Serum immunoglobulin A concentration in infancy, but not human milk immunoglobulin A, is associated with subsequent atopic manifestations in children and adolescents: a 20-year prospective follow-up study.

BACKGROUND: Serum and secretory IgA concentrations have been suggested to be inversely associated with allergic symptoms in children. Furthermore, low maternal milk IgA concentration has been suggested to be associated with the development of cow's milk allergy. OBJECTIVE: Our aim was to explore whether the serum IgA concentrations in infancy and the IgA concentration of maternal milk predict atopic manifestations in childhood and up to age 20 years. METHODS: A cohort of 200 unselected full-term newborns was prospectively followed up from birth to age 20 years with measurement of serum total IgA at ages 2 and 6 months. The mothers were encouraged to maintain exclusive breastfeeding for as long as possible. Total IgA concentration of maternal milk was measured at birth (colostrum, n=169) and at 2 (n=167) and 6 (n=119) months of lactation. The children were re-assessed at ages 5, 11 and 20 years for the occurrence of allergic symptoms, with skin prick testing and measurement of serum IgE. RESULTS: Children and adolescents with respiratory allergic symptoms and sensitization had a higher serum IgA concentration at age 2 months than the non-atopic subjects. Colostrum and breast milk IgA concentrations were not associated with the development of allergic symptoms in the recipient infant. However, maternal milk IgA concentration at 6 months of lactation was inversely associated with elevated serum total IgE and positive skin prick test to tree pollen in the offspring at age 20 years. CONCLUSIONS AND CLINICAL RELEVANCE: Increased serum IgA concentration at age 2 months is associated with the development of subsequent allergic symptoms and sensitization in childhood and adolescence. Maternal milk IgA concentrations are not associated with subsequent allergic symptoms in the recipient infant. The present study provides novel information on the role of IgA in the development of respiratory allergy and sensitization.

Serum cholesterol level in infancy is inversely associated with subsequent allergy in children and adolescents. A 20-year follow-up study.

BACKGROUND: Previous studies suggest an association between an altered lipoprotein profile and atopy. The association has been hypothesized to be due to alterations in the dietary fat intake, a factor possibly contributing to the increase of allergic diseases in industrialized countries. OBJECTIVE: We aimed at assessing whether there is an association between the serum lipid levels in infancy and subsequent development of allergic symptoms in childhood and adolescence. METHODS: A cohort of 200 unselected newborns was prospectively followed up from birth to age 20 years (from 1981 to 2002) with repeated measurements of total cholesterol from birth and throughout the first year of life. The subjects were re-examined at the ages of 5, 11 and 20 years, with assessment of the occurrence of allergic symptoms, skin prick testing (SPT) and measurement of total IgE and of the total, high- and low-density lipoprotein cholesterol. RESULTS: Children and adolescents with allergic symptoms, SPT positivity and an elevated IgE had lower total cholesterol levels in infancy and childhood than the non-atopic subjects. The difference was not detectable in cord blood, but became significant from age 2 months onward. CONCLUSION: The inverse association between the cholesterol level in infancy and subsequent manifestations of atopy seems not to be due to atopy-related dietary alterations, because it was already present in early infancy, when virtually all the infants were on a similar diet, i.e. on exclusive breastfeeding.

Long-term results in children with AML: NOPHO-AML Study Group--report of three consecutive trials.

