Is non-contrast enhanced magnetic resonance imaging cost-effective for screening of hepatocellular carcinoma?

INTRODUCTION: Ultrasound (US) is current standard of care for imaging surveillance in patients at risk for hepatocellular carcinoma (HCC). Magnetic resonance imaging (MRI) has been explored as an alternative, given the higher sensitivity of MRI, although this comes at a higher cost. We performed a cost-effective analysis comparing US and a dual-sequence non-contrast MRI (NCEMRI) for HCC surveillance, in the local setting. METHODS: Cost-effectiveness analysis of no surveillance, US surveillance and NCEMRI surveillance was performed using Markov modelling and microsimulation. At-risk patient cohort was simulated and followed-up for 40 years to estimate their disease status, direct medical costs, and effectiveness. Quality-adjusted life years (QALYs) and incremental cost effectiveness ratio were calculated. RESULTS: 482,000 patients with an average age of 40 years were simulated and followed up for 40 years. The average total costs and QALYs for the three scenarios - no surveillance, US surveillance and NCEMRI surveillance were S$1,193/7.460 QALYs; S$8,099/11.195 QALYs; S$9,720/11.366 QALYs, respectively. CONCLUSION: Despite NCEMRI having a superior diagnostic accuracy, it is a less cost-effective strategy than US for HCC surveillance in the general at-risk population. Future local cost-effectiveness analyses should include stratifying surveillance methods with a variety of imaging techniques (US, NCEMRI, CEMRI) based on patients' risk profiles.

Clinics in diagnostic imaging (197). Left ischiofemoral impingement syndrome.

A 48-year-old woman presented with progressive left hip pain over six months, along with left lower limb weakness for two weeks. Magnetic resonance imaging of the left hip showed narrowing of the left ischiofemoral space, oedema of the left quadratus femoris muscle and left sciatic nerve, and mild bone marrow oedema of the left ischial tuberosity. The diagnosis of left ischiofemoral impingement syndrome was made. The imaging features of ischiofemoral impingement syndrome and the associated aetiologies and complications are discussed.

A meta-analysis of mitral valve repair versus replacement for ischemic mitral regurgitation.

BACKGROUND: The development of ischemic mitral regurgitation (IMR) portends a poor prognosis and is associated with adverse long-term outcomes. Although both mitral valve repair (MVr) and mitral valve replacement (MVR) have been performed in the surgical management of IMR, there remains uncertainty regarding the optimal approach. The aim of the present study was to meta-analyze these two procedures, with mortality as the primary endpoint. METHODS: Seven databases were systematically searched for studies reporting peri-operative or late mortality following MVr and MVR for IMR. Data were independently extracted by two reviewers and meta-analyzed according to pre-defined study selection criteria and clinical endpoints. RESULTS: Overall, 22 observational studies (n=3,815 patients) and one randomized controlled trial (n=251) were included. Meta-analysis demonstrated significantly reduced peri-operative mortality [relative risk (RR) 0.61; 95% confidence intervals (CI), 0.47-0.77; I(2)=0%; P<0.001] and late mortality (RR, 0.78; 95% CI, 0.67-0.92; I(2)=0%; P=0.002) following MVr. This finding was more pronounced in studies with longer follow-up beyond 3 years. At latest follow-up, recurrence of at least moderate mitral regurgitation (MR) was higher following MVr (RR, 5.21; 95% CI, 2.66-10.22; I(2)=46%; P<0.001) but the incidence of mitral valve re-operations were similar. CONCLUSIONS: In the present meta-analysis, MVr was associated with reduced peri-operative and late mortality compared to MVR, despite an increased recurrence of at least moderate MR at follow-up. However, these findings must be considered within the context of the differing patient characteristics that may affect allocation to MVr or MVR. Larger prospective studies are warranted to further compare long-term survival and freedom from re-intervention.

Lack of the antioxidant glutathione peroxidase-1 (GPx1) exacerbates retinopathy of prematurity in mice.

