Combining iron chelators with the nucleoside analog didanosine in anti-HIV therapy.
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Anti-HIV Agents↗
Biomedical subjects
J J Marx
Publications and source records attributed to J J Marx.
Regulation of intracellular iron levels in iron-acceptor and iron-donor cells.
In recent years many new genes and proteins were identified with crucial functions in iron metabolism. This gave an explosion of our knowledge and understanding of iron related disorders. Mutations have been found that are responsible for disturbances in iron transport, leading to either iron overload or iron deficiency. For experts in the field, these new findings clarify the sky and open new routes for exploring hitherto hidden fields of research. For the physician, however, iron metabolism may become even more complicated. In this review, we have tried to assemble all new iron related genes into the context of pathophysiology. Important results from animal experiments, mainly derived from knockout mouse models, are included in this review as they often explain the phenotype of human disease.
Animals↗
Primary and secondary haemochromatosis.
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Hemochromatosis↗
Non-transferrin-bound iron is present in serum of hereditary haemochromatosis heterozygotes.
BACKGROUND: Hereditary haemochromatosis (HH) is a common autosomal recessive disease. Recently, HH heterozygosity has been identified as an independent risk factor for myocardial infarction and cardiovascular mortality. Iron may play an important role in atherogenesis by catalyzing peroxidation of low-density-lipoprotein (LDL), an essential step in atherogenesis. In iron overload conditions, non-transferrin-bound iron (NTBI) is found in serum, which can catalyze lipid peroxidation. We investigated whether sera of HH heterozygotes contain more NTBI than sera of normal controls. METHODS: In 27 treated HH homozygotes, 22 HH heterozygotes and 17 healthy control subjects, conventional parameters of iron status (serum iron, transferrin saturation, serum ferritin) were measured. NTBI was detected using HPLC after addition of nitrilotriacetic acid and pretreatment with cobalt. RESULTS: The conventional parameters of iron status were similar in the HH heterozygous group and the control group. NTBI was significantly higher in homozygotes compared to heterozygotes (1.79 micromol L-1 vs. 0.51 micromol L-1, 95% CI of the difference = 0.6-1.95, P < 0.001), and controls (1.79 micromol L-1 vs. - 0.3 micromol L-1, 95% CI of the difference = 1.36-2.81, P < 0.001). The difference in NTBI between the heterozygous subjects and control subjects was also significant (0.51 micromol L-1 vs. - 0. 3 micromol L-1, 95% CI of the difference = 0.05-1.57, P < 0.05). CONCLUSION: Phlebotomy treated HH homozygotes maintain a high and potentially harmful serum NTBI. HH heterozygotes have a higher serum NTBI than normal controls. The reported increased risk of cardiovascular events in heterozygous haemochromatosis may be explained by NTBI-catalyzed LDL peroxidation.
Cardiovascular Diseases↗
Total hip replacement surgery does not influence RBC survival.
BACKGROUND: RBC survival may be affected by mechanical or oxidative stress as well as the inflammatory effect of surgery, and thus may contribute to postoperative anemia. STUDY DESIGN AND METHODS: RBC survival was studied in otherwise healthy patients who underwent total hip replacement (THR). RBCs of five patients scheduled for elective THR surgery were labeled with (51)Cr 2 weeks before the surgical procedure. The disappearance of (51)Cr-labeled RBCs was calculated for the preoperative period and for the period from postoperative Day 4 on, when blood loss had ceased. RESULTS: The half-life of (51)Cr-labeled RBCs did not change if estimated before (29.0 +/- 4.4 days) and after (27.4 +/- 3.6 days, p = 0.55) surgery. This indicates that the lifespan of RBCs is not influenced by the surgical procedure. CONCLUSION: A decrease in RBC survival does not contribute to the pathogenesis of the anemia found after THR surgery.
Aged↗
Inhibition of human immunodeficiency virus type 1 replication in human mononuclear blood cells by the iron chelators deferoxamine, deferiprone, and bleomycin.
