Can iron be teratogenic?

Several kinds of evidence indicate that elevated iron during the 3-8 week embryonic (organogenesis) period of human gestation may be teratogenic. (1) In the embryonic period, the natural maternal absorption of food iron is 30% below the estimated daily iron loss. (2) As compared with maternal serum, embryonic fetal coelomic fluid contains only one-fourth as much iron but nearly six times the quantity of the iron withholding protein, ferritin. (3) In the embryonic period, intraplacental oxygen pressure is 2-3 times lower than in the subsequent fetal growth period. (4) Iron is a strong inducer of emesis which peaks in the embryonic period. (5) In a murine gestation model, iron was neurotoxic at a sharp peak of 8-9 days. Thus it would be prudent, in human pregnancy, to delay any needed iron supplementation until the embryonic period has been completed.

First trimester curtailment of iron absorption: innate suppression of a teratogen?

In human pregnancies, maternal absorption of iron is markedly curtailed in the first trimester. In a murine model, iron was teratogenic in the analogous embryonic period. Although iron is a weak mutagen, it is a powerful oxidant and a catalyst of formation of hydroxyl radicals. Studies are needed to determine if there might be an association of first trimester iron supplementation with miscarriage/fetal abnormalities.

Is addition of iron to processed foods safe for iron replete consumers?

The great majority of US adults are iron replete; indeed, some are burdened with an excessive amount of the metal. Nevertheless, iron continues to be added by food processors to such items as flour, other grains and ready-to-eat cereals. In some cases, actual added quantities exceed the labeled amounts. Iron is a dangerous pro-oxidant as well as a mutagen and carcinogen. The metal is a serious risk factor for a variety of cardiovascular, endocrine, infectious, neoplasmic, neurodegenerative, orthopedic and respiratory diseases. For many of the conditions, iron can be a sole initiator or a cofactor in promoting the disease. For others, iron deposits are found in relevant tissue sites. For numerous additional diseases, iron is associated with elevated disease incidence. Accordingly, critical evaluation of the indiscriminate practice of adding the metal to processed foods is overdue.

Are iron supplements appropriate for iron replete pregnant women?

Iron replete pregnant women often are routinely advised to take a daily supplement of 30-40mg iron. An extensive review of controlled trials has failed to demonstrate that this practice improves clinical outcome of mother or newborn. However, this iron loading has long been assumed to be harmless. Recently, two hazardous complications of pregnancy, gestational diabetes and pre-eclampsia, have been recognized to be associated with iron loading. Accordingly, it may be appropriate to consider performing, at the patient's initial prenatal medical visit, a serum ferritin test to ascertain iron status. This simple procedure would enable evidence-based medical practice to replace mass medication with iron, a potentially toxic element.

Iron loading: a risk factor for osteoporosis.

Iron loaded persons are at increased risk for infection, neoplasia, arthropathy, cardiomyopathy and an array of endocrine and neurodegenerative diseases. This report summarizes evidence of increased risk of iron loading for osteoporosis. Iron suppresses bone remodeling apparently by decreasing osteoblast formation and new bone synthesis. Low molecular mass iron chelators as well as a natural protein iron chelator, lactoferrin, may be useful in prevention of osteoporosis.

Iron-enriched rice: the case for labeling.

ABSTRACT Genetically modified rice that incorporates twofold to threefold increased amounts of iron is being developed. The product could provide improved nutrition to iron-deficient persons but may be a health hazard to large numbers of humans who are prone to iron overload. Clinical disorders such as African siderosis, beta-thalassemia, hemochromatosis, and alcoholic siderosis are of special concern. Conditions associated with iron loading include fatigue and depression; arthritis; endocrine disorders such as stunted growth, impotence, and diabetes; gastrointestinal maladies; infections and malignancies; several neurological diseases; and, not least, cardiovascular system decay. Therefore, it would be prudent to label sacks of iron-enriched rice to indicate that "this product may be dangerous to persons with iron loading conditions".

Angiotensin II type 2 receptor blockade amplifies the early signals of cardiac growth response to angiotensin II in hypertrophied hearts.

