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Biomedical subjects

B Klinger

Publications and source records attributed to B Klinger.

48 records · Page 3Linked to original sources
PubMed1990

Elimination characteristics of intravenously administered rIGF-I in Laron-type dwarfs.

The distribution and elimination characteristics (Ke alpha, Ke beta, t1/2) of an intravenous bolus of biosynthetic IGF-I administered to 10 patients with Laron-type dwarfism (LTD, 3 children and 7 adults) and 6 healthy volunteers (3 children and 3 adults) are reported. The mean (+/- SD) endogenous level of IGF-I in the LTD patients was 5.24 +/- 2.77 nM/l and in the controls 27.2 +/- 9.4 nM/l. In the LTD patients the mean elimination constant (Ke beta) was 0.004 +/- 0.001 min-1 and t1/2 = 2.6 +/- 0.7 h, whereas in the controls, Ke beta was 0.003 +/- 0.009 min-1 and the t1/2 = 4.4 +/- 0.5 h (p less than 0.05). The more rapid elimination of injected IGF-I in the LTD patients is assumed to be due to the absence of the GH-dependent 150 kDa IGF-I binding protein.

Adolescent↗
PubMed1990

Intravenous administration of recombinant IGF-I lowers serum GHRH and TSH.

Recombinant IGF-I was administered as an iv bolus of 75 micrograms/kg to 10 patients with Laron type dwarfism (3 children aged 9, 11 and 12 years and 7 adults aged 30.6 +/- 3.5 years) and to 8 healthy subjects (mean age 19.9 +/- 12.1 years) and determinations of IGF-I, GHRH, hGH, TSH, and glucose were made before and at 2, 5, 15, 30, 60, 90, and 120 min. The following effects were observed: a. an immediate, marked and sustained drop in blood glucose (p less than 0.001), more prolonged in the patients; b. in both groups, a dramatic rise in plasma hGH (p less than 0.01) which peaked at 60-90 min; in the patients this occurred after an initial immediate fall in plasma hGH (p less than 0.01); c. a progressive decrease of plasma GHRH and TSH (p less than 0.05, 0.02) in both patients and healthy controls. An hypothesis is put forward that acute and time-limited release of somatostatin by IGF-I is the main cause of the hormonal changes registered. As the IGF-I bolus also suppressed circulating insulin levels, the hypoglycemia is considered to be a direct effect of IGF-I.

Adult↗
PubMed1989

Serum GH binding protein activities identifies the heterozygous carriers for Laron type dwarfism.

Measurement of GH-binding protein activity and IGF-I was carried out in the sera of 13 patients with Laron type dwarfism, a syndrome caused by a lack of GH receptors which leads to impairment of IGF-I generation, and those of 16 of their close relatives. GH binding protein activity was measured by incubating 125I-hGH with 100 microliters serum in the presence and in the absence of excess unlabelled hGH, followed by separation of specifically bound 125I-hGH binding protein complexes from free 125I-hGH by gel filtration. The results are expressed as percent specific binding relative to an adult reference serum. IGF-I was determined by RIA after acid extraction on octadecylsilane silica columns. All Laron type dwarfism patients had no, or only negligible GH binding protein activity, which supports the evidence that serum GH binding protein corresponds to the extracellular domain of the membranal GH receptor. Eight of the 16 relatives had serum GH binding protein activity more than 2 SD below the mean for age, a finding considered to denote heterozygocity for their molecular defect disease. The significant correlation (p less than 0.001) between serum GH binding protein activity and IGF-I levels supports this conclusion. The ability to define heterozygotes of Laron type dwarfism will be helpful in genetic counselling.

Adolescent↗
PubMed1988

Effect of acute administration of insulin-like growth factor I in patients with Laron-type dwarfism.

Biosynthetic insulin-type growth factor I (IGF-I) was given as an intravenous bolus of 75 micrograms/kg to 9 patients with Laron-type dwarfism. Rapid onset of hypoglycaemia (-45% of basal level) was associated with a reduction in plasma insulin (-55% of basal level); thus, the lack of growth hormone receptors in this condition does not apply to IGF-I receptors and post-receptor pathways. Long-term treatment may therefore be beneficial in Laron-type dwarfism.

Adult↗
PubMed1982

Radioimmunoassay for 4-hydroxyestrone 4-methyl ether in human urine.

