Biomedical subjects
Publications and source records attributed to K Albertsson-Wikland.
In an extended family with eight individuals with infantile autism, in association with other developmental disorders and fragile (X) (q27.3), DNA techniques were used to investigate linkage between X chromosomal probes and the disorder. F9 was not informative and recombination was found between fragile X and DXS15, DXS51 and DXS52.
Linear growth during the first three years of life can be represented mathematically in terms of the "ICP-growth model", using a combination of a quickly decelerating Infancy component with the addition of a slowly decelerating Childhood component, the latter acting from the second half of the first postnatal year. The growth pattern for supine length of four children with growth hormone (GH) deficiency is related here to the first two components of this growth model. Basically, all four infants displayed a pattern in line with the exponential shape of the Infancy component to the age when GH therapy was initiated. This observation indicates the existence of the Infancy component as it has been adopted for the ICP-model, and also that it represents the part of postnatal linear growth which seems to be independent of GH. The onset of the Childhood component in healthy subjects has been observed as an abrupt increase in growth rate during the second half of the first year of life. A similar abrupt increase was observed in this study at the time of the initiation of GH therapy (16-27 months). This observation gives some further empirical support to the hypothesis that the child's age at onset of the Childhood component defines the as yet undetermined age at which GH begins to exert a significant influence on linear growth. ICP-based growth charts provide an improved instrument for early detection of GH deficiency.
Short children with normal GH responses to arginine-insulin provocation testing and various amounts of spontaneously secreted GH over 24 hours participated in an ongoing study with GH, 0.1 IU/kg/day. A total of 40 prepubertal children have been treated for 1 year. Their mean height velocity increased from 4.6 to 7.5 cm/year. The children with the slowest pretreatment height velocity showed the best increment. An inverse relationship was found between the endogenous GH secretion and the increment in growth; 80% of the children had an endogenous GH secretion of less than 300 milliunits/litre/24 hours, estimated as area under the curve above the calculated baseline. They all showed an increment in height above 2 cm. The remaining 20% all had an endogenous GH secretion of more than 300 milliunits/litre/24 hours, estimated as area under the curve above the calculated baseline. Twenty-four of the children were prepubertal for the following 4 years, and their GH therapy continued. Their height velocity changed from 4.2 cm/year before therapy to 8.1, 6.7, 6.0 and 4.9 cm/year for the 1st, 2nd, 3rd and 4th years on treatment. Many of them have passed their expected final height, but have still not stopped growing. Those children who were in early puberty when GH treatment started went into a rapid growth spurt and have now stopped growing. They have all reached but not improved their expected final height. In 15 of the children GH treatment was stopped after 1-3 years. Their mean height velocity for the first post-treatment year was 5.1 cm/year; thus, for the group as a whole no 'catch down' was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
For 30 years, GH deficient children have been treated with human GH. Earlier, therapy was given by intramuscular injections, but recently subcutaneous injections have been used. For the last few years, many children have been given daily injections, which have proved more effective. The form in which GH is supplied and administered entails taking an inconvenient hospital method into the daily family routine. The need to simplify the method of administration of GH has been fulfilled by a multidose vial for recombinant somatropin, developed to be used in an injection pen, the KabiPen. In the first clinical trial of 40 children, aged 2.5-21 years, all the families found the KabiPen to be much more convenient, less time-consuming, and easier when travelling; it also requires less space in the refrigerator and is easier for the child to handle. Most of the children found the KabiPen injections less painful, due to a finer and sharper needle and a smaller injection volume. Out of the 40 families, as many as 34 wanted to continue with the KabiPen after the 1-month trial.