Replication of human immunodeficiency virus type 1 (HIV-1) can be influenced by iron. Hence, decreasing the availability of iron may inhibit HIV-1 replication. Deferoxamine and deferiprone, both forming catalytically inactive iron-chelator complexes, and bleomycin, by use of which iron catalyzes oxidative nucleic acid destruction, were investigated. Expression of p24 antigen in human monocyte-derived macrophages and peripheral blood lymphocytes (PBL) was reduced by all 3 iron chelators. In PBL, p24 reduction was mirrored by a decrease in proliferation after incubation with deferoxamine or deferiprone, suggesting that viral inhibition is closely linked to a decrease in cellular proliferation. In contrast, clinically relevant bleomycin concentrations reduced p24 levels by approximately 50% without affecting proliferation. When deferoxamine and the nucleoside analogue dideoxyinosine were used in combination, they acted synergistically in inhibiting HIV-1 replication. These observations suggest that iron chelators with different mechanisms of action could be of additional benefit in antiretroviral combination therapy.
Anti-HIV Agents↗
Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients.
OBJECTIVES: Critically ill patients often are anemic, which may impair oxygen delivery. Transfusion of red cells and supplementation with vitamins or iron are the usual therapeutic strategies, whereas only sporadic data are available on the use of epoetin alfa in these patients. We investigated endogenous erythropoietin (EPO) production and the response to epoetin alfa in anemic intensive care unit (ICU) patients. DESIGN: Randomized, open trial. SETTING: Multidisciplinary ICU in a single secondary care center. PATIENTS: Thirty-six critically ill patients admitted to the ICU who became anemic (hemoglobin concentration, <11.2 g/dL or <12.1 g/dL in case of cardiac disease) were randomized to one of three study groups. INTERVENTIONS: All patients received folic acid (1 mg) daily. The control group received no additional therapy, the iron group received 20 mg of iron saccharate intravenously (iv) daily for 14 days. The EPO group received iv iron and epoetin alfa (300 IU/kg) subcutaneously on days 1, 3, 5, 7, and 9. MEASUREMENTS AND MAIN RESULTS: Blood and reticulocyte counts were measured daily for 22 days. Serum EPO, C-reactive protein, serum transferrin receptor, and iron variables were measured on days 0, 2, 6, 10, and 21. Blood loss and red cell transfusions were recorded. Serum EPO concentrations were inappropriately low for the degree of anemia at baseline, with no difference between patients with and without renal failure. Exogenous administration of EPO increased EPO concentrations from 23+/-13 to a maximum of 166+/-98 units/L on day 10 (p < .05). Reticulocyte count increased exclusively in the EPO group from 56+/-33 x 10(9)/L to a maximum of 189+/-97 on day 13 (p < .05). Serum transferrin receptor rose only in the EPO group from 3.7+/-1.4 to 8.6+/-3.1 mg/L on day 10 (p < .05) and remained elevated on day 21, indicating an increase in erythropoiesis. Hemoglobin concentration and platelet count remained identical in the three study groups. CONCLUSION: Endogenous EPO concentrations are low in critically ill patients. The bone marrow of these patients is able to respond to exogenous epoetin alfa, as shown by elevated concentrations of reticulocytes and serum transferrin receptors.
Adult↗
Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women.
Background-The genetic background of hereditary hemochromatosis (HH) is homozygosity for a cysteine-to-tyrosine transition at position 282 in the HFE gene. Heterozygosity for HH is associated with moderately increased iron levels and could be a risk factor for cardiovascular death. Methods and Results-We studied the relation between HH heterozygosity and cardiovascular death in a cohort study among 12 239 women 51 to 69 years of age residing in Utrecht, the Netherlands. Women were followed for 16 to 18 years (182 976 follow-up years). The allele prevalence of the HH gene in the reference group was 4.0 (95% CI 2.9 to 5.4). The mortality rate ratios for HH heterozygotes compared with wild types was 1.5 (95% CI 0.9 to 2.5) for myocardial infarction (n=242), 2.4 (95% CI 1.3 to 3. 5) for cerebrovascular disease (n=118), and 1.6 (95% CI 1.1 to 2.4) for total cardiovascular disease (n=530). The population-attributable risks of HH heterozygosity for myocardial infarction and cerebrovascular and total cardiovascular death were 3. 3%, 8.8%, and 4.0%, respectively. In addition, we found evidence for effect modification by hypertension and smoking. Conclusions-We found important evidence that inherited variation in iron metabolism is involved in cardiovascular death in postmenopausal women, especially in women already carrying classic risk factors.
