Biomedical subjects
Publications and source records attributed to J Perheentupa.
We studied 5-year-old children and their patients in 80 families and observed an association between the hemoglobin concentrations of the children and their parents before and after iron medication. We speculate that inheritance may exert a significant influence; iron deficiency did not explain the finding.
Autoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease characterized by a variable combination of the failure of the endocrine glands. The pathogenesis of this unique autoimmune disease is unknown; unlike many other autoimmune diseases, APECED does not show association to specific HLA haplotypes. Unravelling the APECED locus will identify a novel gene outside the HLA loci influencing the outcome of autoimmune diseases. We have assigned the disease locus to chromosome 21q22.3 by linkage analyses in 14 Finnish families. Linkage disequilibrium studies have significantly increased the informativeness of the analyses and helped to locate the critical DNA region for the APECED locus to just 500 kilobases, a much more precise definition than linkage analyses alone could achieve.
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.
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.
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.
We studied zinc nutrition in exclusively breast-fed infants whose growth deviated from the norm. Their number fell from 200 at birth to 116 at the age of 6 months and 36 at the age of 9 months. The mothers received 0, 20, or 40 mg Zn++ as sulfate daily. Breast milk intake and concentrations of zinc in milk as well as in maternal and infant serum were measured. Individual zinc concentrations in milk showed channeling. The 20-mg supplement had no effect on the parameters measured. In contrast, 40 mg increased the maternal serum zinc concentration by 2 months and slowed the normal decline of milk zinc concentration by 6 months. Maternal supplementation had no effect on infant serum concentrations; they remained lower than adult levels throughout the 1st year of life. Zinc intake was low (about one-tenth of RDA), but it seemed to be adequate; the serum concentrations of the infants were stable after the age of 2 months. Low zinc concentrations in serum were not associated with impaired growth. On the contrary, the infants with the highest rates of growth had the lowest zinc concentrations. The infant serum zinc concentrations were channeled, but they were also influenced by the zinc intake. Reference values for breast-fed infants are given.
Patients with idiopathic Addison's disease have autoantibodies reacting with adrenal cortex. If Addison's disease is associated with other endocrine immune diseases like autoimmune polyglandular diseases (APD) type I and type II, antibodies may recognize all steroid-producing cells. We showed previously that one antigen recognized by APD-I sera is the cytochrome P450c17 hydroxylase. We have now looked for antibodies to P450c17 and to two other key enzymes in the steroid biosynthetic pathway, the P450scc and P450c21, in a series of patients with isolated Addison's disease (8 patients) or with APD-I or APD-II (50 and 9 patients, respectively). The result of antienzyme antibodies were further correlated with the immunofluorescence pattern against adrenal gland, testis, ovary, and placenta, and with the clinical findings presented. In APD-I patients with Addison's disease and in APD-II patients, antibodies to at least one of the P450 enzymes were frequently found (positive findings in 81% and 78%, respectively). Such antibodies were less frequent in APD-I patients without Addison's disease (21%) and in the isolated Addison cases (25%). In APD-I, antibodies recognized as frequently P450c17 and P450scc, specific for all steroid-producing cells as the adrenal specific enzyme P450c21. In contrast, patients with APD-II or with the isolated Addison's disease reacted almost exclusively with P450c21. Immunofluorescence studies showed good correlation with the known fact that the zona glomerulosa of the adrenal cortex is devoid of the P450c17, that the Leydig cells of the testis and the theca interna cells of the ovary express P450c17 and P450scc, and that the placental trophoblasts express only P450scc. The presence of antibodies to P450scc or to at least one of the tested P450 enzymes correlated significantly to gonadal failure in the females but not in the males.