PURPOSE: Glutathione peroxidase-1 (GPx1) is highly expressed during normal retinal maturation; however, its role in retinopathy of prematurity (ROP) is not fully understood. We postulated that GPx1 plays an important role in protecting the premature retina from oxidative injury in a mouse model of ROP. METHODS: ROP was induced in wild-type (WT) and GPx1 knockout (KO) mice by exposing neonatal mice to 75% oxygen from postnatal days 7 to 11, followed by 1 week of room air. Structural effects of ROP were evaluated by retinal histology, and gene expression of retinal pro-angiogenic factors was measured by qRT-PCR. RESULTS: Retinas from ROP GPx1 KO mice had a significantly larger central avascular area compared to those from ROP WT mice (P < 0.001), indicative of a more severe vaso-obliteration. In ROP GPx1 KO mice, retinas also displayed increased preretinal neovascularization (P = 0.05) with a concurrent increase in the expression of vascular endothelial growth factor (P < 0.05) compared to values in ROP WT mice. Elevated oxidative stress was observed in ROP GPx1 KO retinas as evidenced by increased nitrotyrosine immunolabeling (P < 0.01) and superoxide (P < 0.05) in vessels compared to ROP WT retinas. In contrast to these findings of exacerbated retinal vascular injury in GPx1 KO mice, Müller cell gliosis and microglial density were similar in ROP GPx1 KO and ROP WT mice. CONCLUSIONS: GPx1, an important antioxidant enzyme of the premature retina, afforded protection against oxidative stress and oxidative injury in ROP. Lack of GPx1 was associated with increased oxidative stress, an increase in retinal avascular area, upregulation of retinal VEGF, and increased neovascularization in a mouse model of ROP.

Neovascularization is attenuated with aldosterone synthase inhibition in rats with retinopathy.

Neovascularization is a hallmark feature of retinopathy of prematurity and diabetic retinopathy. Type 1 angiotensin receptor blockade reduces neovascularization in experimental retinopathy of prematurity, known as oxygen-induced retinopathy (OIR). We investigated in OIR whether inhibiting aldosterone with the aldosterone synthase inhibitor FAD286 reduced neovascularization as effectively as angiotensin receptor blockade (valsartan). OIR was induced in neonatal Sprague-Dawley rats, and they were treated with FAD286 (30 mg/kg per day), valsartan (10 mg/kg per day), or FAD286+valsartan. The cellular sources of aldosterone synthase, the mineralocorticoid receptor, and 11ß-hydroxysteroid dehydrogenase 2 were evaluated in retinal cells involved in neovascularization (primary endothelial cells, pericytes, microglia, ganglion cells, and glia). In OIR, FAD286 reduced neovascularization and neovascular tufts by 89% and 67%, respectively, and normalized the increase in vascular endothelial growth factor mRNA (1.74-fold) and protein (4.74-fold) and was as effective as valsartan and FAD286+valsartan. In retina, aldosterone synthase mRNA was reduced with FAD286 but not valsartan. Aldosterone synthase was detected in microglia, ganglion cells, and glia, whereas mineralocorticoid receptor and 11ß-hydroxysteroid dehydrogenase 2 were present in all of the cell types studied. Given the location of aldosterone synthase in microglia and their contribution to retinal inflammation and neovascularization in OIR, the effects of FAD286 on microglial density were studied. The increase in microglial density (ionized calcium binding adaptor protein 1 immunolabeling) in OIR was reduced with all of the treatments. In OIR, FAD286 reduced the increase in mRNA for tumor necrosis factor-α, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and monocyte chemoattractant molecule 1. These findings indicate that aldosterone inhibition may be a potential treatment for retinal neovascularization.

Candesartan attenuates diabetic retinal vascular pathology by restoring glyoxalase-I function.

