Nonvascular Diseases Research Articles

Upregulation of miR-146a-5p is associated with increased proliferation and migration of vascular smooth muscle cells in aortic dissection.

BackgroundThis study aimed to investigate whether miR‐146a‐5p was involved in the pathogenesis of thoracic aortic dissection (AD) via regulating the biological function of vascular smooth muscle cells (VSMCs).MethodsCirculating miR‐146a‐5p level was measured by quantitative polymerase chain reaction (qPCR) in AD patients and healthy controls. Human dissected aortic samples were obtained from patients with thoracic AD Stanford type A undergoing surgical repair, and normal control samples were from organ donors who died from nonvascular diseases. The expression level of miR‐146a‐5p was detected using qPCR in each sample. The expression of SMAD4, which is involved in the TGF‐β pathway and indicated as the target gene of miR‐146a‐5p, was measured by qPCR and Western blot analysis at the mRNA level and protein level, respectively. Subsequently, VSMCs were transfected with miR‐146a‐5p mimics or inhibitors in vitro. VSMC proliferation and migration were detected using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide and Transwell assay, respectively. Flow cytometry was used to identify apoptosis. The expression of SMAD4 in VSMCs was determined using qPCR and Western blot analysis.ResultsPlasma level of miR‐146a‐5p is significantly higher in the AD group as compared with the control group. The expression of miR‐146a‐5p was significantly upregulated in dissected aorta compared with controls (P < 0.05). The overexpression of miR‐146a‐5p significantly induced VSMC proliferation and migration in vitro.ConclusionsThe expression of SMAD4 was modulated by miR‐146a‐5p. miR‐146a‐5p induced VSMC proliferation and migration through targeting SMAD4 and hence might be potentially involved in the development of AD.

Retinal vascular tortuosity assessment: inter-intra expert analysis and correlation with computational measurements

BackgroundThe retinal vascular tortuosity can be a potential indicator of relevant vascular and non-vascular diseases. However, the lack of a precise and standard guide for the tortuosity evaluation hinders its use for diagnostic and treatment purposes. This work aims to advance in the standardization of the retinal vascular tortuosity as a clinical biomarker with diagnostic potential, allowing, thereby, the validation of objective computational measurements on the basis of the entire spectrum of the expert knowledge.MethodsThis paper describes a multi-expert validation process of the computational vascular tortuosity measurements of reference. A group of five experts, covering the different clinical profiles of an ophthalmological service, and a four-grade scale from non-tortuous to severe tortuosity as well as non-tortuous / tortuous and asymptomatic / symptomatic binary classifications are considered for the analysis of the the multi-expert validation procedure. The specialists rating process comprises two rounds involving all the experts and a joint round to establish consensual rates. The expert agreement is analyzed throughout the rating procedure and, then, the consensual rates are set as the reference to validate the prognostic performance of four computational tortuosity metrics of reference.ResultsThe Kappa indexes for the intra-rater agreement analysis were obtained between 0.35 and 0.83 whereas for the inter-rater agreement in the asymptomatic / symptomatic classification were between 0.22 and 0.76. The Area Under the Curve (AUC) for each expert against the consensual rates were placed between 0.61 and 0.83 whereas the prognostic performance of the best objective tortuosity metric was 0.80.ConclusionsThere is a high inter and intra-rater variability, especially for the case of the four grade scale. The prognostic performance of the tortuosity measurements is close to the experts’ performance, especially for Grisan measurement. However, there is a gap between the automatic effectiveness and the expert perception given the lack of clinical criteria in the computational measurements.

Age-specific association between blood pressure and vascular and non-vascular chronic diseases in 0·5 million adults in China: a prospective cohort study.