We compared salivary epidermal growth factor (EGF) concentrations in patients with juvenile periodontitis (JP) and periodontally healthy controls. In initial screening of 45 JP patients and a group of healthy controls, significantly higher salivary EGF concentrations were measured in the JP patients. Subsequently, 17 JP patients who had high EGF concentrations in some of their salivary samples were chosen, and a group of age- and sex-matched controls was selected. We then examined their EGF concentrations and EGF secretion rates under standardized conditions in stimulated and unstimulated saliva and studied the expression of EGF receptor (EGF-R) in their gingival tissues. The results showed that the mean EGF concentration (pmol/ml) was slightly higher in JP patients than in controls. However, the difference was statistically significant only in stimulated saliva and when calculated per milligram salivary protein. When EGF release was measured as the rate of EGF secretion (pg/min), significantly higher values were observed in JP patients than in controls both in unstimulated and stimulated saliva. Immunofluorescence microscopy (IF) of gingival samples from JP patients and their controls revealed no quantitative or qualitative differences in the expression of EGF-R. Our results demonstrate the complex nature of salivary EGF release. The elevated rate of salivary EGF secretion in JP patients may be associated with the pathogenetic mechanisms of juvenile periodontitis.
The pathogenetic background of human autoimmunity is only partially understood. By discovering the defective gene causing the autosomal recessive polyglandular autoimmune disease type I (PGD I, APECED) we hope to provide new insights into autoimmune responses in general. Here we have taken advantage of newly developed amplifiable multiallelic microsatellite markers and performed the analyses using the microtiter well format of the polymerase chain reaction. This rapid semiautomated protocol was applied to analyze 62 assigned highly polymorphic loci. The linkage analyses coupled with the EXCLUDE analysis resulted in an exclusion map of this polyglandular autoimmune disease and in the preliminary assignment of the APECED locus to chromosome 22. The method proved to be an effective and economical tool for gene mapping compared with standard blotting and hybridization.
OBJECTIVE: To examine the development of tracking of serum cholesterol concentration from birth to childhood. DESIGN: In a longitudinal study of healthy children, concentrations of total serum cholesterol and triglyceride were determined at birth (n = 193); at 2 (n = 192), 4 (n = 192), 6 (n = 190), 7.5 (n = 118), 9 (n = 188), and 12 months (n = 196); and at 5 years of age (n = 162). Concentrations of cholesterol--very-low-density lipoprotein, low-density lipoprotein, high-density lipoprotein-2 (HDL2), and HDL3--were determined at 2, 6, 9, and 12 months (n = 36) and at 5 years (n = 162). RESULTS: The correlation coefficients of total cholesterol levels during the first year of life with the level at 5 years of age were as follows: at birth .04, at 2 months .36 (P < .001), at 4 months .26 (P < .001), at 6 months .28 (P < .001), at 7.5 months .25 (P < .001), at 9 months .35 (P < .001), and at 12 months .48 (P < .001). The correlation for exclusively breast-fed children between 6 months and 5 years of age was r = .37, P < .001, while that for children receiving partially breast milk, formula, or solid foods was r = .12, P = not significant (NS), and between 9 months and 5 years r = .38, P < .01, and r = .28, P < .05, respectively. The correlation coefficients of the lipoprotein levels between ages 12 months and 5 years were as follows: low-density lipoprotein cholesterol .58 (P < .001), total HDL cholesterol .30 (P < .05), HDL2 cholesterol .34 (P < .05), HDL3 cholesterol .17 (P = NS), very-low-density lipoprotein cholesterol .24 (P = NS), total triglyceride .37 (P < .05), and triglyceride-very-low-density lipoprotein .37 (P < .05). Of the children whose total serum cholesterol level was above the 90th percentile at birth, or at 2, 4, 6, 7.5, 9, or 12 months, 6%, 35%, 29%, 30%, 31%, 33%, and 45%, respectively, were above the 90th percentile at 5 years of age. In retrospect, 45% of the children whose serum cholesterol level was above the 90th percentile at 5 years were above the 90th percentile at the age of 12 months and 80% were in the highest quartile. CONCLUSIONS: The results indicate that tracking of serum cholesterol concentration during the first year of life is stronger when examining children who are receiving a relatively homogenous diet, such as exclusive breast-feeding, and weaker as children are weaned to formula and solid foods. After the weaning process is completed, children's relative serum cholesterol levels have become established and the tracking of serum cholesterol is of the same magnitude as for older children and adolescents.
