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Vascular complications in autosomal dominant polycystic kidney disease. - Nature reviews. Nephrology
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Relentless cyst growth substantially enlarges both kidneys and culminates in renal failure. Patients with ADPKD also have vascular abnormalities; intracranial aneurysms (IAs) are found in âˆ¼10% of asymptomatic patients during screening and in up to 25% of those with a family history of IA or subarachnoid haemorrhage. As the genes responsible for ADPKDâ€”PKD1 and PKD2â€”have complex integrative roles in mechanotransduction and intracellular calcium signalling, the molecular basis of IA formation might involve focal haemodynamic conditions exacerbated by hypertension and altered flow sensing. IA rupture results in substantial mortality, morbidity and poor long-term outcomes. In this Review, we focus mainly on strategies for screening, diagnosis and treatment of IAs in patients with ADPKD. Other vascular aneurysms and anomaliesâ€”including aneurysms of the aorta and coronary arteries, cervicocephalic and thoracic aortic dissections, aortic root dilatation and cerebral dolichoectasiaâ€”are less common in this population, and the available data are insufficient to recommend screening strategies. Treatment decisions should be made with expert consultation and be based on a risk-benefit analysis that takes into account aneurysm location and morphology as well as patient age and comorbidities.
IL-15 induces strong but short-lived tumor-infiltrating CD8 T cell responses through the regulation of Tim-3 in breast cancer. - Biochemical and biophysical research communications
IL-15 has pivotal roles in the control of CD8(+) memory T cells and has been investigated as a therapeutic option in cancer therapy. Although IL-15 and IL-2 share many functions together, including the stimulation of CD8 T cell proliferation and IFN-Î³ production, the different inÂ vivo roles of IL-15 and IL-2 have been increasingly recognized. Here, we explored the different effects of IL-15 and IL-2 on tumor-infiltrating (TI) T cells from resected breast tumors. We found that neither IL-2 nor IL-15 induced intratumoral CD8 T cell proliferation by itself, but after CD3/CD28-stimulation, IL-15 induced significantly higher proliferation than IL-2 during early time points, at day 2, day 3 and day 6. However, the IL-15-induced proliferation leveled off at day 9 and day 12, whereas IL-2 induced lower but progressive proliferation at each time point. Furthermore, IL-15 caused an early and robust increase of IFN-Î³ in the supernatant of TI cell cultures, which diminished at later time points, while the IL-2-induced IFN-Î³ production remained constant over time. In addition, the IL-15-costimulated CD8 T cells presented higher frequencies of apoptotic cells. The diminishing IL-15-induced response was possibly due to regulatory and/or exhaustion mechanisms. We did not observe increased IL-10 or PD-1 upregulation, but we have found an increase of Tim-3 upregulation on IL-15-, but not IL-2-stimulated cells. Blocking Tim-3 function using anti-Tim-3 antibodies resulted in increased IL-15-induced proliferation and IFN-Î³ production for a prolonged period of time, whereas adding Tim-3 ligand galectin 9 led to reduced proliferation and IFN-Î³ production. Our results suggest that IL-15 in combination of Tim-3 blocking antibodies could potentially act as an IL-2 alternative in tumor CD8 T cell expansion inÂ vitro, a crucial step in adoptive T cell therapy.Copyright Â© 2015 Elsevier Inc. All rights reserved.
Realistic non-Newtonian viscosity modelling highlights hemodynamic differences between intracranial aneurysms with and without surface blebs. - Journal of biomechanics
Most computational fluid dynamic (CFD) simulations of aneurysm hemodynamics assume constant (Newtonian) viscosity, even though blood demonstrates shear-thinning (non-Newtonian) behavior. We sought to evaluate the effect of this simplifying assumption on hemodynamic forces within cerebral aneurysms, especially in regions of low wall shear stress, which are associated with rupture. CFD analysis was performed for both viscosity models using 3D rotational angiography volumes obtained for 26 sidewall aneurysms (12 with blebs, 12 ruptured), and parametric models incorporating blebs at different locations (inflow/outflow zone). Mean and lowest 5% values of time averaged wall shear stress (TAWSS) computed over the dome were compared using Wilcoxon rank-sum test. Newtonian modeling not only resulted in higher aneurysmal TAWSS, specifically in areas of low flow and blebs, but also showed no difference between aneurysms with or without blebs. In contrast, for non-Newtonian analysis, bleb-bearing aneurysms showed significantly lower 5% TAWSS compared to those without (p=0.005), despite no significant difference in mean dome TAWSS (p=0.32). Non-Newtonian modeling also accentuated the differences in dome TAWSS between ruptured and unruptured aneurysms (p<0.001). Parametric models further confirmed that realistic non-Newtonian viscosity resulted in lower bleb TAWSS and higher focal viscosity, especially when located in the outflow zone. The results show that adopting shear-thinning non-Newtonian blood viscosity in CFD simulations of intracranial aneurysms uncovered hemodynamic differences induced by bleb presence on aneurysmal surfaces, and significantly improved discriminant statistics used in risk stratification. These findings underline the possible implications of using a realistic model of blood viscosity in predictive computational hemodynamics.Copyright Â© 2014 Elsevier Ltd. All rights reserved.
