BACKGROUND

Evaluation of patients who present to the hospital with a complaint of chest pain or other signs or symptoms suggestive of acute coronary syndrome (ACS) is time-consuming, expensive, and problematic. Recent investigations have indicated that increases in biomarkers upstream from biomarkers of necrosis (cardiac troponins I and T), such as inflammatory cytokines, cellular adhesion molecules, acute-phase reactants, plaque destabilization and rupture biomarkers, biomarkers of ischemia, and biomarkers of myocardial stretch may provide earlier assessment of overall patient risk and aid in identifying patients with higher risk of an adverse event.

UNASSIGNED

The purpose of this review is to provide an overview of the pathophysiology and clinical and analytical characteristics of several biomarkers that may have potential clinical utility to identify ACS patients. These biomarkers (myeloperoxidase, metalloproteinase-9, soluble CD40 ligand, pregnancy-associated plasma protein A, choline, ischemia-modified albumin, unbound free fatty acids, glycogen phosphorylase isoenzyme BB, and placental growth factor) have demonstrated promise and need to be more thoroughly evaluated for commercial development for implementation into routine clinical and laboratory practice.

CONCLUSIONS

Specifications that have been addressed for cardiac troponins and natriuretic peptides will need to be addressed with the same scrutiny for the biomarkers discussed in this review. They include validating analytical imprecision and detection limits, calibrator characterization, assay specificity and standardization, pre-analytical issues, and appropriate reference interval studies. Crossing boundaries from research to clinical application will require replication in multiple settings and experimental evidence supporting a pathophysiologic role and, ideally, interventional trials demonstrating that monitoring single or multiple biomarkers improves outcomes.

Cardiovascular diseases are a leading cause of mortality and morbidity worldwide, with hypertension being a major risk factor. Numerous studies support the contribution of reactive oxygen and nitrogen species in the pathogenesis of hypertension, as well as other pathologies associated with ischemia/reperfusion. However, the validation of oxidative stress-related biomarkers in these settings is still lacking and novel association of these biomarkers and other biomarkers such as endothelial progenitor cells, endothelial microparticles, and ischemia modified albumin, is just emerging. Oxidative stress has been suggested as a pathogenic factor and therapeutic target in early stages of essential hypertension. Systolic and diastolic blood pressure correlated positively with plasma F2-isoprostane levels and negatively with total antioxidant capacity of plasma in hypertensive and normotensive patients. Cardiac surgery with extracorporeal circulation causes an ischemia/reperfusion event associated with increased lipid peroxidation and protein carbonylation, two biomarkers associated with oxidative damage of cardiac tissue. An enhancement of the antioxidant defense system should contribute to ameliorating functional and structural abnormalities derived from this metabolic impairment. However, data have to be validated with the analysis of the appropriate oxidative stress and/or nitrosative stress biomarkers.

BACKGROUND

Diagnosis of cardiac ischaemia in patients attending emergency departments (ED) with symptoms of acute coronary syndromes is often difficult. Cardiac troponin (cTn) is sensitive and specific for the detection of myocardial damage but may not rise during reversible myocardial ischaemia. Ischemia Modified Albumin (IMA) has recently been shown to be a sensitive and early biochemical marker of ischaemia.

RESULTS

This study evaluated IMA in conjunction with ECG and cTn in 208 patients presenting to the ED within three hours of acute chest pain. At presentation, a 12-lead ECG was recorded and blood taken for IMA and cardiac troponin T (cTnT). Patients underwent standardised triage, diagnostic procedures, and treatment. Results of IMA, ECG, and cTnT, alone and in combination, were correlated with final diagnoses of non-ischaemic chest pain, unstable angina, ST segment elevation, and non-ST segment elevation myocardial infarction. In the whole patient group, sensitivity of IMA at presentation for an ischaemic origin of chest pain was 82%, compared with 45% of ECG and 20% of cTnT. IMA used together with cTnT or ECG, had a sensitivity of 90% and 92%, respectively. All three tests combined identified 95% of patients whose chest pain was attributable to ischaemic heart disease. In patients with unstable angina, sensitivity of IMA used alone was equivalent to that of IMA and ECG combined.

CONCLUSIONS

IMA is highly sensitive for the diagnosis of myocardial ischaemia in patients presenting with symptoms of acute chest pain.

