High plasma arginine concentrations in critically ill patients suffering from hepatic failure

Objective: In physiological conditions, the liver plays an important role in the regulation of plasma arginine concentrations by taking up large amounts of arginine from the hepatic circulation. When hepatic failure is present, arginine metabolism may be disturbed. Therefore, we hypothesized high arginine plasma concentrations in critically ill patients suffering from hepatic failure. Design: We prospectively collected blood samples from a cross-section of intensive care unit patients. Setting: Surgical intensive care unit of a Dutch university medical center. Subjects: A total of 52 critically ill patients with clinical evidence of dysfunction of more than two organs were recruited. Measurements: Plasma arginine concentrations were determined by HPLC. We identified correlations of arginine concentrations with organ failure scores and laboratory variables by univariate and multiple regression analyses. Results: High plasma arginine concentrations were found in critically ill patients developing organ failure. Patients who were in the highest quartile of plasma arginine concentrations had significantly lower fibrinogen concentrations, higher lactic acid concentrations, and longer prothrombin time. Stepwise multiple regression analysis showed that concentrations of arginine were independently associated with the presence of hepatic failure (P = 0.03) and renal failure (P = 0.048). In addition, lactic acid proved to be an independent determinant of plasma arginine concentration (P = 0.014). Conclusions: Critically ill patients who suffer from hepatic failure have elevated plasma arginine concentrations. Additional arginine in the treatment of these patients can be harmful, and therefore should not be used as a standard nutritional regimen until further evaluation

N-acetylcysteine reduces oxidative stress in sickle cell patients

Oxidative stress is of importance in the pathophysiology of sickle cell disease (SCD). In this open label randomized pilot study the effects of oral N-acetylcysteine (NAC) on phosphatidylserine (PS) expression as marker of cellular oxidative damage (primary end point), and markers of hemolysis, coagulation and endothelial activation and NAC tolerability (secondary end points) were studied. Eleven consecutive patients (ten homozygous [HbSS] sickle cell patients, one HbSβ0-thalassemia patient) were randomly assigned to treatment with either 1,200 or 2,400 mg NAC daily during 6 weeks. The data indicate an increment in whole blood glutathione levels and a decrease in erythrocyte outer membrane phosphatidylserine exposure, plasma levels of advanced glycation end-products (AGEs) and cell-free hemoglobin after 6 weeks of NAC treatment in both dose groups. One patient did not tolerate the 2,400 mg dose and continued with the 1,200 mg dose. During the study period, none of the patients experienced painful crises or other significant SCD or NAC related complications. These data indicate that N-acetylcysteine treatment of sickle cell patients may reduce SCD related oxidative stress

Analysis of phospholipids in brain tissue by 31P NMR at different compositions of the solvent system chloroform‐methanol‐ water

Brain phospholipids can be quantitated by high‐resolution 31P NMR of crude brain tissue extracts in the solvent system chloroform‐methanol‐water (+EDTA) which was introduced recently (P. Meneses and T. Glonek, J. Lipid Res. 29, 679 (1988)). Phospholipid resonance positions depend on the type of tissue extract and on solvent composition. The effects of systematic variation of the solvent system on phospholipid NMR profiles are presented. Resolution can be optimized by adjustment of the solvent composition. Virtually all phospholipid classes can be resolved, and the major phospholipids in brain: sphingo‐myelin and phosphatidyl‐choline, ‐serine, ‐inositol, ‐ethanolamine, and ‐ethanolamine plasmalogen can be quantitated easily. Additional resonances have been assigned to phosphatidylcholine plasmalogen, alkylacyl‐phosphatidylcholine and phosphatidylinositolbis‐phosphate. NMR offers a rapid method for quantitative analysis of the phospholipid composition in brain tissue which requires minimum sample handling

Resting Brain Perfusion and Selected Vascular Risk Factors in Healthy Elderly Subjects