SummaryBackgroundThe age-specific association between blood pressure and vascular disease has been studied mostly in high-income countries, and before the widespread use of brain imaging for diagnosis of the main stroke types (ischaemic stroke and intracerebral haemorrhage). We aimed to investigate this relationship among adults in China.Methods512 891 adults (59% women) aged 30–79 years were recruited into a prospective study from ten areas of China between June 25, 2004, and July 15, 2008. Participants attended assessment centres where they were interviewed about demographic and lifestyle characteristics, and their blood pressure, height, and weight were measured. Incident disease was identified through linkage to local mortality records, chronic disease registries, and claims to the national health insurance system. We used Cox regression analysis to produce adjusted hazard ratios (HRs) relating systolic blood pressure to disease incidence. HRs were corrected for regression dilution to estimate associations with long-term average (usual) systolic blood pressure.FindingsDuring a median follow-up of 9 years (IQR 8–10), there were 88 105 incident vascular and non-vascular chronic disease events (about 90% of strokes events were diagnosed using brain imaging). At ages 40–79 years (mean age at event 64 years [SD 9]), usual systolic blood pressure was continuously and positively associated with incident major vascular disease throughout the range 120–180 mm Hg: each 10 mm Hg higher usual systolic blood pressure was associated with an approximately 30% higher risk of ischaemic heart disease (HR 1·31 [95% CI 1·28–1·34]) and ischaemic stroke (1·30 [1·29–1·31]), but the association with intracerebral haemorrhage was about twice as steep (1·68 [1·65–1·71]). HRs for vascular disease were twice as steep at ages 40–49 years than at ages 70–79 years. Usual systolic blood pressure was also positively associated with incident chronic kidney disease (1·40 [1·35–1·44]) and diabetes (1·14 [1·12–1·15]). About half of all vascular deaths in China were attributable to elevated blood pressure (ie, systolic blood pressure >120 mm Hg), accounting for approximately 1 million deaths (<80 years of age) annually.InterpretationAmong adults in China, systolic blood pressure was continuously related to major vascular disease with no evidence of a threshold down to 120 mm Hg. Unlike previous studies in high-income countries, blood pressure was more strongly associated with intracerebral haemorrhage than with ischaemic stroke. Even small reductions in mean blood pressure at a population level could be expected to have a major impact on vascular morbidity and mortality.FundingUK Wellcome Trust, UK Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, Chinese Ministry of Science and Technology, and the National Science Foundation of China.

Elevated lysophosphatidic acid levels in the serum and cerebrospinal fluid in patients with multiple sclerosis: therapeutic response and clinical implication

Background: To date, although great effort has been made to identify biomarkers of multiple sclerosis (MS), it remains unclear whether lysophosphatidic acid (LPA) can be used as a biomarker for MS.Methods: This study compared the LPA levels in the serum and cerebrospinal fluid (CSF) in patients with MS in relapse versus in remission and investigated the change in LPA levels in MS patients in relapse after treatment. Forty-one patients with relapsing-remitting MS (RRMS) (21 patients in relapse and 20 patients in remission) and 21 patients with non-inflammatory, non-vascular neurological diseases as controls were included in this study. MS patients in relapse received standard glucocorticoid treatment. LPA concentrations in serum and CSF were measured using an inorganic phosphate quantification assay.Results: LPA levels in the serum and CSF were significantly higher in MS patients in relapse than in MS patients in remission and control patients (P < 0.05). The LPA level in MS patients in relapse was significantly reduced after treatment (P < 0.05).Conclusion: LPA concentrations in the serum and CSF may be used as biomarkers to monitor disease activity and therapeutic response in MS patients.

Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults

Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD). To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes. This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17 854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries. Five CETP variants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels. Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases. Among the 151 217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL. CETP variants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL per rs2303790-G allele; P = 9.4 × 10-47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, the CETP genetic score was not associated with occlusive CVD (18 550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13 759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases with rs2303790 (4090 events; OR, 1.43; 95% CI, 1.13-1.80; P = .003). CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD.

Lipoprotein (a) as a risk factor of ischemic stroke: a case-control study

Background: Undoubtedly, stroke is an important public health problem as well as an important precursor of mortality and morbidity. It also leads to loss of disability adjusted life years as it causes long term severe disability. The objective of this study was to study association of lipoprotein (a) in ischemic stroke patients with matched controls.Methods: This is a prospective case controlled study. The study group includes 100 stroke patients consecutive admitted in medicine/neurology departments of our hospital, and 50 patients as control group admitted for nonvascular diseases. The ethical committee clearance was obtained from the appropriate authority appointed by the institution. Detailed history taking and neurological examination were done in all patientsResults: This case-control study shows that ischemic stroke patients have higher levels of Lp (a) as compared to that of controls. Thus, people with high Lp (a) levels may have higher predilection for developing ischemic stroke. Lp (a) levels do not correspond to stroke severity stroke in our study. Thus, higher Lp (a) levels do not lead to more severe type of stroke. Lp (a) levels do not correlate with the outcome of stroke, hence Lp (a) level may not be a good indicator for assessing prognosis or predicting mortalityConclusions: This case-control study shows that ischemic stroke patients have higher levels of Lp (a) as compared to that of controls. Thus, people with high Lp (a) levels may have higher predilection for developing ischemic stroke factors for stroke like diabetes, smoking and hypertension do not predisposed to higher Lp (a).