Aged↗
Preoperative pulmonary evaluation.
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Humans↗
Iron, atherosclerosis, and ischemic heart disease.
OBJECTIVE: To review the epidemiological and experimental data concerning iron and the development of atherosclerosis and ischemic heart disease. DATA SOURCES: The English-language literature was searched from 1981 through 1998 manually and using MEDLINE and Current Contents. Important references in the articles that were found were also included in this review. RESULTS: There is growing epidemiological evidence for a relationship between iron levels and cardiovascular disease. Some experimental data support the role of iron in the process of lipid peroxidation, the first step in the formation of atherosclerotic lesions. Macrophages and endothelial cells are involved in this process, but the exact mechanism and the sites of the interactions between these cells, iron, and low-density lipoprotein are still unknown. CONCLUSIONS: Strong epidemiological evidence is available that iron is an important factor in the process of atherosclerosis. Epidemiological studies, eg, prospective follow-up studies in blood donors, may clarify the cardiovascular benefits of iron depletion. Knowledge of the molecular mechanism of iron-related cardiovascular disease is still limited. We speculate that catalytically active iron species modify low-density lipoprotein levels to interact with the macrophage oxidized low-density lipoprotein receptor. Both nontransferrin-bound plasma iron and hemoglobin are candidates for such interactions.
Arteriosclerosis↗
High rat food vitamin E content improves nerve function in streptozotocin-diabetic rats.
Antioxidants can improve nerve dysfunction in hyperglycaemic rats. We evaluated whether the standard supplementation of rat food with vitamin E (normally added for preservation purposes) or high-dose vitamin E treatment improves nerve conduction in maturing streptozotocin-diabetic rats, a model widely used to study diabetic neuropathy. Hyperglycaemic rats received food containing 25 mg/kg (non-supplemented), 70 mg/kg (standard food) or 12 g/kg (high-dose) vitamin E. Non-diabetic controls received non-supplemented food. Sciatic and tibial sensory and motor nerve conduction velocity were decreased in all diabetic animals. In comparison with standard feeding, the non-supplemented diabetic rats showed lower plasma vitamin E levels but no significant change in nerve conduction. High-dose treatment prevented nerve dysfunction by 50%, and led to attenuated endoneurial lipid peroxidation (measured as malondialdehyde). We conclude that high doses of vitamin E, but not standard vitamin E supplementation of rat food partially prevent nerve dysfunction in young adult streptozotocin-diabetic rats.
Animals↗
[Diagnosis and treatment of primary hemochromatosis].
Chronic fatigue, arthralgia, infertility, impotence, cardiac disease, diabetes and abnormality of liver enzymes could point to the presence of haemochromatosis. A patient with one of these symptoms, a normal haemoglobin content, but an increased transferrin saturation and serum ferritin level most probably has a primary haemochromatosis. Most primary haemochromatoses have a genetic background. The diagnosis 'HFE-related haemochromatosis' is made when a homozygous Cys282Tyr mutation is found in the HFE-gene. However, in approximately 10% of the patients with the clinical features of primary haemochromatosis this mutation is absent. The treatment of primary haemochromatosis consists of regular phlebotomy. Liver biopsy is indicated if fibrosis, cirrhosis or another hepatic disease is suspected. Family screening of first-grade relatives is indicated for all patients with primary haemochromatosis.
Cysteine↗
Blood-induced joint damage: a human in vitro study.
