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Biomedical subjects

R Rappaport

Publications and source records attributed to R Rappaport.

At least 19 recordsLinked to original sources
PubMed1998

Effects of growth hormone in short children after renal transplantation. French Society of Pediatric Nephrology.

From 1991 to 1993, 90 children having received a kidney graft with a post-transplantation period of at least 12 months were included in a prospective study carried out in 18 French pediatric centers. After informed consent and randomization, children received recombinant human growth hormone (rhGH) (Genotonorm, Pharmacia peptide hormones) 30 U/m2 per week, either immediately on enrollment, for the treated group, or after 1 year of follow-up for the group serving as a control. After 1 year both groups were treated and we analyzed data during the subsequent years. Eighty-five children completed the 1-year study. Growth velocity was significantly increased by rhGH: 7.7 cm with a gain of +0.3 standard deviation score in the treated group versus 4.6 cm in the control group (P<0.0001) during the 1st year. Four factors predicted response to therapy: growth velocity prior to GH therapy, glomerular filtration rate (GFR) at the start, mode of corticosteroid administration, and degree of insulin resistance. After 1 year we observed a moderate, significant decrease in GFR in both groups. Biopsy-proven acute rejection episodes were not significantly more frequent during the 1st year in the group of patients who received rhGH: 9 in 44 versus 4 in 46 patients. The patients who rejected did not differ in terms of age, renal function at the start, and type of immunosuppression, but history of rejection before GH treatment was discriminatory: 6 of 17 children with two or more episodes had a new rejection versus 1 of 22 who had no or only one episode (P=0.01). Glucose tolerance was not modified after 1 year of GH therapy. During the subsequent years of treatment a decrease in growth velocity was noted: 5.9 cm at 2 years, 5.5 at 3 years, and 5.2 cm at 4 years. In conclusion, GH is efficient for improving growth velocity in short transplanted children, inducing clear-cut but limited catch-up growth. The risk of rejection was shown only in patients with a prior history of more than one rejection episode.

Adolescent↗
PubMed1998

Three-year data from a comparative study with recombinant human growth hormone in the treatment of short stature in young children with intrauterine growth retardation.

Growth acceleration and bone maturation were studied for 3 y in 69 children with severe short stature and a history of intrauterine growth retardation (IUGR), to determine the effect of treatment with recombinant human growth hormone (r-hGH). The patients were enrolled in an open, multicentre trial and were randomly allocated to either the treated group (Group 1) or the control group (Group 2). The children in Group 1 were treated daily with 0.2 IU/kg/body weight (0.067 mg/kg) s.c., during 3 y and the children in Group 2 started the study with a 1-y observation period followed by a 3-y treatment period. At birth, their mean weight standard deviation score (SDS) was -2.5 and their mean length SDS -3.5. At baseline, the patients were prepubertal, non-GH deficient, with no known dysmorphic features. Mean age was 4.5 y, bone age was 3.3 y, height SDS was -3.4, height velocity (HV) SDS was -1.6, and body mass index SDS was -1.4. After 1 y of treatment, linear HV in Group 1 increased in comparison with the pre-treatment period (from 5.7 +/- 2.0 to 10.1 +/- 1.7 cm/y; p < 0.001) and with the first year of observation in Group 2 (p < 0.001). Increased HV was sustained during the second and third year of treatment and was significantly higher than at baseline. A similar growth pattern was seen during the 3 y of GH treatment in Group 2. Mean height SDS for chronological age increased by 2.0 +/- 0.7 in the two groups after 3 y of treatment. HV after 1 y of treatment was negatively correlated with growth velocity at baseline. Bone age remained retarded but increased with a mean of almost 4 y after 3 y of treatment in both groups. Even at a dose that is three times the replacement dose treatment with r-hGH was well tolerated. From these results, we conclude that r-hGH treatment over 3 y can induce sustained catch-up growth in young children with severe short stature and a history of IUGR. Long-term studies are needed to assess ultimate effects on final height.