In all, 447 children with acute myeloid leukaemia (AML) have been treated on three consecutive NOPHO studies from July 1984 to December 2001. NOPHO-AML 84 was of moderate intensity with an induction of three courses of cytarabine, 6-thioguanine and doxorubicin followed by four consolidation courses with high-dose cytarabine. The 5-year event-free survival (EFS), disease free survival (DFS) and overall survival (OS) were 29, 37 and 38%. NOPHO-AML 88 was of high intensity with the addition of etoposide and mitoxantrone in selected courses during induction and consolidation. The interval between the induction courses should be as short as possible, that is, time intensity was introduced. The 5-year EFS, DFS and OS were 41, 48 and 46%. In NOPHO-AML 93, the treatment was stratified according to response to first induction course. The protocol utilised the same induction blocks as NOPHO-AML 88, but after the first block, children with a hypoplastic, nonleukaemic bone marrow were allowed to recover before the second block. Consolidation was identical with NOPHO-AML 88. The 5-year EFS, DFS and OS in NOPHO-AML 93 were 48, 52 and 65%. The new NOPHO-AML protocol has been based on experiences from previous protocols with stratification of patients with regard to in vivo response and specific cytogenetic aberrations.

Tumor necrosis factor in children with malignancies.

We measured serum tumor necrosis factor alpha (TNF) concentrations by a double-antibody radioimmunoassay method, with a detection level of 10 ng/liter, in 32 children with malignancies. Seventeen had acute lymphoblastic leukemia, 4 had acute nonlymphocytic leukemia, and 11 had solid tumors. At the diagnosis of malignant disease, 30 of the 32 patients had elevated serum TNF levels ranging up to 450 ng/liter. After complete remission status was achieved, 2-6 months from the diagnosis, the TNF levels were within the range of 130 healthy children who served as the reference group. Most of them had TNF levels below the detection limit. We consider the upper limit of normal to be 40 ng/liter. We conclude that elevated serum TNF concentration may be of potential significance in the diagnosis and follow-up of children with malignant diseases.

Antibody status to HHV-6 in children with leukaemia.

Forty children with acute lymphoblastic (33) or myeloid leukaemia (seven) were studied for IgG and IgM antibodies and IgG avidity against human herpesvirus 6 (HHV-6) at the time of diagnosis, and compared with age-, sex- and season-matched children with various neurological diseases of suspected viral origin. Of the children with leukaemia, 97.5% had IgG antibodies and 40% IgM antibodies to HHV-6 compared with 92.3% and 7.7% of reference subjects (P = 0.005). A seronegative child with leukaemia seroconverted 3 weeks after the diagnosis. The avidity of IgG antibodies (based on the resistance to urea treatment) was high in all children with leukaemia. One reference child had HHV-6-specific IgG antibodies with low avidity, which together with his positive IgM indicated an acute infection. The presence of specific IgM antibodies in 40% of children with leukaemia and the high avidity of IgG suggest a reactivation or an inaproppriate primary response to HHV-6 infection. The results support the conclusion of the role of the HHV-6 infection at the onset of childhood leukaemia.

Anemia in children with cartilage-hair hypoplasia is related to body growth and to the insulin-like growth factor system.

Cartilage-hair hypoplasia (CHH) is a metaphyseal chondrodysplasia characterized by severe short-limbed short stature, hypoplastic hair, and defective immunity. The patients also have anemia. As GH may regulate both body growth and erythropoiesis, we used CHH as a clinical model to study their interrelationships. Retrospective analysis of hematological data of 114 patients showed that the severity of the anemia and macrocytosis in CHH varies with age. The anemia was most severe in early childhood. A prospective study of 21 patients with CHH showed that height correlates with hemoglobin (P = 0.006) and mean corpuscular volume of red blood cells (P < 0.0001). The individual hemoglobin levels correlated with the GH parameters [P = 0.035 for insulin-like growth factor I (IGF-I) and P = 0.002 for IGF-binding protein-3], and the mean corpuscular volume of red blood cell values correlated with fetal hemoglobin. Bone marrow cultures obtained from six patients with CHH showed reduced or totally absent erythroid colony formation, which was not influenced by GH or IGF-I in vitro or by GH treatment in vivo. In patients with CHH, we observed an association between erythropoiesis and growth. We conclude that body growth and erythropoiesis share common regulators. One of these is the GH-IGF-I axis; other factors, as not yet identified, may also be important.

