Targeting Neutrophil Adhesive Events to Address Vaso-Occlusive Crisis in Sickle Cell Patients.

Neutrophils are essential to protect the host against invading pathogens but can promote disease progression in sickle cell disease (SCD) by becoming adherent to inflamed microvascular networks in peripheral tissue throughout the body. During the inflammatory response, leukocytes extravasate from the bloodstream using selectin adhesion molecules and migrate to sites of tissue insult through activation of integrins that are essential for combating pathogens. However, during vaso-occlusion associated with SCD, neutrophils are activated during tethering and rolling on selectins upregulated on activated endothelium that line blood vessels. Recently, we reported that recognition of sLex on L-selectin by E-selectin during neutrophil rolling initiates shear force resistant catch-bonds that facilitate tethering to endothelium and activation of integrin bond clusters that anchor cells to the vessel wall. Evidence indicates that blocking this important signaling cascade prevents the congestion and ischemia in microvasculature that occurs from neutrophil capture of sickled red blood cells, which are normally deformable ellipses that flow easily through small blood vessels. Two recently completed clinical trials of therapies targeting selectins and their effect on neutrophil activation in small blood vessels reveal the importance of mechanoregulation that in health is an immune adaption facilitating rapid and proportional leukocyte adhesion, while sustaining tissue perfusion. We provide a timely perspective on the mechanism underlying vaso-occlusive crisis (VOC) with a focus on new drugs that target selectin mediated integrin adhesive bond formation.

An Allosteric Shift in CD11c Affinity Activates a Proatherogenic State in Arrested Intermediate Monocytes.

Intermediate monocytes (iMo; CD14+CD16+) increase in number in the circulation of patients with unstable coronary artery disease (CAD), and their recruitment to inflamed arteries is implicated in events leading to mortality following MI. Monocyte recruitment to inflamed coronary arteries is initiated by high affinity ß2-integrin (CD11c/CD18) that activates ß1-integrin (VLA-4) to bind endothelial VCAM-1. How integrin binding under shear stress mechanosignals a functional shift in iMo toward an inflammatory phenotype associated with CAD progression is unknown. Whole blood samples from patients treated for symptomatic CAD including non-ST elevation MI, along with healthy age-matched subjects, were collected to assess chemokine and integrin receptor levels on monocytes. Recruitment on inflamed human aortic endothelium or rVCAM-1 under fluid shear stress was assessed using a microfluidic-based artery on a chip (A-Chip). Membrane upregulation of high affinity CD11c correlated with concomitant activation of VLA-4 within focal adhesive contacts was required for arrest and diapedesis across inflamed arterial endothelium to a greater extent in non-ST elevation MI compared with stable CAD patients. The subsequent conversion of CD11c from a high to low affinity state under fluid shear activated phospho-Syk- and ADAM17-mediated proteolytic cleavage of CD16. This marked the conversion of iMo to an inflammatory phenotype associated with nuclear translocation of NF-κB and production of IL-1ß+ We conclude that CD11c functions as a mechanoregulator that activates an inflammatory state preferentially in a majority of iMo from cardiac patients but not healthy patients.

Replacing Saturated Fat With Unsaturated Fat in Western Diet Reduces Foamy Monocytes and Atherosclerosis in Male Ldlr-/- Mice.

OBJECTIVE: A Mediterranean diet supplemented with olive oil and nuts prevents cardiovascular disease in clinical studies, but the underlying mechanisms are incompletely understood. We investigated whether the preventive effect of the diet could be due to inhibition of atherosclerosis and foamy monocyte formation in Ldlr-/- mice fed with a diet in which milkfat in a Western diet (WD) was replaced with extra-virgin olive oil and nuts (EVOND). Approach and Results: Ldlr-/- mice were fed EVOND or a Western diet for 3 (or 6) months. Compared with the Western diet, EVOND decreased triglyceride and cholesterol levels but increased unsaturated fatty acid concentrations in plasma. EVOND also lowered intracellular lipid accumulation in circulating monocytes, indicating less formation of foamy monocytes, compared with the Western diet. In addition, compared with the Western diet, EVOND reduced monocyte expression of inflammatory cytokines, CD36, and CD11c, with decreased monocyte uptake of oxLDL (oxidized LDL [low-density lipoprotein]) ex vivo and reduced CD11c+ foamy monocyte firm arrest on vascular cell adhesion molecule-1 and E-selectin-coated slides in an ex vivo shear flow assay. Along with these changes, EVOND compared with the Western diet reduced the number of CD11c+ macrophages in atherosclerotic lesions and lowered atherosclerotic lesion area of the whole aorta and aortic sinus. CONCLUSIONS: A diet enriched in extra-virgin olive oil and nuts, compared with a Western diet high in saturated fat, lowered plasma cholesterol and triglyceride levels, inhibited foamy monocyte formation, inflammation, and adhesion, and reduced atherosclerosis in Ldlr-/- mice.

