Moral assessment of growth hormone therapy for children with idiopathic short stature

Subjects ranging in age from 50 to 89 years old, either with or without dementia were studied by both ELISA for anti-human T-cell lymphotropic virus type I (HTLV-I) gag 100-130 antibody and by cranial CT in order to clarify the relationship between HTLV-I infection and dementia. The frequency of anti-HTLV-I antibody was found to be significantly higher in the patients with dementia (24/130, 18.5%) than in those without dementia (11/139, 7.9%) (P=0.0169). Among the various types of dementia, HTLV-I seropositivity was found to be significantly associated with vascular dementia (11/48, 23%) (P=0.0087), but not with Alzheimer type dementia. In addition, HTLV-I seropositivity was also associated with Babinski sign, and the severity of cerebral infarction, ventricular dilatation and periventricular lucency on CT. The presence of HTLV-I therefore appears to be one of the risk factors for vascular dementia in HTLV-I endemic areas.     

The treatment with biosynthetic growth hormone (GH) of familial short stature

The effect of growth hormone (GH) treatment in non-GH deficient subjects has been amply studied over the past few years. Although the results of these studies are encouraging, there are still no definitive data since the findings are not comparable due to the different characteristics of the populations examined. In the present study the authors examined the following parameters: stature, height SDS, growth rate, bone age and final height prediction according to Tanner, pubertal stage, before and after treatment with biosynthetic GH at a dose of 1.4 IU/kg of bodyweight for 12 months. The population treated consisted of 10 subjects (5 males and 5 females) aged between 7.3 and 9.5 years old, all prepubertal, with "familial short stature", selected according to the following criteria: stature below the 3rd centile, normal growth rate, normal GH response to stimuli using clonidine and insulin, correlation with parental stature between 25th and 75th centile, bone age correlated to chronological age, absence of other pathologies. After 12 months height SDS moved from -2.75 +/- 0.26 to -2.23 +/- 0.25 (p < 0.5); the growth rate changed from 5.75 +/- 0.63 to 6.66 +/- 0.56 (p < 0.05). No abnormal acceleration of bone age as observed: it moved from 8.2 +/- 0.62 to 9.5 +/- 0.72; all subjects continued to be prepubertal. The expected final stature changed from 154 +/- 2.38 to 159 +/- 0.7 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Dental maturity in children of short stature, with or without growth hormone deficiency

Macrophages are important constituents of the immune system by exerting phagocytosis on invading pathogens as well as secreting various immunoregulatory factors. Generation of human macrophage hybridoma has not been possible so far due to the lack of an appropriate fusion partner cell line. In the present study, an 8'-azaguanine resistant cell line, termed HL-60R, was established by drug selection of the promyelocytic cell line HL-60. This novel cell line showed resistance to high concentrations of 8'-azaguanine and was sensitive to aminopterin. These characteristics make it suitable for serving as a potential fusion partner cell line in the development of macrophage hybridoma. Cell-surface analysis by FACS revealed that HL-60R cells per se do not express MHC-class II molecules or the macrophage marker, CD11b. PEG-mediated fusion of HL-60R was performed with PBMC-derived human macrophages. Fluorescence labelling of ex vivo isolated macrophages prior to fusion and subsequent FACS analysis showed that PEG-4000 is a more effective fusion agent than PEG-1500. The generation of this novel fusion partner cell line opens the possibility for development of human macrophage hybridoma or other cell lines from myelocytic origin. Such hybridoma clones will not only enable a more convenient study of these cell but will also provide an excellent host site for the proper production and expression of various recombinant proteins from myelocytic origin in vitro.     

