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Biomedical subjects

R Rappaport

Publications and source records attributed to R Rappaport.

At least 91 records · Page 5Linked to original sources
PubMed1989

Normal growth hormone (GH) response to GH-releasing hormone in children with thalassemia major before puberty: a possible age-related effect.

The plasma GH response to a single iv bolus dose of 2 micrograms/kg BW synthetic GHRH-(1-44)NH2 was evaluated in 13 prepubertal children with thalassemia major (mean age, 7.6 +/- 0.8 yr) with growth retardation and in 15 prepubertal children with nonendocrine short stature. All of the patients showed a significant increase in plasma GH concentration, with a mean peak of 31.4 +/- 4.5 micrograms/L at 15 min (P less than 0.001 vs. basal values; range, 18.4-65 micrograms/L) after GHRH, which was not different from that of the control group of idiopathic short stature children (40.1 +/- 3.4 micrograms/L; range, 21-65.4 micrograms/L). All but 1 of the thalassemic patients had a normal GH response to the arginine-insulin stimulation test. The mean plasma insulin-like growth factor-I level was low (0.12 +/- 0.05 U x 10(3)/L; range, less than 0.02-0.61 U x 10(3)/L). Analysis of these results as well as previously reported data indicating that older thalassemic patients have an impaired GH response indicates that there may be an age-related pituitary and/or hypothalamic dysfunction in thalassemic children. This study also confirms that the insulin-like growth factor-I decrease occurs before any alteration in GH secretion. These changes might play a role in the early growth retardation that occurs in these patients.

Age Factors↗
PubMed1989

MR imaging of the posterior hypophysis in children.

The posterior lobe of the pituitary gland was studied by MR imaging in 30 children without pituitary gland disease and compared with studies from a group of 13 children with central diabetes insipidus, including eight cases of primary diabetes insipidus and five cases of diabetes insipidus secondary to suprasellar tumors (four proved germinomas, one still unknown tumor). Two components in the sella turcica were identified in all 30 children without pituitary gland disease, and the posterior lobe was identified as a high-intensity structure on T1-weighted images. In all 13 patients with diabetes insipidus, the normal hyperintense signal of the posterior hypophysis was absent on T1-weighted images. Three patients with suprasellar tumors presented with a progressively enlarging pituitary stalk on follow-up. Our findings show that absence of the normal hyperintense signal of the posterior lobe is closely related to a loss of function of the neurohypophysis. Size or signal modification of the pituitary stalk should suggest the development of a suprasellar tumor.

Adolescent↗
PubMed1989

[Central precocious puberty].

Diagnosis of the central origin of precocious puberty is easy in boys on the enlargement of the testes. In girls, conversely, diagnosis of central precocious puberty (CPP) may be difficult, as isolated development of the breast may initially be the only feature. Differentiation of CPP and premature thelarche is nevertheless essential, as CPP always requires neuroradiologic investigations to look for an intracranial space-occupying lesion and may indicate inhibitory treatment. CPP is usually idiopathic in girls and tumor-related in boys. Early secretion of sex steroids increases the rate of growth and bone maturation and may lead to final short stature. LHRH analogues represent a breakthrough in the treatment of CPP.

Child↗
PubMed1989

[Evaluation of diagnostic and therapeutic methods in hyperinsulinism in newborn infants and infants. Apropos of a retrospective study of 26 cases].

This report concerns 26 cases of hyperinsulinism in neonates and infants. Clinically, the syndrome beginning in the neonatal period seems to differ by several aspects from the disease with a later onset: diagnostic difficulties, treatment modalities and long term prognosis. Insulinemia determined when the patient presents with hypoglycemia is often (75 to 80% of cases) normal. The diagnosis of hyperinsulinism has to be based on the clinical characteristics of hypoglycemia (timing of the episodes, response to glucagon) and on specific biological data (C-peptide, plasma ketone bodies and branched-chain amino acids at the time of hypoglycemia induced by fasting). The pathogenesis of hyperinsulinism is still poorly understood and has several etiologies.

Evaluation Studies as Topic↗
PubMed1989

[Endocrine complications caused by cranial irradiation].

Cranial irradiation has become one of the leading causes of growth hormone (GH) deficiency. The risk and time of onset of GH deficiency depend mainly on the dose delivered to the hypothalamo-pituitary region: GH deficiency is infrequent after doses under 20 grays and nearly constant after doses above 45 grays. For a given dose, a younger age at the time of irradiation and administration of the dose over a shorter time period increase the risk of GH deficiency. GH secretion can be adequately evaluated using rapid stimulation tests and is usually well correlated with growth, except in patients with radiation-induced precocious puberty or growth delay due to radiation-induced cartilage lesions.

