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J J Marx

Publications and source records attributed to J J Marx.

At least 73 records · Page 4Linked to original sources
PubMed1997

The management of iron metabolism in recombinant human erythropoietin treated dialysis patients by Dutch nephrologists.

BACKGROUND: The regulation of iron metabolism is an important aspect of r-HuEPO treatment. METHOD: All Dutch nephrologists involved in dialysis were asked to complete a questionnaire about iron metabolism management in dialysis patients. RESULTS: The response rate was 68%, covering 83% of all Dutch dialysis units. Iron status is assessed before starting r-HuEPO by 96% of the respondents, but only 58% waits for the results. Serum ferritin is determined by 98%, MCV by 77%, transferrin saturation by 44%, the percentage hypochromic red blood cells by 6%, bone marrow iron staining by 4%, and serum transferrin receptors by 0%. Serum ferritin is considered to be the most important parameter by 48%, transferrin saturation by 37%, percentage hypochromic red blood cells and serum transferrin receptors by 0%. Of the respondents, 17% determines iron status twice a year, 13% three times, 54% four times, 4% six times, 4% eight times, and 8% twelve times. Iron is given to all patients by 40% of the nephrologists, 60% prescribes iron on indication. Oral substitution is preferred by 90%, but 27% incidentally prescribes intravenous iron without testing the effects of oral iron. Of all haemodialysis patients on r-HuEPO, 16% (SD 18, median 10) receives no iron substitution, 65% (+/- 28, 73) oral iron and 19% (+/- 28, 6) intravenous iron. Of all CAPD patients, 22% (+/- 24, 16) receives no iron substitution, 77% (+/- 24, 81) oral iron, and 1% (+/- 2, 0) intravenous iron. CONCLUSION: There is no communis opinio among Dutch nephrologists on the frequency of iron status assessment, the choice of parameters, the indications for iron substitution, or the decision between oral or intravenous substitution.

Administration, Oral↗
PubMed1997

In vivo mucosal uptake, mucosal transfer and retention of iron in mice.

An improved and sensitive method for studying iron absorption in mice with alterations in body iron stores is described. Mice with varying iron status were given a double isotope-labelled test dose containing 59Fe and 51Cr as a non-absorbable indicator, via an oroesophageal needle. Using a whole-body counter it was possible to measure in vivo the initial mucosal iron uptake and long-term iron retention and to calculate mucosal iron transfer. A significant difference was demonstrated between normal and both anaemic and dietary iron-loaded mice with regard to the various steps of iron absorption. When mice were tested twice for iron absorption, the results were highly reproducible. In conjunction with other parameters, the method described is useful in studying the mechanism and the regulation of iron absorption in mice.

Absorption↗
PubMed1996

Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man.

Previously, hepatic iron overload resembling that in hereditary hemachromatosis (HH) has been found in beta 2-microglobulin knockout (beta 2m-/-) mice. We have now characterized iron metabolism in beta 2m-/- mice. The mutant mice fail to limit the transfer of iron from mucosal cells into the plasma. Transferrin saturation is abnormally high. Pathologic iron depositions occur predominantly in liver parenchymal cells. Reconstitution with normal hematopoietic cells redistributes the iron from parenchymal to Kupffer cells, but does not correct the mucosal defect. We conclude that (a) iron metabolism is defective in the gut mucosa as well as the liver of beta 2m-/- mice; and (b) a beta 2m-dependent gene product is involved in iron homeostasis. Recently, a novel gene of the major histocompatibility complex class I family, HLA-H, has been found to be mutated in a large proportion of HH patients. Our data provide functional support for the proposed causative role of HLA-H mutations in HH.

Absorption↗
PubMed1996

Effects of insulin treatment on endoneurial and systemic oxidative stress in relation to nerve conduction in streptozotocin-diabetic rats.