BACKGROUND: We have previously shown that the acute molecular growth response of new protein synthesis and protein kinase C activation in response to angiotensin II (Ang II) is altered in left ventricular (LV) hypertrophy compared with normal hearts. We have also shown an upregulation of Ang II type 2 (AT2) receptors in hypertrophied hearts relative to controls. Activation of AT2 receptors is proposed to counteract growth effects of AT1 receptor in response to Ang II. Thus, we tested the hypothesis that in hypertrophied hearts, the AT2 receptor mediates inhibitory effects on the new cardiac protein synthesis in response to acute Ang II stimulation. METHODS AND RESULTS: Flaccid buffer-perfused adult normal and hypertrophied rat hearts were perfused with Ang II 10(-8) mol/L plus prazosin 10(-7) mol/L or Ang II plus the AT2 blocker PD 123319 5x10(-7) mol/L. New protein synthesis was measured by the rate of [3H]phenylalanine incorporation into the LV proteins. In normal hearts, Ang II (n=8) increased the rate of [3H]phenylalanine incorporation by 74+/-27% (P<0.05 versus no drug). Treatment with PD123319 (n=8) did not increase protein synthesis compared with Ang II alone (32+/-11% versus Ang II alone, P=NS). In hypertrophied hearts, Ang II alone (n=6) increased the rate of [3H]phenylalanine incorporation only by 23+/-13% (P=NS versus no drug). In contrast, treatment with PD123319 (n=7) induced a 76+/-21% increase in new LV protein synthesis compared with Ang II alone (P<0.05). AT2 receptor blockade in Ang II-stimulated hypertrophied hearts was associated with enhanced membrane protein kinase C translocation and reduced LV cGMP content. CONCLUSIONS: These data support the hypothesis that in adult hypertrophied rat hearts, inhibition of cardiac AT2 receptors, which are upregulated in chronic LV hypertrophy, amplifies the immediate LV growth response to Ang II. This appears to be related to augmented Ang II-stimulated PKC activation and suppression of cGMP signaling.

Underrecognition and undertreatment of asthma in Cape Town primary school children.

BACKGROUND: In view of the high local prevalence of asthma, the extent of recognition and appropriate management of childhood asthma was studied in a large suburban area of Cape Town. DESIGN: Cross-sectional study based on random community sample of schools. METHOD: 1,955 parents of sub B pupils from 16 schools completed a questionnaire, followed by: (i) an interview of the parents of 348 symptomatic children; and (ii) bronchial responsiveness testing on 254 children. The final case group consisted of 242 children with reported asthma or multiple asthma symptoms on both questionnaires. Children in whom asthma was acknowledged were compared with those in whom it was not. RESULTS: Overall, any past or current ('ever') asthma was acknowledged by respondents in only 53% of the children, and current asthma in only 37.1%. While most children had received treatment in the previous 12 months, 66.1% of the recognised group were on current treatment (23.2% on daily treatment), compared with 37% of the unrecognised group (3% daily). Salbutamol and theophylline syrups were the most common types of medication, while inhalers and anti-inflammatory medications were underused. Only a minority of parents reported the child ever having used a peak flow meter, or volunteered knowledge of preventive measures. Current treatment, and to a lesser degree recognition of asthma by parents, were more common among children on medical aid and of higher socio-economic status. CONCLUSIONS: These findings suggest that ways need to be found: (i) to increase the use of current asthma treatment guidelines by practitioners; (ii) to provide access to comprehensive care by children not on medical aid; and (iii) to improve education of parents in home management measures such as severity assessment and avoidance of smoking, allergen and dietary triggers.

The efficacy of alternative spacer devices for delivery of aerosol therapy to children with asthma.

Spacer devices are important aids for use with metered dose inhalers in children with asthma. However, expense and unavailability of commercially produced spacers in developing countries have limited their use. Home-made spacers in the form of cups or bottles are widely used despite a lack of data confirming their efficacy. We investigated the relative efficacy of three spacers (a commercially available spacer, a modified 500-ml cold drink bottle and a polystyrene cup) for delivery of aerosolized drugs to asthmatic children older than 5 years. We also investigated the effect of leaks in the delivery system by comparing delivery via a sealed and an unsealed cold drink bottle. Lung deposition of aerosolized Tc-99m DTPA inhaled via spacer was measured in 30 patients. The median aerosol deposition in the lungs was significantly greater for the conventional spacer than for the cup (31.5% vs 9.5%; Z = -2.8, p = 0.005). Median aerosol deposition for the conventional spacer and sealed bottle were equivalent (40.5% vs 44%). Aerosol deposition from the sealed and unsealed bottle was significantly different (43.5% vs 24%; Z = -2.54, p = 0.01); however, the unsealed bottle was more efficient than the cup. We conclude that a modified 500-ml cold drink bottle is an efficient spacer. Leaks in this system are a major factor affecting the amount of drug deposited. The modified polystyrene cup is not an efficient spacer, delivering between a third and a fifth of the dose that other spacers were capable of delivering.