Both cerebral hypoperfusion and vascular risk factors have been implicated in early aging of the brain and the development of neurodegenerative disease. However, the current knowledge of the importance of cardiovascular health on resting brain perfusion is limited. The aim of the present study was to elucidate the relation between brain perfusion variability and risk factors of endothelial dysfunction and atherosclerosis in healthy aged subjects.Thirty-eight healthy subjects aged 50-75 years old were included. Mean global brain perfusion was measured using magnetic resonance phase contrast mapping and regional brain perfusion by use of arterial spin labeling.Mean global brain perfusion was inversely correlated with caffeine and hematocrit, and positively with end-tidal PCO2. Furthermore, the mean global brain perfusion was inversely correlated with circulating homocysteine, but not with asymmetric dimethylarginine, dyslipidemia or the carotid intima-media thickness. The relative regional brain perfusion was associated with circulating homocysteine, with a relative parietal hypoperfusion and a frontal hyperperfusion. No effect on regional brain perfusion was observed for any of the other risk factors. A multiple regression model including homocysteine, caffeine, hematocrit and end-tidal PCO2, explained nearly half of the observed variability.Both intrinsic and extrinsic factors influenced global cerebral perfusion variation between subjects. Further, the results suggest that the inverse relation between homocysteine and brain perfusion is owing to other mechanisms, than reflected by asymmetric dimethylarginine, and that homocysteine may be a marker of cerebral perfusion in aging brains

Transjugular intrahepatic portosystemic shunt-placement increases arginine/asymmetric dimethylarginine ratio in cirrhotic patients

AIM: To analyze the change of dimethylarginine plasma levels in cirrhotic patients receiving transjugular intrahepatic portosystemic shunt (TIPS)

The relationship between homocysteine and global brain perfusion.

<p>Dashed line shows line of regression (r² = 0.17, p = 0.009).</p

Subject characteristics.

<p>Abbreviations: MMSE  =  mini mental state examination, LDL  =  low density lipoprotein, HDL  =  high density lipoprotein, CV =  cardiovascular WML  =  white matter lesion, ADMA  =  asymmetric dimethylarginine, Arg =  L-arginine.</p

Effects of covariates on brain perfusion.

<p>Regression coefficients refer to change in brain perfusion in mL/100 g/min per unit increase of covariate.</p><p>*Sex omitted due to co-linearity.</p>†<p>p<0.05, ^†† p<0.01 (p-values are not adjusted for multiple comparisons).</p><p>Abbreviations: LDL  =  low density lipoprotein, HDL  =  high density lipoprotein, ADMA  =  asymmetric dimethylarginine, Arg  =  L-arginine.</p

Bone Marrow Alterations and Lower Endothelial Progenitor Cell Numbers in Critical Limb Ischemia Patients

<div><h3>Background</h3><p>Critical limb ischemia (CLI) is characterized by lower extremity artery obstruction and a largely unexplained impaired ischemic neovascularization response. Bone marrow (BM) derived endothelial progenitor cells (EPC) contribute to neovascularization. We hypothesize that reduced levels and function of circulating progenitor cells and alterations in the BM contribute to impaired neovascularization in CLI.</p> <h3>Methods</h3><p>Levels of primitive (CD34⁺ and CD133⁺) progenitors and CD34⁺KDR⁺ EPC were analyzed using flow cytometry in blood and BM from 101 CLI patients in the JUVENTAS-trial (NCT00371371) and healthy controls. Blood levels of markers for endothelial injury (sE-selectin, sICAM-1, sVCAM-1, and thrombomodulin), and progenitor cell mobilizing and inflammatory factors were assessed by conventional and multiplex ELISA. BM levels and activity of the EPC mobilizing protease MMP-9 were assessed by ELISA and zymography. Circulating angiogenic cells (CAC) were cultured and their paracrine function was assessed.</p> <h3>Results</h3><p>Endothelial injury markers were higher in CLI (P<0.01). CLI patients had higher levels of VEGF, SDF-1α, SCF, G-CSF (P<0.05) and of IL-6, IL-8 and IP-10 (P<0.05). Circulating EPC and BM CD34⁺ cells (P<0.05), lymphocytic expression of CXCR4 and CD26 in BM (P<0.05), and BM levels and activity of MMP-9 (P<0.01) were lower in CLI. Multivariate regression analysis showed an inverse association between IL-6 and BM CD34⁺ cell levels (P = 0.007). CAC from CLI patients had reduced paracrine function (P<0.0001).</p> <h3>Conclusion</h3><p>CLI patients have reduced levels of circulating EPC, despite profound endothelial injury and an EPC mobilizing response. Moreover, CLI patients have lower BM CD34⁺-cell levels, which were inversely associated with the inflammatory marker IL-6, and lower BM MMP-9 levels and activity. The results of this study suggest that inflammation-induced BM exhaustion and a disturbed progenitor cell mobilization response due to reduced levels and activity of MMP-9 in the BM and alterations in the SDF-1α/CXCR4 interaction contribute to the attenuated neovascularization in CLI patients.</p> </div