144 research outputs found
Cardiovascular Effects of Urocortin 2 and Urocortin 3 in Patients with Chronic Heart Failure
Aims:
Urocortin 2 and urocortin 3 may play a role in the pathophysiology of heart failure and are emerging therapeutic targets. We aimed to examine the local and systemic cardiovascular effects of urocortin 2 and urocortin 3 in healthy subjects and patients with heart failure.
Methods:
Patients with heart failure (n = 8) and age and gender-matched healthy subjects (n = 8) underwent bilateral forearm arterial blood flow measurement using forearm venous occlusion plethysmography during intra-arterial infusions of urocortin 2 (3.6â36 pmol minâ1), urocortin 3 (360â3600 pmol minâ1) and substance P (2â8 pmol minâ1). Heart failure patients (n = 9) and healthy subjects (n = 7) underwent non-invasive impedance cardiography during incremental intravenous infusions of sodium nitroprusside (573â5730 pmol kgâ1 minâ1 ), urocortin 2 (36â360 pmol minâ1 ), urocortin 3 (1.2â12 nmol minâ1) and saline placebo.
Results:
Urocortin 2, urocortin 3 and substance P induced dose-dependent forearm arterial vasodilatation in both groups (P < 0.05 for both) with no difference in magnitude of vasodilatation between patients and healthy subjects. During systemic intravenous infusions, urocortin 3 increased heart rate and cardiac index and reduced mean arterial pressure and peripheral vascular resistance index in both groups (P < 0.01 for all). Urocortin 2 produced similar responses to urocortin 3, although increases in cardiac index and heart rate were only significant in heart failure (P < 0.05) and healthy subjects (P < 0.001), respectively.
Conclusion:
Urocortins 2 and 3 cause vasodilatation, reduce peripheral vascular resistance and increase cardiac output in both health and disease. These data provide further evidence to suggest that urocortins 2 and 3 continue to hold promise for the treatment of heart failure
Reduced cellularity of bone marrow in multiple sclerosis with decreased MSC expansion potential and premature ageing in vitro
Background: Autologous bone-marrow-derived cells are currently employed in clinical studies of cell-based therapy in multiple sclerosis (MS) although the bone marrow microenvironment and marrow-derived cells isolated from patients with MS have not been extensively characterised. Objectives: To examine the bone marrow microenvironment and assess the proliferative potential of multipotent mesenchymal stromal cells (MSCs) in progressive MS. Methods: Comparative phenotypic analysis of bone marrow and marrow-derived MSCs isolated from patients with progressive MS and control subjects was undertaken. Results: In MS marrow, there was an interstitial infiltrate of inflammatory cells with lymphoid (predominantly T-cell) nodules although total cellularity was reduced. Controlling for age, MSCs isolated from patients with MS had reduced in vitro expansion potential as determined by population doubling time, colony-forming unit assay, and expression of ÎČ-galactosidase. MS MSCs expressed reduced levels of Stro-1 and displayed accelerated shortening of telomere terminal restriction fragments (TRF) in vitro. Conclusion: Our results are consistent with reduced proliferative capacity and ex vivo premature ageing of bone-marrow-derived cells, particularly MSCs, in MS. They have significant implication for MSC-based therapies for MS and suggest that accelerated cellular ageing and senescence may contribute to the pathophysiology of progressive MS. </jats:sec
Prevalence and clinical implications of valvular calcification on coronary computed tomography angiography
Computed Tomography Aortic Valve Calcium Scoring for the Assessment of Aortic Stenosis Progression
Triple-gated motion and blood pool clearance corrections improve reproducibility of coronary 18F-NaF PET
PurposeTo improve the test-retest reproducibility of coronary plaque 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) uptake measurements.MethodsWe recruited 20 patients with coronary artery disease who underwent repeated hybrid PET/CT angiography (CTA) imaging within 3 weeks. All patients had 30-min PET acquisition and CTA during a single imaging session. Five PET image-sets with progressive motion correction were reconstructed: (i) a static dataset (no-MC), (ii) end-diastolic PET (standard), (iii) cardiac motion corrected (MC), (iv) combined cardiac and gross patient motion corrected (2 Ă MC) and, (v) cardiorespiratory and gross patient motion corrected (3 Ă MC). In addition to motion correction, all datasets were corrected for variations in the background activities which are introduced by variations in the injection-to-scan delays (background blood pool clearance correction, BC). Test-retest reproducibility of PET target-to-background ratio (TBR) was assessed by Bland-Altman analysis and coefficient of reproducibility.ResultsA total of 47 unique coronary lesions were identified on CTA. Motion correction in combination with BC improved the PET TBR test-retest reproducibility for all lesions (coefficient of reproducibility: standardâ=â0.437, no-MCâ=â0.345 (27% improvement), standard + BCâ=â0.365 (20% improvement), no-MCâ+âBCâ=â0.341 (27% improvement), MCâ+âBCâ=â0.288 (52% improvement), 2 Ă MCâ+âBCâ=â0.278 (57% improvement) and 3 Ă Câ+âBCâ=â0.254 (72% improvement), all pâ<â0.001). Importantly, in a sub-analysis of 18F-NaF-avid lesions with gross patient motion > 10 mm following corrections, reproducibility was improved by 133% (coefficient of reproducibility: standardâ=â0.745, 3 Ă MCâ=â0.320).ConclusionJoint corrections for cardiac, respiratory, and gross patient motion in combination with background blood pool corrections markedly improve test-retest reproducibility of coronary 18F-NaF PET
Contrast-enhanced computed tomography assessment of aortic stenosis
