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Iron fulfils a central role in many essential biochemical processes in human physiology, which makes proper processing of iron crucial. Although iron metabolism is subject to relatively strict physiological control, in recent years numerous disorders, such as cancer and neurodegenerative diseases, have been linked to deregulated iron homeostasis. Because of its involvement in the pathogenesis of these diseases, iron metabolism constitutes a promising and largely unexploited therapeutic target for the development of new pharmacological treatments. Several iron metabolism-targeted therapies are already under clinical evaluation for haematological disorders, and these and newly developed therapeutic agents will likely have substantial benefit in the clinical management of iron metabolism-associated diseases, for which few efficacious treatments are often available.

Iron fulfils a central role in many essential biochemical processes in human physiology; thus, proper processing of iron is crucial. Although iron metabolism is subject to relatively strict physiological control, numerous disorders, such as cancer and neurodegenerative diseases, have recently been linked to deregulated iron homeostasis. Consequently, iron metabolism constitutes a promising and largely unexploited therapeutic target for the development of new pharmacological treatments for these diseases. Several iron metabolism-targeted therapies are already under clinical evaluation for haematological disorders, and these and newly developed therapeutic agents are likely to have substantial benefit in the clinical management of iron metabolism-associated diseases, for which few efficacious treatments are currently available.

Introduction: Macrophages are the predominant cell capable of removing toxic hemoglobin at sites of tissue injury, and CD163 has been recognized as the hemoglobin scavenger receptor present on the macrophage cell surface. In this study, we explored the levels of soluble CD163 (sCD163) in patients with intracerebral hemorrhage (ICH) to ascertain whether sCD163 was associated with clinicoradiologic features and long-term functional outcomes. Methods: Our ICH cohort was comprised of 50 patients with moderate-sized basal ganglia hematomas. We collected serial serum and cerebrospinal fluid (CSF) at pre-specified timepoints (24 hours, 48 hours, 3-5 days, 6-8 days, and greater than 10 days post-ictus). We also obtained samples from 10 healthy controls. Levels of sCD163 were measured by enzyme-linked immunosorbent assay. A linear mixed model was used to compare sCD163 values among various groups, using a Bonferroni correction for multiple test adjustment. The method of generalized estimating equations was used to determine associations with dichotomized outcomes (modified Rankin Scale score 0-3 versus 4-6). Results: Compared to healthy controls, serum sCD163 was higher in the ICH patients (40.6 versus 128.4 ng/mL). Within the ICH cohort, early values (24 hours to 5 days post-ictus) of serum sCD163 were significantly higher in patients who elaborated minimal perihematomal edema (PHE) (200.3 in patients with less than 10 mL PHE versus 71.8; p = 0.046). 6 to greater than 10 days post-ictus, sCD163 levels tailed off for patients with less PHE whereas levels rose in patients with greater PHE. Continued subacute elevation of sCD163, particularly in the CSF, was highly associated with poorer outcomes, both at discharge and at 90 days (p < 0.001). These associations were independent of age, gender, peak hematoma volume, and ICH score; there was a statistically significant association of CSF sCD163 values with degree of intraventricular hemorrhage (p = 0.04). Conclusions: sCD163 may be a dynamic marker in ICH, with acute levels distinguishing edema patterns and subacute levels predicting functional outcome. Further studies are needed to confirm these findings and explore the pathophysiology behind these observations.

Background Increased monocyte activation and intestinal damage have been shown to be predictive for the increased morbidity and mortality observed in treated people living with human immunodeficiency virus (PLHIV). Methods A cross-sectional analysis of cellular and soluble markers of monocyte activation, coagulation, intestinal damage, and inflammation in plasma and cerebrospinal fluid (CSF) of PLHIV with suppressed plasma viremia on combination antiretroviral therapy and age and demographically comparable HIV-negative individuals participating in the Comorbidity in Relation to AIDS (COBRA) cohort and, where appropriate, age-matched blood bank donors (BBD). Results People living with HIV, HIV-negative individuals, and BBD had comparable percentages of classical, intermediate, and nonclassical monocytes. Expression of CD163, CD32, CD64, HLA-DR, CD38, CD40, CD86, CD91, CD11c, and CX3CR1 on monocytes did not differ between PLHIV and HIV-negative individuals, but it differed significantly from BBD. Principal component analysis revealed that 57.5% of PLHIV and 62.5% of HIV-negative individuals had a high monocyte activation profile compared with 2.9% of BBD. Cellular monocyte activation in the COBRA cohort was strongly associated with soluble markers of monocyte activation and inflammation in the CSF. Conclusions People living with HIV and HIV-negative COBRA participants had high levels of cellular monocyte activation compared with age-matched BBD. High monocyte activation was predictive for inflammation in the CSF.