OBJECTIVE: Advanced glycation end products (AGEs) and the renin-angiotensin system (RAS) are both implicated in the development of diabetic retinopathy. How these pathways interact to promote retinal vasculopathy is not fully understood. Glyoxalase-I (GLO-I) is an enzyme critical for the detoxification of AGEs and retinal vascular cell survival. We hypothesized that, in retina, angiotensin II (Ang II) downregulates GLO-I, which leads to an increase in methylglyoxal-AGE formation. The angiotensin type 1 receptor blocker, candesartan, rectifies this imbalance and protects against retinal vasculopathy. RESEARCH DESIGN AND METHODS: Cultured bovine retinal endothelial cells (BREC) and bovine retinal pericytes (BRP) were incubated with Ang II (100 nmol/l) or Ang II+candesartan (1 µmol/l). Transgenic Ren-2 rats that overexpress the RAS were randomized to be nondiabetic, diabetic, or diabetic+candesartan (5 mg/kg/day) and studied over 20 weeks. Comparisons were made with diabetic Sprague-Dawley rats. RESULTS: In BREC and BRP, Ang II induced apoptosis and reduced GLO-I activity and mRNA, with a concomitant increase in nitric oxide (NO(•)), the latter being a known negative regulator of GLO-I in BRP. In BREC and BRP, candesartan restored GLO-I and reduced NO(•). Similar events occurred in vivo, with the elevated RAS of the diabetic Ren-2 rat, but not the diabetic Sprague-Dawley rat, reducing retinal GLO-I. In diabetic Ren-2 rats, candesartan reduced retinal acellular capillaries, inflammation, and inducible nitric oxide synthase and NO(•), and restored GLO-I. CONCLUSIONS: We have identified a novel mechanism by which candesartan improves diabetic retinopathy through the restoration of GLO-I.

Dose-dependent systolic contribution of differentiated stem cells in post-infarct ventricular function.

BACKGROUND: Differentiation of bone marrow stem cells toward cardiomyocytes has been widely reported in vitro. However, optimum cell types and mechanisms leading to functional improvement in cardiac cell therapy remain unresolved. There is limited evidence showing a dose-dependent effect of transplanted cells in contributing to functional recovery. This study showed that cell transplantation of differentiated cardiomyocyte-like cells (CLCs) and undifferentiated mesenchymal stem cells (MSCs) dose-dependently improved left ventricular function in a rat myocardial infarction model. METHODS: At 1 week after infarction in Wistar rats, 1 × 10(6) MSCs (n = 9) or CLCs (n = 9) and 5 × 10(6) MSCs (n = 18) or CLCs (n = 15) were injected into peri-infarcted myocardium to study their effect after 6 weeks. RESULTS: High-dose CLCs exhibited a dose-response that was significantly more effective than MSCs in recovering cardiac contractility. Superiority of CLCs over MSCs was demonstrated in load-independent measurement of the end-systolic pressure-volume relationship and pre-load recruitable stroke work, but not in the end-diastolic pressure-volume relationship. These findings showed a unique systolic role of CLCs in contractility recovery. Functional improvement mediated by MSCs was mainly derived from preservation of endogenous myocyte function and restriction of chamber dilatation by enhancing intramyocardial angiogenesis during post-infarct ventricular remodeling. Engrafted CLCs showed better survival, were strategically integrated into myofiber-associated collagen V matrix, and exhibited mature sarcomeric cross-striations. Vascular differentiation, but not cardiac, was observed with MSCs. CONCLUSION: These cell type-specific effects suggest that committing stem cells to a cardiac phenotype ex vivo promoted mechanical and functional integration of CLCs into the myofibrillar syncytium of infarcted myocardium.

RILLKKMPSV influences the vasculature, neurons and glia, and (pro)renin receptor expression in the retina.