Delayed progressive bilateral supraclinoid internal carotid artery stenosis in a patient with a ruptured basilar artery aneurysm. - Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia
Cerebral vasospasm is a common radiographic and clinical diagnosis after subarachnoid hemorrhage. Conventional treatments include medical hypertension, hypervolemia, and modest hemodilution. When medical treatments fail in severe vasospasm cases, intra-arterial vasodilation and balloon angioplasty may be useful. We present a 47-year-old woman with a ruptured basilar artery aneurysm who developed severe bilateral internal carotid artery vasospasm requiring bilateral balloon angioplasty. Prior to discharge, the patient's bilateral stenosis had improved. Three months post-discharge, severe restenosis in her bilateral internal carotid arteries occurred; a rare event. Balloon angioplasty has been demonstrated to histologically tear and stretch collagen fibers in the vessel wall and overexpansion of vessels may lead to a neo-intimal reaction that is similar to the one seen after stent placement in the intracranial circulation. Clinicians should be aware of the possibility of delayed and progressive stenosis in vessels treated with angioplasty. Follow-up vascular imaging is necessary after subarachnoid hemorrhage. Future study is required on the treatment paradigms necessary for this delayed restenosis.Copyright Â© 2014 Elsevier Ltd. All rights reserved.
Widening of the basilar bifurcation angle: association with presence of intracranial aneurysm, age, and female sex. - Journal of neurosurgery
Arterial bifurcations represent preferred locations for aneurysm formation, especially when they are associated with variations in divider geometry. The authors hypothesized a link between basilar apex aneurysms and basilar bifurcation (Î±) and vertebrobasilar junction (VBJ) angles.The Î± and VBJ angles were measured in 3D MR and rotational angiographic volumes using a coplanar 3-point technique. Angle Î± was compared between age-matched cohorts in 45 patients with basilar artery (BA) aneurysms, 65 patients with aneurysms in other locations (non-BA), and 103 nonaneurysmal controls. Additional analysis was performed in 273 nonaneurysmal controls. Computational fluid dynamics (CFD) simulations were performed on parametric BA models with increasing angles.Angle Î± was significantly wider in patients with BA aneurysms (146.7Â° Â± 20.5Â°) than in those with non-BA aneurysms (111.7Â° Â± 18Â°) and in controls (103Â° Â± 20.6Â°) (p < 0.0001), whereas no difference was observed for the VBJ angle. A wider angle Î± correlated with BA aneurysm neck width but not dome size, which is consistent with CFD results showing a widening of the impingement zone at the bifurcation apex. BA bifurcations hosting even small aneurysms (< 5 mm) had a significantly larger Î± angle compared with matched controls (p < 0.0001). In nonaneurysmal controls, Î± increased with age (p < 0.0001), with a threshold effect above 35 years of age and a steeper dependence in females (p = 0.002) than males (p = 0.04).The Î± angle widens with age during adulthood, especially in females. This angular widening is associated with basilar bifurcation aneurysms and may predispose individuals to aneurysm initiation by diffusing the flow impingement zone away from the protective medial band region of the flow divider.
