Biomechanical properties and histological structure of sinus of Valsalva aneurysms in relation to age and region

Information on the biomechanical properties of aortic root aneurysms that would facilitate our understanding of their rupture modes is currently unavailable. In this study, whole-thickness wall specimens from aortic root aneurysms were studied in vitro so as to compare the biomechanical properties with gross histomorphology and composition, in relation to age, region, and direction. The stress-strain relationship was determined under uniaxial loading conditions and characterized by the Fung-type material model in terms of optimized material constants; failure properties were recorded. The connective tissue contents of the basic scleroproteins were also determined through computerized histology. Aging had a deleterious influence on the tensile strength of the aneurysmal sinus tissue, causing also stiffening and reduced extensibility that was consistent with the deficient elastin and collagen contents. Direction-dependent differences were demonstrated in the noncoronary sinus, with the circumferential being stiffer and stronger than the longitudinal direction, justified by the preferred collagen reinforcement along that direction there. In the left and right coronary sinus, the material constants and failure properties were essentially the same in the two directions, justified by the arbitrary orientation of medial (collagen and elastin fibers, and cellular) components relative to the circumferential-longitudinal directions. The material characterization results afforded, and the regional and age-related differences in the strength of the sinus wall, i.e. in its capacity to withstand hemodynamic stresses, are hoped to provide novel insight into the pathophysiological mechanisms responsible for the highest incidence of ruptured aortic root aneurysms in the right coronary and noncoronary sinus. © 2012 Elsevier Ltd

Mast-cell leukemia exome sequencing reveals a mutation in the IgE mast-cell receptor beta chain and KIT V654A

Mast cells exit the bone marrow as immature multilineage cells that circulate in the blood and subsequently undergo full differentiation upon reaching a target organ (reviewed in Gilfillan and Tkaczyk1). Unlike other hematopoietic cells, differentiated mast cells continue to express KIT, a transmembrane receptor with a bipartite intracellular kinase domain.1 The main ligand of KIT is stem cell factor (also known as KIT ligand), which stimulates mast-cell survival, development, maturation and activation.1 Mast cells also express a high-affinity cell-surface IgE receptor, FcεRI, which recognizes the Fc portion of IgE and is required for mast-cell survival via signaling through LYN and SYK kinases.1 Mast-cell leukemia (MCL) is an aggressive form of systemic mastocytosis characterized by the overproliferation of atypical mast cells, promastocytes and blasts that produce, among other substances, tryptase.2 MCL is often linked to somatically acquired activating mutations in the KIT receptor that result in uncontrolled ligand-independent signaling by KIT and hyperproliferation of mast cells (reviewed in Ustun et al.3). The KIT D816V mutation causes resistance to imatinib therapy.3 Mutations in TET2 and NRAS have also been described in mastocytosis patients and each of them segregates with the KIT D816V mutation,4, 5 suggesting that more than one lesion is required to drive leukemogenesis. In order to identify novel MCL determinants, we utilized two approaches to undertake the first comprehensive study of the DNA changes in an MCL patient. This study was approved by the Institutional Review Boards of the North Shore-LIJ Health System and the Cold Spring Harbor Laboratory. The patient gave written informed consent in accordance with the Declaration of Helsinki

Functional characterization of KIT and Fc epsilon R1 receptor mutations in Mast Cell Leukemia using Single Cell Network Profiling (SCNP)

Background: A recent report described an imatinib/dasatinib (Imat/Dasat) resistant MCL patient (pt) with mutations in KIT (V654A) and Fc{varepsilon}R1 (L188F) receptors [Spector et al, Leukemia 2011]. The pt did not respond to cytarabine-based induction therapy combined with Dasat or to post-induction Imat. The functional consequence of the receptor mutations on downstream signaling networks, and sensitivity to alternative therapeutics, was unknown. SCNP is a flow cytometry-based assay that quantitatively and simultaneously measures, in single cells, extracellular surface markers and activation of intracellular signaling proteins in response to modulation. SCNP was applied to interrogate downstream signaling networks and network sensitivity to targeted therapeutics by examining: 1) Basal and modulated signaling using stem cell factor (SCF) or α-IgE 2) Effect on basal and modulated signaling of: a) KIT inhibitors Imat, Dasat, and Nilotinib b) PI3K inhibitor GDC-0941 c) SYK inhibitor fostamatinib R406 Methods: Cryopreserved MCL BMMCs and healthy donor BMMCs were processed alongside fresh healthy donor basophils (FHDB) as controls. BMMCs were modulated with SCF for 5 and 15 min +/-KIT or PI3K inhib. MCL BMMCs and FHDB were modulated with α-IgE for 5min +/- fostamatinib. Signaling in the KIT and Fc{varepsilon}R1 pathways was quantified through measurement of p-AKT/ p-ERK/ p-S6 and p-ERK/ p-PLC{gamma}2 / p-SYK levels, respectively, in the MCL population: CD45+, CD34+, CD33+, and CD117+. Results: As previous reported, the V654A KIT mutation did not result in constitutive activation of the PI3K or MAPK pathways in MCL blasts, but was associated with dysfunctional SCF modulated signaling. Specifically, SCNP identified SCF induced p-AKT levels at 5min, higher (2X) compared to CD34+/CD117+ FHDB, and sustained to 15min with no simultaneous induction of p-ERK or p-S6. Consistent with the clinically observed Imat/Dasat resistance of the MCL case, in vitro AKT induction was unaffected by the presence of KIT inhibitors but sensitive to the PI3K inhib GDC-0941. KIT inhibitors and GDC-0941 blocked SCF induced signaling in the healthy BMMC control. Despite robust p-ERK induction in the FHDB control after α-IgE modulation of the Fc{varepsilon}R1 receptor and inhibition by fostamatinib treatment, no basal or α-IgE modulated Fc{varepsilon}R1 receptor signaling was detected in MCL BMMC cells. Conclusions: SCNP functionally characterizes signaling and drug resistance profiles in MCL BMMCs and can potentially inform on therapeutic selection. Despite robust p-ERK induction in the FHDB control after α-IgE modulation of the Fc{varepsilon}R1 receptor and inhibition by fostamatinib treatment, no basal or α-IgE modulated Fc{varepsilon}R1 receptor signaling was detected in the cryopreserved MCL BMMCs. Further studies will elucidate whether the lack of detected signal could be related to the freeze/thaw process and/or to cell-type specific differences