The (pro)renin receptor [(P)RR] is implicated in organ pathology. We examined the cellular location of the (P)RR and whether a putative (P)RR antagonist, RILLKKMPSV, corresponding to the handle region of the prorenin prosegment (handle region peptide [HRP]) influences angiogenesis, inflammation, and neuronal and glial function in rat retina. The (P)RR was localized to retinal vessels, endothelial cells, and pericytes, but most immunolabeling was in ganglion cells and glia. HRP (1 mg/kg per day by IP injection) reduced physiological angiogenesis in developing retina. Moreover, HRP (0.1 mg/kg per day by subcutaneous minipump) reduced pathological retinal angiogenesis, inflammation, and vascular endothelial growth factor and intercellular adhesion molecule-1 mRNA in rats with oxygen-induced retinopathy (OIR) to an extent similar to valsartan (10 mg/kg per day, IP). In contrast to its effects on vasculature, HRP compromised the electroretinogram in shams and OIR and increased phosphorylated extracellular-signal-related protein kinase 1/2 immunolabeling in shams but not in OIR, whereas valsartan did not affect the electroretinogram and reduced extracellular-signal-related protein kinase 1/2 immunolabeling in OIR. Retinal (P)RR mRNA levels were increased in OIR; HRP, but not valsartan, increased (P)RR mRNA levels in shams, whereas both HRP and valsartan reduced (P)RR mRNA levels in OIR. A control peptide (VSPMKKLLIR, 0.1 mg/kg per day) did not influence retinal vasculopathy or function. Circulating HRP levels in rats administered 1 mg/kg per day HRP were undetectable (<3 pmol/L). We conclude that HRP had protective effects on the retinal vasculature similar to those of valsartan; however, unlike valsartan, HRP injured neuro-glia, which may involve the (P)RR, although the undetectable circulating HRP level makes a direct effect of HRP on retinal (P)RR function unlikely.

Differential effect of myocardial matrix and integrins on cardiac differentiation of human mesenchymal stem cells.

Dysregulation of matrix synthesis during myocardial fibrosis in post-infarct ventricular remodeling contributes to ventricular dysfunction. Bone marrow stem cell transplantation prevents functional deterioration following myocardial infarction. However, effect of myocardial extracellular matrix (ECM) on stem cell differentiation is poorly understood. We investigate the role of collagen matrices and integrin system in cardiac differentiation and engraftment of stem cells in infarcted myocardium. Sternum-derived bone marrow mesenchymal stem cells (MSCs) were differentiated into cardiomyocyte-like cells (CLCs). They were characterized using RT-PCR, immunofluorescence, flow cytometry and functional integrin neutralization assays. CLCs were injected into peri-infarct borders of injured myocardium of Wistar rats one week following left anterior descending (LAD) artery ligation. Cardiac function was analyzed via pressure-volume relationships. Cardiac differentiated CLCs displayed collagen V specificity, which was absent in undifferentiated MSCs. Collagen V, but not collagen I matrix, promoted attachment, proliferation and cardiac differentiation of CLCs. In contrast to beta(1), alpha(v) integrin contributed minimally in the attachment of CLCs on collagen matrices. However, inhibition of alpha(v)beta(3,) but not alpha(2)beta(1) integrin, selectively attenuated troponin T, sarcomeric alpha-actin and ryanodine 2 receptor gene expression in CLCs. Both MSC and CLC transplantation prevented chamber dilatation and improved contractile function. However, systolic activity in MSC transplanted animals was accompanied by heightened wall stress as demonstrated by elevated myocardial end-diastolic pressure and prolonged tissue relaxation time. Localization of CLCs in the vicinity of collagen V-expressing myofibers promoted their integration into cardiac syncytium. CLCs may facilitate hemodynamic recovery by preserving tissue elasticity in the peri-infarct borders that sustains contractile efficiency for functional recovery in an actively remodeling infarcted myocardium.

Cell delivery and tracking in post-myocardial infarction cardiac stem cell therapy: an introduction for clinical researchers.

Stem cell-based therapy for patients with post-infarct heart failure is a relatively new and revolutionary concept in cardiology. Despite the encouraging results from pre-clinical studies, outcomes from most clinical trials remain moderately positive while the clinical benefits are largely attributed to transplanted cell-associated paracrine effects in stimulating angiogenesis and protecting endogenous cardiomyocytes. This scenario indicates that there may be a considerably protracted iterative process of conceptual and procedural refinement before true clinical benefits can be fully materialized. At present, many pressing questions regarding cell therapy remain unanswered. In addition to the primary interest in determining the ideal type of stem cells with best cardiogenic potential in vitro and in vivo, there are growing concerns on the impact of the host cardiac milieu on the transplanted cells, including their survival, migration, engraftment, and trans-differentiation as well as contribution to left ventricular function. Effective cell delivery and tracking methods are central to the unraveling of these questions. To date, cell-delivery modalities are yet to be optimized and strategies for safe and effective assessment of cells transplanted in the recipients are to be established. In this review, we discuss cell delivery and tracking modalities that are adopted in the current pre-clinical and clinical studies. We further discussed emerging technologies that are poised to impact the success of cell therapy.