As increased oxidative stress is probably a pathogenetic factor in the development of diabetic complications, we studied nerve function and endogenous antioxidants in plasma, erythrocytes and sciatic nerve of untreated and insulin-treated streptozotocin-diabetic rats. After 18 weeks, the diabetes-induced sciatic nerve conduction velocity deficits were approximately 65% improved by insulin (P < 0.001). Plasma superoxide dismutase was significantly reduced in diabetes (P < 0.01); smaller decreases in plasma catalase and glutathione levels were observed. These changes were corrected by insulin treatment. In erythrocytes, decreased superoxide dismutase (P < 0.05) and increased total glutathione levels (P < 0.05) were found. All effects of diabetes, including a rise in plasma malonyldialdehyde (P < 0.05), were partially reversed by insulin treatment. In nervous tissue, diabetes caused increased catalase activity, uninfluenced by insulin (P < 0.05). Nerve superoxide dismutase and glutathione did not change. The data suggest that in diabetes, changes in systemic rather than endoneurial oxidative stress lead to nerve dysfunction.

Animals↗
PubMed1996

Mechanism underlying the inhibitory effect of high calcium carbonate intake on iron bioavailability from ferrous sulphate in anaemic rats.

The influence of high CaCO3 intake on the bioavailability of Fe from FeSO4 was assessed during Fe repletion of rats with Fe-deficiency-induced anaemia. Fe-deficient rats with a mean blood haemoglobin concentration of 4.1 mmol/l were fed on purified Fe-adequate diets containing either 6.2 or 25.0 g CaCO3/kg (ten rats per group). Haemoglobin repletion after 14 d was significantly depressed by high CaCO3 intake (9.5 v. 9.8 mmol/l for high and low CaCO3 intake respectively; P = 0.03), as was apparent Fe retention (367 v. 552 micrograms/d during days 5-7, P < 0.001; 146 v. 196 micrograms/d during days 19-21, P < 0.001). The concentration of Fe in the liquid phase of the proximal half of the small intestine was significantly lower in the high-CaCO3 group (3.71 v. 5.20 micrograms/g digesta; P = 0.02). Mucosal uptake and mucosal transfer of Fe were determined with orally administered 59Fe and Cr as a non-absorbable marker. Mucosal transfer was significantly diminished by CaCO3 loading (90 v. 100% of mucosal uptake; P = 0.04), whereas mucosal uptake was not. 59Fe retention values at 14 d after administration were not significantly different (57.6 v. 51.9%; P = 0.14). Fe contents of liver and spleen were significantly decreased by high compared with low CaCO3 intake (879 v. 590 micrograms Fe in liver, P < 0.001; 92 v. 63 micrograms Fe in spleen, P < 0.001). It is concluded that high intake of CaCO3 depresses Fe bioavailability in rats. The CaCO3-induced decrease in Fe solubility in the digesta probably was associated with an increased efficiency of mucosal Fe uptake so that the amount of mucosal uptake remained unaltered. The CaCO3-induced decrease in Fe transfer through the mucosal cytoplasm and/or basolateral membrane may have been responsible for the concurrent decrease in Fe bioavailability.

Anemia, Iron-Deficiency↗
PubMed1996

Use of iron chelators in preventing hydroxyl radical damage: adult respiratory distress syndrome as an experimental model for the pathophysiology and treatment of oxygen-radical-mediated tissue damage.

Tissue damage in many diseases is caused by hydroxyl radicals, generated during single electron reduction of oxygen. The first step is usually the formation of the superoxide radical. This radical is constantly formed in all living cells, and in particular during activation of phagocytes or during reoxygenation following ischaemia. Damage, however, only occurs in the presence of catalytic transition metals of which iron is the most important in human pathology. Oxygen-radical-mediated damage can be prevented by iron chelators, as has been demonstrated in numerous in vitro and in vivo experiments. A description is given as to how toxic oxygen products are formed in biological systems, and how organisms succeed in preventing autodestruction by scavenger molecules. The use of iron chelators to prevent oxygen radical damage is reviewed with emphasis on possible clinical applications. The adult respiratory distress syndrome is described in more detail as a model for oxygen-radical-mediated damage that can be successfully prevented with iron chelators.

Free Radical Scavengers↗
PubMed1995

Exogenous protoporphyrin inhibits Hep G2 cell proliferation, increases the intracellular hydrogen peroxide concentration and causes ultrastructural alterations.

