Protective factors in milk and the development of the immune system.

The neonate is immature in certain immunologic functions. The slow development of secretory immunoglobin A (IgA) seems to be compensated by selective transfer of secretory IgM into exocrine secretions on mucous membranes during the first few months of life. Secretory IgA and secretory IgM antibodies against Escherichia coli and poliovirus are already found in the neonate, possibly in response to the maternal anti-idiotypic IgG antibodies transplacentally exposing the fetus. Via such a mechanism, food antibodies could occur before direct food exposure in the infant. Human milk provides large amounts of antibodies (as a crude comparison, about 50 times the amount of antibodies given to a patient with hypogammaglobulinemia). The milk antibodies, dominated by secretory IgA, protect especially against intestinal infections. The milk also contains oligosaccharide analogues to epithelial receptors for bacteria. They, as well as a number of milk components such as lactoferrin and lysozyme, may contribute to host defense. The food antibodies in human milk may influence the infant's immune response to foreign food proteins introduced during weaning.

Growth at the age of 4 years subsequent to early failure to thrive.

Fifty-five children previously investigated for failure to thrive (a rate of weight gain below -2 SD) during at least 6 weeks at 4-18 months of age were followed up and reinvestigated at the age of 4 years. The children were studied in two groups: children with organic causes (OFTT) (n = 21); and children for whom no organic cause was found (nonorganic failure to thrive, NFTT) (n = 34). In children with OFTT, normalization of growth was found for both weight and height attained, as most of the diseases were either amenable to treatment or spontaneously subsided. The only exception was a child with severe encephalopathy. In children with NFTT, much lower values were found, particularly for weight, p less than .01 for both weight and height. Children with a low psychosocial score (less than or equal to 3 adverse factors) showed partial catch-up growth, although significantly lower than that of children with OFFT. Among 13 children with high psychosocial scores (greater than or equal to 4), 6 children had been subjected to strong social and/or psychological intervention. These children showed a more favorable growth pattern compared to children with comparable psychosocial scores where no intervention had been undertaken. The children with NFTT continued to grow slowly, remained meager and seemed to maintain a suboptimal growth pattern, particularly those with higher numbers of risk factors.

A pericentric inversion of chromosome 9 and a rearrangement involving chromosomes 9 and 10, observed in two generations. Clinical description of chromosome 9 (p12-p21) deletion syndrome.

The clinical picture associated with a deletion of a central part of the short arm of chromosome no. 9 is described in two siblings. The clinical signs differ from those described in deletion of the terminal part of the short arm. Pericentric inversion of chromosome no. 9, combined with a rearrangement involving chromosomes 9 and 10, was found in the mother and the maternal grandmother of the propositus.

Infants with low rate of weight gain. II. A study of environmental factors.

Eighty-one infants were investigated to evaluate the clinical significance of low rate of weight gain. An organic etiology was found in 28 infants. The remaining infants were analysed with special respect to their psychosocial environment. Growth was assessed by rate of weight gain. Thirty-four infants had subnormal rates. Comparisons were made with 18 infants with low but normal rates and a control group of 72 infants. Several psychosocial risk factors were overrepresented in infants with subnormal rate of weight gain such as unemployment, ill-health in fathers, dependence on social welfare etc. No significant differences were found in perinatal factors except for birth weight. The magnitude of the load of adverse factors within the family was measured as a score. A significant negative correlation was found between the score obtained and the rate of weight gain.

High incidence of urinary tract infection in patients with coeliac disease.

The concomitant occurrence of urinary tract infection (UTI) and coeliac disease was studied retrospectively among children with coeliac disease. There was a significantly higher risk of first time UTI in children with coeliac disease than in an unselected population of children. In the majority of cases UTI was associated with untreated, active coeliac disease.

Infants with low rate of weight gain. I. A study of organic factors and growth patterns.