4-Hydroxyestrone 4-methyl ether (4-OHE1 4-Me) was converted to its 17-(O-carboxymethyl)oxime and then coupled to bovine serum albumin. The injection of this steroid-protein conjugate into rabbits induced the formation of antibodies with high specificity and affinity for 4-OHE1 4-Me. With this antiserum a radioimmunoassay was developed which allowed the measurement of 4-OHE1 4-Me with a lower limit of detection of 6 pg/tube. Using a simple and practicable method for the hydrolysis and purification of urine, the excretion rates of 4-OHE1 4-Me were reliably measured in healthy human subjects: male children 0.1 microgram/24 h, female children 0.2 micrograms/24 h, men (20-45 years) 0.7 micrograms/24 h, men (greater than 50 years) 0.5 micrograms/24 h, women, follic. 0.5 micrograms/24 h, periov. 0.6 micrograms/24 h, luteal 0.6 micrograms/24 h, women pregn., first trim. 2.3 micrograms/24 h, sec. trim. 2.9 micrograms/24 h, third trim. 5 micrograms/24 h, women postmenop. 0.5 micrograms/24 h. These urinary excretion rates of 4-OHE1 4-Me are significantly lower than those of 4-hydroxyestrone. Comparing the ratios 4-OHE1 4-Me/4-hydroxyestrone with those of 2-hydroxyestrone 2-methyl ether/2-hydroxyestrone, it becomes obvious that endogenous 4-hydroxyestrogens are methylated in vivo to a much lesser extent than the isomeric 2-hydroxyestrogens, a finding which could partly explain why 4-hydroxyestrogens have higher biologic potencies than their 2-hydroxylated isomers

Estrogens, Catechol↗
PubMedDate not supplied

Three year IGF-I treatment of children with Laron syndrome.

Nine prepubertal children with Laron syndrome (6 males, 3 females) aged 0.5 to 14.6 years were treated by daily subcutaneous injections of IGF-I in doses of 150-200 micrograms/kg. All patients completed at least one year of treatment; six completed two years and five three years. During the first year, a significant increase in linear growth velocity, from a mean +/- SD of 4.7 +/- 1.3 to 8.2 +/- 0.8 cm/yr (p < 0.0001), was registered. In the second year the growth velocity was lower, but still significantly higher than before treatment. Bone maturation advanced proportionally with chronological age. A reduction in subcutaneous fat tissue was observed despite the body weight increase. There was no aggravation of the characteristic hypoglycemic episodes; on the contrary, there was a better tolerance to fasting. Significant increases in serum alkaline phosphatase, phosphorus and procollagens were registered throughout the study. In conclusion, IGF-I provides an effective replacement treatment for IGF-I-deficient children, mimicking most effects ascribed to growth hormone.

Adolescent↗
PubMedDate not supplied

Growth hormone treatment increases circulating lipoprotein(a) in children with chronic renal failure.

Cardiovascular disease is the major cause of death in chronic renal failure (CRF) patients managed by dialysis or kidney transplantation. Whilst the use of human growth hormone (hGH) is of established benefit in CRF children particularly in those with short stature, in the present study we assessed in CRF children the effect of hGH treatment on circulating lipoprotein(a) [Lp(a)], a genetically determined cardiovascular risk factor. We studied 15 CRF children treated by dialysis or conventional therapy and after kidney transplantation. Overnight fasting blood samples were collected immediately before and after 6 months hGH treatment. In all but one of the children there was a significant increase in serum Lp(a) over the 6 month treatment period -(+)66.7% over the basal levels (range 14 to 180%). After the hGH treatment, in six children Lp(a) levels were elevated to above 300 mg/l, the cut-off level for increased coronary artery disease (CAD) risk. Concomitantly/children also had an increase in serum levels of IGF-I (+96.4%) and insulin (+85.8%). All children had an accelerated growth velocity during the treatment; there was no effect on serum creatinine. Our study shows that hGH treatment in CRF children, though beneficial in its growth promoting effects, increases the already characteristically high levels of serum Lp(a), a risk factor for CAD, and that serum Lp(a) monitoring during treatment with hGH may be useful in evaluating future cardiovascular risk.

Adolescent↗
PubMedDate not supplied

Growth during and 2 years after stopping GH treatment in prepubertal children with idiopathic short stature.

Forty-six prepubertal children with idiopathic short stature (ISS), 39 boys and 7 girls, with a mean age of 7.4 +/- 1.8 (SD) years, and mean bone age of 4.5 +/- 1.5 years were treated by human growth hormone (GH) 0.1 U/kg/day s.c. for 30.5 +/- 16.2 months (M +/- SD) (2-5 years range) and were followed for 1-2 years after stopping GH. The mean net gain in height at the end of treatment was 1.03 +/- 0.6 SDS and the bone age SDS was accelerated by 0.95 +/- 1.05. Despite a transitory "catch-down" in growth velocity after stopping GH administration, there was a mean height gain at the end of 2 years follow-up of 0.87 SDS. Children who started treatment before age 6.5 benefited more than older ones. In conclusion, the gain in height observed in children with ISS by GH treatment was maintained during 2 years of follow-up after interruption of treatment. Even if this benefit is transitory and not permanent, it may help short children to achieve self-confidence and raise their physical performance at the critical period of school entry.