Adult height in growth hormone (GH)-deficient children treated with biosynthetic GH. The Genentech Growth Study Group

Near-adult height (AH) was determined in 121 children (72 males and 49 females) with GH deficiency (GHD) who were prepubertal when they began treatment with recombinant DNA-derived preparations of human GH. AH as a SD score was -0.7 +/- 1.2 (mean +/- SD), significantly greater than the pretreatment height SD score (-3.1 +/- 1.2), the predicted AH SD score (-2.2 +/- 1.2; Bayley-Pinneau method), and the height SD score at the start of puberty (-1.9 +/- 1.3). In contrast to studies of GH treatment outcome, which used pituitary-derived GH (pit-GH) in lower doses, we found that males did not have a higher AH SD score than females, spontaneous puberty did not diminish AH, and AH was significantly greater than that predicted at the start of GH treatment. In a multiple regression equation, the statistically significant variables (all P < 0.0001) related to AH (r2 = 0.70) were the following: duration of treatment with GH, sex (males were taller than females, as expected for the normal population), age (younger children had a greater AH) and height at the start of GH, and growth rate during first year of GH. For the AH SD score (r2 = 0.47), pretreatment predicted AH, duration of GH, and bone age delay were significant (P < 0.0002) explanatory variables. Bone age delay (chronological age-bone age) had a negative impact on the AH SD score. Target height, etiology of GHD, previous treatment with pituitary GH, and the presence or absence of spontaneous puberty did not significantly improve the prediction of AH. Early diagnosis of GHD and continuous treatment with larger doses of GH to near AH should improve the outcome in children with short stature due to GHD.     

Final height in Turner syndrome patients treated with growth hormone

The first treatment trials on patients presenting with Turner syndrome were successful in accelerating growth velocity. It is therefore essential to know the final height of the patients who were treated in order to ascertain whether or not growth hormone treatment increases final height. We are reporting on a group of 117 patients with Turner syndrome whose growth hormone treatment was initiated in 1986. The mean growth hormone dose was 0.74 IU/kg/week for an average period of 4 years. At the start of treatment, the patients' chronological age was 129/12 years, height -3.8 +/- 1.0 standard deviation scores (SDS) and bone age 10.5 +/- 2.1 years. Mean final height was 147.7 +/- 5.6 cm, i.e. a gain of 1.5 SDS. We noted no significant difference due to the type of chromosomal abnormality, nor to oxandrolone or estrogen-associated treatment. A significant correlation was found between final height, mean parental height, the duration of the treatment, height SDS at the start of treatment and growth hormone peak during pharmacological stimulation tests. However, there was no correlation between growth hormone dosage, chronological age and bone age at the start of treatment. These results show that the growth hormone treatment improves the final heights of patients with Turner syndrome.     

The relationship between stature, growth, and short-term changes in height and weight in normal prepubertal children

Electrical stimulation of the superior laryngeal nerve (SLN) can elicit reflex responses in the cricothyroid (CT) and thyroarytenoid (TA) muscles. We made bilateral recordings of the responses evoked in these muscles in piglets by the stimulation of either the right or the left superior laryngeal nerve (SLN). The stimulus intensity was gradually increased to study the "persistence" of the responses. We observed a direct, ipsilateral response in the CT muscle, and reflex, ipsilateral and crossed responses in both CT and TA muscles. The ipsilateral or contralateral responses obtained in TA muscles, following stimulation of the left SLN, were significantly delayed in comparison with those evoked by stimulation of the right SLN. This delay cannot be explained by the difference in length between the right and the left recurrent laryngeal nerves, but rather by an asymmetry in the sensory afferent pathway. The functional significance of this observation remains to be determined.     

Isolated partial growth hormone deficient short stature with syringomyelia not associated with birth injury

A 59-year-old female with 20-year history of slowly progressing muscle atrophy and sensory disturbance of upper extremities showed short stature, scoliosis, hunger type of sensory dissociation of the upper extremities and pyramidal tract sign of the lower extremities. Magnetic resonance imaging (MRI) clarified hypoplasia of the anterior pituitary lobe, Arnold-Chiari malformation and cervical syringomyelia. Insulin and arginine stimulating tests revealed partial type of isolated growth hormone (GH) deficiency but GH gene analysis detected no defects of GH genes. It was considered to be a rare case of non-hereditary hypopituitarism with Chiari malformation and syringomyelia not associated with perinatal injury, namely a midline anomaly syndrome.     