Albumin concentration is diminished in patients with liver failure. Albumin infusion improves survival of cirrhotic patients with spontaneous bacterial peritonitis, and it is hypothesized that this may be due in part to its detoxifying capabilities. The aim of this study was to perform detailed quantitative and qualitative assessment of albumin function in patients with cirrhosis. Healthy controls and patients with acute deterioration of cirrhosis requiring hospital admission (n = 34) were included. Albumin function was assessed using affinity of the fatty acid binding sites using a spin label (16 doxyl-stearate) titration and electron paramagnetic resonance spectroscopy and ischemia-modified albumin (IMA) was measured. Twenty-two patients developed acute-on-chronic liver failure. Twelve were treated with the Molecular Adsorbents Recirculating System (MARS) and 10 with standard medical therapy. For each parameter measured, the patients' albumin had reduced functional ability, which worsened with disease severity. Fifteen patients died, and IMA, expressed as an albumin ratio (IMAR), was significantly higher in nonsurvivors compared with survivors (P < 0.001; area under the receiver operating curve = 0.8). No change in the patients' albumin function was observed following MARS therapy. A significant negative correlation between IMAR and the fatty acid binding coefficients for sites 1 and 2 (P < 0.001 for both) was observed, indicating possible sites of association on the protein.

CONCLUSIONS

The results of this study suggests marked dysfunction of albumin function in advanced cirrhosis and provide further evidence for damage to the circulating albumin, which is not reversed by MARS therapy. IMAR correlates with disease severity and may have prognostic use in acute-on-chronic liver failure.

OBJECTIVE

We have recently shown high-dose human serum albumin therapy to confer marked histological protection in experimental middle cerebral artery occlusion (MCAo). We have now used diffusion-weighted magnetic resonance imaging (DWI) in conjunction with morphological methods to expand our understanding of this therapeutic approach.

METHODS

Physiologically controlled Sprague-Dawley rats received 2-hour MCAo by the modified intraluminal suture method. Treated rats received 25% human serum albumin solution (1% by body weight) immediately after the MCA was reopened. Vehicle-treated rats received saline. Computer-based image averaging was used to analyze DWI data obtained 24 hours after MCAo and light-microscopic histopathology obtained at 3 days. In a matched series, plasma osmolality and colloid oncotic pressure, as well as brain water content, were determined.

RESULTS

Albumin therapy, which lowered the hematocrit on average by 37% and raised plasma colloid oncotic pressure by 56%, improved the neurological score throughout the 3-day survival period. Within the ischemic focus, the apparent diffusion coefficient (ADC) computed from DWI data declined by 40% in vehicle-treated rats but was preserved at near-normal levels (8% decline) in albumin-treated rats (P<0.001). Albumin also led to higher ADC values within unlesioned brain regions. Histology revealed large consistent cortical and subcortical infarcts in vehicle-treated rats, while albumin therapy reduced infarct volume at these sites, on average, by 84% and 33%, respectively. Total infarct volume was reduced by 66% and brain swelling was virtually eliminated by albumin treatment. Microscopically, while infarcted regions of vehicle-treated rats had the typical changes of pannecrosis, infarcted zones of albumin-treated brains showed persistence of vascular endothelium and prominent microglial activation, suggesting that albumin therapy may help to preserve the neuropil within zones of residual infarction.

CONCLUSIONS

These findings confirm the striking neuroprotective efficacy of albumin therapy in focal cerebral ischemia and reveal that this effect is associated with DWI normalization and a mitigation of pannecrotic changes within zones of residual injury.

OBJECTIVE

The aim of this study was to evaluate the association between ischemia-modified albumin (IMA), lipids and inflammation biomarkers in patients with hypercholesterolemia, and the possible involvement of IMA in atheromatous plaque development and oxidative stress.

METHODS

Glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, oxidized LDL (ox-LDL), ox-LDL autoantibodies, high-sensitivity C reactive protein (hs-CRP), and IMA were measured in 37 subjects with hypercholesterolemia and 37 controls.

RESULTS

Total cholesterol, LDL cholesterol, triglycerides, ox-LDL, ox-LDL autoantibodies, hs-CRP, and IMA were higher in the hypercholesterolemia group, and HDL cholesterol levels were lower in this group. We observed significant correlations between IMA and total cholesterol, LDL cholesterol, ox-LDL antibodies, and hs-CRP levels. Significant correlations were also observed between hs-CRP and total cholesterol, HDL cholesterol, LDL cholesterol, ox-LDL, ox-LDL autoantibodies, and triglycerides.

CONCLUSIONS

Hypercholesterolemia is associated with an increase in inflammatory and oxidative stress biomarkers, and it also reduces the capacity of albumin to bind cobalt owing to ischemia, resulting in an increased IMA. IMA formation appears to be associated with oxidative stress and atheromatous plaque development.