Objectives Non-contrast CT aortic valve calcium scoring ignores the contribution of valvular fibrosis in aortic stenosis. We assessed aortic valve calcific and non-calcific disease using contrast-enhanced CT. Methods This was a post hoc analysis of 164 patients (median age 71 (IQR 66-77) years, 78% male) with aortic stenosis (41 mild, 89 moderate, 34 severe; 7% bicuspid) who underwent echocardiography and contrast-enhanced CT as part of imaging studies. Calcific and non-calcific (fibrosis) valve tissue volumes were quantified and indexed to annulus area, using Hounsfield unit thresholds calibrated against blood pool radiodensity. The fibrocalcific ratio assessed the relative contributions of valve fibrosis and calcification. The fibrocalcific volume (sum of indexed non-calcific and calcific volumes) was compared with aortic valve peak velocity and, in a subgroup, histology and valve weight. Results Contrast-enhanced CT calcium volumes correlated with CT calcium score (r=0.80, p<0.001) and peak aortic jet velocity (r=0.55, p<0.001). The fibrocalcific ratio decreased with increasing aortic stenosis severity (mild: 1.29 (0.98-2.38), moderate: 0.87 (1.48-1.72), severe: 0.47 (0.33-0.78), p<0.001) while the fibrocalcific volume increased (mild: 109 (75-150), moderate: 191 (117-253), severe: 274 (213-344) mm 3 /cm 2). Fibrocalcific volume correlated with ex vivo valve weight (r=0.72, p<0.001). Compared with the Agatston score, fibrocalcific volume demonstrated a better correlation with peak aortic jet velocity (r=0.59 and r=0.67, respectively), particularly in females (r=0.38 and r=0.72, respectively). Conclusions Contrast-enhanced CT assessment of aortic valve calcific and non-calcific volumes correlates with aortic stenosis severity and may be preferable to non-contrast CT when fibrosis is a significant contributor to valve obstruction
Treatment strategies in primary vitreoretinal lymphoma: a 17-center European collaborative study.
IMPORTANCE: The best treatment option for primary vitreoretinal lymphoma (PVRL) without signs of central nervous system lymphoma (CNSL) involvement determined on magnetic resonance imaging or in cerebrospinal fluid is unknown.
OBJECTIVE: To evaluate the outcomes of treatment regimens used for PVRL in the prevention of subsequent CNSL.
DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted at 17 referral ophthalmologic centers in Europe. We reviewed clinical, laboratory, and imaging data on 78 patients with PVRL who did not have CNSL on presentation between January 1, 1991, and December 31, 2012, with a focus on the incidence of CNS manifestations during the follow-up period.
INTERVENTIONS: The term extensive treatment was used for various combinations of systemic and intrathecal chemotherapy, whole-brain radiotherapy, and peripheral blood stem cell transplantation. Therapy to prevent CNSL included ocular radiotherapy and/or ocular chemotherapy (group A, 31 patients), extensive systemic treatment (group B,â21 patients), and a combination of ocular and extensive treatment (group C,â23 patients); 3 patients did not receive treatment. A total of 40 patients received systemic chemotherapy.
MAIN OUTCOMES AND MEASURES: Development of CNSL following the diagnosis of PVRL relative to the use or nonuse of systemic chemotherapy and other treatment regimens.
RESULTS: Overall, CNSL developed in 28 of 78 patients (36%) at a median follow-up of 49 months. Specifically, CNSL developed in 10 of 31 (32%) in group A, 9 of 21 (43%) in group B, and 9 of 23 (39%) in group C. The 5-year cumulative survival rate was lower in patients with CNSL (35% [95% CI, 50% to 86%]) than in patients without CNSL (68% [95% CI, 19% to 51%]; Pâ=â.003) and was similar among all treatment groups (Pâ=â.10). Adverse systemic effects occurred in 9 of 40 (23%) patients receiving systemic chemotherapy; the most common of these effects was acute renal failure.
CONCLUSIONS AND RELEVANCE: In the present series of patients with isolated PVRL, the use of systemic chemotherapy was not proven to prevent CNSL and was associated with more severe adverse effects compared with local treatment
Motion-corrected imaging of the aortic valve with (18)F-NaF PET/CT and PET/MR:a feasibility study
Collective Management Organisations, Creativity and Cultural Diversity
Glycogen synthase kinase 3 (GSK3) is a central regulator of cellular metabolism, development and growth. GSK3 activity was thought to oppose tumourigenesis, yet recent studies indicate that it may support tumour growth in some cancer types including in non-small cell lung carcinoma (NSCLC). We examined the undefined role of GSK3 protein kinase activity in tissue from human NSCLC.The expression and protein kinase activity of GSK3 was determined in 29 fresh frozen samples of human NSCLC and patient-matched normal lung tissue by quantitative immunoassay and western blotting for the phosphorylation of three distinct GSK3 substrates in situ (glycogen synthase, RelA and CRMP-2). The proliferation and sensitivity to the small-molecule GSK3 inhibitor; CHIR99021, of NSCLC cell lines (Hcc193, H1975, PC9 and A549) and non-neoplastic type II pneumocytes was further assessed in adherent culture.Expression and protein kinase activity of GSK3 was elevated in 41% of human NSCLC samples when compared to patient-matched control tissue. Phosphorylation of GSK3α/ÎČ at the inhibitory S21/9 residue was a poor biomarker for activity in tumour samples. The GSK3 inhibitor, CHIR99021 dose-dependently reduced the proliferation of three NSCLC cell lines yet was ineffective against type II pneumocytes.NSCLC tumours with elevated GSK3 protein kinase activity may have evolved dependence on the kinase for sustained growth. Our results provide further important rationale for exploring the use of GSK3 inhibitors in treating NSCLC
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