Downregulation of Talin-1 expression associates with increased proliferation and migration of vascular smooth muscle cells in aortic dissection

BackgroundThis study aimed to assessed whether Talin-1 is involved in the pathogenesis of aortic dissection via regulating vascular smooth muscle cell (VSMC) biological function.MethodsHuman aortic samples were obtained from organ donors who died from nonvascular diseases as normal controls and from patients undergoing surgical repair of thoracic aortic dissection. The expression level and distribution of Talin-1 were detected using westernblot analysis and immunohistochemistry in each sample. We inhibited the expression of Talin-1 via RNA interference in VSMCs. VSMC proliferation was detected by Cell-counting Kit-8 analyses. Scratch test and flow cytometry were used to identify the migration and apoptosis ability. Antibody microarray analysis and qRT-PCR were used to detect some protein and mRNA changes which were induced by Talin-1 downregulation.ResultsTalin-1 was significantly downregulated in the media of aortic dissection samples compared with controls (P < 0.05). Talin-1 knockdown significantly induced VSMC proliferation and migration in vitro. Proteins which involved in cell cycle can be regulated by downregulating Talin-1. Down regulation of Talin-1 can significanly increased the expression of anaphase-promoting complex subunit 2 (APC2) and decreased p19 alternative reading frame (p19ARF), Cullin-3, and beta actin’s expression.ConclusionsTalin-1 induces VSMCs proliferation and migration. It downregulated in aortic dissection, which might play a potential role in the development of aortic dissection.

Fresh fruit consumption and all-cause and cause-specific mortality: findings from the China Kadoorie Biobank.

BackgroundHigher fruit consumption is associated with lower risk of cardiovascular disease (CVD). Substantial uncertainties remain, however, about the associations of fruit consumption with all-cause mortality and mortality from subtypes of CVD and major non-vascular diseases, especially in China.MethodsIn 2004–08, the nationwide China Kadoorie Biobank Study recruited > 0.5 million adults aged 30–79 years from 10 diverse localities in China. Fresh fruit consumption was estimated using an interviewer-administered electronic questionnaire, and mortality data were collected from death registries. Among the 462 342 participants who were free of major chronic diseases at baseline, 17 894 deaths were recorded during ∼ 7 years of follow-up. Cox regression yielded adjusted rate ratios (RRs) for all-cause and cause-specific mortality associated with fruit consumption.ResultsAt baseline, 28% of participants reported consuming fruit ≥ 4 days/week (regular consumers) and 6% reported never/rarely consuming fruit (non-consumers). Compared with non-consumers, regular consumers had 27% [RR = 0.73, 95% confidence interval (CI) 0.70–0.76] lower all-cause mortality, 34% lower CVD mortality (n = 6166; RR = 0.66, 0.61–0.71), 17% lower cancer mortality (n = 6796; RR = 0.83, 0.78–0.89) and 42% lower mortality from chronic obstructive pulmonary disease (COPD) (n = 1119; RR = 0.58, 0.47–0.71). For each of the above, there was an approximately log-linear dose-response relationship with amount consumed. For mortality from site-specific cancers, fruit consumption was inversely associated with digestive tract cancer (n = 2265; RR = 0.72, 0.64–0.81), particularly oesophageal cancer (n = 801; RR = 0.65, 0.50–0.83), but not with cancer of lung or liver.ConclusionsAmong Chinese adults, higher fresh fruit consumption was associated with significantly lower mortality from several major vascular and non-vascular diseases. Given the current low population level of fruit consumption, substantial health benefits could be gained from increased fruit consumption in China.

Stent containing CD44-targeting polymeric prodrug nanoparticles that release paclitaxel and gemcitabine in a time interval-controlled manner for synergistic human biliary cancer therapy.