To evaluate the clinical significance of low rate of weight gain 81 infants wer investigated with a deviation of weight corresponding to a decrease of at least one S.D.-score of weight attained in the current Swedish growth chart. In 28 patients this decrease was of organic origin, notably intestinal disease. Three different growth variables were compared: attained weight (transformed to S.D.-score), change in S.D.-score of attained weight per time unit (= rate of change of deviation in S.D.-score/year) and rate of weight gain in kg/year (transformed to S.D.-score). Twenty-two of 28 infants with organic diseases had a subnormal rate of weight gain whereas only 12 attained subnormal weight for age. The use of rate of weight gain is the most sensitive growth variable and is far better than the use of attained weight as an indicator of ill-health. Change in S.D.-score of attained weight for screening purposes give good agreement with rate of weight gain, provided that age is taken into account.

Clinical disease activity and inflammatory activity in the rectum in relation to mucosal inflammation assessed by colonoscopy. A study of children and adolescents with chronic inflammatory bowel disease.

The relationship between clinical disease activity, rectal inflammatory activity and mucosal inflammation established at total colonoscopy has been studied in 36 young patients with ulcerative colitis (UC) and 24 with Crohn's colitis (CC). Semiformed stools, diarrhea and frequent bowel movements seem to be better indicators of extensive mucosal inflammation of a moderate or severe degree than blood in faeces. There were, however, several patients with a discrepancy between the degree of clinical disease activity and the extent and degree of mucosal inflammation at endoscopic and histologic assessment. In about one-third of the patients with UC and in about half of the patients with CC, who had mucosal inflammatory activity of a moderate or severe degree, the rectal inflammatory activity was of a lower degree. Total colonoscopy seems to be necessary in order to establish the extent and degree of mucosal inflammation.

Plasma triglyceride increase after oral fat load in malabsorption during early childhood.

Plasma triglyceride (TG) levels were determined before and after a test meal of 2 g neutral fat per kg b.w. in 32 children with different malabsorption syndromes, 8 children with transient growth retardation without demonstrable disease and in 29 controls. The increase of plasma TG 120 min after the test meal was found to discriminate between children with malabsorption syndromes and controls during the studied age period, 1 month-3 years. In this respect it was superior to faecal fat determination. Children with transient growth retardation who later spontaneously regained satisfactory growth, although along a lower SD score than the initial one, showed a TG increase after the test meal comparable to that of the controls.

Histological studies of small-intestinal biopsies from infants with low rate of weight gain.

Eighty-one children aged 4-18 months with unsatisfactory weight gain were investigated for organic diseases; the investigation included small-intestinal biopsy. Sixteen had total villous atrophy, in most cases due to gluten intolerance. Transient disease, e.g. cow's milk protein intolerance, was probable in 7 children with subtotal atrophy. In 18 children the only abnormal finding was an increased number of inflammatory cells in the mucosa, a finding which was probably of no clinical significance. Planimetric measurement showed good agreement between the mucosal surface/volume ratio and an ordinary histological grouping of the mucosa. A significant correlation was found between the rate of weight gain during the period preceding investigation and mucosal surface/volume ratio.

On the renal tubular damage in hereditary tyrosinemia and on the formation of succinylacetoacetate and succinylacetone.

Phenylalanine and homogentisate increase the concentration of succinylacetoacetate and succinylacetone both in serum and urine in patients with hereditary tyrosinemia and therefore increase the excretion of 5-aminolevulinate. Both phenylalanine and homogentisate cause a tubular proteinuria which is in agreement with our hypothesis that their metabolites maleylacetoacetate and fumarylacetoacetate are the toxic compounds in hereditary tyrosinemia. The patient with the highest excretion of succinylacetoacetate and succinylacetone has the slightest tubular proteinuria whereas the one with the lowest excretion of these compounds has the more pronounced tubular proteinuria. It is suggested that this is caused by a difference in the ability to reduce the presumed toxic compounds fumarylacetoacetate and maleylacetoacetate, i.e. the precursors of succinylacetoacetate.

Clinical application of evoked EEG responses in infants. III: congenital hypothyroidism.

