Myelodysplasia is in the niche: novel concepts and emerging therapies.

Myelodysplastic syndromes (MDSs) represent clonal disorders mainly of the elderly that are characterized by ineffective hematopoiesis and an increased risk of transformation into acute myeloid leukemia. The pathogenesis of MDS is thought to evolve from accumulation and selection of specific genetic or epigenetic events. Emerging evidence indicates that MDS is not solely a hematopoietic disease but rather affects the entire bone marrow microenvironment, including bone metabolism. Many of these cells, in particular mesenchymal stem and progenitor cells (MSPCs) and osteoblasts, express a number of adhesion molecules and secreted factors that regulate blood regeneration throughout life by contributing to hematopoietic stem and progenitor cell (HSPC) maintenance, self-renewal and differentiation. Several endocrine factors, such as erythropoietin, parathyroid hormone and estrogens, as well as deranged iron metabolism modulate these processes. Thus, interactions between MSPC and HSPC contribute to the pathogenesis of MDS and associated pathologies. A detailed understanding of these mechanisms may help to define novel targets for diagnosis and possibly therapy. In this review, we will discuss the scientific rationale of 'osteohematology' as an emerging research field in MDS and outline clinical implications.

Hepcidin is correlated to soluble hemojuvelin but not to increased GDF15 during pregnancy.

Increased maternal and foetal iron requirements during pregnancy are compensated by an increase of intestinal iron absorption. Animal studies have shown that the expression of the main iron regulator hepcidin is significantly suppressed during pregnancy, but the factors associated with hepcidin suppression remain unknown. To investigate possible suppressors of hepcidin expression during pregnancy we determined serum concentrations of growth-differentiation factor-15 (GDF15), erythropoietin (EPO), soluble hemojuvelin (HJV) and hepcidin in 42 pregnant women at different time points of gestation and correlated them with serum iron and haematological parameters. Serum iron parameters and serum hepcidin concentration significantly decreased during pregnancy, whereas serum concentrations of GDF15, EPO and soluble HJV significantly increased. A negative correlation of hepcidin with EPO and soluble HJV but no correlation between hepcidin and GDF15 was found. Hepcidin and ferritin were positively correlated throughout the pregnancy. Our findings suggest that hepcidin expression is controlled by body iron stores where soluble HJV and EPO may act as suppressors of hepcidin.

Accuracy of bedside antigen tests in the diagnosis of new influenza A/H1N1v infection.

To evaluate the clinical reliability of two rapid influenza detection tests (RIDTs), we analyzed 107 specimens from patients with clinically suspected pandemic influenza A/H1N1v by these tests as well as by real-time PCR as a standard. Both RIDTs had a moderate sensitivity (28-32%), a high specificity (93-99%) and a negative predictive value of 80%. These results will impact on the clinical management and isolation precautions in patients with suspected infection. Although a positive RITD is mostly confirmatory, a negative result in the presence of high clinical likelihood of infection should be interpreted with caution and be re-evaluated by PCR.

Overexpression of p150, a part of the large subunit of the eukaryotic translation initiation factor 3, in colon cancer.

BACKGROUND: P150, a 150 kDa protein, was isolated from virally and oncogene-transformed mouse cell lines, partially purified and cloned. P150 is part of the large subunit of the eukaryotic translation initiation factor 3 with sequence homology to centrosomin A. A significant correlation between p150 expression and malignancy in breast, cervical and esophageal cancer have recently been demonstrated. MATERIALS AND METHODS: Here, 110 colorectal carcinomas of different grades and stages, including lymph node and liver metastases were compared to adjacent normal mucosa by immunohistochemistry of P150. Western blot analysis of selected cases confirmed the expression levels determined by immunohistochemistry. Additionally, immuno-electron and laser scanning microscopy (LSM) was performed. RESULTS: All investigated carcinomas revealed high levels of p150 protein compared to normal adjacent mucosa. The staining intensity was slightly heterogeneous, and positivity was correlated to the tumor grade with statistically significant differences of p150 expression between normal and neoplastic mucosa (p<0.0001, Kruskal-Wallis test). Western blots confirmed higher expression levels of p150 in the tumor. Immunogold labelling and LSM investigation showed high expression levels of p150 on the rough endoplasmic reticulum and polyribosomes, indicating that p150 is translationally active in these tumors. CONCLUSION: Thus, we propose that p150 plays an important role in development and growth of colorectal carcinomas. Furthermore, p150 expression might provide us with reliable information on the biological behaviour of tumors and the clinical course of the disease.

Serum hepcidin concentration in chronic haemodialysis patients: associations and effects of dialysis, iron and erythropoietin therapy.

BACKGROUND: Hepcidin, a liver-derived peptide induced by iron overload and inflammation, is a major regulator of iron homeostasis. As hepcidin decreases gastrointestinal iron absorption and recirculation from monocytes, over-expression is associated with the development of anaemia. METHODS: We studied the associations between circulating hepcidin levels and various laboratory parameters related to anaemia and/or inflammation in 20 patients on chronic haemodialysis. Furthermore, we determined the impact of dialysis and iron and/or erythropoietin (rhEpo) supplementation therapy on hepcidin serum concentrations. The patients were withheld from iron and rhEpo for 2 weeks before study entry. Hepcidin was measured by liquid chromatography-mass spectrometry (LC-MS/MS); serum iron and haematological parameters, cytokines and pro-hepcidin by commercially available enzyme-linked immunosorbent assays (ELISA) or standard automated methods. RESULTS: While hepcidin levels at baseline were not correlated to pro-hepcidin, interleukin-6 or transforming growth factor-beta concentrations, we found significant associations with reticulocyte count (r = -0.55; P = 0.015), serum iron (r = 0.7; P = 0.004) and ferritin levels (r = 0.63; P = 0.004) and transferrin saturation (r = 0.69, P = 0.001). Dialysis using either a high or a low flux biocompatible dialyser resulted in a significant decrease of hepcidin concentrations, which returned to pre-dialysis values before the next dialysis session. When studying the effects of anaemia treatment, we observed a significant reduction of hepcidin levels following administration of rhEpo but not iron. CONCLUSIONS: Hepcidin levels in stable haemodialysis patients appear to reflect systemic iron load, but not inflammation. Due to the negative association between reticulocyte counts and hepcidin, the reduction of circulating hepcidin concentrations by dialysis and/or rhEpo treatment may positively affect erythropoiesis.