Suppression of angiogenesis during diabetes is a recognized phenomenon but is less appreciated within the context of diabetic retinopathy. The current study has investigated regulation of retinal angiogenesis by diabetic serum and determined if advanced glycation end products (AGEs) could modulate this response, possibly via AGE-receptor interactions. A novel in vitro model of retinal angiogenesis was developed and the ability of diabetic sera to regulate this process was quantified. AGE-modified serum albumin was prepared according to a range of protocols, and these were also analyzed along with neutralization of the AGE receptors galectin-3 and RAGE. Retinal ischemia and neovascularization were also studied in a murine model of oxygen-induced proliferative retinopathy (OIR) in wild-type and galectin-3 knockout mice (gal3(-/-)) after perfusion of preformed AGEs. Serum from nondiabetic patients showed significantly more angiogenic potential than diabetic serum (P < 0.0001) and within the diabetic group, poor glycemic control resulted in more AGEs but less angiogenic potential than tight control (P < 0.01). AGE-modified albumin caused a dose-dependent inhibition of angiogenesis (P < 0.001), and AGE receptor neutralization significantly reversed the AGE-mediated suppression of angiogenesis (P < 0.01). AGE-treated wild-type mice showed a significant increase in inner retinal ischemia and a reduction in neovascularization compared with non-AGE controls (P < 0.001). However, ablation of galectin-3 abolished the AGE-mediated increase in retinal ischemia and restored the neovascular response to that seen in controls. The data suggest a significant suppression of angiogenesis by the retinal microvasculature during diabetes and implicate AGEs and AGE-receptor interactions in its causation.

BACKGROUND

Ischemia modified albumin (IMA; Ischemia Technologies, Inc) blood levels rise in patients who develop ischemia during percutaneous coronary intervention (PCI). It is not known whether IMA elevations correlate with increases in other markers of oxidative stress, ie, 8-iso prostaglandin F2-A (iP).

RESULTS

We compared IMA versus iP plasma levels in 19 patients (mean age 62.8+/-11.9 years) undergoing PCI and 11 patients (mean age 64+/-13.6 years) undergoing diagnostic angiography (controls). In the PCI patients, blood samples for IMA and iP were taken from the guide catheter before PCI and after balloon inflations, and from the femoral sheath 30 minutes after PCI. IMA was measured by the albumin cobalt binding (ACB) test and plasma iP by enzyme immunoassay. During PCI, all 19 patients had chest pain and 18 had transient ischemic ST segment changes. IMA was elevated from baseline in 18 of the 19 patients after PCI. Median IMA levels were higher after PCI (101.4 U/mL, 95%CI 82 to 116) compared with baseline (72.8 U/mL, CI 55 to 93; P<0.0001). Levels remained elevated at 30 minutes (87.9 U/mL, CI 78 to 99; P<0.0001) and returned to baseline at 12 hours (70.3 U/mL, CI 65 to 87; P=0.65). iP levels were raised after PCI in 9 of the 19 patients. However, median iP levels were not significantly different immediately (P=0.6) or 30 minutes after PCI (P=0.1). In the control group, IMA and iP levels remained unchanged before and after angiography (P=0.2 and 0.16, respectively).

CONCLUSIONS

IMA is a more consistent marker of ischemia than iP in patients who develop chest pain and ST segment changes during PCI.

Acute coronary syndrome (ACS) is a significant cause of morbidity and mortality worldwide. The proper diagnosis of ACS requires reliable and accurate biomarker assays to detect evidence of myocardial necrosis. Currently, troponin is the gold standard biomarker for myocardial injury and is used commonly in conjunction with creatine kinase-MB (CK-MB) and myoglobin to enable a more rapid diagnosis of ACS. A new generation of highly sensitive troponin assays with improved accuracy in the early detection of ACS is now available, but the correct interpretation of assay results will require a careful consideration of assay characteristics and the clinical setting prior to incorporation into routine practice. B-type natriuretic peptides, copeptin, ischemia-modified albumin, heart-type fatty-acid-binding protein, myeloperoxidase, C-reactive protein, choline, placental growth factor, and growth-differentiation factor-15 make up a promising group of other biomarkers that have shown the ability to improve prognosis and diagnosis of ACS compared with traditional markers.