Adolescent↗
PubMed1988

Disposition of a novel recombinant tissue plasminogen activator, delta 2-89 TPA, in mice.

The pharmacokinetic characteristics of delta 2-89 tPA, characterized by the deletion of the first 89 amino acids at the NH2-terminus of tPA, were evaluated and compared to those of recombinant tPA (rtPA). When they were administered intravenously to mice, a biexponential disposition curve was observed for both tPAs. The plasma half-lives of lambda 1 and lambda 2 phases of delta 2-89 tPA were 15 minutes and 180 minutes which are significantly higher than those of rtPA. A zymogram of mouse plasma taken at various time intervals showed that delta 2-89 tPA retained fibrinolytic activity up to 30 minutes, whereas rtPA could be detected only up to 5 minutes after injection. Autoradiography revealed that most of 125I-delta 2-89 tPA was associated with plasma protein complex.

Amino Acids↗
PubMed1988

Structure-function analysis with tissue-type plasminogen activator. Effect of deletion of NH2-terminal domains on its biochemical and biological properties.

Tissue-type plasminogen activator (t-PA) is a mosaic protein containing several distinct structural domains attached to the serine protease catalytic unit present at its COOH terminus. To investigate structure-function relationships in t-PA, we deleted the NH2-terminal domains, finger and epidermal growth factor, by genetic engineering. The genes for the parent and mutant t-PA were expressed in a bovine papilloma virus-dependent mammalian cell system. The secreted proteins were purified to homogeneity. The mutant protein was processed to the expected size of about 60 kDa compared to approximately 68 kDa for the parent t-PA, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fibrin autography. While the mutant t-PA had amidolytic activity comparable to native t-PA, it did not bind appreciably to fibrin. Consequently, fibrin-dependent enzymic activity, i.e. plasminogen activation in the presence of soluble fibrin and fibrinolysis were lower than with native recombinant t-PA. The effect of deletion of NH2-terminal domains on the plasma half-life (t1/2) was investigated by injecting native and mutant t-PA into mice. While the majority of the t-PA disappeared initially with a t1/2 of about 2 min, mutant t-PA cleared at a much slower rate with t1/2 of about 50 min. These findings suggest that the NH2-terminal domains of t-PA not only determine its specificity for binding to fibrin but also mediate its clearance from plasma in vivo. Furthermore, the catalytic unit in t-PA seems to function autonomously.

Cell Line↗
PubMed1988

Construction and expression of hybrid plasminogen activators prepared from tissue-type plasminogen activator and urokinase-type plasminogen activator genes.

Recent data from several studies have suggested that the non-protease domains in tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) determine their biological specificities, including binding to fibrin clots and survival in the circulatory system (Van Zonneveld, A.-J., Veerman, H., and Pannekoek, H. (1986) Proc. Natl. Acad. Sci. U. S. A. 83, 4670-4674; Rijken, D. C., and Emeis, J. J. (1986) Biochem. J. 238, 643-646). Structural manipulations (e.g. deletions, additions, or substitutions) in these domains can thus be utilized to maximize the desired biological effects. Using recombinant DNA technology, we constructed a number of hybrid molecules from the t-PA and u-PA genes. In hybrid A, the epidermal growth factor and finger domains of t-PA (residues 1-91) were replaced by the epidermal growth factor and kringle of u-PA (residues 1-131). In hybrids B and C, the u-PA kringle (residues 50-131) was inserted either before (residue 92) or after (residue 261) the double-kringle region of t-PA. All these hybrid PAs containing three kringles were expressed in mouse fibroblast cells (C-127). The hybrid proteins were synthesized in predominantly a single-chain form with molecular weights of 70,000-80,000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and were enzymatically active as assayed by the fibrin-agar plate method. In vitro studies on the binding of hybrid PAs to fibrin showed that hybrid B, like t-PA, possesses affinity toward fibrin, while hybrid A shows lower binding. This suggests that the finger domain, which is not present in hybrid A, plays a role in conferring fibrin affinity to the hybrid PAs. The enzymatic activities of the hybrids were compared with that of recombinant t-PA (rt-PA) expressed in the same vector/host system and found to be similar in activity toward a chromogenic peptide substrate. In addition, plasminogen activation with all the hybrid-PAs, as with rt-PA, was stimulated by fibrin, with the order of activity being rt-PA greater than or equal to hybrid B greater than hybrid C greater than hybrid A. This study shows the feasibility of shuffling functional domain(s) of known specificity in plasminogen activators which may lead to the design of a superior thrombolytic agent.