The role of luteinizing hormone-beta gene polymorphism in the onset and progression of puberty in healthy boys.

An immunologically anomalous LH with two point mutations in its beta-subunit gene (Trp8Arg and Ile15Thr) has recently been described. This polymorphism is common in Finland; 28% of the population are homo- or heterozygous for the variant allele. To assess the effect of the LH variant on LH action, we correlated its presence in a group of 49 healthy boys with the onset and progression of puberty. This group was followed-up longitudinally from a mean age of 11.7 +/- 0.1 yr for 3 yr at 3-month intervals. In addition, we studied the prevalence of the variant LH in boys with constitutional pubertal delay (testicular volume < or = 4 mL after 13.5 yr of age). The LH beta gene status of each subject in this study was judged from a single venous blood sample using two immunofluorometric LH assays with different combinations of monoclonal antibodies: one detecting both the variant and wild-type LH, and the other detecting only wild-type hormone. Of the boys with pubertal onset at a normal age, 36 (74%) were homozygous for the wild-type LH beta allele, 12 (24%) were heterozygous, and 1 (2%) was homozygous for the variant LH beta allele. Clear differences in pubertal parameters were found between the boys with normal and mutated (homo- or heterozygous) LH genotypes. During the follow-up, the boys with the mutated genotype had smaller testicular volumes (P < 0.03), were shorter (P < 0.02), had slower growth rates (P < 0.04), and had lower serum insulin-like growth factor I-binding protein-3 levels (P < 0.03) than the boys with the normal LH genotype. In the boys with delayed onset of puberty, the frequency of the variant LH beta allele did not differ from that in the reference population, indicating that the variant LH is not associated with conditions due to disturbed control of the reactivation of GnRH secretion. We conclude that during the progression of puberty, the variant LH may be less active in stimulating testicular growth than wild-type LH. Thus, the gene may affect tempo, contributing to the wide normal variation in pubertal progression in healthy boys. Our results also suggest that the variant LH not only affects the course of puberty, but is already involved in the regulation of the GH-insulin-like growth factor I axis during childhood.

Serum transferrin and ferritin in pubertal boys: relations to body growth, pubertal stage, erythropoiesis, and iron deficiency.

We studied serum transferrin and ferritin concentrations in relation to individual body growth, stage of puberty, blood hemoglobin, and red blood cell iron (RBCI) in 60 prepubertal or early pubertal boys at 3-mo intervals for 18 mo. One-third of the boys had increased serum transferrin concentrations and almost all had decreased ferritin concentrations during the followup. No change in mean transferrin was observed but the individual 18-mo increments in transferrin correlated positively with the increments in hemoglobin (r = 0.55, P < 0.001) and in estimated RBCI (r = 0.31, P = 0.02). Serum transferrin remained stable at different genital stages, but ferritin was lower in the pubertal than in the prepubertal boys. Transferrin concentrations at 18 mo correlated positively with the preceding weight velocities. The rise in transferrin did not lead to an increase in iron-deficiency anemia. In contrast, transferrin rose in boys whose hemoglobin increased. In pubertal boys with relatively ample iron status, serum transferrin may be an indicator of increased availability of iron for erythropoiesis. The declining ferritin concentration indicates that part of the extra iron is mobilized through redistribution from stores to red blood cell mass and is generally associated with greatly increasing absorption. Thus, the pubertal changes in transferrin and ferritin are not necessarily indications of iron deficiency.

Physiological anemia of early development in the rat: characterization of the iron-responsive component.