BACKGROUND

Previous studies have demonstrated that ischemia-modified albumin (IMA) is a useful marker for the diagnosis of ischemic events. It was also recently demonstrated that IMA levels increase in the acute phase of cerebrovascular diseases. Yet the data regarding IMA levels in various types of cerebrovascular events are insufficient. The aim of this study was to evaluate IMA levels in various types of cerebrovascular events such as ischemic stroke, subarachnoid hemorrhage (SAH), and intracranial hemorrhage.

METHODS

This case-controlled study consisted of 106 consecutive patients, 43 with brain infarction (BI), 11 with brain hemorrhage (ICH), 52 with SAH, and a 43-member control group. We investigated whether there was a statistical correlation between these 3 groups and the control group. The relations among the 3 groups were also examined. Comparisons among groups were done with analysis of variance.

RESULTS

Mean serum IMA levels were 0.280 +/- 0.045 absorbance units (ABSU) for BI patients, 0.259 +/- 0.053 ABSU for ICH patients, 0.243 +/- 0.061 ABSU for SAH patients, and 0.172 +/- 0.045 ABSU for the control group.There was a statistically significant difference between the mean IMA levels of BI, ICH, and SAH patients and the mean control patient IMA levels (P b .0001).

CONCLUSIONS

Ischemia-modified albumin levels are high in cerebrovascular diseases. Ischemia-modified albumin measurement can also be used to distinguish SAH from BI during the acute phase of cerebrovascular event in the emergency department.

BACKGROUND

Current practice for suspected acute coronary syndrome (ACS) involves troponin testing 10-12 hours after symptom onset to diagnose myocardial infarction (MI). Patients with a negative troponin can be investigated further with computed tomographic coronary angiography (CTCA) or exercise electrocardiography (ECG).

OBJECTIVE

We aimed to estimate the diagnostic accuracy of early biomarkers for MI, the prognostic accuracy of biomarkers for major adverse cardiac adverse events (MACEs) in troponin-negative patients, the diagnostic accuracy of CTCA and exercise ECG for coronary artery disease (CAD) and the prognostic accuracy of CTCA and exercise ECG for MACEs in patients with suspected ACS. We then aimed to estimate the cost-effectiveness of using alternative biomarker strategies to diagnose MI, and using biomarkers, CTCA and exercise ECG to risk-stratify troponin-negative patients.

METHODS

We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations; Cumulative Index of Nursing and Allied Health Literature (CINAHL), EMBASE, Web of Science, Cochrane Central Database of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), NHS Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment database from 1985 (CTCA review) or 1995 (biomarkers review) to November 2010, reviewed citation lists and contacted experts to identify relevant studies.

METHODS

Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool and prognostic studies using a framework adapted for the project. Meta-analysis was conducted using bayesian Markov chain Monte Carlo simulation. We developed a decision-analysis model to evaluate the cost-effectiveness of alternative biomarker strategies to diagnose MI, and the cost-effectiveness of biomarkers, CTCA or exercise ECG to risk-stratify patients with a negative troponin. Strategies were applied to a theoretical cohort of patients with suspected ACS. Cost-effectiveness was estimated as the incremental cost per quality-adjusted life-year (QALY) of each strategy compared with the next most effective, taking a health-service perspective and a lifetime horizon.

RESULTS

Sensitivity and specificity (95% predictive interval) were 77% (29-96%) and 93% (46-100%) for troponin I, 80% (33-97%) and 91% (53-99%) for troponin T (99th percentile threshold), 81% (50-95%) and 80% (26-98%) for quantitative heart-type fatty acid-binding protein (H-FABP), 68% (11-97%) and 92% (20-100%) for qualitative H-FABP, 77% (19-98%) and 39% (2-95%) for ischaemia-modified albumin and 62% (35-83%) and 83% (35-98%) for myoglobin. CTCA had 94% (61-99%) sensitivity and 87% (16-100%) specificity for CAD. Positive CTCA and positive-exercise ECG had relative risks of 5.8 (0.6-24.5) and 8.0 (2.3-22.7) for MACEs. In most scenarios in the economic analysis presentation, high-sensitivity troponin measurement was the most effective strategy with an incremental cost-effectiveness ratio (ICER) of less than the £20,000-30,000/QALY threshold (ICER £7487-17,191/QALY). CTCA appeared to be the most cost-effective strategy for patients with a negative troponin, with an ICER of £11,041/QALY. However, when a lower MACE rate was assumed, CTCA had a high ICER (£262,061/QALY) and the no-testing strategy was optimal.

CONCLUSIONS

There was substantial variation between the primary studies and heterogeneity in their results. Findings of the economic model were dependent on assumptions regarding the value of detecting and treating positive cases.

