated with favorable outcome after two years both in the univariate analysis (OR 0.19, CI 0.05-0.82, P = 0.026) and after adjustment for age and sex (OR 0.19, CI 0.04-0.88, P = 0.033). In the SVD group, plasma C3 and C3a levels were elevated at both time points but showed no significant associations with outcome. CONCLUSIONS: Plasma C3 and C3a levels are elevated after CE and SVD stroke but show associations with outcome only in CE stroke.

Prevention and treatment of coronary distal embolization in the setting of acute myocardial infarction: pharmacologic approach.

Distal embolization (DE) of atherothrombotic debris into the coronary microcirculation occurs both in stable and unstable coronary syndromes. Despite the well recognized clinical significance of periprocedural myocardial infarction (MI) in stable percutaneous coronary intervention (PCI), the impact of DE has a much higher prognostic impact in the acute setting, and especially in ST-elevation myocardial infarction, where DE is a main determinant of no-reflow phenomenon. The present review aims to describe the pathophysiology of DE and to summarize the currently available pharmacological strategies to prevent and treat DE in the setting of MI, especially focusing on antithrombotic, antiinflammatory and vasodilator agents.

[Acute illness following chicken pox: spleen infarction as a complication of varicella zoster infection]. / Acuut ziek na waterpokken: miltinfarcten als complicatie van varicella-zosterinfectie.

BACKGROUND: Varicella zoster virus (VZV) infection can cause temporary acquired protein S or C deficiency via cross reacting antibodies and consequently inducing a hypercoagulable state. CASE DESCRIPTION: A 6-year-old girl with a history of congenital cardiac disease was seen at an Emergency Department with acute chest pain, dyspnoea and fever, seven days after developing chicken pox. Diagnostic tests revealed massive infarction of the spleen, and a protein S and C deficiency. In addition, blood cultures revealed a Lancefield group A ß-haemolytic streptococcus (GABHS). The patient recovered fully after treatment with low molecular weight heparin and antibiotics. CONCLUSION: In this patient, septic emboli caused splenic infarction. Thromboembolic complications should be suspected in children with VZV who present with acute symptoms, in particular if bacterial superinfection is found.

Immuno-inflammatory activation in acute cardio-embolic strokes in comparison with other subtypes of ischaemic stroke.

Few studies have examined the relationship between inflammatory biomarker blood levels, cardioembolic stroke subtype and neurological deficit. So the aim of our study is to evaluate plasma levels of immuno-inflammatory variables in patients with cardio-embolic acute ischaemic stroke compared to other diagnostic subtypes and to evaluate the relationship between immuno-inflammatory variables, acute neurological deficit and brain infarct volume. One hundred twenty patients with acute ischaemic stroke and 123 controls without a diagnosis of acute ischaemic stroke were evaluated. The type of acute ischaemic stroke was classified according to the TOAST classification. We evaluated plasma levels of IL-1beta, TNF-alpha, IL-6 and IL-10, E-selectin, P-selectin, sICAM-1,sVCAM-1, vWF, TPA and PAI-1. Patients with ischaemic stroke classified as cardio-embolic (CEI) showed, compared to other subtypes, significantly higher median plasma levels of TNF-alpha , IL-6 and IL-1beta. Furthermore stroke patients classified as lacunar showed, compared to other subtypes, significantly lower median plasma levels of TNF-alpha, IL-6 and IL-1beta. Multiple linear regression showed a significant association between the Scandinavian Stroke Scale (SSS) score at admission and diagnostic subtype, infarct volume of cardio-embolic strokes and some inflammatory variables. Our findings confirm that cardio-embolic strokes have a worse clinical presentation and produce larger and more disabling strokes than other ischaemic stroke subtypes reporting a possible explanation of higher immuno-inflammatory activation of the acute phase.

D2-40 in breast cancer: should we detect more vascular emboli?