The use of drug-eluting stents (DESs) is a promising strategy for non-vascular diseases, especially human biliary cancer. However, the implementation of DESs suffers from two major obstacles: the side effects of drugs and the difficulty of controlling the drug release. These problems can be overcome if the stent elutes targeting nanoparticles that release drugs at time intervals that are dictated by the mechanisms of those drugs. We designed temporally controlled polymeric multi-prodrug nanoparticles (TCMPNs) that can be eluted from stents comprising polyurethane (PU) nanofiber as a polymeric matrix and paclitaxel (PTX)-loaded, CD44-targeting, hyaluronic acid-conjugated poly(lactic-co-glycolic acid) and gemcitabine (GEM) (P-H-G). TCMPNs enable two different types of drugs to be released temporally; PTX is released first owing to the collapse of the structure in the endosomes, and GEM, which induces synergistic anticancer activities, is hydrolyzed from P-H-G later in response to low pH. Embedded in the PU nanofiber, the TCMPNs demonstrate low initial burst behavior and sustainable release of the prodrug in vitro. Furthermore, TCMPN-eluting stents (TESs) exhibit continuous synergistic efficacy as available targeted cellular uptake prodrug delivery systems in tumor-bearing mice. These results demonstrate that this technology will open up cancer therapy by combining localized delivery and functional multi-drug-loaded nanoparticles.

Gamma-glutamyltransferase-friend or foe within?

Gamma-glutamyltransferase (GGT) is a liver enzyme, which is located on the plasma membranes of most cells and organ tissues, but more commonly in hepatocytes, and is routinely used in clinical practice to help indicate liver injury and as a marker of excessive alcohol consumption. Among the liver enzymes, important advances have especially been made in understanding the physiological functions of GGT. The primary role of GGT is the extracellular catabolism of glutathione, the major thiol antioxidant in mammalian cells, which plays a relevant role in protecting cells against oxidants produced during normal metabolism; GGT, therefore, plays an important role in cellular defence. Beyond its physiological functions, circulating serum GGT has been linked to a remarkable array of chronic conditions and diseases, which include nonalcoholic fatty liver disease, vascular and nonvascular diseases and mortality outcomes. This review summarizes the available epidemiological and genetic evidence for the associations between GGT and these adverse outcomes, the postulated biologic mechanisms underlying these associations, outlines areas of outstanding uncertainty and the implications for clinical practice.

The regulatory role of smooth muscle 22 on the proliferation of aortic smooth muscle cells participates in the development of aortic dissection

The aim of this study was to determine the role of smooth muscle 22 (SM22) in aortic dissection (AD) vascular remodeling and its regulatory mechanism on vascular smooth muscle cell function. Seven patients who underwent surgery for AD with no genetic predisposition and seven organ donors who died from nonvascular diseases were selected. In each aorta sample, the levels of SM22 were detected using immunohistochemistry and Western blot analysis. We inhibited the expression of SM22 with the application of RNA interference in human aortic smooth muscle cells (HASMCs). Cell-counting Kit-8 (Dojindo, Kumamoto, Japan) analyses were used to detect HASMC proliferation. Furthermore, the intracellular calcium concentration was detected using Rhod-2/AM (Dojindo) staining. SM22 was significantly downregulated in the media of AD samples compared with controls (P< .05). In an invitro study, downregulation of SM22 can significantly promote HASMC proliferation. Our research further revealed that cells treated with nifedipine can inhibit the promoter activity of SM22 downregulation on HASMC proliferation. Intracellular calcium concentration was a significantly varied during the process. SM22 regulates HASMC function activity through intracellular calcium. It presents a downregulation in AD, which might play a potential role in vascular remodeling of AD.

A phenome-wide association study of a lipoprotein-associated phospholipase A2 loss-of-function variant in 90 000 Chinese adults.