Cell Line↗
PubMed1988

MRI of hypothalamic hamartomas in children.

Eight cases of hypothalamic hamartomas (HH) diagnosed in children by clinical, biological and CT studies have been explored by MRI and compared with a control group of twenty children without hypothalamohypophyseal signs. MRI revealed the hamartoma in all cases. Its location and position relative to the floor of the third ventricle was precisely determined. The signal intensity of the lesion was identical to that of normal grey matter on T1-weighted images (300/600.28), but an hyperintense signal was observed over T2-weighted images (1800.60/120) in seven of the eight cases. These data suggest that HH are somewhat different in structure from normal brain tissue. MRI variations in signal intensity should be taken into account in the diagnostic work-up of these lesions.

Child↗
PubMed1988

Estrogen receptors in cultured rabbit articular chondrocytes: influence of age.

Primary cultures of pubertal and prepubertal rabbit articular cartilage cells were performed. Total homogenates or cell extracts were used to determine the specific binding of 17 beta-estradiol. A comparative study was undertaken with tissue minces homogenized without enzymatic treatment. Scatchard analysis of cell or tissue extracts revealed the presence of a high-affinity receptor with Kd values of 0.55 +/- 0.16 nM and 0.12 +/- 0.03 nM in prepubertal and pubertal rabbit chondrocytes respectively. A significant difference in the affinity of estrogen receptor for its ligand as a function of age was observed. In contrast there was no significant difference in the number of binding sites expressed as fmol per mg DNA between the two age groups. The ligand binding specificity was as expected for an estrogen receptor and the sedimentation coefficient was 3.2 S when analyzed by ultracentrifugation on sucrose density gradient in presence of 0.4 M KCl and 8.1 S in low salt conditions. The binding sites, labeled with [125I]estradiol, were specifically immunoprecipitated by a monoclonal antibody to the estrogen receptor (JS34/32).

Aging↗
PubMed1988

Human pituitary growth hormone (hGH) and Creutzfeldt-Jakob disease: results of an epidemiological survey in France, 1986.

An epidemiological inquiry has been done in France after the notification in the USA and England of four cases of Creutzfeldt-Jakob disease in patients previously treated with hGH. Between 1959, when hGH treatment in France was started, and August 1985, the date the survey began, 1698 patients were registered for treatment. Current information (less than three months old) was obtained for 1620 patients (95.4%). Death was reported in 31 patients, but none could be related to Creutzfeldt-Jakob or similar disease. Pathological events were observed in 213 living patients (13.1%). Among them, four were diseases classified as possibly related to a viral infection. The first case had acute lymphoid leukaemia; the second case had polyradiculoneuritis associated with hepatitis. In both cases the disease resolved completely. Two other patients had acute encephalitis which started less than two years after the onset of treatment and which resolved spontaneously. Even though the acute evolution and the spontaneous clinical recovery are not consistent with Creutzfeldt-Jakob disease, a relationship with hGH therapy could not be completely excluded. Finally, five treated children had later malignancies which raises the question of the long-term secondary effects of hGH upon cellular proliferation.

Adolescent↗
PubMed1988

Growth hormone response to growth hormone-releasing hormone (hp GHRH1-44) as an index of growth hormone secretory dysfunction after prophylactic cranial irradiation for acute lymphoblastic leukemia (24 grays).

The growth hormone response to growth hormone releasing hormone hp GHRH1-44 (2 micrograms/kg i.v.) was studied in 19 prepubertal children who had been irradiated with 24 Gy for acute lymphoblastic leukemia (ALL) or lymphosarcoma (LS) at a mean chronological age of 4 10/12 years (limits 10/12 to 9 years). They were evaluated after a mean time interval of 4 8/12 +/- 3/12 years and compared to 14 prepubertal children with constitutional short stature (CSS). The individual responses to GHRH were decreased in all but three of the irradiated children. The mean GH response was 16.7 +/- 2.5 ng/ml as compared to 52.6 +/- 8.5 ng/ml in the control group (p less than 0.001). The GH response to GHRH was not correlated with the GH response to arginine-insulin tolerance test (AITT). A decreased response to GHRH with values between 12.5 and 19.4 ng/ml was observed in four cases with normal growth rates and normal GH responses to AITT. These results suggest that an impaired GH response to GHRH is a frequent finding after cranial irradiation for ALL or LS and may be the only sign of GH secretory dysfunction. It is probably indicative of early hypothalamic impairment of GH secretion.