CONCLUSIONS

Although presentation troponin has suboptimal sensitivity, measurement of a 10-hour troponin level is unlikely to be cost-effective in most scenarios compared with a high-sensitivity presentation troponin. CTCA may be a cost-effective strategy for troponin-negative patients, but further research is required to estimate the effect of CTCA on event rates and health-care costs.

BACKGROUND

The National Institute for Health Research Health Technology Assessment programme.

OBJECTIVE

Nitric oxide (NO) exerts both protective and detrimental actions in a variety of biological systems. During acute reperfusion following myocardial ischaemia, a rapid overproduction of free radicals, including NO, may occur. We investigated the effects of the NO synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME) and NG-monomethyl-L-arginine (L-NMMA), and the substrate for NO synthesis, L-arginine, on heart function during ischaemia and reperfusion injury.

METHODS

Spontaneously beating, isolated working rabbit hearts, perfused with modified Krebs-Henseleit buffer containing 1.2 mM palmitate bound to 3% bovine serum albumin, were subjected to 15 min of aerobic perfusion followed by 35 min of global, no-flow ischaemia and 30 min of aerobic reperfusion.

RESULTS

Throughout the reperfusion period there was a marked impairment in the recovery of mechanical function, measured as the product of heart rate x peak systolic pressure (rate-pressure product). Addition of L-NAME (3 microM) prior to the onset of ischaemia, but not at reperfusion, caused an immediate and significant increase in the recovery of mechanical function throughout the reperfusion period. The protective action of L-NAME was abolished by L- (but not D-) arginine (100 microM). L-NAME did not cause ischaemia as it did not alter glycogen or lactate content of aerobically perfused hearts. Furthermore, it did not prevent glycogen loss or lactate accumulation during 35 min of ischaemia, suggesting that the effects of L-NAME were not due to metabolic alterations during ischaemia itself. L-NMMA (30 microM) added prior to ischaemia, but not at reperfusion, also had a protective effect which was seen later in the reperfusion period. Addition of L- (but not D-) arginine (100 microM) prior to the onset of ischaemia resulted in an improved recovery of mechanical function only at 15 min of reperfusion.

CONCLUSIONS

These results suggest that: (1) the recovery of mechanical function of hearts subjected to ischaemia-reperfusion injury can be improved by modulation of myocardial NO synthesis, (2) inhibition of NO synthesis (with L-NAME or L-NMMA) may offer prolonged protection whereas its stimulation (with L-arginine) provides only brief protection, and (3) the reasons for the pharmacological effectiveness of these divergent strategies may be due to the formation of peroxynitrite from NO and superoxide anion during reperfusion.

OBJECTIVE

To develop contemporary, comprehensive guidelines for the appropriate and efficient use of albumin, nonprotein colloid, and crystalloid solutions.

METHODS

A systematic, literature-based, consensus exercise employing a modified Delphi method.

METHODS

Thirty-one medical and allied health professionals from 26 University Hospital Consortium (Oak Brook, Ill) member institutions were initially chosen to participate. Participants were selected on the basis of their recognized research in the use of albumin, nonprotein colloid, and crystalloid solutions, and/or experience in the review of appropriateness of such use. A total of 24 participants completed the exercise.

METHODS

Group responses were statistically analyzed in an iterative consensus development process. Five separate questionnaire rounds were designed to establish criteria for the appropriate use of albumin, nonprotein colloid, and crystalloid solutions.

RESULTS

Consensus guidelines were developed outlining the appropriate use of these products for 12 clinical indications, including hemorrhagic shock, nonhemorrhagic (maldistributive) shock, hepatic resection, thermal injury, cerebral ischemia, nutritional intervention, cardiac surgery, hyperbilirubinemia of the newborn, cirrhosis and paracentesis, nephrotic syndrome, organ transplantation, and plasmapheresis.

CONCLUSIONS

The Delphi method, a systematic, literature-based consensus process, was shown to be useful in the development of complex clinical practice guidelines for the use of albumin, nonprotein colloid, and crystalloid solutions. It is anticipated that the guidelines will assist health care providers to develop local institutional policies and procedures for the appropriate and efficient use of albumin and albumin alternatives. Institutions reviewing and updating existing local guidelines may use the University Hospital Consortium guidelines as a model for comparison.