Age Determination by Skeleton↗
PubMedDate not supplied

Intronic mutation in the growth hormone (GH) receptor gene from a girl with Laron syndrome and extremely high serum GH binding protein: extended phenotypic study in a very large pedigree.

Laron syndrome (LS) is a hereditary form of GH resistance due to molecular defects in the GH receptor (GHR). Most of the identified mutations are located in the extracellular domain of the receptor, resulting in a lack of serum GHBP in the majority of LS patients. We present an LS patient with supranormal levels of serum GHBP, in addition to 35 of her relatives. The proband is a 3.5 year-old Druse girl with severe short stature (height SDS -5.1), high GH (250 micrograms/l), low IGF-I (2.7 nmol/l) and IGFBP-3 (410 micrograms/l), both unresponsive to exogenous GH. The binding capacity of the serum GHBP was 22 nM (adult reference serum, 0.7 nM), with an affinity constant Ka = 1.9 x 10(9) M-1 comparable to that of normal sera (Ka = 1.7-2.1 x 10(9) M-1). The apparent MW of the GHBP was approximately 60-80 kDa, similar to that of control sera. In the proband's sister, parents, grandparents and uncles, extremely high GHBP values were observed (43.0 +/- 4.8 RSB, n = 10) compared with normal adults (0.81 +/- 0.06 RSB) (p << 0.001). The remaining subjects had normal or moderately elevated GHBP levels. Serum GH in adults with high GHBP was significantly elevated above control values (6.0 +/- 0.9 micrograms/l vs 0.76 +/- 0.13 microgram/l, p < 0.001). Serum IGF-I and IGFBP-3 levels were normal in all the subjects, with the exception of an aunt (IGF-I 3.9 nmol/l) and the proband's sister (IGFBP-3 460 micrograms/l). All the subjects' heights were within the normal range. Analysis of the GHR gene performed in the proband revealed an as yet undescribed homozygous intronic point mutation. It consists of a G-->T substitution at nucleotide 785-1 preceding exon 8, a sequence that encodes the transmembrane domain. This mutation, which destroys the invariant dinucleotide of the splice acceptor site, is expected to alter GHR mRNA splicing and to be responsible for skipping exon 8. The resulting truncated protein that retains GH binding activity is probably no longer anchored in the cell membrane, affecting signal transmission in the homozygous patient and causing high GHBP levels in the heterozygous relatives.

Adolescent↗
PubMedDate not supplied

Serum insulin-like growth factor-I (IGF-I) levels during long-term IGF-I treatment of children and adults with primary GH resistance (Laron syndrome).

Serum IGF-I levels were measured in 14 patients (9 children and 5 adults) with Laron syndrome (LS) during long-term treatment by IGF-I. Recombinant IGF-I (FK-780, Fujisawa Pharmaceutical Co. Ltd., Japan) was administered once daily subcutaneously before breakfast for 3-5 years to the children and for 9 months to the adults. The initial daily dose was 150 micrograms/kg for children and 120 micrograms/kg for adults. Before initiation of treatment the mean overnight fasting levels of serum IGF-I in the children was 3.2 +/- 0.8 nmol/l (mean +/- SEM), rising to 10 +/- 1.7 nmol/l during long-term treatment even on a dose of 120 micrograms/kg/day. The serum IGF-I levels 4 hours after injection rose from 31.2 +/- 3.5 to 48 +/- 2 nmol/l. In the adult patients, the initial basal IGF-I was 4.1 +/- 0.7 nmol/l, rising to 16.1 +/- 3.84 nmol/l after 8-9 months treatment. Serum IGF-I levels at 4 hours after injection rose in the adult patients from 24.1 +/- 5.8 up to 66.8 +/- 15.4 nmol/l. A progressively increasing half-life during long term exogenous administration of IGF-I to patients with Laron syndrome was demonstrated by following serum IGF-I dynamics after injection. Based on the fact that no antibodies to IGF-I were detected and on findings in previous studies, it is speculated that the increasing serum IGF-I levels during long-term IGF-I treatment are caused by an increase in serum IGFBP-3 induced by chronic IGF-I administration. It is concluded that treatment with IGF-I necessitates regular monitoring of serum IGF-I levels; in patients in whom the age adjusted maximal levels are exceeded, a reduction of the daily IGF-I dose is indicated to avoid undesirable effects.

Adolescent↗