Peritumoral emboli assessed on hematoxylin-eosin-stained slides are taken into account for treatment of patients with operable breast cancer. We assessed whether immunostaining with D2-40 improves the prognostic significance of emboli in a group of tumors with a large immunohistochemical sampling and a long-term follow-up. Topography, number, and extension of hematoxylin-eosin and D2-40 emboli were compared in 94 node-negative breast cancers (median number of immunostained slides per tumor: 3). Metastasis-free survival of patients with or without hematoxylin-eosin and/or D2-40 emboli were evaluated (median follow-up of 178 months). Hematoxylin-eosin emboli were detected in 14 (15%) tumors and were located at distance from the tumor. D2-40 emboli were detected in 39 (41%) tumors and was often multiple (n=30), extensive (n=23), located within (n=13), close to (n=10) or at distance from the tumor (n=16). The 12 distant hematoxylin-eosin and D2-40 emboli were located in the same vessels (seven missed at the first hematoxylin-eosin examination and secondarily diagnosed by D2-40 staining). A difference in metastasis-free survival was found only between patients with no D2-40 emboli and those with distant D2-40 emboli (P=0.02). D2-40 emboli located within or close to the tumor had no prognostic value. Comparing the metastasis-free survival of patients with or without hematoxylin-eosin emboli, the prognostically unfavorable significance of hematoxylin-eosin emboli was improved when taking into account the seven patients with missed emboli at the first examination and secondarily diagnosed by D2-40 staining (P=0.006 vs 0.003). To conclude, D2-40 increases the diagnostic sensitivity of emboli in breast carcinoma and the high incidence of D2-40 emboli might be related to the number of immunostained slides per case. Nevertheless, only distant D2-40+ emboli had a prognostic impact. In practice, D2-40 might be useful to detect missed hematoxylin-eosin emboli especially in cases without any other prognostically unfavorable criterion.

[Coronary microembolization: perfusion-contraction mismatch secondary to myocardial inflammation]. / Koronare Mikroembolisation: Perfusions-Kontraktions-Mismatch durch inflammatorische Reaktion des Myokards.

Atherosclerotic plaque rupture is a key event in the pathogenesis of acute coronary syndromes and during coronary interventions. Atherosclerotic plaque rupture does not necessarily lead to thrombotic occlusion of a coronary artery and subsequent myocardial infarction. Milder forms may result in the embolization of atherosclerotic and/or thrombotic debris into the coronary microcirculation. The characteristic consequences of coronary microembolization are arrhythmias, microinfarcts, and a reduced coronary reserve. Experimental studies revealed that an inflammatory reaction is causally involved in the progressive contractile dysfunction following coronary microembolization. Thus, anti-inflammatory treatment appears as a promising strategy to protect patients from the consequences of coronary microembolization.

Increased levels of antiphospholipid antibodies in a woman with left atrial myxoma and systemic embolisms.

We describe a case of a 45-y-old woman with a left atrial myxoma, mild to moderate constitutional symptoms and systemic embolisms. Increased levels of antiphospholipid antibodies were detected at admission to the hospital and were gradually normalized after the surgical removal of the tumor. It is known that myxomas have the peculiar ability to induce a systemic inflammatory state with constitutional symptoms, probably mediated by the production of inflammatory mediators in the tumor. This case suggests that myxomas might have also been implicated in the production of antiphospholipid antibodies. Antiphospholipid antibodies could be just a by-product of the systemic inflammatory response. However, they could also have a role in the thrombosis on the myxoma surface and systemic embolisms.

Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation.

A close relationship exists between regional myocardial blood flow (RMBF) and function during acute coronary inflow restriction (perfusion-contraction matching). However, the relationship of flow and function during coronary microvascular obstruction is unknown. In 12 anesthetized dogs, the left circumflex coronary artery was perfused from an extracorporeal circuit. After control measurements, 3,000 microspheres (42 micrometer diameter) per milliliter per minute inflow were injected to cause a microembolism (ME, n = 6). With unchanged systemic hemodynamics and RMBF, posterior systolic wall thickening (PWT) decreased from 19.8 +/- 1.9% SD at control to 13.3 +/- 4.0, 10.3 +/- 3.8, and 6.9 +/- 4.7% (P < 0.05 vs. control) at 1, 4, and 8 h, respectively. For comparison, inflow was progressively reduced to match PWT to that of the ME group at 1, 4, and 8 h (stenosis, STE, n = 6). RMBF in the STE group was reduced in proportion to PWT. Infarct size was not different among groups (6.5 +/- 4.5 vs. 3.4 +/- 3.2%). However, the number of leukocytes infiltrating the area at risk was significantly greater in the ME group than in the STE group. Coronary microembolization results in perfusion-contraction mismatch and is associated with an inflammatory response.