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been implicated in development of atherosclerosis; however, recent randomized trials of Lp-PLA2 inhibition reported no beneficial effects on vascular diseases. In East Asians, a loss-of-function variant in the PLA2G7 gene can be used to assess the effects of genetically determined lower Lp-PLA2. Methods: PLA2G7 V279F (rs76863441) was genotyped in 91 428 individuals randomly selected from the China Kadoorie Biobank of 0.5 M participants recruited in 2004–08 from 10 regions of China, with 7 years’ follow-up. Linear regression was used to assess effects of V279F on baseline traits. Logistic regression was conducted for a range of vascular and non-vascular diseases, including 41 ICD-10 coded disease categories. Results: PLA2G7 V279F frequency was 5% overall (range 3–7% by region), and 9691 (11%) participants had at least one loss-of-function variant. V279F was not associated with baseline blood pressure, adiposity, blood glucose or lung function. V279F was not associated with major vascular events [7141 events; odds ratio (OR) = 0.98 per F variant, 95% confidence interval (CI) 0.90-1.06] or other vascular outcomes, including major coronary events (922 events; 0.96, 0.79-1.18) and stroke (5967 events; 1.00, 0.92-1.09). Individuals with V279F had lower risks of diabetes (7031 events; 0.91, 0.84-0.98) and asthma (182 events; 0.53, 0.28-0.98), but there was no association after adjustment for multiple testing. Conclusions: Lifelong lower Lp-PLA2 activity was not associated with major risks of vascular or non-vascular diseases in Chinese adults. Using functional genetic variants in large-scale prospective studies with linkage to a range of health outcomes is a valuable approach to inform drug development and repositioning.

Epigenetic regulation of soluble guanylate cyclase (sGC) β1 in breast cancer cells.

Soluble guanylate cyclase (sGC) is a heterodimer composed of α and β subunits. The loss of sGCβ1 has been implicated in several vascular and nonvascular diseases. Our analysis showed that higher levels of sGCβ1 in breast cancer tissues are correlated with greater survival probability than lower sGCβ1 levels. However, there is no information on sGC regulation by epigenetic mechanisms. We examined the role of histone deacetylase (HDAC) inhibitors in regulating sGCα1 and -β1 expression in human breast cancer MDA-MB-231 and MDA-MB-468 cell lines. The class I HDAC inhibitors increased the expression of sGCβ1 more than sGCα1. Transient overexpression of HDAC3, but not HDAC1 or HDAC2, significantly reduced sGCβ1 mRNA. Chromatin immunoprecipitation assay confirmed an enhanced binding of HDAC3 to the sGCβ1 proximal promoter, which could be reversed by panobinostat (LBH-589) treatment. Mutations at the CCAAT binding sequence, a major element regulating sGCβ1 expression, markedly reduced the efficacy of LBH-589 in augmenting sGCβ1 promoter activity. LBH-589 markedly enhanced the binding of nuclear transcription factor Y, subunit α, to the sGCβ1 promoter (CCAAT binding sequence). In summary, HDAC3 is an endogenous antagonist of sGCβ1 expression. Inhibition of HDAC3 with targeted therapy could benefit treatment of the diseases associated with sGCβ1 down-regulation and/or deficiency such as cancer and several vascular-related diseases.-Sotolongo, A., Mónica, F. Z., Kots, A., Xiao, H., Liu, J., Seto, E., Bian, K., Murad, F. Epigenetic regulation of soluble guanylate cyclase (sGC) β1 in breast cancer cells.

Pharmacologic Vitreolysis in Vascular Diseases of the Retina.

Vascular diseases of the retina such as diabetic retinopathy and vascular occlusions account for a large proportion of visual morbidity and blindness worldwide. The role of vitreous in the pathogenesis of these conditions has been increasingly recognized. Despite advances in the surgical technique of pars plana vitrectomy, the use of intravitreal agents for the lysis of vitreous has received attention, guided largely by promising results from the trials involving patients with non-vascular retinal diseases such as vitreomacular traction. The purpose of this review is to provide a comprehensive summary of the present knowledge on pathophysiologic basis of pharmacologic vitreolysis and its efficacy in vascular diseases of the retina. A review of completed and ongoing clinical trials will be presented, along with insights into future directions of this therapy.

Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis.

ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasma-derived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease.

