[The role of zinc in the homeostasis of the human organism]. / A cink szerepe az emberi szervezet homeosztázisában.

The concentrations of essential metal ions in various compartments of the human body are accurately regulated (homeostasis). Irregularities in the accumulation or depletion of the trace elements may lead to well characterized diseases. This review covers the metabolism of zinc regulations by which the intracellular and extracellular levels are kept in physiological range, biological functions, as well as pathological states that develop in its altered metabolism. The focus is on the molecular mechanisms of zinc ion traffic between compartments of the body and cells and their sequestration, gene regulations that regulate the ion fluxes via biological membranes and their storage, zinc-mediated cell and tissue damages, and development of symptoms in zinc deficiency is also discussed.

Studies of a naturally occurring sulfur-induced copper deficiency in Przewalski's gazelles.

The Przewalski's gazelles in the Hudong area of the Qinghai Lake area in China were affected by an ailment characterized by pica, emaciation, dyskinesia, loss of appetite, and anemia. Concentrations of copper (Cu) in soil and forage from affected and unaffected areas were similar and within the normal range, but concentrations of sulfur (S) in soil and forage were significantly higher (P < 0.01) in affected than in unaffected areas. Concentrations of Cu in blood, hair, and liver from the affected Przewalski's gazelles were significantly lower (P < 0.01) than those in healthy animals. Affected Przewalski's gazelles showed a hypochromic microcytic anemia and a low level of ceruloplasmin. Oral administration of copper sulphate (CuSO(4)) prevented and cured the disease. We conclude that the disorder of Przewalski's gazelles was caused by secondary Cu deficiency, mainly due to high S content in forage.

[Chronic lead poisoning-- a" forgotten" cause of anemia]. / Intoxicatia cronica cu plumb--o cauza "uitata" a sindromului anemic.

We present the case of a female patient with a chronic hypersideremic anemia associated with digestive and neurological symptoms, with a long time ignored toxic history. The diagnose was based on very high levels of lead in serum and urine, very high levels of D-aminolaevulinic acid in the urine, and the presence of basophilic stippling of erythrocytes in the smear of the patient. Lead intoxication was due to ingestion of home-made alcohol (domestic devices made from lead mixtures) and of yogurt preserved in lead-glazed mugs.

Subchronic and chronic toxicity of ingested 1,3-dichloropropene in dogs.

The potential toxicologic effects to dogs of 1,3-dichloropropene (1, 3-D), a soil fumigant used for the control of nematodes, were investigated. The 13-week subchronic toxicity study consisted of male and female beagle dogs (4/sex/dose group) given approximately 0, 5, 15, or 41 mg 1,3-D/kg body wt/day (approximately equivalent amounts of cis and trans isomers) via their diets. The 1-year chronic toxicity study consisted of male and female beagle dogs (4/sex/dose group) provided diets delivering approximately 0, 0.5, 2. 5, or 15 mg/kg body wt/day. The test material was stabilized in the feed by microencapsulation in a starch/sucrose matrix (80/20). In both the 13-week and the 1-year studies, the primary effect of 1,3-D in male and female dogs ingesting a dosage of >/=15 mg/kg/day was hypochromic, microcytic anemia. The anemia was regenerative, with increased erythropoietic activity characterized by polychromasia of erythrocytes and increased numbers of reticulocytes in peripheral blood. In the 13-week study, the anemia in dogs given 41 mg/kg/day progressively worsened over time, while the anemia in dogs given 15 mg/kg/day remained relatively constant between 42 and 90 days of dosing. Partial reversal of the anemia of high-dose animals occurred during a 5-week recovery period following the 13-week dosing regimen. In the 13-week study, terminal fasted body weights of males given 15 or 41 mg/kg/day were decreased 3 and 28%, respectively, and body weights of females given 5, 15, or 41 mg/kg/day were decreased 4.5, 12, and 24%, respectively, relative to controls. Males given 5 mg/kg/day for 13 weeks had no change in body weights relative to controls. In the 1-year study, the hypochromic microcytic anemia in dogs given 15 mg/kg/day remained relatively constant in severity between 3 and 12 months of treatment. Histopathologic alterations associated with anemia in the 1-year study consisted of increased hematopoiesis of the bone marrow and increased extramedullary hematopoiesis of the spleen. Body weights of males given 15 mg/kg/day were 5-12% lower than controls during the first 13 weeks of the study and 13-19% lower than controls during the remaining 9 months. Body weights of females given 15 mg/kg/day were 5-14% lower than controls over the majority of the dosing period. Males and females given 0.5 or 2.5 mg/kg/day for 1 year had no change in body weights relative to controls. A no-observed-effect level of 2.5 mg/kg/day was established for male and female dogs from the 1-year study.