Adolescent↗
PubMed1998

Development of a fluorescent focus identification assay using serotype-specific monoclonal antibodies for detection and quantitation of rotaviruses in a tetravalent rotavirus vaccine.

A fluorescent focus identification assay (FFIDA) was developed for use in experimental studies and for quantitation of the components in a tetravalent live oral rotavirus vaccine. The assay utilizes four serotype-specific neutralizing monoclonal antibodies (MAb) to detect and quantify individual rotaviruses by immunofluorescence staining of fixed virus-infected monkey kidney cells. In mixed virus infections, all four MAb, W1 (serotype 1), 1C10 (serotype 2), R1 (serotype 3), and S4 (serotype 4), specifically stain the relevant homologous serotype without exhibiting any cross-reactivity against the other serotypes. Furthermore, the test is sensitive enough to differentiate at least twofold (0.3 log) differences in virus titer. The results of testing four individual experimental vaccine lots three or more consecutive times showed that all four lots contained similar proportions of the four vaccine strains as detected by the classical plaque neutralization identification test. The rapidity and efficiency of the FFIDA are desirable attributes that make it suitable for use in studies requiring identification and quantitation of one or more of the four major rotavirus serotypes.

Animals↗
PubMed1997

Cleavage furrow establishment by the moving mitotic apparatus.

The midpoint of the mitotic apparatus is fixed in the future division plane long before the division mechanism develops, and this static relationship has been considered essential in speculations concerning division mechanism establishment. The purpose of the present investigation was to determine whether prevention of the static relationship affects the establishment process. Sand dollar eggs were reshaped into cylinders by confinement in an elastic capillary tube and, beginning about 20 min before cleavage, the mitotic apparatus was kept in reciprocal motion by alternately compressing the poles. When the movement was continuous and the excursions were 25, 50 or 75 microm, furrow activity developed near the midpoint of the region underlain by the mitotic apparatus. The acuteness of the furrow decreased as the distance the mitotic apparatus was moved increased. When the movement was made discontinuous by allowing the mitotic apparatus to pause at the end of each excursion, the results depended upon the duration of the pause. Pauses 30 s long resulted in a single furrow formed in the midpoint of the entire region underlain by the mitotic apparatus. When the pauses were 45 s long, furrowing activity developed in both regions where the mitotic apparatus was allowed to pause. The results indicated that the normal static relation between the mitotic apparatus midpoint and the division plane is unnecessary for division mechanism establishment. They also demonstrate that a restricted region of contractile activity can be established in the cortex despite experimentally induced spreading and dilution of mitotic apparatus effect.

Animals↗
PubMed1997

Serologic correlates of immunity in a tetravalent reassortant rotavirus vaccine trial. US Rotavirus Vaccine Efficacy Group.

The correlation of antibody responses (serum rotavirus IgA and neutralizing antibody to serotype G1-G4 human rotaviruses and rhesus rotavirus [RRV]) in a reassortant rotavirus vaccine trial with protection against rotavirus infection or disease was investigated. Most subjects administered 4 x 10(5) pfu of either the serotype G1 monovalent or serotype G1-G4 tetravalent vaccine seroconverted for at least one of the six antibodies (85% and 91%, respectively). However, fewer than one-third seroconverted to any prototype G1-G4 human rotavirus. Analyses of covariance indicated that higher prevaccination neutralizing antibody titers negatively affected postvaccination titers. Significant relationships were found between several postvaccination rotavirus antibody titers and protection, and serotype-specific correlates of protection were identified between anti-Wa titers and G1 illnesses (P = .03) and between anti-RRV titers and G3 illnesses (P < .001). Overall, however, serotype-specific immunity was no more significant than heterotypic immunity, and no specific titer of any antibody analyzed was a reliable indicator of protection.