Deviation from optimal vascular caliber control at middle cerebral artery bifurcations harboring aneurysms. - Journal of biomechanics
Cerebral aneurysms form preferentially at arterial bifurcations. The vascular optimality principle (VOP) decrees that minimal energy loss across bifurcations requires optimal caliber control between radii of parent (râ‚€) and daughter branches (r1 and r2): râ‚€(n)=râ‚(n)+râ‚‚(n), with n approximating three. VOP entails constant wall shear stress (WSS), an endothelial phenotype regulator. We sought to determine if caliber control is maintained in aneurysmal intracranial bifurcations. Three-dimensional rotational angiographic volumes of 159 middle cerebral artery (MCA) bifurcations (62 aneurysmal) were processed using 3D gradient edge-detection filtering, enabling threshold-insensitive radius measurement. Radius ratio (RR)=râ‚€(3)/(râ‚(3)+râ‚‚(3)) and estimated junction exponent (n) were compared between aneurysmal and non-aneurysmal bifurcations using Student t-test and Wilcoxon rank-sum analysis. The results show that non-aneurysmal bifurcations display optimal caliber control with mean RR of 1.05 and median n of 2.84. In contrast, aneurysmal bifurcations had significantly lower RR (0.76, p<.0001) and higher n (4.28, p<.0001). Unexpectedly, 37% of aneurysmal bifurcations revealed a daughter branch larger than its parent vessel, an absolute violation of optimality, not witnessed in non-aneurysmal bifurcations. The aneurysms originated more often off the smaller daughter (52%) vs. larger daughter branch (16%). Aneurysm size was not statistically correlated to RR or n. Aneurysmal males showed higher deviation from VOP. Non-aneurysmal MCA bifurcations contralateral to aneurysmal ones showed optimal caliber control. Aneurysmal bifurcations, in contrast to non-aneurysmal counterparts, disobey the VOP and may exhibit dysregulation in WSS-mediated caliber control. The mechanism of this focal divergence from optimality may underlie aneurysm pathogenesis and requires further study.Copyright Â© 2014 Elsevier Ltd. All rights reserved.
Widening and high inclination of the middle cerebral artery bifurcation are associated with presence of aneurysms. - Stroke; a journal of cerebral circulation
The middle cerebral artery (MCA) bifurcation is a preferred site for aneurysm formation. Wider bifurcation angles have been correlated with increased risk of aneurysm formation. We hypothesized a link between the presence of MCA aneurysms and the angle morphology of the bifurcation.Three-dimensional rotational angiography volumes of 146 MCA bifurcations (62 aneurysmal) were evaluated for angle morphology: parent-daughter angles (larger daughter Ð¤1, smaller daughter Ð¤2), bifurcation angle (Ð¤1+Ð¤2), and inclination angle (Î³) between the parent vessel axis and the plane determined by daughter vessel axes. Statistics were evaluated using Wilcoxon rank-sum analysis and area under the receiver operator characteristic curve.Aneurysmal bifurcations had wider inclination angle Î³ (median 57.8Â° versus 15.4Â°; P<0.0001). Seventy-five percent of aneurysmal MCAs had Î³ >10Â°, compared with 25% nonaneurysmal. Ð¤1 and Ð¤2, but especially Ð¤1+Ð¤2, were significantly larger in aneurysmal bifurcations (median 171.3Â° versus 98.1Â°; P<0.0001). Sixty-seven percent of aneurysmal bifurcations had Ð¤1+Ð¤2 >161Â°, compared with 0% nonaneurysmal MCAs. An optimal threshold of 140Â° was established for Ð¤1+Ð¤2 (area under the curve, 0.98). Sixty-eight percent of aneurysms originated off the daughter branches. Seventy-six percent of them originated off the branch with the largest branching angle, specifically if this was the smaller daughter branch. Wider Ð¤1+Ð¤2 correlated with aneurysm neck width, but not dome size.MCA bifurcations harboring aneurysms have significantly larger branching angles and more often originate off the branch with the largest angle. Wider inclination angle is strongly correlated with aneurysm presence, a novel finding. The results point to altered wall shear stress regulation as a possible factor in aneurysm development and progression.Â© 2014 American Heart Association, Inc.