Serum growth hormone-binding protein is decreased in prepubertal children with idiopathic short stature

Every activity of a medical practitioner may be subjected to court control. This creates not only uncertainty gut also anger amongst most physicians. However, it is clear that no court judgement against a physician will be made without the competent support of independent medical experts. On the basis of the relevant legal literature and judgments, the present article is an attempt to consider medical errors in the administration of contrast media, to describe the required medical informed consent before such measures, and to discuss the ever increasing importance of adequate documentation in the light of malpractice proceedings. importance of adequate documentation in the light of malpractice proceedings. This is followed by a discussion of the very important medical necessity to inform the patient about recommended behaviour after injections of such contrast media, the responsibility question in both civil and criminal terms in case of an incident, and various tips for steps to be taken in the case of a liability action.     

Final height after combined growth hormone and gonadotrophin-releasing hormone analogue therapy in short healthy children entering into normally timed puberty

Four estrous beagles were inseminated with 1 x 10(8) sperm into both the right and left uterine horns, and the uterine horn and oviduct on one side were removed under anesthesia after 7 hr and 24 hr, respectively. The lumen of the uterine horns and oviducts was flushed with canine capacitation medium (CCM), and movement of the sperm in CCM was assessed by phase-contrast microscopy. In a second experiment, ejaculated sperm obtained from 5 normal beagles was incubated in CCM supplemented with oviductal flush fluid (OF-CCM) at 38 degrees C with 5% CO2 in air. Motility of sperm, and percentages of hyperactivated sperm (%HA) and acrosome-reacted sperm (%AR) among freely swimming (FS) sperm were investigated until 24 hr after the start of incubation. After 7 hr of incubation the sperm was coincubated with canine oocytes in OF-CCM for 2 hr, and the number of zona pellucida-binding (zona-binding) sperm was then counted. The %HA among the sperm in the oviductal flush fluid both 7 hr (mean +/- S.E.; 15.0 +/- 2.4%) and 24 hr (77.5 +/- 5.2%) after intrauterine insemination were significantly higher than in the uterine flush fluid (P < 0.05, 0.01, respectively). The motility and %HA among FS-sperm in OF-CCM were higher than in the control medium without oviductal fluid. However, there was no difference in the %AR between OF-CCM and control medium. The number of zona-binding sperm in OF-CCM (8 +/- 1) was significantly greater than in control medium (5 +/- 1) (P < 0.05). These results suggest that oviductal fluid in the estrous bitch maintains sperm motility and induces sperm capacitation.     

Water and sodium retention during short-term administration of growth hormone to short normal children

OBJECTIVE: To find out whether leptin can attenuate hypometabolic torpor-like states of metabolic rate (MR) in adult lean animals, as it attenuates the morning suppression of thermoregulatory thermogenesis in suckling-age rat pups. DESIGN: Leptin effects on MR and food intake were studied in mice aged 4-7 months, in which a high incidence of exaggerated circadian reductions of MR had been induced by chronic food-restriction and, for comparison, in free-feeding mice. PROTOCOL: Continuous recordings of MR, for a group of seven mice maintained at an ambient temperature of 24 degrees C, while they were repeatedly-with pauses of at least six days-treated for three consecutive days with either recombinant murine leptin (20, 200 or 600 pmol x g(-1) x d[-1]) or saline. RESULTS: Leptin treatment caused dose-dependent 5-15% increases in energy expenditure by moderating the decreases in MR during the circadian minima, without affecting either the MR during the circadian maxima or food intake. Similar treatment of free-feeding mice caused dose-dependent decreases of food intake without changing MR. CONCLUSION: Leptin controls thermoregulatory energy expenditure when food supplies are scarce and changes food intake, rather than energy expenditure, when food is abundant.     

Overnight growth hormone concentrations are usually normal in pubertal children with idiopathic short stature--a Clinical Research Center study

To estimate the incidence of low growth hormone (GH) concentration in children and adolescents with idiopathic short stature, overnight GH levels were measured in 167 subjects. The results were compared with data from 132 normal children of similar pubertal stage, bone age, or body mass index. The majority of short children had normal overnight GH concentrations in a distribution not significantly different from that observed in normal children. However, in 6% of children grouped by pubertal stage and in 13% of children grouped by bone age, overnight GH levels were below the 95% confidence limits of normal. The overnight GH levels were above normal in 6%. The observed frequencies of both low and high GH levels were significantly greater than expected (P < 0.001). However, when body mass index was included in the analysis, only 5% of the children had low GH measures, and only 4% had high GH measures (both not significant). This frequency of low overnight GH levels in short children is considerably less than that reported by others. Thus, these data do not support the hypothesis that a deficiency of spontaneous GH secretion is a common cause of short stature. We conclude that standard GH stimulation tests, despite their limitations, remain the best definitive test of GH secretion. Subsequent overnight GH studies may be useful, however, in selected clinical settings such as previous cranial irradiation or other central nervous system disorder.     