The purpose of this study was to determine the circumstances under which the postnatal decline in concentration of hemoglobin in the rat can be modified by administration of iron. Base-line dietary regimens contained iron in what is considered an optimal amount, and additional iron-dextran administration to the dams had no significant influence on the concentration of hemoglobin in the pups. However additional iron when administered directly to the pups in the form of iron-dextran or heat-treated red cells did elevate the concentration of hemoglobin. The administration of iron was effective only before weaning at 21 days of age; subsequently, there was no significant effect. The age-related difference in hemoglobin-responsiveness corresponded to the effects of iron treatment on the concentration of serum iron. Between 11 and 21 days of age, serum iron values under base-line dietary conditions were low but they became increased in response to iron treatment. After 21 days of age, base-line serum iron values rose abruptly and were no longer substantially augmented by iron treatment. The findings suggest that a physiological period of low serum iron restricts the production of hemoglobin. During this period, administration of iron in greater than physiological doses was effective in raising the serum iron and the concentration of hemoglobin.

Manifestation of iron deficiency at various levels of dietary iron intake.

The purpose of this study was to determine the interrelationships between iron stores, serum iron, hemoglobin, myoglobin, and cytochrome c under conditions of iron deficiency that did not interfere with normal growth. Rats were given diets containing from 7 to 500 mg iron per kilogram of diet during a period of 3 weeks of rapid growth between weaning at 21 days and approaching sexual maturity at 42 days. We found that the level of iron intake required for a maximum concentration of hemoglobin was similar to that which results in a maximum level of tissue cytochrome c. The severity of iron deficiency anemia was proportionally similar to the degree of depletion of muscle cytochrome c at all levels of iron intake below 25 mg/kg diet. The results indicate that even the mildest degree of nutritional iron deficiency anemia also affected tissue cytochrome c and could impair cytochrome-dependent mitochondrial function.

Vitamin E supplementation in very-low-birth-weight infants: long-term follow-up at two different levels of vitamin E supplementation.

This study evaluates the need of vitamin E supplementation in very-low-birth-weight infants by long-term follow-up of plasma vitamin E status during the first 15 mo of life, with two different levels of supplementation. The subjects were 51 newborn infants with birth weights less than or equal to 1520 g. During hospitalization the infants were fed human milk. On the third day of life oral vitamin E supplementation of less than or equal to 10 mg/d was started in all infants. In addition, 23 infants selected at random were given intramuscular vitamin E (20 mg/kg/d) during the first 3 d. The data indicate that the 10 mg/d supplement resulted in an adequate plasma concentration of vitamin E. After cessation of supplementation at age 3 mo, the risk of low plasma vitamin E levels increased. Although intramuscular administration resulted in long-lasting increments in mean plasma vitamin E values, some later levels in these infants were marginal.

Relationship between hemoglobin concentration and transferrin saturation in iron-sufficient infants.

Ten groups of healthy infants and children from 2 months to 15 years of age were studied, each consisting of 98 to 238 subjects. In young infants whose serum ferritin values indicated ample storage iron, the concentration of hemoglobin was found to bear a significant relationship to the degree of iron saturation of transferrin. This phenomenon was evident throughout the range of transferrin saturation until 1 year of age but became undetectable or less significant from 2 to 15 years of age. We postulate that the production of hemoglobin could be influenced through a broader range of transferrin saturation in rapidly growing infants than in the older child or adult.

Selenium status of exclusively breast-fed infants as influenced by maternal organic or inorganic selenium supplementation.

A longitudinal dietary Se supplementation study on lactating mothers was performed to determine the possibilities of improving the Se status of exclusively breast-fed infants. A total of 200 mothers randomized into three groups received either no Se supplements, 100 micrograms of selenite, or 100 micrograms of yeast-Se daily. Maternal and infant serum Se concentrations showed a linear correlation during exclusive breast-feeding. Yeast-Se in the dose administered was safe and more effective than selenite in increasing the Se concentrations of maternal serum and milk, and infant serum. The mean estimated daily Se intakes of the infants were 7.7 +/- 2.2, 8.9 +/- 2.2, and 11.5 +/- 4 micrograms, in the control, selenite, and yeast-Se groups respectively. Though the infant Se intakes of the unsupplemented and selenite-supplemented mothers were below the lower limit of the safe and adequate range as set by the US National Research Council, their serum Se concentrations increased steadily over the 6-mo study period. As maternal serum Se also increased by over 50% during the same period the results suggest that a maternal daily intake of 50-75 micrograms is adequate during lactation.