OBJECTIVE

AGEs have been implicated in renal disease associated with ageing, diabetes and other age-related disorders. Reactive oxygen species (ROS) promote formation of AGEs, which cause AGE-receptor-mediated ROS generation with activation of signalling pathways leading to tissue injury and further AGE accumulation. ROS generation is regulated by the Src homology 2 domain-containing transforming protein C1 (Shc1) isoform p66(Shc), whose deletion has been shown to protect from tissue injury induced by ageing, diabetes, hyperlipidaemia and ischaemia-reperfusion by preventing oxidative stress. This study was aimed at assessing the role of p66(Shc) in the modulation of oxidative stress and oxidant-dependent renal injury induced by AGEs.

METHODS

For 10 weeks, male p66 (shc) knockout (KO) and wild-type (WT) mice were injected with 60 microg/day albumin modified or unmodified by N epsilon-(carboxymethyl) lysine (CML). Mice were then killed for the assessment of renal function and structure, as well as systemic and renal tissue oxidative stress.

RESULTS

Upon CML injection, KO mice, in contrast to WT mice, showed no or only mild forms of proteinuria, glomerular hypertrophy, mesangial expansion, glomerular sclerosis, renal/glomerular cell apoptosis and extracellular matrix upregulation. Moreover, KO mice had lower circulating and tissue AGEs than WT mice and unchanged plasma isoprostane 8-epi-prostaglandin-F(2alpha) levels, renal/glomerular CML, 4-hydroxy-2-nonenal, AGE receptor and NAD(P)H oxidase 4 (NOX4) content (and expression of the corresponding genes), and nuclear factor kappaB activation (NFkappaB). Mesangial cells from KO mice exposed to CML showed no or slight increase in ROS levels and NFkappaB activation, again at variance with WT cells.

CONCLUSIONS

These data indicate that p66(Shc) participates in the pathogenesis of AGE-dependent glomerulopathy by mediating AGE-induced tissue injury and further AGE formation through ROS-dependent mechanisms involving NFkappaB activation and upregulation of Nox4 expression and NOX4 production.

BACKGROUND

Ischemia-modified albumin (IMA)is a new biological marker of ischemia. Previous studies have found increased serum IMA levels after myocardial ischemia, but no study has investigated the possibility that stroke modifies IMA blood levels.

METHODS

We studied 118 consecutive patients presenting within 3 h of the onset of an acute neurological deficit [84 brain infarctions (BI), 18 brain hemorrhages (ICH) and 16 transient ischemic attacks lasting less than 1 h or epileptic seizures]. Serum samples were obtained for all patients at initial presentation and repeated only in patients with stroke at 6, 12 and 24 h. IMA was measured by the albumin-cobalt-binding test (Ischemia Technologies, Denver, Colo., USA).

RESULTS

The initial median IMA (bootstrap 95% confidence interval, CI) was 83 U/ml (79-86) and 86 U/ml (75-90) in patients with BI and ICH, respectively (p = 0.76), and was 73 U/ml (58-79) in others (p = 0.003 compared with BI, and p = 0.017 with ICH). Baseline IMA levels correlated with the National Institutes of Health Stroke Scale [Spearman correlation coefficient: 0.34 (p = 0.002) in BI, 0.61 (p = 0.008) in ICH]. During the first 24 h, IMA levels increased in BI patients (median, 9.1%; bootstrap 95% CI, 5.2-11.5), whereas no change was observed in ICH patients (median, 1.2%; bootstrap 95% CI, -7.8 to 6.8).

CONCLUSIONS

IMA blood levels may be a biomarker for early identification of acute stroke. Further studies are required to investigate the role of IMA in the early detection of acute stroke.

BACKGROUND

Maternal perception of reduced fetal movement (RFM) is associated with increased risk of stillbirth and fetal growth restriction (FGR). RFM is thought to represent fetal compensation to conserve energy due to insufficient oxygen and nutrient transfer resulting from placental insufficiency.

OBJECTIVE

To identify predictors of poor perinatal outcome after maternal perception of reduced fetal movements (RFM).

METHODS

Prospective cohort study.

METHODS

305 women presenting with RFM after 28 weeks of gestation were recruited. Demographic factors and clinical history were recorded and ultrasound performed to assess fetal biometry, liquor volume and umbilical artery Doppler. A maternal serum sample was obtained for measurement of placentally-derived or modified proteins including: alpha fetoprotein (AFP), human chorionic gonadotrophin (hCG), human placental lactogen (hPL), ischaemia-modified albumin (IMA), pregnancy associated plasma protein A (PAPP-A) and progesterone. Factors related to poor perinatal outcome were determined by logistic regression.