The effect of exclusive lactation on lipid levels was investigated by evaluating serum concentrations of total and lipoprotein cholesterol, triglyceride (TG), and apoprotein (apo) B in mothers during and after exclusive, prolonged lactation. Serum total cholesterol concentrations were measured at delivery (n = 195), at 2 (n = 165), 6 (n = 119), 9 (n = 74), and 12 months (n = 32) of lactation, and 2 months (n = 27) after ending this exclusive lactation. In a subgroup of 34 mothers, serum levels of very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein 2 (HDL2), HDL3, and LDL apo B were determined at 2, 6, 9, and 12 months of lactation. The mean value of serum total cholesterol concentrations decreased from 6.2 +/- 0.12 (SEM; n = 195) at delivery to 4.8 +/- 0.1 mmol/L (n = 116) at 6 months of exclusive lactation (P < .001). The average decrement in total cholesterol level was 0.80 mmol/L (P < .001) from delivery to 2 months of lactation and 0.55 mmol/L (P < .001) from 2 to 6 months of lactation, and levels were stable thereafter. In the 27 mothers who were exclusively breast-feeding their infants at 9 months of lactation and whose serum cholesterol levels were measured 2 months after the end of lactation, cholesterol levels increased rapidly to 5.7 +/- 0.21 mmol/L (P = .001). In the subgroup of 34 mothers who were examined more closely, the course just described was also true for serum TG, LDL and VLDL cholesterol, and LDL apo B levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Cartilage-hair hypoplasia is an osteochondrodysplasia with short-limbed short stature. The cartilage-hair hypoplasia gene is exceptionally prevalent in Finland; more than 100 patients have been identified. We have analyzed the growth of 100 Finnish patients and present cartilage-hair hypoplasia-specific growth charts of height and weight for height. The disproportions were analyzed by sitting height, subischial leg height, sitting height:height ratio, and span-height difference. The stature was short at birth with a mean relative length of -3.0 SD. The median adult height was 131.1 cm (-7.9 SD, range 110.7 to 149.0 cm) for 15 males and 122.5 cm (-7.9 SD, range 103.7 to 137.4 cm) for 20 females. The progression of the growth failure was partly explained by weakness or absence of pubertal growth spurt. Weight for height was above normal median in childhood and increased further at puberty. Most of the adults were overweight. The adults' mean relative head circumference was -0.9 SD. Growth was disturbed both in the limbs and in the spine, more severely in the limbs. Adult height showed no correlation with the midparent height. The charts are useful for assessment of growth, prediction of adult height, detection of superimposed disorders, and evaluation of growth-accelerating therapy.
The total serum cholesterol concentration of infants was investigated at birth (n = 193) and at the ages of 2 (n = 192), 4 (n = 192), 6 (n = 190), 9 (n = 188), and 12 months (n = 196). Concentrations of cholesterol--very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein-2 (HDL2), HDL3--and apoprotein B were analyzed in 36 infants at 2, 6, 9, and 12 months of age. Serum cholesterol concentration rose significantly more slowly in the weaned infants compared with exclusively breast-fed infants. The mean difference in total serum cholesterol value between the exclusively breast-fed and weaned infants was largest at ages 2 (0.9 mmol/L, P less than .001), 4 (0.6 mmol/L, P less than .01), and 6 months (0.5 mmol/L, P less than .01). The LDL cholesterol concentration was lower in weaned infants compared with exclusively breast-fed infants at age 2 and 6 months; the mean difference in LDL cholesterol value was 0.9 mmol/L at age 2 months (P less than .001) and 0.7 mmol/L at age 6 months (P less than .025). Also, the apoprotein B concentration was lower in weaned infants; the mean difference was 24 mg/dL at age 2 months (P less than .01) and 30 mg/dL at age 6 months (P less than .05). The apoprotein B-LDL cholesterol ratio was stable and similar in both feeding groups through the year. The HDL2 cholesterol concentration was lower in the formula-fed than in breast-fed infants at 2 months of age while the VLDL and HDL3 cholesterol concentrations were independent of the diet.(ABSTRACT TRUNCATED AT 250 WORDS)
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This minireview deals with the presence of epidermal growth factor (EGF) in human tear fluid. It explains the occurrence of EGF in tear fluid, the origin of EGF and its dependency on tear fluid dynamics. The alterations in tear fluid EGF concentrations that occur during diseases of the ocular surface are described and discussed in the context of the current knowledge about the interaction between EGF and EGF receptors. The possible clinical implications of topical treatment with EGF are considered.