Identification of a retinal aldosterone system and the protective effects of mineralocorticoid receptor antagonism on retinal vascular pathology.

Blockade of the renin-angiotensin-aldosterone system (RAAS) is being evaluated as a treatment for diabetic retinopathy; however, whether the mineralocorticoid receptor (MR) and aldosterone influence retinal vascular pathology is unknown. We examined the effect of MR antagonism on pathological angiogenesis in rats with oxygen-induced retinopathy (OIR). To determine the mechanisms by which the MR and aldosterone may influence retinal angiogenesis; inflammation and glucose-6-phosphate dehydrogenase (G6PD) were evaluated in OIR and cultured bovine retinal endothelial cells (BRECs) and bovine retinal pericytes (BRPs). In OIR, MR antagonism (spironolactone) was antiangiogenic. Aldosterone may mediate the pathogenic actions of MR in the retina, with 11beta-hydroxysteroid dehydrogenase type 2 mRNA being detected and with aldosterone stimulating proliferation and tubulogenesis in BRECs and exacerbating angiogenesis in OIR, which was attenuated with spironolactone. The MR and aldosterone modulated retinal inflammation, with leukostasis and monocyte chemoattractant protein-1 mRNA and protein in OIR being reduced by spironolactone and increased by aldosterone. A reduction in G6PD may be an early response to aldosterone. In BRECs, BRPs, and early OIR, aldosterone reduced G6PD mRNA, and in late OIR, aldosterone increased mRNA for the NAD(P)H oxidase subunit Nox4. A functional retinal MR-aldosterone system was evident with MR expression, translocation of nuclear MR, and aldosterone synthase expression, which was modulated by RAAS blockade. We make the first report that MR and aldosterone influence retinal vasculopathy, which may involve inflammatory and G6PD mechanisms. MR antagonism may be relevant when developing treatments for retinopathies that target the RAAS.

Valsartan but not atenolol improves vascular pathology in diabetic Ren-2 rat retina.

BACKGROUND: To determine whether angiotensin type 1 receptor blockade (AT1-RB) or antihypertensive therapy per se, attenuates acellular capillaries and proliferating endothelial cells in the retina of diabetic Ren-2 rats. METHODS: Eight-week-old hypertensive Ren-2 rats were made diabetic (streptozotocin, 55 mg/kg) or nondiabetic (0.1 mol/L citrate buffer) and studied for 20 weeks. Diabetic Ren-2 rats received by gavage the AT1-RB valsartan at 4, 10, or 40 mg/kg/d or the beta1-adrenergic receptor blocker atenolol at 30 mg/kg/d. Systolic blood pressure (BP) was measured every 4 weeks. Acellular capillaries (devoid of pericytes and endothelial cells) were counted on trypsin digests. Proliferating endothelial cells were evaluated using double immunolabeling for isolectin and proliferating cell nuclear antigen. RESULTS: Systolic BP was unchanged in control Ren-2 rats throughout the study (186.6 +/- 3.5 mm Hg, nondiabetic; 185.0 +/- 0.7 mm Hg, diabetic; week 20). In diabetic Ren-2 rats, 4 and 10 mg of valsartan and atenolol reduced systolic BP to a similar extent, and at 20 weeks were comparable to diabetic Sprague Dawley rats (123.0 +/- 1.4 mm Hg). In diabetic Ren-2 rats, 40 mg of valsartan reduced systolic BP (110.9 +/- 1.1 mm Hg, 20 weeks) below that of Sprague Dawley rats. Acellular capillaries and proliferating endothelial cells were increased by 3- and 1.6-fold, respectively, in diabetic Ren-2 controls and reduced with 4 and 10 mg of valsartan and further reduced with 40 mg of valsartan. Atenolol had no effect on retinal pathology in diabetic Ren-2 rats. CONCLUSIONS: Blockade of the renin-angiotensin system but not antihypertensive therapy with atenolol reduces vascular pathology in diabetic Ren-2 retina, suggesting that angiotensin II is a causative factor and therapeutic target in diabetic retinopathy.