Iron: mammalian defense systems, mechanisms of disease, and chelation therapy approaches.

During the past 6 decades, much attention has been devoted to understanding the uses, metabolism and hazards of iron in living systems. A great variety of heme and non-heme iron-containing enzymes have been characterized in nearly all forms of life. The existence of both ferrous and ferric ions in low- and high-spin configuration, as well as the ability of the metal to function over a wide range of redox potentials, contributes to its unique versatility. Not surprisingly, the singular attributes of iron that permit it to be so useful to life likewise render the metal dangerous to manipulate and to sequester. All vertebrate animals are prone to tissue damage from exposure to excess iron. In order to protect them from this threat, a complex system has evolved to contain and detoxify this metal. This is known as the iron withholding defense system, which mainly serves to scavenge toxic quantities of iron and also for depriving microbial and neoplastic invaders of iron essential for their growth. Since 1970, medical scientists have become increasingly aware of the problems involved in cellular iron homeostasis and of the disease states related to its malfunctioning. Scores of studies have reported that excessive iron in specific tissue sites is associated with development of infection, neoplasia, cardiomyopathy, arthropathy and a variety of endocrine and neurologic deficits. Accordingly, several research groups have attempted to develop chemical agents that might prevent and even eliminate deposits of excess iron. A few of these drugs now are in clinical use, e.g. deferiprone (L1). In the present review, we focus on recent developments in (i) selected aspects of the iron withholding defense system, and (ii) pharmacologic methods that can assist the iron-burdened patient.

The etiology of the anemia of chronic disease and infection.

Anemia of infection and chronic disease has traditionally been considered a disorder associated with infections/inflammation. We instead propose that the anemia of infection and chronic disease confers protection from pathogen or neoplastic invasion. There is substantial microbiological and medical research that indicates that the anemia of infection and chronic disease may be a non-specific immunological defense. We suggest it is analogous to fever, which was also originally considered to be a disorder in need of treatment but which is now seen as a positive response of the host to microbial invasion. We suggest that these two non-specific defenses against microorganism proliferation may have evolved together as complementary strategies the body employs to ward off disease.

Clinical significance of aero-allergen identification in the western Cape.

Positive identification and documentation of the seasonal variation of aero-allergens and the immune responses to them has important implications for the timing of allergen avoidance measures and the selection of patients suitable for immunotherapy. The relative abundance of aero-allergens in the Cape Peninsula during 1984-1987 was measured by continuous volumetric air sampling, using a Burkard spore trap. Mould spore counts of greater than 3,000 spores/m3 were found throughout the year and were only exceeded by pollen grains in the months of September and October (range 4,800-7,400 spores/m3). Gramineae and Compositae spores were found perennially in significant numbers. Pollen from allergenic trees peaked at fixed times each year: oak in August; plane in September and pine between August and October. Grasses found on the Peninsula include sweet vernal, Bermuda grass, rye grass, common reed, Johnson grass, brome grass, canary grass, annual meadow and kikuyu. In vivo skin tests in 209 children with known allergic disease were positive to Dermatophygoides pteronyssimus (73%), South African grasses (38%), tree pollens (22.4%), flower and weed pollens (19.6%), cat (27%), dog (12%) and feathers (18.6%). One-third of the 1,372 children screened at Red Cross War Memorial Children's Hospital Allergy Service had positive specific IgE responses to environmental allergens. Investigation of 62 children possibly allergic to grass using the radio-allergosorbent test revealed positive results in 25 (41%). Of these, 92% were positive to Timothy grass, a grass not occurring in the Cape Peninsula. Knowledge of cross-reactivity profiles for local allergens minimises the number of tests required in allergy diagnosis.