Antibodies, Viral↗
PubMed1997

A 5-year prospective study of growth hormone (GH)-deficient children treated with GH before the age of 3 years. French Serono Study Group.

The aim of the study was to assess the efficacy of GH therapy in GH-deficient children treated before the age of 3 yr. A noncomparative multicenter prospective study included 49 children (22 girls and 27 boys) with isolated GH deficiency (n = 19) or multiple pituitary hormone deficiency (n = 30) treated with daily s.c. injections (0.6 U/kg.week) for 3-5 yr. They were divided into two groups according to their height SD score for chronological age (CA) at the initiation of therapy: group A consisted of 8 patients presenting an initial height within the normal range (< 2 SD below the mean) followed for 2-5 yr, and group B consisted of 25 children followed for 5 yr among 41 patients with initial growth retardation. In group A, the mean height SD score increased from -1.1 +/- 0.6 to 0.35 +/- 1.0 SD (P < 0.001) in the first year and remained in the normal range throughout the following 4 yr. In group B after 4 yr of treatment, the mean height SD score for age had increased from -3.6 +/- 1.0 SD (time zero) to -0.9 +/- 1.2 SD. During the fourth year of therapy, the mean height gain of 0.2 +/- 0.2 SD was significant (P < 0.001). After 5 yr of treatment, a plateau was reached with a corresponding height SD score (CA) of -0.8 +/- 1.2 SD (95% confidence interval between -1.3 and -0.2 SD). This value remained significantly below normal for age (P < 0.001), indicating that catch-up growth was incomplete. Only four patients (16%) remained below -2SD for CA. The 5-yr height gain was negatively correlated with the height SD score at the start of treatment (r = -0.6; P < 0.005) and the first year height gain was the most predictive parameter. There was no significant influence of intrauterine growth retardation, body mass index and age at the start of treatment, or parental target height. Bone maturation was significantly retarded over CA by a mean value of 1.1 +/- 0.9 yr (P < 0.0001), with a mean bone age/CA ratio of 0.8 +/- 0.2 after a mean treatment duration of 5.1 +/- 1.1 yr. In conclusion, the rapid and almost complete return to normal height obtained in this study supports the need for GH treatment in early diagnosed GH-deficient children. The present dosage may be considered the minimum to obtain satisfactory catch-up growth ensuring a favorable outcome for these children. In addition, it allowed growth at a rate normal for age in patients diagnosed before growth retardation.

Body Height↗
PubMed1997

Comparison of immunocytochemical and molecular features with the phenotype in a case of incomplete male pseudohermaphroditism associated with a mutation of the luteinizing hormone receptor.

We report the case of an infant who presented at birth with a hypoplastic phallus associated with hypospadias. Low testosterone production, normal serum levels of steroid precursors, and increased LH in response to LH-releasing hormone supported a defect in Leydig cell differentiation or function. Conventional microscopic study of the testes showed fibroblastic cells in the interstitium. However immunocytochemical analysis using anti-LH receptor and anti-P450c17 antibodies demonstrated that about one third of these cells were Leydig cells or precursors of Leydig cells. No histological feature could distinguish the latter cells from fibroblasts. A homozygous substitution of cysteine 133 for arginine was found in the extracellular domain of the receptor. This is the first naturally occurring missense mutation found in the extracellular domain of the LH receptor. COS-7 cells transfected with the mutant receptor exhibited a marked impairment of hCG binding, whereas some cAMP production could be observed at high hCG concentrations. We propose that the partial impairment of LH receptor function, as reflected by the presence of Leydig cells, was responsible for the incomplete male pseudohermaphroditism observed in our patient.

Animals↗
PubMed1996

Divergence of VP7 genes of G1 rotaviruses isolated from infants vaccinated with reassortant rhesus rotaviruses.