An early rise in urine N-telopeptide predicts the growth response of normal prepubertal short children to growth hormone therapy

The effects of growth hormone (GH) therapy on biochemical markers of bone turnover were investigated in 11 short prepubertal children without GH deficiency by measuring serum osteocalcin, a marker for bone formation, and urinary concentrations of pyridinium cross-linked amino acids of collagen (PCL), and the peptide-bound pyridinoline residue N-telopeptide (NT), which are specific markers for bone resorption. GH treatment for three months increased bone turnover in this group of children: urinary PCL concentrations increased from 69 +/- 6.2 to 114 +/- 9.3 nmol/mmol Cr (p < 0.01), and urinary NT levels increased from 512 +/- 65 to 766 +/- 74 pmol BCE/mumol Cr (p = 0.058). Serum osteocalcin concentrations increased from 13.64 +/- 2.57 ng/ml to 26.45 +/- 1.39 ng/ml (p < 0.01). The increment in 12-hour urinary concentrations of PCL was highly correlated with the increment in 12-hour urinary NT levels (r = 0.92, p < 0.01). Stepwise multiple regression analysis revealed that the urinary concentrations of NT after 3 months of GH therapy were the best predictor of growth after 12 months of treatment (r = 0.78, F = 7.9, p = 0.037).     

Oral administration of arginine enhances the growth hormone response to growth hormone releasing hormone in short children

We have evaluated the effect of oral administration of arginine chlorhydrate on the growth hormone response to growth hormone releasing hormone in a group of nine short prepubertal children (six boys and four girls). Arginine chlorhydrate 10 g, administered orally 60 min before an i.v. bolus injection of growth hormone releasing hormone 1-29, 1 microgram/kg, significantly enhanced the growth hormone response to the neuropeptide, confirming the results of previous studies which used the i.v. route. Furthermore, our data strengthen the view that the effects of arginine chlorhydrate on growth hormone secretion are mediated by inhibition of endogenous somatostatin release.     

The influence of growth hormone (rhGH) therapy on tooth formation in idiopathic short statured children

The purpose of this preliminary study was to evaluate tooth formation in children with idiopathic short stature, before and during treatment with recombinant growth hormone (rhGH). Twenty-nine short-statured children ages 6 to 13 years were assigned into two treatment groups, an "experimental" group (n = 18), which received rhGH, and a "control" group (n = 11), which was observed for 1 year before commencing rhGH treatment. Clinical and radiographic records were obtained at the initial, year 1, and year 2 visits. Tooth formation and stature were assessed by calculating Z-scores, appropriate for the age and gender of each child. Delta-Z scores, which measure the change in Z-score over time, were also calculated between annual visits. Height was measured and recorded every 3 months, and Z-score statural norms for age and gender were derived from the 1977 National Center for Health Services national probability sampling. Tooth formation standards were derived from Moorrees et al. A matched control sample for tooth development was derived from untreated children. Tooth formation was initially delayed although the degree of reduction in stature exceeded the initial degree of delay in tooth formation. During this 2-year study, rhGH therapy had a significant influence on acceleration or gain in stature, but did not have a significant influence on tooth formation.     

Effects of luteinizing hormone-releasing hormone analog-induced pubertal delay in growth hormone (GH)-deficient children treated with GH: preliminary results