Children irradiated for brain tumours constitute an increasing group of patients who will require GH therapy. High-dose cranial irradiation is necessary for cure, but inevitably causes GH deficiency within a few years. In 19 patients investigated between 2 and 9 years after irradiation, the spontaneous 24-hour GH secretion was markedly reduced. The secretory pattern indicated loss of regulating hypothalamic hormones. After exogenous GHRH was administered, the pituitary was able to respond with a prompt GH release, showing that pituitary function was unaffected. Ten prepubertal children growing at 3.8 +/- 0.3 cm/year were treated with GH, 0.1 IU/kg/day s.c. Their growth rate increased to 8.2 +/- 0.4 cm in the first year. An increased growth rate was also maintained in the second year.
Growth, age at menarche and spontaneous GH secretion were studied in girls after treatment for acute lymphoblastic leukemia (ALL). These girls had normal prepubertal growth but subnormal pubertal growth. Mean final height was 1 SD less than expected before puberty. The average age at menarche was significantly lower than the normal mean for Swedish girls. The mean 24-hour GH secretion was severely blunted and there was no increase during puberty. We suggest that girls treated for ALL, including CNS irradiation, have a relative GH insufficiency which becomes clinically obvious only when the girls cannot respond to the increased demands for GH in puberty.
The relationship between height and amount of GH measured during a 24-h period was studied in 127 children who were growing at different rates. Of the children, 88 were prepubertal (3-16 yr old) and 39 were pubertal (10-16 yr old). The height of each child was expressed as the SD score, i.e. height in relation to the sex- and age-matched Swedish reference groups, and spontaneous GH secretion was estimated by taking integrated 20-min blood samples for a 24-h period, i.e. 72 samples/child. In a few children, discrete samples were taken in parallel with the integrated 20-min samples with virtually the same results. Plasma GH was estimated in each sample using a polyclonal RIA method. To compare different 24-h GH profiles, the profiles were analyzed using a computer program (Pulsar). One objective of the study was to determine if less frequent sampling and/or shorter sampling periods yielded the same information as that obtained by 20-min sampling for the whole 24-h period. To determine if less frequent sampling provided the same information as that obtained by the 20-min period, we simulated 40- and 60-min periods by pooling two or three consecutive samples. No difference was found between 20- and 40-min sampling, but with 60-min sampling the mean calculated baseline plasma GH concentrations increased, and the GH concentration within peaks [the area under the curve above the baseline (AUCb)] decreased markedly. A 30-min sampling interval thus seems to be a valid practical compromise. To determine if sampling periods shorter than 24 h provided the same information, we divided the profiles, which started at 0900 h, into two 12-h, three 8-h and four 6-h periods. A graded decrease in AUCb and a corresponding increase in the baseline was found with the shorter periods, indicating that the whole 24-h period is necessary for GH sampling. Another objective of the study was to determine whether there was a correlation between 24-h GH secretion and the height, age, and sex of the children. In the prepubertal children, the height (in SD scores) was highly correlated (r = 0.69; P less than 0.001) with GH AUCb during the 24-h period. Height also correlated with AUCb estimated over shorter time periods; the correlation diminished with decreasing time. In the pubertal children, a nonlinear correlation (r = 0.36; P less than 0.05) was found between height and 24-h GH (AUCb).(ABSTRACT TRUNCATED AT 400 WORDS)
A total of 23 previously untreated and 28 previously treated GH deficient children were included for at least 12 months in a trial of recombinant somatropin, 0.1 IU/kg/day given by subcutaneous injection. All the children increased their height velocity over the pretreatment values, to nearly 11 cm/year, corresponding to a significant increase in height of 1 SD score for chronological age. The increase in height SD score for bone age was also statistically significant. No adverse effects were recorded, though one child experienced local itching and redness at the injection site which did not recur after a short cessation of therapy. One child developed detectable antibodies to recombinant somatropin, but the binding capacity was low and no clinical symptoms or growth attenuation occurred. Recombinant somatropin was shown to be safe and effective during the first year of therapy in children with GH deficiency.