Dietary and prophylactic iron supplements : Helpful or harmful?

Mild hypoferremia represents an aspect of the ability of the body to withhold iron from pathogenic bacteria, fungi, and protozoa, and from neoplastic cells. However, our iron-withholding defense system can be thwarted by practices that enhance iron overload such as indiscriminate iron fortification of foods, medically prescribed iron supplements, alcohol ingestion, and cigarette smoking. Elevated standards for normal levels of iron can be misleading and even dangerous for individuals faced with medical insults such as chronic infection, neoplasia, cardiomyopathy, and arthritis. We are becoming increasingly aware that the wide-spread hypoferremia in human populations is a physiological response to insult rather than a pathological cause of insult, and that attempts to correct the condition by simply raising iron levels may not only be misguided but may actually impair host defense.

Acute alterations in diastolic left ventricular chamber distensibility: mechanistic differences between hypoxemia and ischemia in isolated perfused rabbit and rat hearts.

Changes in diastolic chamber distensibility (DCD) during hypoxemia and ischemia were studied in isolated-buffer-perfused rabbit hearts. Two minutes of hypoxemia (low PO2 coronary flow) resulted in a shift of the diastolic pressure-volume curve to the left, i.e., distensibility was decreased (hypoxemic contracture). In contrast, 2 minutes of ischemia (zero coronary flow) resulted in an initial shift of the diastolic pressure-volume curve to the right indicating increased distensibility, which was followed by a later (30 minutes) shift to the left (ischemic contracture). Two minutes of ischemia superimposed on hypoxemia caused complete reversal of contracture. A quick stretch and release applied to the myocardium reversed late ischemic contracture but did not effect early hypoxemic contracture. The role of intracellular pH in modulating changes in DCD during hypoxia and ischemia was studied using phosphorus-31 nuclear magnetic resonance spectroscopy of isolated-buffer-perfused rat hearts that demonstrated changes in DCD similar to rabbit hearts during hypoxemia and ischemia. Intracellular pH decreased from 7.03 +/- 0.02 to 6.87 +/- 0.03 (p less than .01) during 2 minutes of ischemia but did not change significantly during 4 minutes of hypoxemia. When 2 minutes of ischemia were superimposed on hypoxemia, pH decreased from 6.99 +/- 0.01 during hypoxemia to 6.88 +/- 0.02 after 2 minutes of ischemia (p less than .01), concomitant with the complete reversal of hypoxemic contracture. These results suggest different mechanisms for late ischemic and early hypoxemic contracture and also suggest an explanation for the opposite initial changes in DCD seen after brief periods of ischemia and hypoxemia. The early development of contracture during hypoxemia and rapid redevelopment of diastolic tension after quick stretching are consistent with the hypothesis that hypoxemic contracture results from persistent Ca++-activated diastolic tension secondary to impaired calcium resequestration by the sarcoplasmic reticulum. In contrast, the late development of contracture during global ischemia and reversal by quick stretching is compatible with rigor bond formation. The initial increase in distensibility during early ischemia and the reversal of hypoxemic contracture by a brief period of superimposed ischemia probably is the result of two factors present during ischemia but not during hypoxemia: the collapse of the coronary vasculature and loss of the "erectile" effect and, the rapid development of intracellular acidosis, which has been shown to affect myofibrillar calcium sensitivity, and this may lead to a decrease in Ca++ activated diastolic tension.

Cytotoxin (leukotoxin) production by Pasteurella haemolytica: requirement for an iron-containing compound.

In studies of Pasteurella haemolytica type 1 cytotoxin, filter-sterilized culture supernatants from organisms grown in RPMI-1640 tissue culture medium generally have been used. Supplementation of the medium with 7% bovine fetal serum was shown to be necessary for maximal cytotoxin production, as measured by percentage of bovine peripheral blood leukocytes that were killed. The serum-induced increase in cytotoxicity could not be explained simply by a greater percentage of increase in the number of viable organisms produced in the enriched medium. There also was no correlation between encapsulation of the organisms and cytotoxin production. Several natural iron-containing proteins including transferrin, lactoferrin, conalbumin, and hemoglobin stimulated cytotoxin production in lieu of bovine fetal serum, leading to the conclusion that one function of serum supplementation may be to increase the medium's iron concentration. A number of additional iron-containing and iron-chelating compounds were tested, with the conclusion that the iron concentration of the growth medium, as well as the presence of a suitable carrier molecule, may be critical for efficient cytotoxin production by P haemolytica.