Child↗
PubMed1988

Leydig cell insufficiency after testicular irradiation for acute lymphoblastic leukemia.

Leydig cell function in 21 boys with acute lymphoblastic leukemia who had been treated by bilateral direct testicular irradiation (12 X 2 Gy) at 8.4 +/- 0.7 years, was evaluated 3.8 +/- 0.4 years after irradiation. At the time of irradiation all were prepubertal and at evaluation 12 were prepubertal and 9 pubertal. Leydig cell insufficiency, indicated by a low plasma testosterone response to chorionic gonadotrophin and/or an increase in basal level of plasma luteinizing hormone, was observed in 19/21 patients. The children who were the youngest at testicular irradiation were more vulnerable. Spontaneous virilization occurred in 3 of the older children and resulted from compensated Leydig cell dysfunction.

Adolescent↗
PubMed1988

[Treatment with growth hormone: results and new perspectives].

The use of human growth hormone is being extensively reevaluated in children with hypopituitarism, as we enter a new phase with sufficient supply of recombinant hGH. Simultaneously much emphasis has been placed on the methods of measurement of GH secretion in order to define a more appropriate cutoff level defining partial GH deficiency. Among non conventional indications of hGH, Turner syndrome has turned out to be most important with very encouraging short term results. The extension of hGH therapy to other clinical groups, as non endocrine short stature is still under careful investigation in many groups. A long term follow-up is necessary to assess the true benefit of such a treatment and the absence of metabolic and immunological side effects. We should keep a critical attitude toward the very likely extension of the use of hGH considering that many areas, principally in adults, remain to be explored.

Growth Disorders↗
PubMed1988

1-year treatment with recombinant somatropin in prepubertal and pubertal growth hormone deficient patients: results from a French multicentre trial.

In this French study with recombinant somatropin, the stimulation of growth in 32 prepubertal (age 10.0 +/- 3.5 years; mean +/- SD) and 19 pubertal (age 14 +/- 1.5 years) GH deficient children was compared; the stimulation of growth was similarly good in the two groups. The height velocity SD scores increased from -2.5 +/- 1.7 and -0.9 +/- 1.5 to 2.2 +/- 1.9 and 1.6 +/- 1.6 in prepubertal and pubertal children, respectively. Expressed as cm/year, these correspond to increases from 3.2 +/- 1.3 cm/year and 4.1 +/- 1.2 cm/year to 8.1 +/- 1.5 cm/year and 8.6 +/- 1.9 cm/year in the prepubertal and pubertal patients, respectively. Safety and tolerance were good and the immunogenicity of Genotonorm was low.

Adolescent↗
PubMed1988

[Treatment of craniopharyngiomas in children. Retrospective analysis of 50 cases].

In order to evaluate the results of surgery and radiotherapy upon craniopharyngiomas in children, the authors review their own series of 50 cases treated from 1968 to 1985 and the literature. After subtotal removal, the recurrence-free survival rate, 10 years postoperatively, was 37%. This rate was significantly higher (72%) when the subtotal removal was followed by irradiation with a dose of 50 to 55 grays: however, deafness and severe neuro-psychological and intellectual sequelae were frequent in these patients. After radical excision the rate of recurrence was the lowest, with a 10 year-recurrence-free survival rate of 88%. The postoperative mortality was low in case of pre-chiasmatic craniopharyngiomas, but high in case of retro-chiasmatic ones. Nevertheless, it appears from the recent literature data that impressive surgical improvements are to be expected from new surgical routes, associated with the use of the most recent technologies. The conclusions of this study are: 1. Radical excision is the treatment of choice; 2. If radical excision is not possible, surgery should be followed by irradiation to lower the risk of recurrence; 3. However, in view of the dangers of radiotherapy to the growing brain, it should be delayed as long as possible, particularly in the case of young children, and used only when tumor recurrence has been demonstrated.

Adolescent↗
PubMed1987

Preliminary results of authentic recombinant somatropin treatment in human growth hormone deficient children. French Collaborative Study.

A total of 50 children with hGH deficiency have been enrolled in a multicentre open trial of recombinant somatropin in France. Recombinant somatropin, 0.2 IU/kg s.c., was administered 3 times/week (0.6 IU/kg/week). Results are available after 3 months' treatment for 24 of the patients (11 prepubertal, 13 pubertal). The mean growth rate increased from 3.8 +/- 1.5 cm/year to 9.9 +/- 3.6 cm/year. Only one child developed anti-hGH antibodies with a very low binding capacity of 0.02 mg/litre; adverse events were uncommon and probably unrelated to treatment.

Adolescent↗