OBJECTIVE: To investigate mechanisms underlying cartilage damage caused by brief exposure of cartilage to blood, such as that occurring during intraarticular bleeding. METHODS: Human articular cartilage was cultured for 4 days in the presence of blood (components; 7.5-50% volume/volume). The synthesis of cartilage matrix, as determined by proteoglycan synthesis (incorporation of 35SO4(2-)), was measured directly after exposure and after a recovery period of 20 days, during which the cartilage was cultured in the absence of blood or blood components. The production of the cytokines interleukin-1 (IL-1) and tumor necrosis factor a (TNFalpha), which have a destructive effect on cartilage, was determined by enzyme-linked immunosorbent assay, and the viability of chondrocytes was determined by measuring lactate dehydrogenase release and with electron microscopy. The involvement of oxygen metabolites was evaluated by using N-acetylcysteine. RESULTS: Brief exposure to blood resulted in dose-dependent inhibition of proteoglycan synthesis. The combination of mononuclear cells and red blood cells was responsible for this effect. The effect was irreversible, independent of IL-1 and TNFalpha production, and was accompanied by chondrocyte death. These effects were partially prevented by N-acetylcysteine. CONCLUSION: Brief exposure of cartilage to blood, as occurs after a single episode or a limited number of bleeding episodes, results in lasting cartilage damage in vitro, in which cytotoxic oxygen metabolites play a role.
Aged↗
Mineralocorticoid status and endocrine dysfunction in severe hemochromatosis.
Selective iron deposition in the zona glomerulosa of the adrenal cortex is observed in hemochromatosis. Hypoaldosteronism should be excluded before starting venesection, to avoid long-term volume depletion. We evaluated the aldosterone status in patients with hemochromatosis. As other endocrine organs can be affected by the disease as well, we simultaneously evaluated anterior pituitary, gonadal, thyroid and pancreatic beta-cell activity. Nine patients with hereditary or acquired hemochromatosis and highly increased plasma ferritin levels were investigated. In patients, liver cirrhosis had been confirmed histologically. Five patients complained of sexual dysfunction, and one had impaired glucose tolerance. Plasma aldosterone (PA) and renin activity (PRA) were measured after a period of normal (100 mmol/day) and low (10 mmol/day) sodium intake. A combined anterior pituitary function test and a glucagon stimulation test were undertaken to evaluate other endocrine functions. Both PA and PRA levels were decreased in one patient with liver cirrhosis, who also presented attenuated cortisol, prolactin and gonadotrophin secretion. No patients had signs of primary hypoaldosteronism with hyperreninemia. Hypogonadotropic hypogonadism was observed in 3 males and 1 female. Pituitary ACTH reserve was impaired in 2, GH and prolactin response in 1, and thyroid function in none of the patients. Glucagon-stimulated plasma C-peptide was impaired in one patient. In conclusion, primary aldosterone deficiency was not observed in patients with severe iron overload. Hyporeninemic hypoaldosteronism was found in one patient who also presented other endocrinopathies. Hypogonadotropic hypogonadism is the most frequent endocrine abnormality in hemochromatosis.
Adrenal Glands↗
The concept of iron bioavailability and its assessment.
In this review a broad overview of historical and current methods for the assessment of iron bioavailability was given. These methods can be divided into iron solubility studies, iron absorption studies, endpoint measures, and arithmetic models. The pros and cons of all methods were discussed. First, studies on in vitro and in vivo iron solubility have been described. The disadvantages of iron solubility include the impossibility of measuring absorption or incorporation of iron. Furthermore, only the solubility of nonheme iron, and not heme iron, can be studied. Second, we focused on iron absorption studies (either with the use of native iron, radioiron or stable iron isotopes), in which balance techniques, whole-body counting or postabsorption plasma iron measurements can be applied. In vitro determination of iron absorption using intestinal loops or cell lines, was also discussed in this part. As far as absorption studies using animals, duodenal loops, gut sacs or Caco-2 cells were concerned, the difficulty of extrapolating the results to the human situation seemed to be the major drawback. Chemical balance in man has been a good, but laborious and expensive, way to study iron absorption. Whole-body counting has the disadvantage of causing radiation exposure and it is based on a single meal. The measurement of plasma iron response did not seem to be of great value in determining nutritional iron bioavailability. The next part dealt with endpoint measures. According to the definition of iron bioavailability, these methods gave the best figure for it. In animals, the hemoglobin-repletion bioassay was most often used, whereas most studies in humans monitored the fate of radioisotopes or stable isotopes of iron in blood. Repletion bioassays using rats or other animals were of limited use because the accuracy of extrapolation to man is unknown. The use of the rat as a model for iron bioavailability seemed to be empirically based, and there were many reasons to consider the rat as an obsolete model in this respect. The double-isotope technique was probably the best predictor of iron bioavailability in humans. Disadvantages of this method are the single meal basis and the exposure to radiation (as far as radioisotopes were used). Finally, some arithmetic models were described. These models were based on data from iron bioavailability studies and could predict the bioavailability of iron from a meal.