Previous studies have shown a close relationship between maturation of the central nervous system and development of evoked EEG responses. In this study, 13 infants with congenital hyperthyroidism were examined between the ages of one week and 17 weeks in an attempt to evaluate the degree of developmental retardation and the influence of hormonal treatment. It was found that visual evoked responses were abnormal in 12 of the patients, the most common abnormality being an immature abnormal response pattern. Latency was increased significantly in 10 of the 11 patients who were diagnosed before the age of six months, but was normal in the remaining two who were diagnosed later. A significant reduction of photic driving occurred in only two patients; it was the sole abnormality in one of them. Both the response pattern and latency became normal during treatment. The authors conclude that recording visual evoked responses is a simple and useful method of evaluating cerebral function in congenital hypothyroidism, both before and during treatment.

Relationship between results of laboratory tests and inflammatory activity assessed by colonoscopy in children and adolescents with ulcerative colitis and Crohn's colitis.

The relationship between the results of nine laboratory tests and inflammatory activity in the colon assessed macroscopically (macro) and histologically (hist) has been studied in 60 children and adolescents, 36 with ulcerative colitis (UC), and 24 with Crohn's colitis (CC). The mean duration of disease was 38 months. Eleven patients were newly diagnosed and not treated. Special attention was paid to severe and extensive colitis (SEC), in other words, moderate or severe inflammation in at least six of eight colon segments. A significant correlation was found between some laboratory parameters and the inflammatory activity of colonic mucosa. In UC, the following abnormal laboratory test results only occurred in SEC/macro: thrombocytosis, low serum albumin, and high serum orosomucoid. The combination of low serum iron and low or normal total iron binding capacity (TIBC) occurred in seven cases, six of whom had SEC/macro. Eleven of the 17 patients with SEC/macro had at least one of these four test results. SEC/hist was indicated only by thrombocytosis and high orosomucoid. In CC, a combination of low serum iron and low TIBC only occurred in SEC/macro. Thirteen of 36 patients with UC (36%) and four of 24 with CC (17%) had no abnormal test results.

The diagnostic value of colonoscopy compared with rectosigmoidoscopy in children and adolescents with symptoms of chronic inflammatory bowel disease of the colon.

Seventy-eight young patients with symptoms of chronic inflammatory bowel disease (IBD) of the colon have been investigated to determine to what degree colonoscopy adds important information for the diagnosis of IBD in addition to results of the routine procedures, including rectosigmoidoscopy carried out at the same time. After colonoscopy IBD was established in 4 of 12 patients classified as non-IBD after the routine procedures. Eleven of 18 patients with the routine diagnosis indeterminate colitis (IC) could after colonoscopy be differentiated into UC or probable CC. In 30 of 31 cases classified as UC the routine diagnosis was confirmed by colonoscopy. Routine diagnosis as probable CC was changed to definite CC in 3 of 10 cases. In all cases but one with previously established IBD it was possible to confirm the diagnosis. Thirty-seven of 70 patients with established IBD of the colon had no radiologic evidence of colitis.

Cow's milk protein intolerance in children is connected with impaired lymphoblastic responses to mitogens. Preliminary report.

The lymphoblastic responses of peripheral blood lymphocytes to mitogens were analyzed in 36 infants and children aged 1-28 months. The patients had confirmed or suspected cow's milk protein intolerance (CMPI). Immediately after a positive provocation test 12 out of 14 patients with repeatedly confirmed CMPI showed more than 30% decrease of their lymphoblastic responses to pokeweed mitogen and concanavalin A compared with their initial values. In 10 infants the response to phytohemagglutinin was similarly decreased. In 4 out of 12 infants with previously confirmed CMPI, but with no reaction at challenge, similar decreases were seen to some of the mitogens. In patients with suspected CMPI, but with no obvious reaction to the challenge with cow's milk, generally an increase of the lymphoblastic responses was seen compared with the initial values.

Duplication in the hypoxanthine phosphoribosyl-transferase gene caused by Alu-Alu recombination in a patient with Lesch Nyhan syndrome.

We have determined the structure, at the nucleotide sequence level, of a duplication in the hprt gene in a patient with Lesch-Nyhan syndrome (LN). The duplication extends over exons 7 and 8 and approximately 1.8 kb of the surrounding hprt sequence. The duplication junction is localized within two Alu sequences and has apparently been generated by unequal homologous recombination. This is the second reported case of a partial duplication of the hprt gene in an LN patient, and the first that involves an Alu-Alu recombination.