Time course of flow-induced adaptation of carotid artery biomechanical properties, structure and zero-stress state in the arteriovenous shunt

Numerous studies have provided evidence of diameter adaptation secondary to flow-overload. but with ambiguous findings vis a vis other morphological parameters and information on the biomechanical aspects of arterial adaptation is rather incomplete. We examined the time course of large-artery biomechanical adaptation elicited by long-term flow-overload in a porcine shunt model between the carotid artery and ipsilateral jugular vein. Post-shunting, the proximal artery flow was doubled and retained so until euthanasia (up to three months post-operatively), without pressure change. This hemodynamic stimulus induced lumen diameter enlargement, accommodated by elastin fragmentation and connective tissue accumulation. as witnessed by optical and confocal microscopy. Heterogeneous mass growth of the adventitia was observed at the expense of the media. associated with declining residual strains and opening angle at three months. The in vitro elastic properties of shunted arteries determined by inflation/extension testing were also modified, with the thickness pressure curves shifted to larger thicknesses and the diameter pressure curves shifted to larger diameters at physiologic pressures, resulting in normalization of intramural and shear stresses within fifteen and thirty days. respectively. We infer that the biomechanical adaptation in moderate flow-overload leads to normalization of intimal shear, without, however, restoring compliance and distensibility at mean in vivo pressure to control levels

Time course of flow-induced adaptation of carotid artery biomechanical properties, structure and zero-stress state in the arteriovenous shunt

Numerous studies have provided evidence of diameter adaptation secondary to flow-overload. but with ambiguous findings vis a vis other morphological parameters and information on the biomechanical aspects of arterial adaptation is rather incomplete. We examined the time course of large-artery biomechanical adaptation elicited by long-term flow-overload in a porcine shunt model between the carotid artery and ipsilateral jugular vein. Post-shunting, the proximal artery flow was doubled and retained so until euthanasia (up to three months post-operatively), without pressure change. This hemodynamic stimulus induced lumen diameter enlargement, accommodated by elastin fragmentation and connective tissue accumulation. as witnessed by optical and confocal microscopy. Heterogeneous mass growth of the adventitia was observed at the expense of the media. associated with declining residual strains and opening angle at three months. The in vitro elastic properties of shunted arteries determined by inflation/extension testing were also modified, with the thickness pressure curves shifted to larger thicknesses and the diameter pressure curves shifted to larger diameters at physiologic pressures, resulting in normalization of intramural and shear stresses within fifteen and thirty days. respectively. We infer that the biomechanical adaptation in moderate flow-overload leads to normalization of intimal shear, without, however, restoring compliance and distensibility at mean in vivo pressure to control levels

Community Healthcare Delivery Post-Hurricane Sandy: Lessons from a Mobile Health Unit

In the aftermath of Hurricane Sandy the North Shore LIJ Health System (NS-LIJ HS) organized and launched its first mobile health unit (MHU) operation to some of New York\u27s hardest hit communities including Queens County and Long Island, NY. This document describes the initiation, operational strategies, outcomes and challenges of the NS-LIJ HS community relief effort using a MHU. The operation was divided into four phases: (1) community needs assessment, (2) MHU preparation, (3) staff recruitment and (4) program evaluation and feedback. From November 16th through March 21st, 2013 the Health System launched the MHU over 64 days serving 1,160 individuals with an age range of 3 months to 91 years. Vaccination requests were the most commonly encountered issue, and the most common complaint was upper respiratory illness. The MHU is an effective resource for delivering healthcare to displaced individuals in the aftermath of natural disaster. Future directions include the provision of psychosocial services, evaluating strategies for timely retreat of the unit and methods for effective transitions of care

Local Hemodynamics and Intimal Hyperplasia at the Venous Side of a Porcine Arteriovenous Shunt

Venous anastomotic intimal hyperplasia (IH) observed in the arteriovenous shunt (AVS) has been associated with disturbed hemodynamics. This study aims to correlate hemodynamics with wall histology and wall mechanics by examining the flow field in AVS with computational fluid dynamics using experimental data taken from in vivo experiments. Input data to the computational model were obtained in vivo one month after AVS creation; adjacent vessels were submitted to histological and mechanical examination. The 3-D shunt geometry was determined using biplane angiography. Ultrasound measurements of flow rates were performed with perivascular flow probes and pressures were recorded through intravascular catheters. These data were considered as boundary conditions for calculation of the unsteady flow field. Numerical findings are suggestive of strong Dean vortices toward both vein flow exits, verified by color Doppler. The high wall shear stresses (WSSs) and their gradients appear to be related to areas of IH and vessel wall stiffening, as evidenced in preliminary histological and mechanical studies of the venous wall. Additionally, suture line hyperplasia seems to be aggravated by the high WSS gradients noted at the transition line from graft to vein