Iron, infection, and neoplasia.

In nearly all forms of life, the number and diversity of enzymes that contain iron or that depend on the presence of this metal for activity are impressive. Not surprisingly, chemical mechanisms have been evolved by many organisms that permit them to solubilize and acquire iron while at the same time depriving their competitors or their pathogens of this element. Proteins such as transferrin and lactoferrin that are employed by vertebrate hosts for iron transport and acquisition can, to some extent, withhold the metal from the siderophores of invading bacteria and fungi. Attempts also are made by animal hosts to withhold iron from protozoa and neoplastic cells. Unfortunately, pathogenic microorganisms have developed a variety of counter measures that are especially dangerous in hosts stressed by iron overload in specific fluids, tissues, or cells. In recent years, however, a number of possible methods and agents for strengthening iron-withholding defense have become apparent. Nearly 3,000 papers on various aspects of iron withholding are contained in the 18-year Medline Database and numerous reviews have been published since 1966. The present paper will focus on developments that have been reported within the past 2 1/2 years.

Acute severe asthma. A prospective study of the precipitating factors in 40 children.

A prospective study was undertaken to determine the factors precipitating acute severe asthma in children attending the Red Cross War Memorial Children's Hospital, Cape Town. A comparison in terms of recent exposure to possible precipitating factors was made between 40 known asthmatics presenting with acute severe asthma and 40 known asthmatics who were clinically well. Exposure to known allergens had occurred in 7 cases. The time of onset of symptoms bore no relationship to meteorological changes in temperature, humidity or average pressure. Drug compliance in both groups was of the order of 50%. The majority of severe asthma attacks were associated with infection of the respiratory tract. The importance of infection as a precipitating factor in a severe asthma attack is discussed with reference to the cholinergic, adrenergic and immunological mechanisms.

Cyclic accumulation of zinc by Candida utilis during growth in batch culture.

Intracellular accumulation of zinc by Candida utilis NRRL-Y-7634 was mediated by an energy-and temperature-dependent, highly specific process exhibiting saturation kinetics. In zinc-supplemented medium, uptake occured only during the lad and late-exponential phases; this type of transport did not occur with zinc in bacteria nor with iron in either yeast or bacteria. Cells of C. utilis did not possess a zinc-efflux system; they could reduce their level of intracellular zinc only by dilution of the metal into daughter cells. Zinc-deficient organisms accumulated 12 times more zinc than did cells of the same culture age grown in zinc-supplemented medium. The varied, but experimentally reproducible levels of intracellular zinc that occured in response to the physiological and environmental parameters had no detectable effects on respiration, rate of growth, total cell yield, or cell viability. Neither the mechanism underlying the cyclic accumulation of sinc nor the function of such behaviour are understood.

Stimulation of bone formation in vivo by phosphate supplementation.

The effect of phosphate supplementation on bone remodeling was assessed in six mature, healthy beagle dogs. The phosphate supplement was given in divided doses orally, daily for 12 weeks in the form of a neutral potassium phosphate preparation. The dose averaged 108 mg P/kg per day, which is double the normal canine phosphorus intake. Bone remodeling was assessed by measurement, at sacrifice, of areas of cortical bone containing different color-coded tetracyclines which had been continuously administered during 12-week control and treatment periods; remodeling was assessed kinetically during the control and treatment periods by replicate studies employing 47Ca intravenously. Both techniques demonstrated that the principal effect of phosphate supplementation was a significant stimulation of bone formation. Within cortical bone, formation was doubled, from an average of 2.7% to 5.3% per year. The major location of new bone deposits was endosteal. Whole skeletal mineral accretion, measured kinetically, increased 45% above an average control value of 0.154 g/day. These studies suggest that, in the adult dog, "normal" plasma phosphate levels are suboptimal for new bone formation. Even with this short duration of administration, phosphate produced microscopic calcification of the renal parenchyma. However, there was no biochemical evidence of renal functional impairment.