Asymmetrical dimethylarginine (ADMA) in critically ill patients: high plasma ADMA concentration is an independent risk factor of ICU mortality

0.001) and bilirubin (b=0.121, 95% CI: 0.031-0.212; P=0.009) concentration as markers of hepatic function. Twenty-one (40%) patients deceased during their ICU stay. In a logistic regression model, plasma ADMA ranked as the first and strongest predictor for outcome, with a 17-fold (95% CI: 3-100) increased risk for ICU death in patients who were in the highest quartile for ADMA. CONCLUSIONS: In critically ill patients, plasma ADMA concentration is a strong and independent risk factor for ICU mortality, and hepatic dysfunction is the most prominent determinant of ADMA concentration in this population

Asymmetric Dimethylarginine, Endothelial Nitric Oxide Bioavailability and Mortality in Sepsis

Background: Plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxidesynthase, are raised in patients with chronic vascular disease, causing increased cardiovascular risk and endothelialdysfunction, but the role of ADMA in acute inflammatory states is less well defined.Methods and Results: In a prospective longitudinal study in 67 patients with acute sepsis and 31 controls, digitalmicrovascular reactivity was measured by peripheral arterial tonometry and blood was collected at baseline and 2–4 dayslater. Plasma ADMA and L-arginine concentrations were determined by high performance liquid chromatography. Baselineplasma L-arginine: ADMA ratio was significantly lower in sepsis patients (median [IQR] 63 [45–103]) than in hospital controls(143 [123–166], p,0.0001) and correlated with microvascular reactivity (r = 0.34, R2 = 0.12, p = 0.02). Baseline plasma ADMAwas independently associated with 28-day mortality (Odds ratio [95% CI] for death in those in the highest quartile($0.66 mmol/L) = 20.8 [2.2–195.0], p = 0.008), and was independently correlated with severity of organ failure. Increase inADMA over time correlated with increase in organ failure and decrease in microvascular reactivity.Conclusions: Impaired endothelial and microvascular function due to decreased endothelial NO bioavailability is a potentialmechanism linking increased plasma ADMA with organ failure and death in sepsis

Design of the ExCersion-VCI study: The effect of aerobic exercise on cerebral perfusion in patients with vascular cognitive impairment

There is evidence for a beneficial effect of aerobic exercise on cognition, but underlying mechanisms are unclear. In this study, we test the hypothesis that aerobic exercise increases cerebral blood flow (CBF) in patients with vascular cognitive impairment (VCI). This study is a multicenter single-blind randomized controlled trial among 80 patients with VCI. Most important inclusion criteria are a diagnosis of VCI with Mini-Mental State Examination ≥22 and Clinical Dementia Rating ≤0.5. Participants are randomized into an aerobic exercise group or a control group. The aerobic exercise program aims to improve cardiorespiratory fitness and takes 14 weeks, with a frequency of three times a week. Participants are provided with a bicycle ergometer at home. The control group receives two information meetings. Primary outcome measure is change in CBF. We expect this study to provide insight into the potential mechanism by which aerobic exercise improves hemodynamic status

Increased Asymmetric Dimethylarginine in Severe Falciparum Malaria: Association with Impaired Nitric Oxide Bioavailability and Fatal Outcome

Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is a predictor of mortality in critical illness. Severe malaria (SM) is associated with decreased NO bioavailability, but the contribution of ADMA to the pathogenesis of impaired NO bioavailability and adverse outcomes in malaria is unknown. In adults with and without falciparum malaria, we tested the hypotheses that plasma ADMA would be: 1) increased in proportion to disease severity, 2) associated with impaired vascular and pulmonary NO bioavailability and 3) independently associated with increased mortality. We assessed plasma dimethylarginines, exhaled NO concentrations and endothelial function in 49 patients with SM, 78 with moderately severe malaria (MSM) and 19 healthy controls (HC). Repeat ADMA and endothelial function measurements were performed in patients with SM. Multivariable regression was used to assess the effect of ADMA on mortality and NO bioavailability. Plasma ADMA was increased in SM patients (0.85 µM; 95% CI 0.74–0.96) compared to those with MSM (0.54 µM; 95%CI 0.5–0.56) and HCs (0.64 µM; 95%CI 0.58–0.70; p<0.001). ADMA was an independent predictor of mortality in SM patients with each micromolar elevation increasing the odds of death 18 fold (95% CI 2.0–181; p = 0.01). ADMA was independently associated with decreased exhaled NO (rs = −0.31) and endothelial function (rs = −0.32) in all malaria patients, and with reduced exhaled NO (rs = −0.72) in those with SM. ADMA is increased in SM and associated with decreased vascular and pulmonary NO bioavailability. Inhibition of NOS by ADMA may contribute to increased mortality in severe malaria