Curvature effect on hemodynamic conditions at the inner bend of the carotid siphon and its relation to aneurysm formation. - Journal of biomechanics
Although high-impact hemodynamic forces are thought to lead to cerebral aneurysmal change, little is known about the aneurysm formation on the inner aspect of vascular bends such as the internal carotid artery (ICA) siphon where wall shear stress (WSS) is expected to be low. This study evaluates the effect of vessel curvature and hemodynamics on aneurysm formation along the inner carotid siphon. Catheter 3D-rotational angiographic volumes of 35 ICA (10 aneurysms, 25 controls) were evaluated in 3D for radius of curvature and peak curvature of the siphon bend, followed by univariate statistical analysis. Computational fluid dynamic (CFD) simulations were performed on patient-derived models after aneurysm removal and on synthetic variants of increasing curvature. Peak focal siphon curvature was significantly higher in aneurysm bearing ICAs (0.36 Â± 0.045 vs. 0.30 Â± 0.048 mm(-1), p=0.003), with no difference in global radius of curvature (p=0.36). In CFD simulations, increasing parametric curvature tightness (from 5 to 3mm radius) resulted in dramatic increase of WSS and WSS gradient magnitude (WSSG) on the inner wall of the bend. In patient-derived data, the location of aneurysms coincided with regions of low WSS (<4 Pa) flanked by high WSS and WSSG peaks. WSS peaks correlated with the aneurysm neck. In contrast, control siphon bends displayed low, almost constant, WSS and WSSG profiles with little spatial variation. High bend curvature induces dynamically fluctuating high proximal WSS and WSSG followed by regions of flow stasis and recirculation, leading to local conditions known to induce destructive vessel wall remodeling and aneurysmal initiation.Copyright Â© 2014 Elsevier Ltd. All rights reserved.
Superior performance of cone-beam CT angiography in characterization of intracranial atherosclerosis. - Journal of neurosurgery
Intracranial atherosclerotic disease (ICAD) carries a high risk of stroke. Evaluation of ICAD has focused on assessing the absolute degree of stenosis, although plaque morphology has recently demonstrated increasing relevance. The authors provide the first report of the use of ultra-high-resolution C-arm cone-beam CT angiography (CBCT-A) in the evaluation of vessel stenosis as well as plaque morphology.Between August 2009 and July 2012, CBCT-A was used in all patients with ICAD who underwent catheter-based angiography at the authors' institution (n = 18). Lesions were evaluated for maximum degree of stenosis as well as plaque morphological characteristics (ulcerated, calcified, dissected, or spiculated) via digital subtraction angiography (DSA), 3D-rotational angiography (3DRA), and CBCT-A. The different imaging modalities were compared in their assessment of absolute stenosis as well as their ability to resolve different plaque morphologies.Lesions were found to have similar degrees of stenosis when utilizing CBCT-A compared with 3DRA, but both 3DRA and CBCT-A differed from DSA in their assessment of the absolute degree of stenosis. CBCT-A provided the most detailed resolution of plaque morphology, identifying a new plaque characteristic in 61% of patients (n = 11) when compared with DSA and 50% (n = 9) when compared with 3DRA. CBCT-A identified all lesion characteristics visualized on DSA and 3DRA.CBCT-A provides detailed spatial resolution of plaque morphology and may add to DSA and 3DRA in the evaluation of ICAD. Further prospective study is warranted to determine any benefit CBCTA-A may provide in clinical decision making and risk stratification over existing conventional imaging modalities.
Enhanced specialized transduction using recombineering in Mycobacterium tuberculosis. - mBio
G: enetic engineering has contributed greatly to our understanding of Mycobacterium tuberculosis biology and has facilitated antimycobacterial and vaccine development. However, methods to generate M.Â tuberculosis deletion mutants remain labor-intensive and relatively inefficient. Here, methods are described that significantly enhance the efficiency (greater than 100-fold) of recovering deletion mutants by the expression of mycobacteriophage recombineering functions during the course of infection with specialized transducing phages delivering allelic exchange substrates. This system has been successfully applied to the CDC1551 strain of M.Â tuberculosis, as well as to a Î”recD mutant generated in the CDC1551 parental strain. The latter studies were undertaken as there were precedents in both the Escherichia coli literature and mycobacterial literature for enhancement of homologous recombination in strains lacking RecD. In combination, these measures yielded a dramatic increase in the recovery of deletion mutants and are expected to facilitate construction of a comprehensive library of mutants with every nonessential gene of M.Â tuberculosis deleted. The findings also open up the potential for sophisticated genetic screens, such as synthetic lethal analyses, which have so far not been feasible for the slow-growing mycobacteria.Genetic manipulation of M.Â tuberculosis is hampered by laborious and relatively inefficient methods for generating deletion mutant strains. The combined use of phage-based transduction and recombineering methods greatly enhances the efficiency by which knockout strains can be generated. The additional elimination of recD further enhances this efficiency. The methods described herein will facilitate the construction of comprehensive gene knockout libraries and expedite the isolation of previously difficult to recover mutants, promoting antimicrobial and vaccine development.Copyright Â© 2014 Tufariello et al.
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