Monocyte TREM-1 membrane expression in non-infectious inflammation

Sterile or non-infectious inflammation and severe infection are accompanied by very similar events. Damage (or danger)-associated molecular patterns and pathogen-associated molecular patterns trigger the release of inflammatory mediators and modulate the expression of cell surface receptors. The increased expression on monocytes and neutrophils of triggering receptor expressed on myeloid cells 1 is a hallmark of both infectious and non-infectious inflammation.     

Screening for hemochromatosis.

BACKGROUND: Hereditary hemochromatosis is the most common autosomal recessive disorder in populations of northern European descent. ISSUES: Many experts consider hemochromatosis to be an almost ideal disease for population screening because it essentially fulfills almost all the criteria for screening proposed by the WHO. However, others disagree and suggest that more data are required particularly with regard to the natural history and penetrance of the disease. There is also disagreement about the best diagnostic/screening test for the disease and the performance of these tests in the context of screening. Other concerns are the variability and lack of standardization in screening test measurements, the selection of screening threshold values and the identification of false positive cases. The advent of a genetic test for the condition has brought other worries with regard to informed consent and the ethical, legal and social implications of screening particularly in relation to medical and general discrimination. Other important issues include compliance, cost effectiveness and the evidence that screening has lessened the burden of disease in the community. CONCLUSIONS: At the present time, we believe that further data regarding both the exact disease burden and the outcomes of screening studies particularly in the general community are required before widespread population screening is introduced.     

Serum ferritin.

(1) Brief introduction to iron metabolism and the biochemistry of ferritin. (2) Early studies of circulating ferritin. (3) Methods for measuring serum ferritin concentrations -- immunoradiometric, radioimmuno- and enzyme-linked immuno assays based on liver or spleen ferritin -- an evaluation of these techniques. (4) Serum ferritin concentrations in normal subjects -- definition of normality -- relationship between storage iron and serum ferritin concentrations -- changes during development from birth to old age -- iron deficiency -- variability of serum ferritin concentration -- evaluation of use of ferritin assay for assessment of storage iron levels. (5) Serum ferritin concentrations in disease -- hemochromatosis -- secondary iron overload -- liver damage -- infection and chronic disease -- cancer. (6) Assay of serum ferritin with antibodies to ferritins other than liver or spleen -- ferritinemia and cancer. (7) Properties of serum ferritin -- molecular weight -- iron content -- isoelectric focusing patterns -- carbohydrate content -- immunological properties. (8) Physiology of circulating ferritin -- release of ferritin from tissues -- origin of circulating ferritin -- clearance from the plasma -- iron and protein turnover. (9) Summary -- factors influencing serum ferritin concentrations and clinical use of ferritin estimations.     

Duodenal iron proteins in idiopathic hemochromatosis.

This study was undertaken to assess the relationship between iron absorption and the concentration of duodenal iron proteins in normal subjects and patients with idiopathic hemochromatosis (IH). Biopsies were obtained endoscopically from the duodenum in 17 normal subjects, 3 of whom were mildly iron deficient, and 7 patients with untreated IH. The absorption of both heme and nonheme iron was increased in IH despite a 20-fold elevation in serum ferritin. Immunoassays using MAb were used to measure transferrin, H-rich ferritin, and L-rich ferritin in mucosal samples. Mucosal transferrin concentrations in normal subjects did not correlate with either iron status or iron absorption, indicating that mucosal transferrin plays no physiological role in iron absorption. Mucosal transferrin was significantly lower in IH, presumably because of a decrease in mucosal transferrin receptors. Mucosal H and L ferritin concentrations were directly related to body iron stores and inversely related to iron absorption in normal subjects. In IH, mucosal H and L ferritin failed to increase in parallel with the serum ferritin, but were appropriate for the level of iron absorption. The relationship of mucosal H/L ferritin in IH did not differ from that observed in normal subjects. Our findings indicate that the major abnormality in duodenal iron proteins in IH is a parallel decrease in the concentration of H- and L-rich ferritin. It is not evident whether this is the result or the cause of the absorptive abnormality.     