Objectives: Serum biomarkers representing inflammatory activity in vulnerable carotid plaques may be used to identify high-risk patients for cerebral ischemic events. We aimed to analyze the relationship between concentrations of four novel biomarkers and neurological symptoms: Neopterin, PTX3, sCD163, and sTREM-1. In addition, we analyzed the relationship between these markers and the presence of coronary (CAD) and peripheral (PAD) artery disease.Design and methods: Serum biomarker levels were determined in 100 patients undergoing carotid endarterectomy: 33 for stroke, 32 for transient ischemic attack, and 23 for amaurosis fugax. 12 Patients were asymptomatic. Risk factors for atherosclerotic disease and history of CAD and PAD were also assessed.Results: Symptomatic patients did not show significantly elevated biomarker levels compared to asymptomatic patients and levels did not differ among symptomatic subgroups. Neopterin levels were elevated in patients with concomitant coronary and peripheral artery disease (CAD (32%) 10.2 +/- 6.6 vs no CAD (68%) 7.6 +/- 2.9 nmol/L, PAD (20%) 12.3 +/- 7.4 vs no PAD (80%) 7.5 +/- 3.0 nmol/L, pConclusion: Our findings suggest that serum neopterin and sTREM-1 levels may be related to the presence of atherosclerotic disease, but not to carotid plaque vulnerability. (C) 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Cardiovascular surgery with cardiopulmonary bypass is associated with postoperative organ injury, which severely affects patient morbidity and mortality. Multiple cardiopulmonary bypass–related mechanisms have been linked to the development of tissue damage, including hypoperfusion, ischemia–reperfusion, and induction of a proinflammatory response. Hemolysis, resulting in increased plasma free hemoglobin concentrations, is generally considered an inevitable but relatively harmless side effect of cardiopulmonary bypass. Recently, however, evidence has been mounting that plasma free hemoglobin scavenges intravascular nitric oxide, thereby attenuating its bioavailability. Any significant reduction in nitric oxide, the most important endogenous vasodilator, impairs tissue perfusion and induces organ injury development. Moreover, urinary free hemoglobin contributes to renal damage, specifically by catalysis of reactive oxygen species formation. In this review, the effects of increased free hemoglobin levels on nitric oxide metabolism are discussed. In addition, we review the role of free hemoglobin in organ injury development, potential sources of free hemoglobin during cardiovascular surgery, and therapeutic options to attenuate the consequences of hemolysis. We propose that hemolysis is more than an innocent bystander effect of cardiopulmonary bypass–assisted surgery. Therapeutic interventions to attenuate the effects of hemolysis seem crucial in the reduction of postoperative morbidity and mortality after cardiovascular surgery. Cardiovascular surgery with extracorporeal circulation is associated with considerable postoperative morbidity and mortality, especially among patients undergoing complex procedures such as combined coronary artery bypass grafting (CABG) and valve surgery, Bentall procedures, and open repair of thoracic and thoracoabdominal aortic aneurysms.

Intolerance to fava beans in subjects with glucose-6-phosphate-dehydrogenase deficiency (favism) may lead to severe hemolytic crises and decreased renal function. Renal biopsy findings exploring the molecular mechanisms of renal damage in favism have not been previously reported. We report a case of favism-associated acute kidney injury in which renal biopsy showed acute tubular necrosis and massive iron deposits in tubular cells. Interestingly, iron deposit areas were characterized by the presence of oxidative stress markers (NADPH-p22 phox and heme-oxigenase-1) and macrophages expressing the hemoglobin scavenger receptor CD163. In addition, iron deposits, NADPH-p22 phox, hemeoxigenase- 1 and CD163 positive cells were observed in some glomeruli. These results identify both glomerular and tubular involvement in favism-associated acute kidney injury and suggest novel therapeutic targets to prevent or accelerate recovery from acute kidney injury. Language: en

Paul Guyre: I have a long-term interest in the physiology, function, and responses of monocytes and macrophages, which has been a major research focus since my postdoctoral fellowship with Dr. Allan Munck, who first discovered glucocorticoid receptors. My work initially gravitated toward understanding how glucocorticoids and cytokines regulate Fc receptors for IgG [1], and this led to our discovery of the glucocorticoid-induced macrophagespecific glycoprotein now known as CD163 [2].

The hemoglobin-haptoglobin scavenger receptor (CD163/HbSR) is a monocyte/macrophage-restricted transmembrane protein of the scavenger receptor cysteine-rich family.[1][1] Antigen expression is related to monocyte/macrophage differentiation, with weak expression on peripheral blood monocytes and

Background The Fulani are known to have a lower parasitaemia and less clinical episodes of malaria as compared to the Dogon sympatric ethnic group, living in Mali. Higher circulating malaria-specific antibody titers and increased pro-inflammatory cytokine levels have been shown in Fulani individuals. Several studies have tried to link haptoglobin (Hp) phenotypes with susceptibility to malaria, but without consensus. This study investigated the role of Hp phenotypes and cytokine levels in Dogon and Fulani during asymptomatic Plasmodium falciparum infection. Methods Two different cohorts were combined in this study: a 2008 cohort with 77 children aged between two and ten years and a 2001 cohort, with 82 children and adults, aged between 11 and 68 years. Hp phenotypes in plasma were measured by Western Blot. Circulating levels of sCD163, IL-6, IL-10, IFN-¿ and TNF were measured by ELISA. Multiple regression analysis was performed to associate Hp phenotypes with cytokine profiles. In addition, in vitro stimulation of peripheral blood mononuclear cells (PBMCs) with Hp:Hb complexes was performed and cytokine release in corresponding supernatants were measured using cytometric bead array. Results The results revealed a higher Hp2-2 phenotype prevalence in the Fulani. The Hp2-2 phenotype was associated with a higher susceptibility to P. falciparum infection in Dogon, but not in Fulani. In concordance with previous studies, Fulani showed increased inflammatory mediators (IL-6, IFN-¿) and additionally also increased sCD163 levels compared to Dogon, irrespective of infection. Furthermore, infected individuals showed elevated sCD163 levels compared to uninfected individuals, in both Fulani and Dogon. Multiple regression analysis revealed that the Hp1-1 phenotype was associated with higher levels of TNF and IFN-¿, as compared to the Hp2-2 phenotype. In vitro stimulation of PBMCs with Hb:Hp1-1 complexes resulted in a pro-inflammatory cytokine profile, whilst stimulation with Hb:Hp2-2 complexes showed a more balanced profile. Conclusions Ethnicity might be an important confounder on the Hp phenotype-dependent susceptibility to malaria and future studies could consider taking this into account when designing new immunological studies. Although, the relatively small sample size used in this study warrens for precautions in the interpretation of the data and these findings should ideally be validated in a bigger cohort.