3.0 T cardiovascular magnetic resonance in patients treated with coronary stenting for myocardial infarction: evaluation of short term safety and image quality

Purpose To evaluate safety and image quality of cardiovascular magnetic resonance (CMR) at 3.0 T in patients with coronary stents after myocardial infarction (MI), in comparison to the clinical standard at 1.5 T. Methods Twenty-five patients (21 men; 55 ± 9 years) with first MI treated with primary stenting, underwent 18 scans at 3.0 T and 18 scans at 1.5 T. Twenty-four scans were performed 4 ± 2 days and 12 scans 125 ± 23 days after MI. Cine (steady-state free precession) and late gadolinium-enhanced (LGE, segmented inversion-recovery gradient echo) images were acquired. Patient safety and image artifacts were evaluated, and in 16 patients stent position was assessed during repeat catheterization. Additionally, image quality was scored from 1 (poor quality) to 4 (excellent quality). Results There were no clinical events within 30 days of CMR at 3.0 T or 1.5 T, and no stent migration occurred. At 3.0 T, image quality of cine studies was clinically useful in all, but not sufficient for quantitative analysis in 44% of the scans, due to stent (6/18 scans), flow (7/18 scans) and/or dark band artifacts (8/18 scans). Image quality of LGE images at 3.0 T was not sufficient for quantitative analysis in 53%, and not clinically useful in 12%. At 1.5 T, all cine and LGE images were quantitatively analyzable. Conclusion 3.0 T is safe in the acute and chronic phase after MI treated with primary stenting. Although cine imaging at 3.0 T is suitable for clinical use, quantitative analysis and LGE imaging is less reliable than at 1.5 T. Further optimization of pulse sequences at 3.0 T is essential

Pilot Study of the Association of the DDAH2 −449G Polymorphism with Asymmetric Dimethylarginine and Hemodynamic Shock in Pediatric Sepsis

Genetic variability in the regulation of the nitric oxide (NO) pathway may influence hemodynamic changes in pediatric sepsis. We sought to determine whether functional polymorphisms in DDAH2, which metabolizes the NO synthase inhibitor asymmetric dimethylarginine (ADMA), are associated with susceptibility to sepsis, plasma ADMA, distinct hemodynamic states, and vasopressor requirements in pediatric septic shock.In a prospective study, blood and buccal swabs were obtained from 82 patients ≤ 18 years (29 with severe sepsis/septic shock plus 27 febrile and 26 healthy controls). Plasma ADMA was measured using tandem mass spectrometry. DDAH2 gene was partially sequenced to determine the -871 6g/7 g insertion/deletion and -449G/C single nucleotide polymorphisms. Shock type ("warm" versus "cold") was characterized by clinical assessment. The -871 7g allele was more common in septic (17%) then febrile (4%) and healthy (8%) patients, though this was not significant after controlling for sex and race (p = 0.96). ADMA did not differ between -871 6g/7 g genotypes. While genotype frequencies also did not vary between groups for the -449G/C SNP (p = 0.75), septic patients with at least one -449G allele had lower ADMA (median, IQR 0.36, 0.30-0.41 µmol/L) than patients with the -449CC genotype (0.55, 0.49-0.64 µmol/L, p = 0.008) and exhibited a higher incidence of "cold" shock (45% versus 0%, p = 0.01). However, after controlling for race, the association with shock type became non-significant (p = 0.32). Neither polymorphism was associated with inotrope score or vasoactive infusion duration.The -449G polymorphism in the DDAH2 gene was associated with both low plasma ADMA and an increased likelihood of presenting with "cold" shock in pediatric sepsis, but not with vasopressor requirement. Race, however, was an important confounder. These results support and justify the need for larger studies in racially homogenous populations to further examine whether genotypic differences in NO metabolism contribute to phenotypic variability in sepsis pathophysiology

Contrast-enhancement cardiac magnetic resonance imaging beyond the scope of viability