Randomized phase III trial evaluating the role of erythropoietin in the prevention of chemotherapy-induced anemia.

PURPOSE: Although erythropoietin (EPO) is known to be useful in treating chemotherapy-induced anemia, few data are available on its potential preventive role. The aim of this study was to evaluate the ability of EPO in preventing the development of clinically significant anemia in patients treated with chemotherapy. PATIENTS AND METHODS: Sixty-two early-stage breast cancer patients undergoing accelerated adjuvant chemotherapy were randomized to receive EPO 150 U/kg three times a week or no additional treatment. Chemotherapy consisted of six cycles of cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2 (CEF) intravenously on day 1, every 2 weeks with the support of granulocyte colony-stimulating factor (G-CSF), 5 microg/kg subcutaneously from day 4 to day 11. RESULTS: Throughout the six cycles of chemotherapy, EPO-treated patients maintained stable values of hemoglobin, whereas control patients developed a progressive anemia. At the end of chemotherapy, the mean (+/- SD) hemoglobin decrease in the control group was 3.05 g/dL (+/- 1.0; 95% confidence interval [CI], 2.6 to 3.5), whereas in the EPO group it was 0.8 (+/- 1.4; 95% CI, 0.3 to 1.4). Clinically significant anemia (hemoglobin < or = 10 g/dL) occurred in 16 patients (52%; 95% CI, 33 to 69) in the control arm and in no patient (0%; 95% CI, 0 to 14) in the EPO arm (P = .00001). CONCLUSION: EPO prevents anemia in patients undergoing chemotherapy. Further trials are required to identify subsets of patients in which the preventive use of this drug could be cost-effective.

Increases in hemoglobin concentration and iron needs in response to growth hormone treatment.

We studied 36 children with short stature during the initial 6 months of recombinant human growth hormone treatment and found an elevation in the mean concentration of hemoglobin (p < 0.001). The elevation was highest in the eight patients with bone dysplasia (p < 0.001). The mean concentration of serum ferritin decreased (p < 0.01) and that of serum transferrin increased (p < 0.001). The prevalence of iron deficiency increased from 6 patients (17%) with initial deficiency to 20 (56%) patients after therapy, indicating that iron supplementation should be considered in children treated with recombinant human growth hormone.

Prolonged clinical use of a heme oxygenase inhibitor: hematological evidence for an inducible but reversible iron-deficiency state.

The heme oxygenase inhibitor tin (Sn4+)-mesoporphyrin, administered to two 17-year-old Crigler-Najjar type I patients during a 400-day study to lower plasma bilirubin levels, also produced changes, beginning approximately 50 days after initiation of treatment, in hematological and iron metabolism indices consistent with the development of iron deficiency anemia. These indices were responsive to iron supplementation and reverted to normal after termination of inhibitor treatment. Tin-mesoporphyrin enhances biliary heme excretion and inhibits intestinal heme oxygenase when administered orally or parenterally; the changes in blood indices could thus reflect, in part, blockade of heme catabolism and therefore of uptake of heme-derived iron, by intestinal epithelium. This action of the inhibitor suggests that such agents may facilitate studies involving aberrant metabolism of heme-derived iron in humans and that they merit further investigation with respect to their potential value in enhancing iron disposal in certain disorders such as those related, for example, to transfusion-induced iron overload states.