To study the effect of delaying epiphyseal fusion on the growth of GH-deficient children, we studied 14 pubertal, treatment naive, GH-deficient patients (6 girls and 8 boys) in a prospective, randomized, placebo-controlled trial. Chronological age was 14.5 +/- 0.5 yr, and bone age was 11.6 +/- 0.3 yr (mean +/- SEM) at the beginning of the study. Patients were assigned randomly to receive GH and LH-releasing hormone (LHRH) analog (n = 8) or GH and placebo (n = 6) during 3 yr, with planned continuation of GH treatment until epiphyseal fusion. Patients were measured with a stadiometer and had serum LHRH tests, serum testosterone (boys), serum estradiol (girls), and bone age performed every 6 months. Patients treated with GH and LHRH analog showed a clear suppression of their pituitary-gonadal axis and a marked delay in bone age progression. We observed a greater gain in height prediction in these patients than in the patients treated with GH and placebo after 3 yr of treatment (mean +/- SEM, 14.0 +/- 1.6 vs. 8.0 +/- 2.4 cm; P < 0.05). These preliminary findings suggest that delaying epiphyseal fusion with LHRH analog in pubertal GH-deficient children treated with GH increases height prediction and may increase final height compared to treatment with GH alone.     

Weight relative to height before and during growth hormone therapy in prepubertal children

We used the Genentech National Cooperative Growth Study database to examine differences in weight relative to height (weight for height standard deviation score or WTHTZ) in 3460 patients at enrollment and after one year of therapy with recombinant human growth hormone (rhGH), and in a subset of 450 patients treated for three years with rhGH. The major diagnostic categories were idiopathic growth hormone deficiency (IGHD), organic GH deficiency (OGHD), and idiopathic short stature (ISS). Children with IGHD and ISS were underweight for height at baseline but had a progressive increase in WTHTZ during three years of rhGH therapy. The same pattern applied to children with IGHD associated with septo-optic dysplasia and CNS trauma or infection. However, children with OGHD associated with craniopharyngiomas, other CNS tumors, leukemia, or CNS irradiation were overweight when starting rhGH and showed a decrease in WTHTZ during the first year of rhGH therapy. The increase in WTHTZ during rhGH treatment in children with ISS and OGHD suggests that the GH-induced increase in muscle mass exceeded loss of fat mass. Because children with neoplasm-related OGHD were overweight at baseline, the decline in WTHTZ during the first year of rhGH therapy suggests that loss of fat mass is the predominant effect in this subgroup.     

Pretreatment with somatostatin analog SMS 201-995 potentiates growth hormone (GH) responsiveness to GH-releasing factor in short children

Previous studies in children have shown inconsistent, poorly reproducible GH responses to exogenous GH-releasing factor (GRF), with wide individual variability. In the present study, we tested the hypothesis that prior administration of the long-acting somatostatin analog, SMS 201-995 (SMS), will enhance GH responsiveness to a subsequent GRF challenge. Two study protocols were employed in 37 children with short stature [M = 31, F = 6, ages 11.8 +/- 1.6 yr (mean +/- SEM), height -2.25 +/- 0.55 SDS (SD scores)]. In both studies, each subject served as his/her own control. In the first study, which was designed to determine optimal SMS dose and regimen, SMS, in doses ranging from 0.8-2.2 micrograms/kg sc, was randomly administered or omitted at 0800 h after an overnight fast, and a GRF bolus (50 micrograms, iv) was given 4 h later. In the second study, we employed a protocol identical to study 1 except for the use of standard doses of SMS (1 microgram/kg, sc) and GRF (1 microgram/kg, iv) and an additional 1-h delay of the GRF injection. Plasma GH levels were measured every 20 min from 0800 h until 2 h after the GRF injection in both studies. In study 1 (n = 12; M = 10, F = 2), SMS significantly suppressed spontaneous GH secretion (expressed as the mean +/- SEM GH AUC during the 4-h SMS-GRF interval, AUC 1:2.2 +/- 0.4 vs. 6.2 +/- 0.9 micrograms/L.h; P < 0.001), GH responsiveness to GRF (GH AUC during the 2 h after the GRF injection, AUC 2: 41.5 +/- 7.8 vs. 85.0 +/- 13.5 micrograms/L.h; P < 0.001), and the GH peak response (17.4 +/- 3.1 vs. 36.0 +/- 6.2 micrograms/L; P < 0.001), compared to control tests. In contrast, in study 2 (n = 25; M = 21, F = 4), whereas spontaneous GH secretion was still suppressed during the 5-h SMS-GRF interval (AUC 1:3.8 +/- 0.4 vs. 7.4 +/- 1.1 micrograms/L.h; P < 0.001), both the GH peak response (56.7 +/- 5.5 vs. 30.5 +/- 3.0 micrograms/L; P < 0.0001) and the GH AUC (AUC 2: 103.7 +/- 10.3 vs. 77.5 +/- 6.8 micrograms/L.h; P < 0.05) after GRF administration were significantly augmented by pretreatment with SMS, compared to control tests. Taken together, these results indicate that a priming SMS dose of 1 microgram/kg has a significant permissive effect on GH responsiveness to exogenous GRF administered 5 h later.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of short- and long-term dexamethasone treatment on growth and growth hormone (GH)-releasing hormone (GRH)-GH-insulin-like growth factor-I axis in conscious rats