Abstract T MP55: Utility of 4D-MRA to Measure Blood Flow Velocity in Cerebral Major Arteries

Transcranial Doppler is widely used clinically to measure blood flow velocity (BFV) in cerebral major arteries. This method, however, has a limitation in that its successful measurement depends on the accessibility of patients’ cranial window and the technical ability of operators. We therefore developed a novel method to measure BFV in cerebral major arteries with 4D-MRA, which was less susceptible to patients and the conditions of the operators. Methods: 4D-MRA was performed with a 3T MR unit (Achieva TX; Philips Medical Systems) using arterial spin labeling methods. The blood flow through the internal carotid arteries (ICA) and the basilar artery (BA) within imaging range was visualized by using look-locker readout methods. BFV was calculated by dividing the flow distance traveled in the arteries by the time elapsed. BFV of 34 patients (non-vascular disease:11, ICA stenotic disease:6, moyamoya disease:9, and cerebral aneurysm:8) were measured using the 4D-MRA method and the 2D phase contrast method. Results: In the case of patients with non-vascular diseases, mean BFV of the right ICA, the left ICA, and the BA was 24.5±7.0, 23.3±6.9, and 17.2±5.1 cm/sec, respectively. Correlation between BFV values from the 4D-MRA method and those from the 2D phase contrast method was statistically significant (r=0.78, p&lt;0.01). In the case of patients with ICA severe stenosis (more than 90%), BFV of the stenotic ICA was decreased to 9~11cm/sec (40~50% of BFV of the contralateral ICA). In the case of patients with advanced-stage moyamoya disease, BFV of the ICA was decreased to 9~16cm/sec (30~50% of BFV of the BA). The BFV decreases were related to CBF reduction in some cases if the development of the collateral circulation was insufficient. In the patients with aneurysm, BFV of the artery proximal to aneurysm tended to be increased except for the decrease in cavernous ICA giant aneurysm. Conclusions: We could steadily obtain BFV in all patients by using the 4D-MRA method without any operational difficulties. In this preliminary study, we observed BFV decrease in ICA stenotic disease and moyamoya disease, and BFV increase in cerebral aneurysm. This novel 4D-MRA method to measure BFV may become a promising tool for pathophysiological evaluation of cerebrovascular diseases.

Increased intravitreal adenosine 5'-triphosphate, adenosine 5'-diphosphate and adenosine 5'-monophosphate levels in patients with proliferative diabetic retinopathy.

Extracellular purines play important role in ocular physiology, diabetes, vascular remodelling and adaptation to inflammation. This study was aimed to evaluate intravitreal purine levels in patients with diabetic retinopathy (DR) and other non-vascular vitreoretinal eye diseases. Vitreous samples were collected at the start of the three-port pars plana vitrectomy. Study group comprised 55 eyes operated due to sight-threatening forms of DR, including eyes of 24 patients with proliferative DR. Of the 143 non-diabetic controls, 112 had rhegmatogenous retinal detachment and 31 macular hole or pucker. Intravitreal purine concentrations were determined using a combination of bioluminescent [adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP)] and fluorometric [adenosine 5'-monophosphate (AMP), adenosine, inosine] enzyme-coupled sensing assays. Compared with non-diabetic controls, DR eyes contained significantly higher (p < 0.01) concentrations of ATP (4.2 ± 0.6 versus 34.5 ± 13.7 nm; mean ± SEM), ADP (19.5 ± 2.7 versus 43.7 ± 14.5 nm) and AMP (1290 ± 115 versus 1876 ± 190 nm). Intravitreal adenosine and inosine levels varied within submicromolar to low micromolar range, and their concentrations did not differ between the groups studied. High concentrations of intravitreal nucleotides ATP, ADP and AMP may be related to the pathogenesis of sight-threatening forms of DR.

Biomarker Profiling by Nuclear Magnetic Resonance Spectroscopy for the Prediction of All-Cause Mortality: An Observational Study of 17,345 Persons