A large placebo-controlled efficacy trial of the rhesus tetravalent (RRV-TV) and serotype G1 monovalent (RRV-S1) rotavirus vaccines was conducted in 1991-1992 at 24 sites across the United States. Protection was 49% and 54% against all diarrhea but 80% and 69% against very severe gastroenteritis for the two vaccines, respectively. Post-vaccination neutralizing antibody titers to the G1 Wa strain, whose VP7 protein is nearly identical to that of the D strain of rotavirus contained in both vaccines, did not correlate with protection against subsequent illness with G1 strains. This result raised the possibility that in infants who developed post-vaccination neutralizing antibody to Wa, breakthrough (i.e., vaccine failure-the occurrence of rotavirus diarrhea after immunization) may have been due to infection by G1 strains that were sufficiently antigenically distinct from the vaccine strain to evade the neutralizing antibodies elicited by vaccination. To test this hypothesis, we initially compared post-vaccination neutralizing antibody titers of vaccinees against Wa and G1 breakthrough strains using sera from subjects who experienced breakthrough. Post-immunization neutralizing antibody titers to Wa elicited by vaccination were significantly (P < 0.001) greater than to the breakthrough strains subsequently obtained from these subjects. This difference did not, however, correlate with lack of protection since similar differences in titer to Wa and breakthrough strains were found using post-vaccination sera from vaccinees who either experienced asymptomatic rotavirus infections or no infections. To determine the genetic basis for these differences, we compared the VP7 gene sequences of Wa with vaccine strain D, 12 G1 breakthrough strains, and 3 G1 control strains isolated during the same trial from placebo recipients. All breakthrough strains were distinct from Wa and D in antigenically important regions throughout the VP7 protein, but these differences were conserved between breakthrough and placebo strains. Furthermore, a comparative analysis of the deduced amino sequences form VP7 genes of G1 rotaviruses from 12 countries indicated that four distinct lineages have evolved. All breakthrough and control strains from the U.S. vaccine trial were in a lineage different from strain D, the serotype G1 vaccine strain. Although the overall results do not support our original hypothesis that immune selection of antigenically distinct escape mutants led to vaccine breakthrough in subjects with a neutralization response to Wa, it cannot be excluded that breakthrough could be partially due to antigenic differences in the VP7 proteins of currently circulating G1 strains.

Amino Acid Sequence↗
PubMed1996

Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer.

About 1.4% of the general population are heterozygous carriers of the gene for ataxiatelangiectasia (A-T), an autosomal recessive progressive neurologic syndrome in which cancer incidence of homozygotes is approximately 100-fold greater than the general population's rates. The hypothesis that A-T heterozygotes are predisposed to breast cancer was tested by the unbiased statistically powerful index-test method based on molecular genotyping. The A-T gene carrier status of 775 blood relatives in 99 A-T families was determined by tracing the A-T gene in each family through tightly linked flanking DNA markers. There were 33 women with breast cancer who could be genotyped; 25 of these were A-T heterozygotes, compared to an expected 14.9 (odds ratio 3.8, 95% confidence limits 1.7-8.4, one-sided p = .0001). This demonstrates that the A-T gene predisposes heterozygotes to breast cancer. For the 21 breast cancers with onset before age 60, the odds ratio was 2.9 (1.1-7.6, p = .009) and for the 12 cases with onset at age 60 or older, the odds ratio was 6.4 (1.4-28.8, p = .002). Thus the breast cancer risk for A-T heterozygous women is not limited to young women but appears even higher at older ages. Of all breast cancers in the United States, 6.6% may occur in women who are A-T heterozygotes. This proportion is several fold greater than the estimated proportion of carriers of BRCA1 mutations in breast cancer cases with onset at any age.

Adult↗
PubMed1996

Three years of GH treatment in Turner's syndrome: complex effect of GH dosage on growth parameters. French Pediatric Clinics and Sanofi-Winthrop.