Animals↗
Nerve conduction and antioxidant levels in experimentally diabetic rats: effects of streptozotocin dose and diabetes duration.
Oxidative stress supposedly plays a role in the pathogenesis of diabetic neuropathy. We have studied whether a variation in the streptozotocin (STZ) dose or diabetes duration affects the outcome of measurements of oxidative damage in relation to nerve conduction. In experiment 1, we induced diabetes in rats using 40 or 60 mg/kg STZ intravenously and assessed sciatic nerve conduction velocity. After 18 weeks, we measured plasma malondialdehyde (MDA) and red blood cell (RBC) and nerve glutathione levels. We observed a dose-dependent effect of STZ on body weight, and to a lesser extent on nerve conduction, but not on RBC or nerve glutathione and plasma MDA. In experiment 2, we administered a fixed dose of STZ (40 mg/kg) and measured antioxidants and MDA in RBCs, plasma, and sciatic nerve after 2, 4, 8, and 18 weeks in diabetic and control rats. RBC glutathione decreased in diabetic animals initially, but did not differ from control values after week 4. Plasma total glutathione increased until week 8. The ratio of total to oxidized glutathione in the sciatic nerve from diabetic animals paralleled the decrease observed in RBCs, and subsequently increased compared with controls. Nerve catalase increased in diabetic animals. Endoneurial MDA remained unchanged, whereas plasma MDA increased and RBC superoxide dismutase (SOD) decreased in the diabetic group. We conclude that differences in antioxidant levels between STZ-diabetic and control rats depend on the duration of hyperglycemia. Furthermore, dose-related effects of STZ on nerve conduction are not reflected in endoneurial lipid peroxidation or glutathione.
Animals↗
Haematocrit in elite athletes.
It is possible to increase haemoglobin (Hb) and haematocrit (Ht) to non-physiological values by injecting recombinant human erythropoietin (rhEPO). Although this treatment may result in a better performance of athletes, it may also cause a health risk. To prevent doping with rhEPO, the Union Cycliste Internationale has decided to exclude male cyclists with Ht>0.50 and female cyclists with Ht>0.47 from competition. These cut-off values, however, may result in a non-justified exclusion of clean athletes. To test this hypothesis, we measured the Ht of elite athletes (50 men and 41 women) during a total study period of 43 months. Ht was compared with that in healthy control subjects (134 men and 144 women). No significant differences in Ht were detected between male elite athletes and their references and female elite athletes and their references (P>0.05). In both populations, however, male subjects were found with Ht>0.50, 6 controls and 5 elite athletes (4 highlanders and 1 lowlander). In the female subjects 5 controls but not one of the athletes exceeded a Ht>0.47. "Increased" Ht values among athletes were mainly seen in highlanders. The study shows that it is very difficult to set up a decision value for Ht with regard to doping by erythropoietin.
Adult↗
Potential role of CCR5 polymorphism in the development of AIDS dementia complex.
The chemokine receptor CCR5 and to a lesser extent CCR2b and CCR3 have been shown to serve as coreceptors for HIV-1 entry into macrophages. Individuals that are homozygous for a defective CCR5 allele (DeltaCCR5) are highly, but not fully, resistant to infection with HIV-1. Here, we want to emphasize the importance of DeltaCCR5 in in vitro as well as in vivo studies. We provide data that suggest that CCR5 polymorphism may affect the onset of AIDS dementia complex in vivo and data that show that HIV-1 replication is influenced by the DeltaCCR5 allele in vitro. Knowing the CCR5 genotype of an individual will help to better interpret research results and may even provide new information about mechanisms of disease.
AIDS Dementia Complex↗