Inflammation in high-grade carotid stenosis: a possible role for macrophages and T cells in plaque destabilization.

BACKGROUND AND PURPOSE: Inflammatory mechanisms have been implicated in the pathogenesis of atherosclerosis. In this study, we investigated whether the extent of inflammatory infiltration in high-grade stenoses of the internal carotid artery (ICA) correlates to clinical features of plaque destabilization. METHODS: Endarterectomy specimens from 37 consecutive patients undergoing surgery for high-grade ICA stenosis were stained immunocytochemically for macrophages (CD68) and T cells (CD3). The staining was quantified by planimetry of immunostained areas (CD68) or counting individual cells (CD3). Clinical evidence of plaque instability was provided by the preoperative assessment of recent ischemic symptoms attributable to the stenosis and of the occurrence of cerebral microembolism in transcranial Doppler ultrasound monitoring of the ipsilateral middle cerebral artery. RESULTS: The percentage of macrophage-rich areas and number of T cells per mm2 section area were larger in recently symptomatic patients than in asymptomatic patients (macrophages: 18+/-10% versus 11+/-4%, P=0.005; T cells: 71.2+/-34.4 versus 40.5+/-31.4 mm2, P=0.005). The presence of microembolism was associated with an increase in macrophage-rich areas (P=0.011). Macrophage (19+/-10% versus 9+/-3%, P=0.0009) and T cell (71.5+/-39.0 versus 46.4+/-22 mm2, P=0.045) infiltration were more pronounced in predominantly atheromatous than in fibrous plaques, but did not correlate significantly to the presence of surface ulceration or luminal thrombosis. CONCLUSIONS: Our data suggest a role of plaque-infiltrating macrophages and T cells in the clinical destabilization of high-grade ICA stenoses. Inflammatory mechanisms may be a therapeutic target in patients with symptomatic ICA disease.

Anticorpos Anticardiolipina associado à presença de trombos em átrio esquerdo e aorta descendente / Anticardiolipin antibody associated with thrombosis and descent aortic

Os autores apresentam o caso de um paciente de 68 anos de idade com evento agudo de embolia arterial periférica. Na investigaçao diagnóstica constatou-se a presença de anticorpos antifosfolipídios tipo anticardiolipina associado a trombose cardíaca e de aorta descendente. Ressalta-se a importância da pesquisa do anticorpo antifosfolipídio em pacientes com história de fenômenos embólicos sem outros fatores de riscos manifestos.

[Emboligenic mitral papillary fibroelastoma and positive antiphospholipid antibodies]. / Fibroelastoma papilar mitral embolígeno y anticuerpos antifosfolípidos positivos.

Cardiac papillary fibroelastoma has been associated to high levels of antiphospholipid antibodies, either primary or in the context of systemic lupus erythematosus. We present the case of a young female with several episodes of peripheral emboli. Two-dimensional echocardiography demonstrated a tumor on the anterior mitral leaflet. The mass was resected and histologically showed a papillary architecture covered by hyperplasic endocardial cells on a layer of connective tissue and a central core of collagen and elastic fibers. The immunologic study demonstrated high titers of anticardiolipin antibodies, complement consumption and positive antinuclear antibodies. The patient keep high anticardiolipin antibodies titers at follow-up but embolization has not recurred and has no symptoms.

Primary antiphospholipid syndrome (PAPS). Two case reports and therapeutic implications.

Antiphospholipid antibodies (aPL) interfere with the coagulation system and can cause thrombosis and other clotting disorders. The combination of recurrent venous thrombosis, arterial embolism and recurrent fetal loss is nowadays considered to be primary antiphospholipid syndrome (PAPS), provided an underlying systemic lupus erythematosus (SLE) has been excluded and aPL have been detected. We report on two patients with PAPs, and show the course of their IgG- and IgM-anticardiolipin antibody (aCL) titers during immunosuppressive therapy with prednisone and azathioprine or cyclophosphamide. Over a period of 18 months this therapy was effective in preventing relapses of thrombo-embolism and other complications. Therapy with cyclophosphamide resulted in normalization of the aCL titers in one of the two reported cases. Azathioprine treatment reduced the aCL titer in the other patient, without fully normalizing it. Based on our observation, we propose to treat PAPS-associated severe and recurrent thrombo-embolic complications by aggressive immunosuppression, including azathioprine and cyclophosphamide.