OBJECTIVE: There have been few studies of GH dose responses in Turner's syndrome. We have therefore compared the growth effect of two doses of subcutaneous GH: 0.45 (D1) or 0.90 (D2) IU/kg/week. DESIGN: Multicentre study with two parallel randomized groups treated with D1 or D2 dose for one year, then with D2 for the second and third years in both groups. PATIENTS: Ninety-seven girls with Turner's syndrome aged from 4.8 to 16.5 years. RESULTS: The first mean height velocity (HV) was significantly higher with D2. At one year the girls changed from D1 to D2 showed a further acceleration in HV. During second and third years HV remained above the mean for untreated Turner girls, in both groups. Mean cumulative height gains over the 3 years were 1.06 and 1.17 SDS/CA (Ranke's Turner standard) in groups G1 and G2 respectively. Bone maturation, over 36 months, was 33.7 (G1) and 31.9 (G2) months. CONCLUSION: These results suggest that, if a higher initial GH dose is associated with a greater net initial height gain, the duration of treatment might affect the long-term results. Intermittent treatment should be considered.

Adolescent↗
PubMed1996

Serum rotavirus neutralizing-antibody titers compared by plaque reduction and enzyme-linked immunosorbent assay-based neutralization assays.

Comparisons in rotavirus neutralizing-antibody responses were made with sera collected from vaccinated infants. The methods were a plaque reduction assay and a new enzyme-linked immunosorbent assay-based neutralization assay. Agreement of 94% was found in detecting at least fourfold seroresponses, and correlation coefficients between titers obtained by the two methods showed excellent agreement, indicating that either could be used reliably.

Antibodies, Viral↗
PubMed1994

Cleavage in conical sand dollar eggs.

Previous experiments have shown that the mitotic apparatus and the surface can interact and produce functional furrows in various unusual geometrical circumstances. The consistent development of the furrow in the plane equidistant from the aster centers has led to conjecture about the need for a special structural configuration of the subsurface in the future cleavage plane. In most experiments involving altered cell geometry, the relation between each aster and nearby surface was symmetrical, and the effect of that symmetry upon the position and orientation of the cleavage mechanism in the cortex has not been systematically analyzed. The normal symmetry of sand dollar eggs can be changed by reshaping them into cones. When the cone and mitotic axes are parallel, the aster center closer to the vertex is also closer to the nearby surface, and the cleavage plane develops on the vertex side of the midpoint between the asters. A mitotic apparatus oriented perpendicular to the cone axis produces in the base of the cone a normal unilateral furrow that advances toward the vertex, and a second contractile band that isolates the vertex region. This event only occurs when the surface is conical and the mitotic apparatus is perpendicular to the cone axis. Furrow formation is not restricted to the plane of the metaphase plate or the midpoint between the aster centers. The orientation of mitotic apparatus-produced contractile bands is not limited to the circumstances in normal cytokinesis, but may vary according to surface contour. These results confirm predictions of the Harris and Gewalt model of contractile ring induction.

Animals↗
PubMed1994

True hermaphroditism: genetic variants and clinical management.

The diagnosis and management of 22 patients with true hermaphroditism are described. Sixteen of them were first seen before the age of 4 months. The initial manifestations were ambiguous genitalia in 20 cases (two of them identified prenatally by ultrasound examination), isolated clitoromegaly in one, and penile hypospadias plus unilateral cryptorchidism in one. All patients but one had at least one palpable gonad. Eleven of the twelve patients examined before the age of 6 months had basal plasma testosterone levels > 0.4 ng/ml. In older patients the stimulation test was necessary to demonstrate male testosterone secretion. The most common peripheral karyotype was 46,XX (17 cases); the other karyotypes were 47,XXY (1 case) and mosaicism 46,XX/46,XY (2 cases) or 46,XX/47,XXY (2 cases). One of the patients with the 46,XX karyotype had 46,XX/46,XY on fibroblast culture; four had the SRY gene in their leukocytes and one in the tissue taken at gonadal biopsy. A vagina was found in all patients at laparotomy, and a uterus was found in 17 cases (as a hemiuterus in 9). Genitography failed to demonstrate a uterus in only one case. The testicular tissue was dysgenetic but the ovarian tissue was normal. Sex assignment was male in 8 patients (reoriented by us in 2) and female in 14 patients (reoriented by us in 3). Spontaneous pubertal development occurred in the 4 patients (2 boys, 2 girls) with gonadal tissue who reached pubertal age. We conclude that true hermaphroditism is a heterogeneous condition in terms of its genetic background, with a prevalence of the 46,XX karyotype. There may be mosaicism with a Y-bearing cell line limited to the gonad (its frequency is probably underestimated), a paternal meiotic exchange between X and Y occurring in 46,XX cases with SRY, or a lack of the SRY gene, suggesting that other genes working independently of SRY may also determine testicular differentiation.