Infant vitamin B-6 status changes with age and with formula feeding.

To study the effect of type of feeding on infant vitamin B-6 status, we determined erythrocyte pyridoxal 5'-phosphate concentration (EPLP) and erythrocyte aspartate aminotransferase basal activity (EASTo) and its activation coefficient (alpha EAST) in 109 infants at 2, 4, 6, 9, and 12 mo of age. Thirty-six infants were exclusively breast-fed for 9 mo. Forty-six infants were exclusively breast-fed for 6 mo, and then given solid foods in addition. Twenty-seven infants were weaned by 2-3 mo to an adapted cow milk-based formula (15 g protein/L and 0.6 mg pyridoxine/L) and given solid foods from 3 to 4 mo. Infant vitamin B-6 status was age-dependent; it was highest at 4 mo and thereafter gradually approached adult values. The larger the intake of formula, the higher the vitamin B-6 status. In formula-fed infants at ages 2-6 mo, 71-96% of the EPLP values and 57-70% of the EASTo values were above the 95th percentile, and 35-53% of the alpha EAST values were below the 5th percentile for these values in breast-fed infants. These findings raise the question of whether the vitamin B-6 content of formulas, especially in relation to protein content, should be reduced.

Cu nutrition in infants during prolonged exclusive breast-feeding: low intake but rising serum concentrations of Cu and ceruloplasmin.

We studied Cu intake and nutrition in exclusively breast-fed infants by determining Cu and ceruloplasmin concentrations in maternal and infant sera, as well as milk intakes and concentrations. The infants numbered 200 at birth, 116 at age 6 mo, 36 at 9 mo, and 7 at 12 mo. Postpartum the mean maternal serum concentrations of Cu and ceruloplasmin were high, but decreased in 4 mo to the level of nonpregnant women, and remained thereafter stable. The median milk Cu concentration decreased throughout lactation. In contrast, the mean infant serum concentrations of Cu and ceruloplasmin increased with age reaching adult levels by age 6 mo. The infant serum concentrations were independent of the milk concentrations which in turn were independent of the maternal serum concentrations and the degree of maternal supplementation (none, 2, or 4 mg Cu++ with Fe++ and Zn++). Neither maternal nor infant serum concentrations reflected intake of Cu. The daily Cu intake varied up to 10-fold between infants. No signs of Cu deficiency were detected during exclusive breast-feeding.

Copper supplementation: failure to increase plasma copper and ceruloplasmin concentrations in healthy infants.

Plasma copper and ceruloplasmin concentrations at ages 0, 2, 4, 6, 9, and 12 mo were longitudinally evaluated in our Finnish nutritional survey of 200 infants. The infants, who were weaned by age 3.5 mo, were randomly assigned to receive either a liquid cow-milk-based formula containing 1.3 mumol Cu/L (n = 16) or the same formula supplemented with 7.8 mumol Cu/L as Cu sulfate (n = 16). They were compared with exclusively breast-fed infants. Plasma Cu and ceruloplasmin concentrations increased steadily and similarly in all three groups from 4.6 +/- 0.2 mumol/L (means +/- SEM) and 0.9 +/- 0.1 mumol/L, respectively, in umbilical samples to 19.7 +/- 0.3 mumol/L and 3.2 +/- 0.1 mumol/L, respectively, at age 12 mo. Our results indicate that concentrations of plasma Cu and ceruloplasmin in healthy full-term infants are resistant to dietary supplementation.

Reference ranges for erythrocyte pyridoxal 5'-phosphate concentration and the erythrocyte aspartate transaminase stimulation test in lactating mothers and their infants.