Although the inhibitory effects of a chronic excess of glucocorticoids (GC) on body growth and GH secretion are well established, the mechanisms involved remain unclear. In this study, we examined the chronic effects of a high dose of dexamethasone (DEX) on spontaneous GH secretion and insulin-like growth factor (IGF)-I in conscious rats. The animals were given daily i.p. injections of DEX (200 microg/day) for either one or four weeks. Body growth assessed by tibia length and serum IGF-I levels was significantly inhibited 1 week after treatment. By contrast, spontaneous GH secretion was not altered 1 week after the treatment. Neither hypothalamic GRH and somtatostain mRNA levels nor GH responses to GRH from single somatotropes were affected 1 week after the treatment. Four weeks after DEX treatment, body growth of the rats was noticeably suppressed. Interestingly, spontaneous GH secretion, hypothalamic GRH mRNA levels and GH responses to GRH were all inhibited 4 weeks after treatment. Pituitary GRH receptor mRNA levels were not altered 1 week after treatment, but increased after 4 weeks. These results indicate that a high dose of DEX initially impairs IGF-I production and subsequently inhibits spontaneous GH secretion in rats. Inhibition of spontaneous GH secretion resulting from chronic GC excess is due, at least in part, to the impairment of hypothalamic GRH synthesis and pituitary GH responsiveness. An increase in the pituitary GRH receptor may be caused by decreased GRH secretion.     

Effect of various therapeutic protocols on growth and final height of children with acute lymphoblastic leukemia or non-Hodgkin's lymphoma

A total of 74 children suffering from acute lymphoblastic leukaemia (ALL) or non-Hodgkin lymphoma (NHL) were involved in a retrospective analysis of their physical growth during and after the therapy. Out of this total number, 54 children were subjected to radiochemotherapy in compliance with the VII/(81) scheme, and another 20 children in compliance with the LSA2L2 scheme. At the beginning of the therapy the average height-standard deviation score (H-SDS) for both groups of patients corresponded with the population average. The patients subjected to the VII/(81) scheme showed, throughout the observation period of five years from the beginning of the therapy, a height normal for their age group. Contrary to this observation, the patients subjected to the LSA2L2 scheme experienced a significantly different growth in the period under observation and continually lost height in comparison to the normal population. The same results were experienced with a smaller group of patients whose growth was followed up for eight years from the beginning of therapy. 16 patients (VII/81 n = 4/LSA2L2 n = 12) reached their final height. For the patients of the VII/(81) scheme the final height showed an average H-SDS of 0.27 and for the patients of the LSA2L2 scheme of -1.22 (p = 0.068). Considering that the same cranial radiotherapy (max. 18 Gy for both schemes) and a comparable intensive induction therapy were applied, it must be concluded that the intensity and duration of the maintenance treatment are the critical factors initiating a different growth behaviour of the two groups subjected to radiochemotherapeutical schemes.     

Short- and long-term outcome of patients treated with cyclosporin for severe acute ulcerative colitis

The effect of core material properties on the process of compression and physical properties of compression-coated tablets were investigated using microcrystalline cellulose as the coating material (mantle). Three model core materials: borosilicate glass, silicone rubber, and steel, each of different Young's modulus, were selected to give a range of core mechanical properties. Coated tablets were prepared using a single-punch press, with facilities for monitoring the compression cycle and analysis of data using the Heckel (1) equation. This analysis showed a considerable effect of different core materials on the compression process, (i) as an unanchored core, and (ii) due to core material type with differing Young's modulus.