Serum ferritin assay.

Ferritin is an iron storage protein of high-molecular weight which is primarily present in the liver, spleen, and bone marrow. A very sensitive immunoradiometric assay has been developed which permits determination of serum concentrations in normal persons and in patients with a variety of different disorders. In normal subjects, the serum ferritin concentration correlates very well with total body iron stores as measured by phlebotomy. The serum ferritin concentration is reduced in patients with iron-deficient anemia and is significantly higher in patients who are anemic for other reasons. Subject areas discussed in this review include the details of the immunoradiometric procedure, the sensitivity and accuracy of the assay, factors influencing the assay, values characteristic of a variety of clinical disorders, and the utility of the assay in clinical medicine and public health.     

Monocyte chemoattractant protein-1 in human atheromatous plaques.

Monocytes appear to be central to atherogenesis both as the progenitors of foam cells and as a potential source of growth factors mediating intimal hyperplasia, but the chemical messages which stimulate the influx of monocytes into human atheroma remain unknown. Monocyte chemoattractant protein-1 (MCP-1) is a recently described molecule with powerful monocyte chemotactic activity expressed by monocytes, vascular endothelial cells, and smooth muscle cells in culture. To begin to address the role of MCP-1 in vivo, we examined 10 normal arteries and 14 diseased human arteries for MCP-1 expression by in situ hybridization. MCP-1 mRNA was detected in 16% of 10,768 cells counted in human carotid endarterectomy specimens with highest expression seen in organizing thrombi (33%) and in macrophage rich areas bordering the necrotic lipid core (24%) as compared to the fibrous cap (8%) and the necrotic lipid core itself (5%). Based on immunohistochemical staining of serial sections and on cell morphology, MCP-1 mRNA appeared to be expressed by vascular smooth muscle cells (VSMC), mesenchymal appearing intimal cells (MICs), and macrophages. By contrast, few cells expressing MCP-1 mRNA were found in normal arteries (less than 0.1%). These data suggest a potential role for MCP-1 in mediating monocytic infiltration of the artery wall.     

Hepatic zinc in hemochromatosis

Since an intestinal absorptive interaction between iron and zinc has been described in animals and humans, the possibility of increased accumulation of zinc as well as iron in the liver was studied in patients with hereditary hemochromatosis. Hepatic zinc was determined by atomic absorption spectrophotometry in liver biopsy specimens from 21 homozygotes for hemochromatosis, 21 normal liver samples from autopsies, and 15 cases of cirrhosis unrelated to iron overload. Mean hepatic zinc concentrations in the three groups were compared by one-way analysis of variance. Hemochromatosis patients had hepatic iron determinations by atomic absorption spectrophotometry, and iron absorption studies using 59Fe and total body counting had been previously documented in 18 of the 21 hemochromatosis patients. The mean hepatic zinc was significantly increased at 25.9 +/- 26.7 mumol/g (dry weight) in the hemochromatosis patients, as compared to 4.99 +/- 1.51 mumol/g in the control patients (p less than 0.05), and 2.13 +/- 1.13 mumol/g in the cirrhosis patients without iron overload (p less than 0.05). Hepatic zinc concentration was elevated in hemochromatosis patients who had either normal histology, fibrosis, and cirrhosis. Hepatic zinc concentration was not directly related to patient age, hepatic iron concentration, or iron absorption. In conclusion, hepatic zinc was increased approximately fivefold in patients with hemochromatosis. This finding suggests the concomitant hepatic accumulation of zinc as well as iron in this disorder, possibly by means of increased intestinal absorption of zinc and hepatic sequestration.     

Hereditary hemochromatosis

Hereditary hemochromatosis is a relatively common genetic disorder characterized by excess dietary iron absorption and deposition in tissues with resulting end-organ damage. Early diagnosis and initiation of therapeutic phlebotomy can provide a normal life expectancy for affected individuals.     