Child↗
PubMed1994

Growth retardation in children receiving long-term total parenteral nutrition: effects of ornithine alpha-ketoglutarate.

We evaluated the effect of ornithine ketoglutarate (OKG) in reversing abnormal growth in six prepubertal children receiving total parenteral nutrition (TPN) for 5-10 y. They were 1-4 SDs below their expected 50th percentile for height. The energy and nitrogen intakes were unchanged from 8 mo before the beginning of the study until its completion. Two consecutive periods of 5 mo each were studied. OKG (15 g) was added to the parenteral solution during the first period (OKG+) but not during the second period (OKG-). Height velocity (HV) increased (P < 0.05) from a median of 3.8 cm/y to 6.45 cm/y (range 1.8-6.7) during the OKG+ period, and decreased (P < 0.05) to a median of 3.65 cm/y in the OKG- period. Plasma concentrations of insulin-like growth factor 1 (IGF1), glutamine, and glutamate increased (P < 0.05) during the OKG+ period. Variations of IGF1 concentrations correlated with HV variations (r = 0.82, P < 0.005) during both periods. This study demonstrates that OKG is associated with statural growth acceleration and increased IGF1 concentrations.

Adolescent↗
PubMed1994

Nonparallel changes of growth hormone (GH) and insulin-like growth factor-I, insulin-like growth factor binding protein-3, and GH-binding protein, after craniospinal irradiation and chemotherapy.

We studied the GH-insulin-like growth factor-I (IGF-I) axis serially over 24-36 months in six patients with medulloblastoma who underwent surgical removal of the tumor followed by craniospinal irradiation therapy for 6 weeks and then chemotherapy for 42 weeks. Eighteen and 24 months after beginning irradiation there was a decline in the peak GH secretory response to acute stimulation with arginine/insulin hypoglycemia. Six months after irradiation and during chemotherapy there was a transient decline in IGF-I, IGF binding protein-3 (IGFBP-3), and GH-BP values (respective mean values of 56.1 +/- 9.0 ng/mL, 1.1 +/- 0.2 microgram/mL, and 7.6 +/- 3.3% of radioactivity as compared to time 0 values: 13%%o/- 15 ng/mL, 2.2 +/- 0.2 micrograms/mL, and 20.0 +/- 4.0%, P < 0.001), although provoked GH secretion was normal at this time. The IGF-I, IGFBP-3, and GH-BP returned to pretreatment ranges by 12-36 months after initiation of the study. There was also a decline in body mass index and serum protein values at 6 months, suggesting suboptimal nutrition during this period. Six months after irradiation in ligand and immunoblot analysis there was a decline in IGFBP-3 and an abnormal electrophoretic mobility of IGFBP-2 that were both normalized at 36 months. In one patient we observed a high level of IGFBP-3 proteolysis at this time. This study demonstrates that before the decrease of GH secretion in patients receiving cranial irradiation there is a transient phase of GH insensitivity that may be characteristic of the acute therapeutic phase including the chemotherapy. This partial insensitivity may explain the early growth retardation observed in these patients.

Adolescent↗