A total of 47 prepubertal children with hGH deficiency were treated for up to 6 months with recombinant somatropin. All the children markedly increased their growth rate; 21 of them were naïve (not previously treated with hGH), and increased their growth rate from 4.2 +/- 0.2 cm/year to 13.9 +/- 0.9 cm/year (calculated from growth data after 6 months' treatment, n = 11). Of the 47 children, 26 had been previously treated for 2 +/- 0.3 years (range 0.3-8.3 years) with pituitary hGH. After a period of 0.9 +/- 0.03 years (range 5-15 months) without any hGH therapy, their growth rate increased from 2.9 cm/year to 11.1 cm/year on recombinant somatropin therapy (calculated from growth data after 6 months' treatment, n = 10). One child reacted with temporary local erythema at the injection site. Anti-hGH antibodies, with a binding capacity of 0.02 mg/litre, were detected in 1 of the 16 children after 6 months of therapy. No adverse effect on her growth rate was seen. No changes in levels of antibodies to Escherichia coli proteins were detected. No other allergic manifestations or systemic side-effects were demonstrable.
hGH has been used in the treatment of hGH deficient children for nearly 30 years. The optimum treatment regimen is, however, still unknown. Generally, administration has been by 2 or 3 intramuscular injections/week and the total weekly dose has been 0.3-0.5 IU/kg. Many factors are known to influence the effect of treatment, such as the dose and the age of the child. In animal studies, the optimum growth rate occurs when the physiological pulse frequency of growth hormone is simulated (i.e. intravenous infusions of growth hormone every 3 hours in the rat). In humans, optimal growth rates occur in children in whom the spontaneous secretion of hGH is associated with many peaks (pulses) of high amplitude. In hGH deficient children, growth rate increases when the weekly dose of hGH is administered daily rather than 2-3 times/week, thereby optimizing the body's utilization of the hormone. The hGH plasma profile after daily subcutaneous hGH injections is, however, different from the hGH plasma profiles of children growing normally, in whom hGH secretion is episodic with many sharp pulses during the day and night. Whether simulation of normal hGH plasma profiles will increase the growth rate in hGH deficient children and normalize their adult height requires further investigation.
Longitudinal growth was studied in 27 children after radiotherapy for a brain tumor. Growth deviation (greater than or equal to 1 SD) was found in 56% of the children after 2 years and was most profound in prepubertal children aged between 3 and 8 years at the time of irradiation. In this group growth velocity was markedly reduced and no catch up was seen. In all children studied growth hormone (GH) secretion, measured as the spontaneous secretion over 24 hours, was found to be severely disturbed. Our conclusion is that all children with a growth deviation greater than or equal to 1 SD after radiotherapy (greater than or equal to 40 Gy) to the hypothalamo-hypophyseal region should be considered GH deficient. In such children GH treatment can be initiated without further testing.
Growth retardation due to growth hormone (GH) deficiency is common in children after radiotherapy to the brain. Different methods for assessment of GH secretion were compared in 19 children who had received radiotherapy to the brain as part of treatment for a tumor of the brain, eye or epipharynx. GH was measured over a 24-hour period (72 sampling periods of 20 min each), as well as after administration of growth hormone-releasing hormone (GHRH) and arginine-insulin (AITT) tests. We found the 24-hour GH profile to be disturbed in all children; there was a low overall secretion with few peaks of low amplitude but a diurnal rhythm still discernable. In 16 children a prompt rise in GHRH after GHRH1-40 was seen indicating hypothalamic damage. The GH response after GHRH was not found to be correlated to the spontaneous secretion over 24 h. The results of the AITT showed discrepancies to the 24-hour GH profile in individual cases making this test unreliable in spite of a good overall correlation between the tests. Therefore, we suggest measurement of spontaneous secretion when GH-secretory capability is to be evaluated after cranial irradiation for a brain tumor.