Idiopathic hemochromatosis

Hemochromatosis is a rare disorder in which about four times the normal amount of iron is absorbed in the intestine, resulting in the accumulation of iron in the skin, liver, pancreas and heart. Radiographic features may include a small liver on plain abdominal films, increased hepatic density on computed tomographic imaging, and loss of liver signal on magnetic resonance imaging as a result of the strong paramagnetic effect of iron. Management includes phlebotomy and supportive treatment of damaged organs.     

Hereditary hemochromatosis

Hereditary hemochromatosis (HH) is an autosomal recessive iron overload disorder that affects more than one million Americans. This underdiagnosed disorder is associated with high morbidity and mortality, which can be prevented with early identification and treatment. A DNA test that can identify asymptomatic at-risk individuals before biochemical indicators are positive is available commercially. Nurses need current knowledge about HH for two main reasons: (1) to ensure that at-risk individuals receive comprehensive information before genetic testing, and (2) to play a significant role in preventing chronic morbidity and premature death caused by HH.     

Analysis of ferritin genes in Parkinson disease.

BACKGROUND: Genes that regulate iron metabolism may be involved in increasing brain iron content in Parkinson disease (PD). The ferritin L-chain is one of these genes, but the rare insertional mutations that cause neuroferritinopathy with basal ganglia degeneration have not yet been identified in PD. METHODS: We used denaturing HPLC (DHPLC) to investigate 124 PD patients and 180 controls for variations in the coding and in the 5' untranslated regions of the H- and L-ferritin genes. RESULTS: In the H-ferritin gene, we found one new and rather common intronic polymorphism and the K54R substitution in two controls. The L-ferritin gene showed a very common L55L polymorphism and four other types of DNA variations, three of which were in the patient cohort. A mutation of the conserved His133 to Pro was found in a PD patient and in his daughter. The patient did not show signs of neuroferritinopathy, but the mutation was associated with low L-ferritin levels and with mild chronic anemia. CONCLUSIONS: The results support the hypothesis that DNA variations in the ferritin genes are not a common cause for PD.     

Enzyme immunoassay for human ferritin.

We describe an enzyme immunoassay with use of beta-D-galactosidase for quantitation of ferritin in human serum. The minimum detectable ferritin concentration is 0.25 microgram/L of serum, which is comparable to results obtained by radioimmunoassay. The correlation coefficient between values determined by enzyme immunoassay and radioimmunoassay was 0.95 (n - 1 = 85, p less than 0.001).     

Increased ferritin gene expression in atherosclerotic lesions.

To identify genes potentially implicated in atherogenesis, a cDNA library was constructed from human atherosclerotic aorta and differentially screened with 32P-labeled-cDNAs prepared from human normal and atherosclerotic aortas. Two cDNA clones exhibiting higher hybridization to the 32P-labeled cDNAs from atherosclerotic vessels were isolated and identified to be genes encoding L-ferritin and H-ferritin, respectively. Northern blot analysis confirmed that the expression of both ferritin genes was notably higher in human and rabbit atherosclerotic aortas than in their normal counterparts. A time-course study illustrated that both L- and H-ferritin mRNAs were markedly increased in aortas of rabbits after feeding with a high cholesterol diet for 6 wk, which was also the time period after which the formation of lesions became evident. In situ hybridization revealed that both L- and H-ferritin mRNAs were induced in endothelial cells and macrophages of human early lesions. The signals were also detected in the smooth muscle cells of advanced lesions. Immunostaining further identified the presence of ferritin protein in atherosclerotic lesions. On the other hand, Prussian blue stain revealed the presence of iron deposits in advanced lesions but not in early human or rabbit lesions. Further experiments with cultured human monocytic THP-1 cells and aortic smooth muscle cells demonstrated that ferritin mRNAs were subjected to up-regulation by treatment with IL-1 or TNF, while TGF, PDGF, and oxidized LDL did not affect the expression of either ferritin gene in both cell lines. Collectively, these results clearly demonstrate that ferritin genes are susceptible to induction in the course of plaque formation.