Search

Objective Vaso-occlusive crisis (VOC) is a complex process that occurs in patients with sickle cell disease (SCD) and is often associated with pain and urgent hospitalization. A major instigator of VOC is microvascular obstruction by pathologically stiffened sickle red blood cells (RBCs), and thus, therapy relies heavily on optimizing intravenous fluid (IVF) hydration to increase RBC deformability. However, no evidence-based guidelines regarding the choice of IVF currently exist. We therefore analyzed alterations in biomechanical properties of sickle RBCs isolated from patients with homozygous SCD (hemoglobin SS) after exposure to different osmolarities of clinical IVF formulations. Methods Atomic force microscopy (AFM) was used to assess stiffness of RBCs after exposure to different IVFs. A microfluidic model of the human capillary system was used to assess transit time (TT) and propensity to occlusion after exposure to the different IVF formulations. Results Sickle RBCs exposed to normal saline (NS) had increased stiffness, TTs, and propensity to microchannel occlusion compared to other osmolarities. Conclusion NS, an IVF formulation often used to treat patients with SCD during VOC, may induce localized microvascular obstruction due to alterations of sickle RBC biomechanical properties. [ABSTRACT FROM AUTHOR]

Background: Urinary tract infection (UTI) is one of the most common diseases in children, and urinary angiotensinogen (U‐AGT) is a new biomarker gathering attention in many renal diseases. U‐AGT reflects intrarenal renin–angiotensin system (RAS) activity. We conducted a study to measure U‐AGT in children <4 months old with UTI. Methods: All children <4 months old who came to Toshima Hospital with fever between January 2015 and December 2015 were included. Patients were divided into a UTI group and a non‐UTI group, and U‐AGT was measured. Results: Median U‐AGT was higher in patients with UTI compared with patients without UTI: (0.56 ng/dL, range, 0.025–2.753 ng/dL vs 0.13 ng/dL, range, 0.008–1.697 ng/dL, respectively; P < 0.05). Conclusions: U‐AGT is elevated in UTI patients, and RAS activation may contribute to renal injury caused by UTI. [ABSTRACT FROM AUTHOR]

Although the processes of haemostasis and thrombosis have been studied extensively in the past several decades, much of the effort has been spent characterizing the biological and biochemical aspects of clotting. More recently, researchers have discovered that the function and physiology of blood cells and plasma proteins relevant in haematologic processes are mechanically, as well as biologically, regulated. This is not entirely surprising considering the extremely dynamic fluidic environment that these blood components exist in. Other cells in the body such as fibroblasts and endothelial cells have been found to biologically respond to their physical and mechanical environments, affecting aspects of cellular physiology as diverse as cytoskeletal architecture to gene expression to alterations of vital signalling pathways. In the circulation, blood cells and plasma proteins are constantly exposed to forces while they, in turn, also exert forces to regulate clot formation. These mechanical factors lead to biochemical and biomechanical changes on the macro- to molecular scale. Likewise, biochemical and biomechanical alterations in the microenvironment can ultimately impact the mechanical regulation of clot formation. The ways in which these factors all balance each other can be the difference between haemostasis and thrombosis. Here, we review how the biomechanics of blood cells intimately interact with the cellular and molecular biology to regulate haemostasis and thrombosis in the context of health and disease from the macro- to molecular scale. We will also show how these biomechanical forces in the context of haemostasis and thrombosis have been replicated or measured in vitro. [ABSTRACT FROM AUTHOR]

We previously suggested that gut bacteria may be involved in the onset of Kawasaki disease (KD). In this study, we evaluated the production of heat shock proteins (hsps) and superantigens (sAgs) by microorganisms isolated from the jejunal mucosa of 19 children with KD in the acute phase and from 15 age-matched control children. We identified 13 strains of Gram-negative microbes from patients with KD; these microbes produced large amounts of hsp60 and induced pro-inflammatory cytokine production by peripheral blood mononuclear cells. The Gram-negative microbes also elicited endogenous hsp60 production, leading to the secretion of anti-inflammatory intereukin-10 (IL-10). We also identified 18 strains of Gram-positive cocci that had superantigenic properties and which induced the expansion of Vβ2 T cells in vitro. All bacteria identified in this study were antibiotic resistant. These data suggest that sAg and hsps produced by gut bacteria might be involved in KD. [ABSTRACT FROM AUTHOR]

CYP1A1 and CYP1B1 gene expression is dramatically upregulated by shear stress in human umbilical vein endothelial cells (HUVEC). CYP1A1 and 1B1 are capable of metabolizing arachidonic acid into epoxyeicosatrienoic acids (EETs). EETs are increased by shear stress in endothelial cells and mediate changes in gene transcription. We hypothesize that the increase in CYP1A1 or 1B1 regulates the expression of other shear stress responsive genes. We sought to 1) determine whether protein levels of CYP1A1 and 1B1 are also increased by shear stress, 2) examine the effect of siRNA knockdown of CYP1A1 or 1B1 on endothelin-1 (ET-1) expression, and 3) determine if CYP1A1 and 1B1 are expressed in human arteries. HUVEC (P3-5) were exposed to arterial levels of shear stress (25 dynes/cm2) for 24 hours. Densitometry of Western blots showed CYP1B1 protein significantly upregulated by flow. ET-1 is a potent vasoconstrictor which is downregulated by shear stress, siRNA knockdown of CYP1B1 resulted in a 2.7 fold increase in ET-1 mRNA, suggesting that a 1B1 metabolite mediates the shear stress down regulation of ET-1. CYP1A1 and 1B1 protein was observed in the endothelium of human coronary arteries. Although CYP1A1 and 1B1 are thought to be important in response to environmental toxins, these data suggest these genes have an important physiological function in the response of endothelial cells to mechanical forces. [ABSTRACT FROM AUTHOR]