Las estadísticas de morbilidad y mortalidad en La Habana entre 1870 y 1877: Ambrosio González del Valle y la Junta Superior de Sanidad / Statistics on morbidity and mortality in Havana between 1870 y 1877: Ambrosio González del Valle and the Superior Council of Sanitary services

El presente trabajo forma parte de una serie de estudios que realiza sobre la situación de la Higiene, la Sanidad Pública y la epidemiología los siglos XIX y XX. La importancia de los estudios de morbilidad y mortalidad por enfermedades infecto-contagiosas, y de las epidemias causadas por ellas, reflejan a veces alteraciones profundas en una comunidad. Las afectaciones demográficas provocadas por las epidemias pueden causar perturbaciones importantes en los más diversos aspectos de la vida de una región, de ahí que resulte conveniente realizar estudios detallados del factor epidémico como complementación de los estudios de otro tipo (económico, político o social) que han permitido distinguir etapas diferentes en un determinado proceso histórico. El objetivo del presente trabajo es comparar algunos aspectos de las estadísticas compiladas por Ambrosio González del Valle y Cañizo, con las que aparecen en los registros de la Junta Superior de Sanidad, para el período de 1870 -1877.

The present work is part of a series of studies carried out on the situation of the Hygiene, the Public Sanity and the epidemiology in the XIX and XX centuries. The importance of the morbility and mortality studies for infect-contagious illnesses, and of the epidemics caused by them, which sometimes reflect deep alterations in the community. The demographic affectations caused by the epidemics can cause important interferences in the most diverse aspects in the life of a region, with the result that it is convenient to carry out detailed studies of the epidemic factor as complementation of the studies of another type (economic, political or social) that have allowed to distinguish different stages in a certain historical process. The objective of the present work is to compare some aspects of the statistics compiled by Ambrosio González of the Valley and Hurdle, with those that appear in the registrations of the Superior Meeting of Sanity, for the period of 1870 -1877.

Las estadísticas de morbilidad y mortalidad en La Habana entre 1870 y 1877: Ambrosio González del Valle y la Junta Superior de Sanidad / Statistics on morbidity and mortality in Havana between 1870 y 1877: Ambrosio González del Valle and the Superior Council of Sanitary services

El presente trabajo forma parte de una serie de estudios que realiza sobre la situación de la Higiene, la Sanidad Pública y la epidemiología los siglos XIX y XX. La importancia de los estudios de morbilidad y mortalidad por enfermedades infecto-contagiosas, y de las epidemias causadas por ellas, reflejan a veces alteraciones profundas en una comunidad. Las afectaciones demográficas provocadas por las epidemias pueden causar perturbaciones importantes en los más diversos aspectos de la vida de una región, de ahí que resulte conveniente realizar estudios detallados del factor epidémico como complementación de los estudios de otro tipo (económico, político o social) que han permitido distinguir etapas diferentes en un determinado proceso histórico. El objetivo del presente trabajo es comparar algunos aspectos de las estadísticas compiladas por Ambrosio González del Valle y Cañizo, con las que aparecen en los registros de la Junta Superior de Sanidad, para el período de 1870 -1877.(AU)

The present work is part of a series of studies carried out on the situation of the Hygiene, the Public Sanity and the epidemiology in the XIX and XX centuries. The importance of the morbility and mortality studies for infect-contagious illnesses, and of the epidemics caused by them, which sometimes reflect deep alterations in the community. The demographic affectations caused by the epidemics can cause important interferences in the most diverse aspects in the life of a region, with the result that it is convenient to carry out detailed studies of the epidemic factor as complementation of the studies of another type (economic, political or social) that have allowed to distinguish different stages in a certain historical process. The objective of the present work is to compare some aspects of the statistics compiled by Ambrosio González of the Valley and Hurdle, with those that appear in the registrations of the Superior Meeting of Sanity, for the period of 1870 -1877.(AU)