[The prevention of congenital developmental anomalies in rats]. / Profilaktika vrozhdennykh anomalii razvitiia u krys.

Preventive administration of Eleutherococcus XXX extract during prenatal and pre-embryonic periods of development prevents embryotoxic effect of subsequent treatment of pregnant rats with ethanol and sodium salicylate. Eleutherococcus abolishes embryotoxic and teratogenic effects of ethanol manifested against the background of experimental syndrome of iron deficit in pregnant females. Mechanism of its antiteratogenic action is probably based on stimulation of cell detoxification mechanisms, increase in energy potential of cells, as well as on stabilization of structural and functional state of cell membranes.

Experimental selenium toxicity in guinea pigs: haematological studies.

Haematological studies were conducted in recently weaned guinea pigs fed selenium-enriched barley (organic selenium) and barley mixed with sodium selenite (inorganic selenium). An attempt was made to study the effect of sodium arsenite supplementation in sodium selenite toxicity. A significant (p less than 0.01) decrease was noticed in the mean values of haemoglobin, haematocrit, mean corpuscular haemoglobin and mean corpuscular volume thereby indicating a microcytic hypochromic anaemia. The anaemia was comparatively more marked in guinea pigs fed selenium-enriched barley than in those kept on barley mixed with sodium selenite. There was a significant decrease in total leucocyte count which was the result of lymphocytopenia in organic toxicity and a decrease in both neutrophils and lymphocytes in inorganic toxicity. Dietary supplementation with sodium arsenite resulted in less reduction in the mean values of different erythrocytic indices thereby indicating that addition of sodium arsenite has some protective effect against toxicity with sodium selenite.

Studies on the role of iron in zinc toxicity in chicks.

The interaction of dietary iron and zinc was studied in chicks. Zinc was found to be more toxic in iron-deficient animals than iron-supplemented animals as measured by hemoglobin concentrations and growth. Analyses of the kidney and liver for iron and zinc were carried out. As the level of iron was increased from 0-1000 ppm supplementation, the concentration of liver zinc increased. The organ levels of iron were decreased as the dietary zinc levels were increased from 0-5000 ppm. Radioisotope studies using 65Zn revealed that the iron content of the diet did not affect absorption of zinc. Administration of the isotope, either in an intestinal segment or intravenously, resulted in more zinc being taken up by the liver in the iron supplemented animals. This was especially noted when the ratio of the isotope in liver to that in the blood was compared. Gel chromatography of kidney and liver homogenates revealed that iron deficiency resulted in less zinc being eluted in a volume characteristic of metallothionein compared to homogenates of organs from iron supplemented animals. The results indicate that iron-supplemented animals have a greater capacity for sequestering zinc on metallothionein than do iron-deficient animals. Conversely, iron-deficient chicks were more susceptible to the effects of zinc toxicity than are iron-adequate chicks.

Studies on the role of iron in the reversal of cadmium toxicity in chicks.

Studies were conducted to determine the effect of dietary iron (Fe) levels ranging from a deficiency to an excess on the toxicity of cadmium (Cd) in chicks. In Fe-deficient animals, cadmium was found to be more toxic than in Fe supplemented animals as measured by growth. The liver Cd burdens were increased significantly in the presence of dietary Fe supplementation, and there was a significant Cd-Fe interaction in the Cd concentration of the kidney, indicating that iron deficiency increased the concentration of Cd in the kidneys of those chicks receiving this element. Cd tended to reduce the Fe concentration in both the liver and kidney. The absorption of Cd as measured by the amount of 109Cd that disappeared from an isolated duodenal segment in one h was not affected by the Fe content of the diet, but the amount of isotope appearing in the liver compared to the amount present in the blood was increased in the Fe supplemented chicks. Separation of the Cd binding ligands by column chromatography revealed that more of the Cd in the liver, but not the kidney, was associated with ligands which eluted in a column volume that contained metallothionein in those chicks receiving Fe than in the livers from Fe deficient animals. The inverse relationship between the amount of Cd bound to the metallothionein containing fraction and toxicity may be related causally.