Antibody-dependent cell-mediated cytotoxicity to beta-lactoglobulin-coated cells with sera from children with intolerance of cow's milk protein.

The capacity of serum antibodies against beta-lactoglobulin to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) was analysed in sera from children with cow's milk protein intolerance (CMPI). The children with CMPI were divided into three groups according to clinical features: delayed-onset CMPI with gastrointestinal symptoms (n = 8); immediate-onset CMPI with gastrointestinal and skin symptoms (n = 8); and immediate-onset CMPI with skin symptoms only (n = 8). The CMPI groups were compared with children with untreated (n = 9) or treated (n = 8) coeliac disease and a control group (n = 22). Sera from the children were examined for cytotoxic effects using lymphocytes from healthy adults as effector cells and radiolabelled beta-lactoglobulin-coated erythrocytes from the same donor as target cells. In addition, IgG and IgA serum antibodies against beta-lactoglobulin were determined with ELISA. Sera from children with CMPI and gastrointestinal symptomatology showed a significantly increased capacity to induce ADCC reactivity as compared with controls. This increased capacity was seen in sera from those with immediate as well as delayed onset of the gastrointestinal symptoms. In contrast, sera from children who had an immediate-onset CMPI with only skin symptoms mediated no such increase in ADCC reactivity. Moreover, children with coeliac disease with a few exceptions, demonstrated low ADCC reactivity, despite the fact that they had high levels of antibodies against beta-lactoglobulin. ADCC may be an immunopathogenic mechanism in certain cases of CMPI with gastrointestinal symptoms.

Coeliac disease in children of short stature without gastrointestinal symptoms.

Eighty-seven children with short stature (height more than 2 SD below the mean for age and sex) were investigated by small intestinal biopsy. There was no obvious reason for their growth retardation found by routine examination and they had no gastrointestinal symptoms. Coeliac disease was found in two children and probable coeliac disease in two children. Although the prevalence of coeliac disease was comparatively low in this study of Swedish children with short stature, it emphasizes the fact that coeliac disease must be considered in a child with short stature even in the absence of gastrointestinal symptoms.

Serum antibodies against native, processed and digested cow's milk proteins in children with cow's milk protein intolerance.

Children with or without cow's milk protein intolerance were investigated for serum antibodies to native cow's milk proteins, processed cow's milk proteins and native- and pepsin-digested beta-lactoglobulin. Antibodies of IgG and IgA isotypes were determined with ELISA and those of IgE isotype with RAST. Children who exhibited slowly appearing untoward reactions to cow's milk feeding had significantly higher titres of IgG antibodies against both native and digested beta-lactoglobulin than children with an immediate type of reaction or no intolerance. The IgG antibodies to pepsin-digested beta-lactoglobulin were efficiently inhibited by native beta-lactoglobulin even at low concentrations, which suggests that there were no antibodies specific for the degraded proteins. The children with slow reactions to cow's milk also tended to have higher antibody levels of the IgG and IgA isotypes to both native and processed cow's milk. Antibodies to this mix of antigens discriminated less well, however, than the antibodies to isolated beta-lactoglobulin between the groups of children with slowly appearing reactions, with immediate reactions and the controls. Seven out of nine children with an immediate type of reaction to cow's milk protein had IgE antibodies against cow's milk protein determined with the RAST, while this type of antibodies could not be demonstrated in any child in the two other groups. Using processed or digested protein as antigen did not increase the sensitivity of the antibody determinations.

Secretory IgA antibodies against cow's milk proteins in human milk and their possible effect in mixed feeding.

Antibodies of the secretory IgA type against cow's milk proteins were consistently found in human milk. With the assumption that such antibodies can help to prevent or at least diminish the contact between native cow's milk proteins and the lymphoid system of babies on mixed feeding, the levels of antibodies of various immunoglobulin classes against bovine milk proteins were measured in different groups of babies. Those on artificial feeds who had been on mixed feeding of human milk and cow's milk for less than 1 week had significantly higher levels of IgG antibodies to cow's milk proteins than those who had been on mixed feeding for a period longer than 3 weeks.