RESULTS

22.1% of pregnancies ended in a poor perinatal outcome after RFM. The most common complication was small-for-gestational age infants. Pregnancy outcome after maternal perception of RFM was related to amount of fetal activity while being monitored, abnormal fetal heart rate trace, diastolic blood pressure, estimated fetal weight, liquor volume, serum hCG and hPL. Following multiple logistic regression abnormal fetal heart rate trace (Odds ratio 7.08, 95% Confidence Interval 1.31-38.18), (OR) diastolic blood pressure (OR 1.04 (95% CI 1.01-1.09), estimated fetal weight centile (OR 0.95, 95% CI 0.94-0.97) and log maternal serum hPL (OR 0.13, 95% CI 0.02-0.99) were independently related to pregnancy outcome. hPL was related to placental mass.

CONCLUSIONS

Poor perinatal outcome after maternal perception of RFM is closely related to factors which are connected to placental dysfunction. Novel tests of placental function and associated fetal response may provide improved means to detect fetuses at greatest risk of poor perinatal outcome after RFM.

Ischemia modified albumin (IMA), as measured using the albumin cobalt binding test, is currently the most promising biomarker for early detection of ischemia before the onset of irreversible cardiac injury. This paper reviews the information available on IMA, including its pathophysiology, analysis, clinical applications and future perspectives. The data provided was identified by a search of MEDLINE using the terms IMA, biomarkers and ischemia. IMA may be useful to cover the complete diagnostic window of patients presenting with acute coronary syndromes (ACS) in the Emergency Department, along with the electrocardiogram and cardiac troponins. Preliminary data regarding the significance of IMA in the prognosis of either ACS or following revascularization need further study.

OBJECTIVE

Animal studies showed that human albumin therapy is strongly neuroprotective in focal ischemia. The aim of our study was to determine if relatively high serum albumin level is associated with decreased risk of poor outcome in ischemic stroke patients.

METHODS

Seven hundred fifty-nine consecutive patients with acute ischemic stroke were included. Functional outcome was measured 3 months after stroke using modified Rankin Scale (mRS). Poor outcome was defined as mRS >3 or death. Serum albumin level was measured within 36 hours after stroke onset.

RESULTS

Patients with poor outcome had significantly lower serum albumin level than patients with nonpoor outcome (34.1+/-7.4 versus 36.8+/-6.7 g/L). On logistic regression analysis, serum albumin level remained independent predictor of poor outcome (odds ratio [OR]: 0.43; 95% confidence interval [CI]: 0.26 to 0.70).

CONCLUSIONS

Relatively high serum albumin level in acute stroke patients decreases the risk of poor outcome.

OBJECTIVE

To clarify the presence of oxidative stress in patients with primary angle-closure glaucoma (PACG) and to investigate the relationship between oxidative stress and PACG.

METHODS

Fifty patients with primary angle-closure glaucoma and fifty healthy controls of matched age and gender were included in the study prospectively. Serum samples were obtained to detect the oxidation degradation products malondialdehyde (MDA), conjugated diene (CD), 4-hydroxynonenal (4-HNE), advanced oxidation protein products (AOPP), protein carbonyl (PC), ischemia-modified albumin (IMA) and 8-hydroxydeoxyguanosin (8-OHdG).

RESULTS

The concentration of MDA and CD in PACG patients was significantly higher than those of the control subjects (P<0.05, P<0.01). The serum 4-HNE concentrations were increased in PACG patients, but the differences with those of the healthy controls were not statistically significant. Compared to normal subjects, there was significant higher in serum AOPP and PC in PACG patients (P<0.01). PACG patients had higher levels of 8-OHdG in serum with respect to the comparative group of normal subjects (P<0.01). When plasma IMA levels in the PACG group were compared with those in the control group, significant increases in IMA were observed in the former (P<0.05).

CONCLUSIONS

Our study demonstrated that IMA is a new biomarker available for assessing oxidative stress in PCAG. Oxidative stress is an important risk factor in the development of primary angle-closure glaucoma. Increased levels of oxidative stress products may be associated with primary angle-closure glaucoma.