An unusual case of intrauterine symptomatic neonatal liver failure.

UNLABELLED: We present an unusual case of neonatal liver failure. Isolated ascites was diagnosed in a female fetus at week 34 gestational age upon routine ultrasound. In the 35th week of gestation a cesarean section was carried out after puncture of fetal ascites. After birth the patient showed symptoms and complications of acute liver failure with portal hypertension. High serum ferritin concentrations, MRI findings compatible with tissue iron overload and no evidence for infectious disease or inborn errors of metabolism suggested possible neonatal hemochromatosis (NH). HFE gene mutation analysis studies of the child and parents were negative. An anti-oxidative and iron chelating therapy was introduced, followed by clinical stabilisation of the newborn and normalisation of liver function. The liver biopsy at 4 month of age showed mild fibrosis with a few iron-loaded hepatocytes and macrophages. At 2 years of age the child was virtually healthy. CONCLUSION: The clinical course of our patient indicates that the pathological changes in the liver being associated with presumptive NH may be reversible when NH is diagnosed early and antioxidative and chelating therapy is immediately initiated.

Four consecutive renal transplantations in a patient with adenine phosphoribosyltransferase deficiency.

We report a patient with complete adenine phosphoribosyltransferase deficiency and urolithiasis, in whom 4 consecutive cadaveric renal transplantations were performed; 2,8-dihydroxyadenine crystal nephropathy recurred within weeks in the first and second graft when the patient was not treated with allopurinol immediately after transplantation. In the third graft, recurrence of disease could be prevented by immediate allopurinol treatment. This graft was lost due to chronic allograft nephropathy without significant crystal deposition. After a fourth transplantation, again without initial allopurinol, the disease recurred following an initial vascular rejection. Addition of allopurinol significantly improved renal function of the 2nd and 4th graft. This case indicates that outcome of renal transplantation in patients with adenine phosphoribosyltransferase deficiency critically depends on immediate postoperative pharmacotherapy with allopurinol, which is able to prevent 2,8-dihydroxyadenine nephropathy in the graft. Furthermore, rapid recurrence of disease without allopurinol seems to be triggered by delayed graft function and acute rejection.

Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis.

Baseline platelet production is dependent on thrombopoietin (TPO). TPO is constitutively produced and primarily regulated by receptor-mediated uptake by platelets. Inflammatory thrombocytosis is thought to be related to increased interleukin-6 (IL-6) levels. To address whether IL-6 might act through TPO to increase platelet counts, TPO was neutralized in vivo in C57BL/10 mice treated with IL-6, and hepatic TPO mRNA expression and TPO plasma levels were studied. Transcriptional regulation of TPO mRNA was studied in the hepatoblastoma cell line HepG2. Furthermore, TPO plasma levels were determined in IL-6-treated cancer patients. It is shown that IL-6-induced thrombocytosis in C57BL/10 mice is accompanied by enhanced hepatic TPO mRNA expression and elevated TPO plasma levels. Administration of IL-6 to cancer patients results in a corresponding increase in TPO plasma levels. IL-6 enhances TPO mRNA transcription in HepG2 cells. IL-6-induced thrombocytosis can be abrogated by neutralization of TPO, suggesting that IL-6 induces thrombocytosis through TPO. A novel pathway of TPO regulation by the inflammatory mediator IL-6 is proposed, indicating that the number of platelets by themselves might not be the sole determinant of circulating TPO levels and thus of thrombopoiesis. This regulatory pathway might be of relevance for the understanding of reactive thrombocytosis.

Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload.

BACKGROUND & AIMS: Imbalances of iron homeostasis are accompanied by alterations of intestinal iron absorption. The identification of divalent-metal transporter 1 (DMT1) and ferroportin 1 (FP1) has improved our understanding of transmembrane iron trafficking. To gain insight into the regulatory properties of these transporters in the duodenum, we studied their expression in patients with hereditary hemochromatosis (HFE-associated and non-HFE-associated), secondary iron overload, and iron deficiency. METHODS: DMT1, FP1 messenger RNA (mRNA), and protein expression were analyzed in duodenal biopsy specimens from patients by means of TaqMan real-time polymerase chain reaction, Western blotting technique, and immunohistochemistry. RESULTS: DMT1 and FP1 mRNA levels are positively correlated with each other in all patient groups (P < 0.001). Moreover, DMT1 and FP1 mRNA levels were significantly increased in patients with iron deficiency, HFE and non-HFE hemochromatosis, whereas they were unchanged in patients with secondary iron overload. Alterations in DMT1 and FP1 mRNA levels were paralleled by comparable changes in the duodenal expression of these proteins. In patients with normal iron status or iron deficiency, significant negative correlations between DMT1, FP1 mRNA, and serum iron parameters were found, which were absent in subjects with primary hemochromatosis. CONCLUSIONS: DMT1 and FP1 are centrally involved in iron uptake/transfer in the duodenum and in the adaptive changes of iron homeostasis to iron deficiency and overload.