The clinical applications of cardiovascular magnetic resonance imaging with contrast enhancement are expanding. Besides the direct visualisation of viable and non-viable myocardium, this technique is increasingly used in a variety of cardiac disorders to determine the exact aetiology, guide proper treatment, and predict outcome and prognosis. In this review, we discuss the value of cardiovascular magnetic resonance imaging with contrast enhancement in a range of cardiac disorders, in which this technique may provide insights beyond the scope of myocardial viability

Prevention of hepatorenal toxicity with Sonchus asper in gentamicin treated rats

<p>Abstract</p> <p>Background</p> <p><it>Sonchus asper </it>possesses antioxidant capacity and is used in liver and kidney disorders. We have investigated the preventive effect of methanolic extract of <it>Sonchus asper </it>(SAME) on the gentamicin induced alterations in biochemical and morphological parameters in liver and kidneys of Sprague-Dawley male rat.</p> <p>Methods</p> <p>Acute oral toxicity studies were performed for selecting the therapeutic dose of SAME. 30 Sprague-Dawley male rats were equally divided into five groups with 06 animals in each. Group I received saline (0.5 ml/kg bw; 0.9% NaCl) while Group II administered with gentamicin 0.5 ml (100 mg/kg bw; i.p.) for ten days. Animals of Group III and Group IV received gentamicin and SAME 0.5 ml at a dose of 100 mg/kg bw and 200 mg/kg bw, respectively while Group V received only SAME at a dose of 200 mg/kg bw. Biochemical parameters including aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-glutamyltransferase (γ-GT), total cholesterol, triglycerides, total protein, albumin, creatinine, blood urea nitrogen (BUN), total bilirubin and direct bilirubin were determined in serum collected from various groups. Urinary out puts were measured in each group and also assessed for the level of protein and glucose. Lipid peroxides (TBARS), glutathione (GSH), DNA injuries and activities of antioxidant enzymes; catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD) were determined in liver and renal samples. Histopathological studies of liver and kidneys were also carried out.</p> <p>Results</p> <p>On the basis of acute oral toxicity studies, 2000 mg/kg bw did not induce any toxicity in rats, 1/10^thof the dose was selected for preventive treatment. Gentamicin increased the level of serum biomarkers; AST, ALT, ALP, LDH, γ-GT, total cholesterol, triglycerides, total protein, albumin, creatinine, BUN, total and direct bilirubin; as were the urinary level of protein, glucose, and urinary output. Lipid peroxidation (TBARS) and DNA injuries increased while GSH contents and activities of antioxidant enzymes; CAT, POD, SOD decreased with gentamicin in liver and kidney samples. SAME administration, dose dependently, prevented the alteration in biochemical parameters and were supported by low level of tubular and glomerular injuries induced with gentamicin.</p> <p>Conclusion</p> <p>These results suggested the preventive role of SAME for gentamicin induced toxicity that could be attributed by phytochemicals having antioxidant and free radical scavenging properties.</p

First-pass perfusion CMR two days after infarction predicts severity of functional impairment six weeks later in the rat heart

<p>Abstract</p> <p>Background</p> <p>In humans, dynamic contrast CMR of the first pass of a bolus infusion of Gadolinium-based contrast agent has become a standard technique to identify under-perfused regions of the heart and can accurately demonstrate the severity of myocardial infarction. Despite the clinical importance of this method, it has rarely been applied in small animal models of cardiac disease. In order to identify perfusion delays in the infarcted rat heart, here we present a method in which a T₁weighted MR image has been acquired during each cardiac cycle.</p> <p>Methods and results</p> <p>In isolated perfused rat hearts, contrast agent infusion gave uniform signal enhancement throughout the myocardium. Occlusion of the left anterior descending coronary artery significantly reduced the rate of signal enhancement in anterior regions of the heart, demonstrating that the first-pass method was sensitive to perfusion deficits. <it>In vivo </it>measurements of myocardial morphology, function, perfusion and viability were made at 2 and 8 days after infarction. Morphology and function were further assessed using cine-MRI at 42 days. The perfusion delay was larger in rat hearts that went on to develop greater functional impairment, demonstrating that first-pass CMR can be used as an early indicator of infarct severity. First-pass CMR at 2 and 8 days following infarction better predicted outcome than cardiac ejection fraction, end diastolic volume or end systolic volume.</p> <p>Conclusion</p> <p>First-pass CMR provides a predictive measure of the severity of myocardial impairment caused by infarction in a rodent model of heart failure.</p