Early identification of ambulatory persons at high short-term risk of death could benefit targeted prevention. To identify biomarkers for all-cause mortality and enhance risk prediction, we conducted high-throughput profiling of blood specimens in two large population-based cohorts. 106 candidate biomarkers were quantified by nuclear magnetic resonance spectroscopy of non-fasting plasma samples from a random subset of the Estonian Biobank (n = 9,842; age range 18-103 y; 508 deaths during a median of 5.4 y of follow-up). Biomarkers for all-cause mortality were examined using stepwise proportional hazards models. Significant biomarkers were validated and incremental predictive utility assessed in a population-based cohort from Finland (n = 7,503; 176 deaths during 5 y of follow-up). Four circulating biomarkers predicted the risk of all-cause mortality among participants from the Estonian Biobank after adjusting for conventional risk factors: alpha-1-acid glycoprotein (hazard ratio [HR] 1.67 per 1-standard deviation increment, 95% CI 1.53-1.82, p = 5×10⁻³¹), albumin (HR 0.70, 95% CI 0.65-0.76, p = 2×10⁻¹⁸), very-low-density lipoprotein particle size (HR 0.69, 95% CI 0.62-0.77, p = 3×10⁻¹²), and citrate (HR 1.33, 95% CI 1.21-1.45, p = 5×10⁻¹⁰). All four biomarkers were predictive of cardiovascular mortality, as well as death from cancer and other nonvascular diseases. One in five participants in the Estonian Biobank cohort with a biomarker summary score within the highest percentile died during the first year of follow-up, indicating prominent systemic reflections of frailty. The biomarker associations all replicated in the Finnish validation cohort. Including the four biomarkers in a risk prediction score improved risk assessment for 5-y mortality (increase in C-statistics 0.031, p = 0.01; continuous reclassification improvement 26.3%, p = 0.001). Biomarker associations with cardiovascular, nonvascular, and cancer mortality suggest novel systemic connectivities across seemingly disparate morbidities. The biomarker profiling improved prediction of the short-term risk of death from all causes above established risk factors. Further investigations are needed to clarify the biological mechanisms and the utility of these biomarkers for guiding screening and prevention.

ROLE OF TRANS-CATHETER EMBOLIZTAION OF UTERINE ARTERY IN UTERINE BLEEDING

Background: Abnormal uterine bleeding in terms of menstrual disorders and postmenopausal bleeding are common clinical problems in both primary and secondary care. Advances in diagnostic and therapeutic technologies have offered opportunities to improve the outcomes of women suffering with these complaints. Interventional radiology is a relatively new, exciting and rapidly evolving subspecialty of radiology in which both vascular and non-vascular diseases are treated by minimally invasive approaches. Uterine-artery embolization was introduced as an alternative technique for treating cases with vaginal bleeding . Since then it has become increasingly accepted as a minimally invasive, uterine-sparing procedure Aim of the work: The aim of this work is to evaluate role of trans-arterial embolization of uterine artery in uterine bleeding . Patients and methods: The study was carried out on twenty patients suffering from uterine bleeding for different causes. Those patient undergoes pelic us ( trans abdominal & trans vaginal ) , Doppler Us exam & in some cases MRI to determine cause of abnormal uterine bleeding before the embolization. Then after embolization those patient had been followed up for 6 months with pelvic UD & Doppler . In 7 patient interstitial fibroids was diagnosed as the cause of the abnormal uterine bleeding . other 6 patient uterine AVM ( all of them after gynecological procedure ) was the cause. In the rest ( 7 patient ) no specific lesion was diagnosed by US or MRI only increased vascularity of the uterus was detected by the Doppler exam. Results: The most common presenting symptoms of the patients abnormal bleeding, were anemia, low back pain, had frequency of micturition and dyspareunia .All our 20 patient had marked improvement – most shows disappearance of symptoms - after the procedure. All severs from post embolization syndrome ( nausea, vomiting & abdominal pain ).No major complication had occurred for any of our patient. Conclusion: UAE is the best treatment for abnormal uterine bleeding that not only stop the bleeding but also preserve uterus & can keep the patient fertile for further conception. UAE is save & has no major complication , however , it’s a high coast technique. Keywords: uterine bleeding , Fibroids , embolization.

Imaging of the cavernous sinus lesions

This educational paper reviews the normal anatomy of the cavernous sinus (CS) and the imaging findings of common and uncommon lesions of this region. CS lesions may arise from different components of the CS or from adjacent structures and spaces. They can be classified as tumoral, inflammatory/infectious, vascular and congenital. Tumoral lesions include benign (meningiomas, pituitary adenomas, schwannomas) and malignant neoplasms (chondrosarcomas, chordomas, nasopharyngeal carcinomas, leukemia, metastases). Inflammatory/infectious conditions comprise: Tolosa Hunt, abscess, Lemierre syndrome and thrombophlebitis. Vascular lesions include: hemangiomas, carotido-cavernous fistula, aneurysms, arteriovenous malformations. Congenital conditions include the epidermoid cyst, dermoid cyst and fatty deposits. Although imaging features of non-vascular CS diseases are most often non-specific, careful analysis of the adjacent structures suggests the correct diagnosis. In vascular pathology, characteristic MR imaging findings are observed.