Aluminium-induced, reversible microcytic anemia in chronic renal failure: clinical and experimental studies.

Ten chronic hemodialysis patients with severe aluminium (Al) intoxication developed a microcytic anemia despite oral iron supplementation. Their microcytosis was reversible after deionization of the dialysis water. Ten age and sex matched hemodialysis patients who were not Al intoxicated but who had a comparable treatment schedule and time on dialysis had no such microcytosis. In order to investigate a possible direct role of Al we intoxicated uremic rats by daily (6/7 days a week) intraperitoneal injections of 30 nmoles/day of aluminium. After 3 months, the Al-intoxicated uremic rats had a significantly lower hematocrit (34.7%), hemoglobin (12.0 g/dl), and MCV (52.5 fl) than the control, vehicle-injected uremic animals (37.4%, 13.1 g/dl and 60.4 fl., respectively). The reticulocyte counts of the intoxicated rats were increased. Serum iron and transferrin iron binding capacity were unchanged. Thus aluminium intoxication of the uremic organism leads to a microcytic anemia possibly by interfering directly with normal hemoglobin synthesis.

Effects of diet and nutrition on drug therapy.

Foods containing biochemically active substances have been used therapeutically throughout the ages and continue to function as important adjuncts to drug therapy. But naturally-occurring substances can also have adverse effects, as can the food additives of today. Food--drug interactions can alter the effect of therapeutic agents or cause adverse reactions where none had existed. These problems are often aggravated in elderly patients, who may suffer from malnutrition (e.g., protein insufficiency) or altered food metabolism. Malnutrition in the elderly can be caused by disease, socioeconomic factors, or simply by the deterioration of eating habits. Although nutritional requirements decrease with age, the elderly still need nutrients for the repair of normal structures and for energy. The nutritional needs of the elderly remain poorly defined. Drugs can alter food metabolism, which, in turn, can affect drug action. Many food--drug interactions are well documented; drug absorption and drug elimination are often affected by an altered food metabolism. Particular problems include salicylate-induced iron deficiency, poor monitoring of vitamin metabolism and the effects of vitamin underuse and overuse, and lack of knowledge about the effects of long-term drug use on vitamin metabolism. An additional problem is the presence of potentially harmful materials in non-prescription products.

Comparative toxicity of feeding dried urban sludge and an equivalent amount of cadmium to swine.

Three rations, an 18.71% protein swine starter diet (control), a basal diet containing 83 micrograms of Cd/g of diet, or a basal diet containing 50% Chicago sewage sludge (CSS) providing 83 micrograms Cd/g of diet, were given to weanling pigs for 9 weeks. Depressed growth occurred in both groups given Cd-treated diets in comparison with growth in pigs fed the control ration. Microcytic, hypochromic anemia occurred in the group given the Cd-supplemented diet, but there were no significant differences in the hematologic values between pigs in the control and CSS-supplemented diets. Toxicosis probably resulted from combining CSS as 50% of the diet due to a deficiency of available protein or other essential nutrients or from the accumulation of hazardous chemical residues including Cd, Cu, Cr, Hg, Ni, or Zn. An increased amount of Fe in the CSS-treated ration apparently protected the pigs against the microcytic, hypochromic anemia.

Treatment of primary osteoporosis with fluoride and calcium. Clinical tolerance and fracture occurrence.

Thirty-six patients with primary osteoporosis were treated for up to six years with sodium fluoride, calcium supplements, and, in 24 patients, vitamin D. Major adverse reactions (synovitis, painful plantar fascial syndrome, recurrent vomiting, or anemia) occurred in 15 patients (42%). New vertebral fractures occurred at a rate of 329 fractures per 1,000 years of observation. Almost half of them occurred during the first year of therapy, and they were only one sixth as frequent in 12 patients who had fluoride-induced increased trabeculation on vertebral roentogenograms. Nevertheless, until long-term safety and antifracture efficacy are better established, this regimen should continue to be restricted to investigational use.