Ultrastructural hepatocellular abnormalities in early stages of erythropoietic protoporphyria lead to hepatobiliary changes that cause overt liver disease in 5-10% of patients, not infrequently progressing to fulminant hepatic failure. This cannot be attributed solely to protoporphyrin crystal deposition in the liver. Hepatic redox systems have therefore been postulated as an equivalent for the photoreaction of protoporphyrin. We studied the dark effects of protoporphyrin and hematoporphyrin on HL60 and Hep G2 cells. Cell proliferation and intracellular H2O2 concentrations were assessed and related to the ultrastructural morphology. The incubation with protoporphyrin and hematoporphyrin resulted in a dose- and time-dependent inhibition of proliferation indices of Hep G2 cells. Flow cytometric analyses of intracellular H2O2 concentrations demonstrated a dose-dependent increase in both cell lines upon incubation with protoporphyrin. Hep G2 cells displayed ultrastructural alteration of the endoplasmatic reticulum and plasma membranes. Also 'cell blebbing' occurred. We conclude that exogenous protoporphyrin increases the intracellular H2O2 concentration and exerts a cytotoxic dark effect. This may contribute to the liver injury observed in erythropoietic protoporphyria.

Carcinoma, Hepatocellular↗
PubMed1995

The treatment of older adult patients with acute myeloid leukemia by triple infusion chemotherapy.

Adult patients (> or = 56 years old) with acute myeloid leukemia (AML) received induction therapy consisting of daunorubicin (60 mg/m2), etoposide (80 mg/m2), and cytarabine (200 mg/m2) daily for 5 days by continuous i.v. infusion (120 hours). The initial protocol was modified so that patients who were not hypoplastic after the first cycle of chemotherapy received a second cycle of treatment, utilizing 30 mg/m2 of daunorubicin/24 hours for 5 days plus etoposide and cytarabine as used in the first cycle. Two courses of consolidation with etoposide and cytarabine at the same dose and schedule were given. Patients were then maintained on cytarabine monthly. Twelve of 29 previously untreated patients (41%) achieved complete remission (CR). Excluding patients with secondary AML, 48% of all patients (11/23) achieved CR, including 56% > or = 70 years old. The median duration of CR was 41 weeks and median survival of CR patients was 54 weeks. Six of 13 patients (46%) with relapsed AML achieved CR. Toxicity in these older adult patients has been mild. Two patients (8%) had severe mucositis and one had severe (bloody) diarrhea. Most patients developed a mild transient asymptomatic rash. Triple infusion chemotherapy (TIC) may be as effective as other chemotherapy regimens for AML in older adults and has acceptable toxicity.

Acute Disease↗
PubMed1995

Post-operative erythropoiesis is limited by the inflammatory effect of surgery on iron metabolism.

The decrease in haemoglobin concentration commonly observed after major surgery is usually corrected by red cell transfusions or oral iron medication. The increased awareness of blood-transmissible diseases has led to the restrictive use of homologous blood and to interest in alternatives for correcting anaemia. We investigated the pathophysiology of postoperative anaemia by studying variables of erythropoiesis, iron metabolism, and inflammation in 48 consecutive patients who underwent total hip replacement. Haemoglobin concentration remained low during 14 days after surgery with only a mild increase in erythropoietin concentration and reticulocyte count. No increase in serum transferrin receptor concentration was observed during the first 2 weeks after surgery. Postoperative serum ferritin increased, whereas serum iron, transferrin and transferrin saturation decreased significantly. There was a marked increase in interleukin-6 and C-reactive protein with maximal values on the 1st and 4th post-operative day, respectively. At 6 weeks after surgery, haemoglobin concentration and variables of iron metabolism were almost at the preoperative level and serum transferrin receptor concentration was significantly increased, indicating increased erythropoietic activity. These changes were preceded by the normalization of interleukin-6 and C-reactive protein levels. Haemoglobin, iron, transferrin, and ferritin concentrations were not influenced by iron therapy during the postoperative period and no differences of erythropoietic and iron variables were observed between transfused and non-transfused patients. In conclusion, post-operative erythropoiesis is associated with an inflammatory effect of surgery on iron metabolism, which can explain, despite a slightly increased production of erythropoietin, the persistence of anaemia and the lack of effect of iron supplementation after surgery.

Aged↗
PubMed1995

The difference in liver pathology between sporadic and familial forms of porphyria cutanea tarda: the role of iron.