Ischemia-reperfusion (I/R) associated with small-for-size liver transplantation (SFSLT) impairs liver graft regeneration. Mesenchymal stem cells (MSCs) have the capability, under specific conditions, of differentiating into hepatocytes. Hepatocyte growth factor (HGF) has potent anti-apoptotic and mitogenic effects on hepatocytes during liver injury, and has been utilized in many experimental and clinical applications. In this study, we implanted HGF-expressing MSCs into liver grafts via the portal vein, using a 30% small-for-size rat liver transplantation model. HGF, c-met expression, hepatic injury and liver regeneration were assessed after liver transplantation. Our study demonstrated that MSCs over-expressing HGF prevented liver failure and reduced mortality in rats after SFSLT. These animals also exhibited improved liver function and liver weight recovery during the early post-transplantation period. Using green fluorescent protein (GFP) gene as a marker, we demonstrated that the engrafted cells and their progeny incorporated into remnant livers and produced albumin. These findings suggest that MSCs genetically modified to over-express HGF and implanted in the liver graft, may offer a novel approach to promoting liver regeneration after small-for-size transplantations.

BACKGROUND

Early recognition of acute coronary syndrome (ACS) is essential. Cardiac troponins are not consistently elevated within the first hours after symptom onset.

OBJECTIVE

Review current guidelines recommendations regarding biomarkers in the early assessment of ACS and review the evidence for using established and specific new diagnostic biomarkers.

METHODS

MEDLINE and EMBASE.

METHODS

Articles on diagnostic accuracy of ACS biomarkers.

METHODS

Relevance of clinical domain, adequacy of measures of clinical utility and outcome assessment.

RESULTS

The 73 articles identified on early biochemical markers CK-MB, myoglobin, heart-type fatty acid binding protein (H-FABP), ischemia modified albumin (IMA), pregnancy-associated plasma protein A, glycogen phosphorylase isoenzyme BB and myeloid-related protein 8/14 often did not quantify clinical utility correctly.

CONCLUSIONS

IMA and H-FABP seem to be promising biomarkers in the early assessment of ACS. There is an urgent need for adequately designed diagnostic studies of (novel) ACS markers against contemporary troponin assays.

OBJECTIVE

Opioids, including remifentanil, have been demonstrated to confer cardiac protection against ischemia reperfusion injury in animals. This study evaluated whether remifentanil preconditioning is protective in first-time elective on-pump coronary artery bypass surgery patients receiving a standardized fentanyl (25 μg/kg in total) and propofol anesthetic.

METHODS

A prospective, double blind, randomized, controlled study.

METHODS

University hospital; single institution.

METHODS

Forty patients scheduled for first-time elective, on-pump coronary artery bypass surgery for at least 3 diseased vessels.

METHODS

Patients randomized to the remifentanil group (n = 20) received a 1 μg/kg bolus followed by a 0.5 μg/kg/min infusion for 30 minutes after induction but before sternotomy, while the control group (n = 20) received normal saline. Serial samples for measurement of creatine kinase (CK-MB), cardiac troponin I (cTnI), ischemia-modified albumin (IMA) and heart-type fatty-acid-binding protein (hFABP) were taken at baseline, prebypass, T = 10 minutes, 2, 6, 12, and 24 hours after cross-clamp release, to assess the degree of myocardial damage.

RESULTS

Patients in the remifentanil group had lower levels of CK-MB from T = 2 hours to 24 hours, cTnI from T = 10 minutes to T = 12 hours, IMA from T = 10 minutes to T = 2 hours and h-FABP from T = 10 minutes to T = 12 hours (p < 0.05). The time to tracheal extubation was shorter in patients in the remifentanil group. The overall lengths of ICU and hospital stays were not different.

CONCLUSIONS

The addition of remifentanil to the anesthesia regimen reduced the degree of myocardial damage. This incremental benefit may be attributable either to remifentanil itself or to an overall increased opioid dose, the latter may be necessary to trigger cardiac protection.

At present, the risk of myocardial damage by endurance exercise is under debate because of reports on exercise-associated increases in cardiac biomarkers troponin and B-type natriuretic peptide (BNP); these markers are typically elevated in patients with acute myocardial infarction and chronic heart failure, respectively. Exercise-associated elevations of cardiac biomarkers can be present in elite and in recreational athletes, especially after prolonged and strenuous endurance exercise bouts (e.g., marathon and ultratriathlon). However, in contrast to cardiac patients, it is still unclear if the exercise-associated appearance or increase in cardiac biomarkers in obviously healthy athletes represents clinically significant cardiac insult or is indeed part of the physiological response to endurance exercise. In addition, elevations in cardiac biomarkers in athletes after exercise may generate difficulties for clinicians in terms of differential diagnosis and may result in inappropriate consequences. Therefore, the aim of this article is to provide an overview of exercise-associated alterations of the cardiac biomarkers troponin T and I, ischemia-modified albumin, BNP, and its cleaved inactive fragment N-terminal pro BNP for the athlete, coach, scientist, and clinician.