Thirty-one children who were short but not GH deficient, whose serum GH responses to provocative tests were normal, and whose spontaneous GH secretion was low received daily sc injections of human GH (Crescormon; 0.1 IU/kg BW) for 1 yr. Their initial serum insulin-like growth factor I (IGF-I) and IGF-II responses to GH were compared with their 1-yr growth response to therapy. In the prepubertal group (n = 18) the growth rate of all but two children increased 3.4 +/- 0.2 (+/- SEM) cm (from 4.1 +/- 0.2 to 7.5 +/- 0.3 cm/yr). The mean increment in the growth rate of the pubertal group was 5.2 +/- 0.5 cm. In both groups the growth increase was strongly correlated with both the percent increase in serum IGF-I and the percent increase in serum IGF-II during the first 10 days of treatment. No correlation was found between the basal growth rate and basal serum IGF-I or IGF-II levels. In the prepubertal group of children, both the percent increase in serum IGF-I levels in response to GH and the age at start of treatment were predictors of long term growth. We conclude that this subgroup of normal short children with low spontaneous GH secretion and high percent increase in serum IGF values benefits from GH treatment with an increased growth rate.
Four boys with the combination of infantile autism and the fragile-X syndrome were given oral folic acid and placebo, according to a double-blind crossover design. One boy's behaviour appeared to improve on folic acid, but another boy did not seem to be affected at all. For the remaining two boys the results were equivocal. Further study of folic acid in the treatment of autistic boys with the fragile-X syndrome is warranted.
Sixteen children (10 boys, 6 girls) on treatment for some years with i.m. injections twice or thrice weekly of human growth hormone (hGH; Crescormon Kabi Vitrum), participated in a prospective study. The weekly amount of hGH (8, 12, or 16 IU) was kept the same in each child, but divided into daily (7) s.c. injections at bedtime. The growth rate increased in all children during the first year on s.c. daily hGH (5.3 to 7.4 cm/year; 1.95 to 4.27 SDS). This increased growth rate did not persist during the second year on daily s.c. hGH, but an increased growth rate did not persist during the second year on daily s.c. hGH, but an increased predicted final height was found. The plasma profile of hGH was followed: i.m. injected hGH gave mostly a high (200 mU/l) plasma level of some hours (wide intra- and interpatient variation), and s.c. injected hGH a lower max level of longer duration (wide inter patient variation). The daily s.c. regimen of hGH was extremely well accepted by the children and their parents and no GH-antibodies or other adverse effects were found. We recommend daily s.c. injection of hGH as an alternative in the treatment of GH-deficient children.
A study of 31 children with short stature was initiated in 1982. They received subcutaneous injections of pituitary hGH, 0.1 IU/kg/day; no adverse effects were seen and none of the patients acquired antibodies. Only the results of the first year are presented, as final height has not yet been attained. A high growth response was seen in 29 of the 31 children; they experienced an initial rise of IGF-1, IGF-2, alkaline phosphatase and procollagen III. The best response was obtained in the child with the lowest levels of endogenous pulsatile hGH secretion.
Total plasma carnitine was analysed in 19 women, with uncomplicated pregnancies, who underwent elective caesarean section, and in their neonates. The women were given a balanced glucose (glucose group) or saline (saline group) infusion, group allocation being on a random basis. The carnitine levels in maternal or infant plasma did not differ between these two groups. At delivery, the mean maternal carnitine value, 17.4 +/- 1.25 mumol/l, was lower than the mean infant value, 25.9 mumol/l +/- 2.67 (mean +/- SE, p less than 0.005) and lower than the mean value in non-pregnant, fertile women, i.e. 40.9 +/- 1.22 mumol/l. The mean carnitine value in the unfed neonate had not changed when the infant was 4 hours old. A positive correlation was found between carnitine levels in maternal and infant plasma (p less than 0.01). At delivery, the levels of non-esterified fatty acids and 3-OH-butyrate in infant plasma were different in the two groups, but not at 4 hours of age. The results suggest that the maternal carnitine level is the most important factor governing plasma carnitine levels in the neonate.
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