Porphyria cutanea tarda is a disorder of porphyrin metabolism, of which familial and sporadic forms have been described. Factors such as iron seem necessary for porphyria cutanea tarda to become clinically manifest. To study the relationship between iron and uroporphyrins in hepatocytes of patients with porphyria cutanea tarda, a morphological and morphometrical study was performed in 13 liver biopsies of patients with porphyria cutanea tarda (eight with sporadic porphyria cutanea tarda and five with familial porphyria cutanea tarda). In addition, possible differences in clinical and biochemical features and in histopathological findings between patients with sporadic porphyria cutanea tarda and familial porphyria cutanea tarda were investigated. Familial porphyria cutanea tarda patients presented at a younger age than sporadic porphyria cutanea tarda patients (42.4 +/- 5.3 vs. 57.3 +/- 8.6 years). Biochemical features were not different between sporadic porphyria cutanea tarda and familial porphyria cutanea tarda patients. Uroporphyrin crystals and a variable degree of liver siderosis were detected in the biopsies of all 13 patients. Uroporphyrin crystals were often found close to ferritin-like iron deposits. The morphometrical analysis showed that an increased mean area fraction of ferritin iron was associated with an increased mean area fraction of uroporphyrin crystals in hepatocytes of sporadic porphyria cutanea tarda and familial porphyria cutanea tarda patients. Moreover, the amount of uroporphyrin crystals was significantly higher in livers of familial porphyria cutanea tarda than sporadic porphyria cutanea tarda patients. These findings are consistent with the hypothesis that uroporphyria is precipitated by an iron-dependent process.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Copper, zinc-superoxide dismutase and hydrogen peroxide: a hydroxyl radical generating system.

Because superoxide (O2-.) is a mediator of inflammation, Cu,Zn-superoxide dismutase (Cu,Zn-SOD) has been employed as an anti-inflammatory compound. However, Cu,Zn-SOD can increase intra- and extracellular H2O2. This may react with the Cu atom of SOD in a Fenton-type reaction producing the hydroxyl radical (.OH). With a non-physiological concentration of H2O2 (0.8 mmol/l) to stimulate chemiluminescence (CL) at a level < 2 mV, it was observed that the addition of Cu,Zn-SOD (100 micrograms/ml) yielded an increase of 204.7 +/- 78.2 mV (P < 0.05). This increase in CL depended on the concentrations of H2O2 and Cu,Zn-SOD and was only seen with luminol (reacts with O2-. and .OH) but not with lucigenin (reacts with O2-.). No CL was observed when Cu,Zn-SOD was heat inactivated, or when Mn-SOD was used. Dissipators of H2O2, copper chelators and .OH scavengers attenuated this CL. In electron paramagnetic resonance, with the use of the spin-trap dimethylpyrroline-N-oxide (DMPO), it was demonstrated that, in the reaction between H2O2 and Cu,Zn-SOD, .OH was generated. The oxidation of keto-methylthiobutyric acid (KMB) to ethylene, assessed by gas chromatography, demonstrated that H2O2/Cu,Zn-SOD-generated .OH can react with KMB and not only with the SOD molecule itself. We conclude that H2O2 reduces SOD-bound Cu2+ to Cu1+ which, in reaction with H2O2 catalyses its reduction to OH. Whether this 'pro-inflammatory' reaction occurs in vivo remains to be established.

Acridines↗
PubMed1994

Lower homologous blood requirement in autologous blood donors after treatment with recombinant human erythropoietin.

The risk of blood-borne diseases has substantially increased the use of autologous blood transfusion. Many autologous donors, however, still need homologous transfusions. To find out whether recombinant erythropoietin (rhEPO) reduces requirements for homologous blood transfusion, we carried out a randomised, controlled trial, in which patients were stratified according to blood volume. We studied 95 autologous blood donors undergoing elective hip surgery. 50 patients were randomly assigned 500 U/kg rhEPO subcutaneously twice a week for 3 weeks, and 45 patients received no treatment (control group). The patients each donated two units of blood before surgery. Only 5 (10%) rhEPO-treated patients received homologous transfusions compared with 16 (36%) controls (p < 0.01). rhEPO was most useful in patients with a blood volume below 4 L and an estimated blood loss below 2 L or with a blood volume of 4-5 L and blood loss of 1-2 L. Continued administration of rhEPO caused no further increase in reticulocyte counts after the fourth injection, which was accompanied by a pronounced depletion of storage iron. rhEPO treatment had no effect on renal function, platelet count, or blood pressure. Subcutaneous rhEPO is an effective and safe way to reduce exposure to homologous blood in autologous donors. Its use can be restricted to a subpopulation of autologous blood donors, which improves the cost-effectiveness of this expensive approach.