To study the source of immunoreactive epidermal growth factor (ir-EGF) released by thrombin formation we removed 99.9% of the leukocytes normally present in platelet-rich plasma and induced coagulation with 30 mM of Ca2+. The absence of leukocytes did not reduce the amount of ir-EGF released; thus platelets are most likely the only source of the ir-EGF released during aggregation. To identify the site of ir-EGF in platelets we exposed washed platelets to collagen or thrombin and compared the kinetics of releases of ir-EGF, beta-thromboglobulin (bTG, an alfa-granule marker), ATP (dense granule marker), N-acetyl-beta-D-glucosaminidase (NAGA, a lysosome marker) and lactate dehydrogenase (LDH, a cytoplasmic marker). Release of ir-EGF started immediately and continued linearly. The process differed clearly from the releases of the granule markers, which occurred readily, and were completed in a few minutes. The release of ir-EGF also differed from the leakage of LDH, the start of which was delayed greater than 5 min, but then proceeded linearly. Cytochalasin B inhibited the release of hEGF, but demecolcine had no effect. We conclude that the ir-EGF released from platelets during aggregation derives neither from the granules nor the cytoplasma. The assembly of cytoskeleton is needed for its release.
As part of a prospective study of children with bacterial meningitis we analyzed in 36 patients of our hospital the fluid balance on admission and during the first three days of treatment. On admission 10 of them (28%) had inappropriate antidiuretic hormone secretion SIADH, 10 (28%) hypo-osmolal and 10 (28%) iso-osmolal contraction. Six patients (17%) had no clear fluid disorder. The patients with SIADH had significantly lower mean serum NA+ (127 vs. 132 mEq/l, p less than 0.01) and higher mean urine Na+ (111 vs. 26 mEq/l, p less than 0.01) concentration as well as higher mean urinary Na+/K+ ratio (2.23 vs. 0.365, p less than 0.005) than the patients with hypo-osmolal contraction. They also tended to be younger and have a shorter history of fever. The patients with SIADH had a less strict fluid restriction than the patients with hypo-osmolal contraction, and their fluid balance normalized more slowly. Our findings support initial water restriction for all children with bacterial meningitis.
During a nutritional study of 198 infants, seven became allergic to cow's milk. The seven infants showed acute cutaneous manifestations during cow's milk challenge tests in hospital and six had increased levels of IgE cow's milk-specific antibodies. Neither in the development of the levels of immunoglobulins G, A and M, nor in that of the cow's milk-specific antibodies of these isotypes did these seven patients differ from the remaining infants. Beta-lactoglobulin content and levels of cow's milk-, and beta-lactoglobulin-specific antibodies and of immunoglobulins A, G and M were measured in samples of colostrum and milk from the mothers of the seven infants with cow's milk allergy and from a comparison group (non-atopic mothers of non-atopic infants). The milk of the mothers whose infants became allergic to cow's milk contained less IgA through the lactation: 95% confidence intervals of the groups did not overlap. The difference was most marked in the colostrum. All other measurements were similar in the two groups. This suggests that an infant is more likely to develop cow's milk allergy if the mother's colostrum had a low total IgA content.