We determined reference ranges for erythrocyte pyridoxal 5'-phosphate concentrations (EPLP) and erythrocyte aspartate transaminase basal activities (EASTo) and activation coefficients (alpha EAST) in lactating mothers and infants from data of mothers receiving a vitamin B-6 supplement and infants breast-fed by mothers with adequate vitamin B6 status. The mothers' vitamin B6 status was assessed on the third day postpartum (pp) (n = 91) and at 2 mo (n = 114), 4 mo (n = 117), 6 mo (n = 110), and 9 mo (n = 40) pp and that of the exclusively breast-fed infants at 2 mo (n = 90), 4 mo (n = 106), and 6 mo (n = 99). We also examined 9-mo-old infants (n = 39) who, besides breast milk, had received solids after 6 mo, and 12-mo-old infants (n = 100) who had received solids beginning at 4-6 mo and dairy products at 9 mo. Values indicating deficiency for at least two of the three indexes distinguished the 5-10% of mothers and infants with the lowest vitamin B6 status. The reference ranges for EPLP, EASTo, and alpha EAST for infants and for mothers during the first months of lactation differ from those reported earlier for adults.

Zinc supplementation of infant formula.

The effect of zinc supplementation of infant formula on zinc nutrition and growth of healthy infants was studied longitudinally from birth to age 12 mo. The zinc-supplemented group (n = 16) received the same formula as the unsupplemented group (n = 16) except for the addition of 61 mumol (4 mg) Zn/L as sulfate. After age 2 mo in the breast-fed and unsupplemented groups the mean serum zinc concentration remained stable at approximately 9.9 mumol/L. The zinc supplement increased the mean serum zinc concentration to 13.0 mumol/L by age 6 mo. With increasing intake of solid foods, the concentration fell by age 9 mo to the same concentration as in the other groups. The supplement did not increase the velocity of weight or length growth. In their growth the unsupplemented infants were not inferior to the breast-fed or zinc-supplemented infants.

Formula feeding results in lower selenium status than breast-feeding or selenium supplemented formula feeding: a longitudinal study.

Thirty-two infants completely weaned by age 3.2 mo were randomized into two groups. Unsupplemented group was fed cow's milk-based liquid formula containing 3-5 micrograms Se/L. Se-supplemented group received the same formula supplemented with 20 micrograms Se/L. A third group consisted of exclusively breast-fed infants (51 at age 4 mo, 41 at 6 mo, 12 at 9 mo). Mean serum Se concentration in unsupplemented group decreased from 41 to 31 micrograms/L during the first 2 mo and remained constant until age 6 mo increasing gradually thereafter. In Se-supplemented group it increased steadily from 41 to 68 micrograms/L at age 6 mo and remained constant while supplemented formula was used. In breast-fed group it increased steadily until age 9 mo, between the levels of the two formula-fed groups, when it reached the concentration of Se-supplemented group. At age 12 mo no significant differences were present among the three groups.

sIgA- and IgM-containing cells in the intestinal mucosa of iron-deficient rats.

The effect of iron deficiency on the jejunal mucosa was studied in postweaning rats that had received a 3-wk regimen of either iron-deficient or iron-sufficient diet (iron content 6 and 50 mg/kg diet) and in rats given the iron-sufficient diet for 1 wk after the initial 3-wk iron-deficient diet. Morphometric analysis showed little difference in villous height but a significant decrease in mitotic index of the crypt epithelial cells in the iron-deficient group. Direct immunoperoxidase studies showed that iron-deficient rats had substantially fewer sIgA- and IgM-containing cells than iron-sufficient rats. This abnormality was reversed after a 1-wk iron-sufficient diet. We conclude that iron deficiency may impair local immunity in the intestinal mucosa, sensitizing the surface epithelial cells to damage by noxious agents. Similar changes might lead to the syndrome of iron-deficiency anemia and hypoproteinemia in children.