Aged↗
PubMed1994

Iron-chelating agents in non-iron overload conditions.

PURPOSE: To review the current clinical experience with iron chelators in non-iron overload conditions. DATA SOURCES: The English-language literature was searched from 1983 through 1992 manually and using MEDLINE. STUDY SELECTION: Original articles, case reports, and abstracts addressing iron chelation. DATA EXTRACTION: Selected reports that described clinical applications of iron chelators in non-iron overload conditions were classified according to their stated mechanism of interference with disease activity. Articles stating the rationale for clinical use of iron chelators were also included. RESULTS: Iron chelators were used in non-iron overload conditions to produce antioxidant effects, antiproliferative effects, and antiprotozoal effects and for aluminum chelation. In addition, several reports described singular observations in various diseases. Deferoxamine is the only iron chelator available for clinical studies. The treatment-related (side) effects appear to be associated with patient iron levels. CONCLUSIONS: Randomized clinical trials are needed to confirm the promising effects of iron chelators in non-iron overload conditions. Oral iron chelators with fewer toxic effects are especially needed.

Aluminum↗
PubMed1994

Low-dose aspirin does not prevent thrombovascular accidents in low-risk haemodialysis patients during treatment with recombinant human erythropoietin.

Treatment of the anaemia of renal disease with recombinant human erythropoietin results in an improvement of haemostasis and an increased risk of thrombovascular accidents. In this prospective, placebo-controlled, double-blind, and cross-over study, the effects of low-dose acetylsalicylic acid (30 mg daily) on thrombotic and bleeding events during the initial period of treatment with erythropoietin in anaemic haemodialysis patients without previous thrombovascular accidents or known increased risk for thrombosis were investigated. During correction of the haematocrit and the first 3 months thereafter, group A (n = 68) received placebo and group B (n = 69) 30 mg acetylsalicylic acid daily. Cross-over took place after the 3rd month of a stable haematocrit. The study ended 3 months later. Target haematocrit (30-35%) was reached in 12.4 +/- 8 weeks (M +/- SD). In group A the bleeding time was 382 +/- 285 s, decreasing to 282 +/- 208 before cross-over (P < 0.01), and increasing to 395 +/- 271 (P < 0.05) thereafter. In group B the bleeding time was 390 +/- 381 s, 406 +/- 267 (NS), and 285 +/- 238 (P < 0.05) respectively. Twenty-two thrombovascular accidents were seen (16%, 13 during acetylsalicylic acid and 9 during placebo, NS), including 17 fistula thromboses. The incidence of bleeding events was not significantly different between regimens. In conclusion, erythropoietin treatment resulted in a reduction of the bleeding time. When 30 mg acetylsalicylic acid was taken during the treatment, the bleeding time did not decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Recombinant human erythropoietin in autologous blood donors: a dose-finding study.

A dose-finding study of recombinant human erythropoietin (rhEPO) was performed in 60 autologous donors who donated 2 units of blood prior to orthopaedic or vascular surgery. The correction of phlebotomy-induced anaemia was studied in four groups of 15 patients who received 500 U/kg, 250 U/kg, 125 U/kg or no (controls) rhEPO subcutaneously twice per week during a 3-week period. Haemoglobin concentration in the 500 U/kg, 250 U/kg and 125 U/kg group and in the controls reached respectively 99.2, 98.8, 91.9 and 87.1% of pre-phlebotomy value. Flow cytometric analysis of reticulocytes showed a steady increase of reticulocyte count as the dose increased. Maximal levels of high fluorescence reticulocytes which represent early changes of erythropoiesis were reached after 7 d and decreased thereafter in each group. Serum ferritin decreased significantly to approximately 50% of baseline values in all groups; no differences in the decrease of serum ferritin were observed between the patients who received rhEPO and the controls. No severe adverse events were observed. This study demonstrates a dose-related effect of rhEPO on erythropoiesis in autologous donors during the first 2 weeks. No further increase of reticulocytes was observed despite continued rhEPO therapy, which may be due to the inability of the mononuclear phagocytic system to release additional iron. To restore pre-phlebotomy haemoglobin concentration, a dose of 250 U/kg rhEPO was sufficient.

Aged↗