Vitronectin receptor: tissue specific expression or adaptation to culture?
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Cells, Cultured↗
Biomedical subjects
M Horton
Publications and source records attributed to M Horton.
Autosomal dominant microcephaly with mental retardation.
A 3-year-old girl, her mother, and maternal uncle had microcephaly and mental retardation. Their facial appearance is characterized by deep-set eyes, short philtrums, and a "beaked" nose. The mother and uncle live in an adult foster care facility because of mental retardation. The 3-year-old girl has a developmental quotient of 55. Mother has normal phenylalanine level and the child's chromosomes are normal. This appears to be a first report of a autosomal dominant form of microcephaly associated with mild to moderate mental retardation in contrast to absent or mild mental retardation described in earlier reports.
Child, Preschool↗
The osteoclast functional antigen, implicated in the regulation of bone resorption, is biochemically related to the vitronectin receptor.
We have defined the structure of the Osteoclast Functional Antigen (OFA) by immunological and biochemical means. OFA is an abundant surface antigen in human and animal osteoclasts and has been characterized previously by monoclonal antibodies 13C2 and 23C6, one of which mimicks the inhibitory activity of calcitonin on osteoclastic bone resorption. By the following criteria we show that OFA is a member of the integrin family of extracellular matrix receptors and is identical, or at least highly related, to the vitronectin receptor (VNR) previously isolated from placenta and melanoma cells. Immunoprecipitation analysis demonstrates that OFA from osteoclasts and a monkey kidney cell line Vero is a heterodimeric molecule of 140 kD (alpha chain) and 85 kD (beta chain) under nonreducing conditions; on reduction at least one low molecular mass (alpha') species (of approximately 30-kD size) is released, resulting in a 120/100-kD dimer. Immunoblots of OFA isolated from osteoclasts and Vero cells and VNR purified from placenta and probed with heterosera to OFA and monoclonal antibodies to platelet gp111a (VNR beta chain) show immunological cross-reactivity between the alpha chains of OFA and VNR and the use of gp111a as a beta chain by both. OFA from Vero cells binds to an Arg-Gly-Asp containing peptide (GRGDSPPK) isolating a heterodimer recognized by anti-OFA monoclonal antibodies, 13C2 and 23C6. Immunohistochemical analysis showed a similar tissue distribution in humans for the antigen recognized by anti-OFA antibodies, a monoclonal antibody, LM142, raised to melanoma VNR, polyclonal antibodies to the placental VNR and a monoclonal antibody to the presumptive VNR beta chain, platelet glycoprotein 111a. Finally, NH2 terminal amino acid sequencing showed that the amino-terminus of the monkey alpha chain was identical in the 12 assigned residues to that of human VNR alpha chain. The beta chain sequence of OFA differed at least 1 (and up to 4) positions from platelet gp111a (VNR beta) in the first 18 amino acids sequenced. These, and other, data provide the first indication of a function for the VNR and suggest that cell-cell and cell-extracellular matrix interactions involving integrins may play an important role in bone physiology.
Amino Acid Sequence↗
Is it sexual abuse? Confusion caused by a congenital anomaly of the genitalia.
Because of the increasing number of reports of sexual abuse of children, pediatricians should become more familiar with the examination of the genitalia of prepubertal children and learn to recognize physical indicators of abuse. Although some physicians may not recognize abnormal findings on examination, in other cases, unusual physical findings may be reported erroneously as possible abuse. The authors report a case of an unusual genital finding in a child which was suspected initially as being caused by sexual abuse but was subsequently determined to be a congenital anomaly. An external examination using a colposcope was useful in delineating the normal appearance of the tissues in question.
Child Abuse↗
Nuclear acceptor sites for steroid hormone receptors: comparisons of steroids and antisteroids.
The respective chromatin binding sites (acceptor sites) for both the avian oviduct progesterone receptor (PR) and the rabbit uterine estrogen receptor (ER) reported by two separate laboratories are compared. Support for a saturable, high affinity binding to the chromatin acceptor sites by both receptors is described. Nonradiolabelled PR or ER compete with their homologous radiolabelled receptors for binding. However, there is no competition between the heterologous ER and PR for the nuclear binding sites. In both receptor systems, evidence for a receptor dependent, receptor specific binding, which mimics the binding measured in vivo, is reported. With both the PR and ER, evidence for extensive masking in chromatin of many of the acceptor sites is described. The PR and ER acceptor sites appear to be composed of specific acceptor proteins bound to DNA. The dissociation of these proteins from DNA causes a loss of specific binding. Reannealing of these same chromatin protein fractions, but not other protein fractions, back to the DNA reinstates the specific PR binding. Antibodies against the PR acceptors proteins are described. These antibodies block PR but not ER binding to the chromatin acceptor sites, supporting the steroid receptor specific acceptor sites. In the rabbit uterine system, the ER acceptor proteins dissociate from chromatin in three distinct fractions according to their affinity for the DNA. Each of these fractions contains acceptor activity in that each can be reannealed to the DNA to reconstitute specific ER binding sites, i.e. those which are saturable, high affinity, and receptor dependent. Interestingly, the antiestrogen receptor complexes do not bind to one fraction of acceptor proteins which does bind the native estrogen receptor complex. This ER acceptor protein fraction contains two regions of acceptor activity in the molecular mass range of 50,000 and 12,000 daltons. The latter species is in the size range of the PR acceptor proteins. This difference in binding to chromatin acceptor sites by the estrogen receptor, complexed with an estrogen or antiestrogen, may explain the differential regulation of gene expression and the differential biological response to antiestrogens compared to the native estrogens.
Animals↗
Characterization of the chromatin acceptor sites for the avian oviduct progesterone receptor using monoclonal antibodies.
Monoclonal antibodies (MAb) against the chromatin acceptor sites for the avian oviduct progesterone receptor were prepared with highly purified hen oviduct acceptor proteins reconstituted to hen DNA. Addition of the MAbs to a cell-free assay blocked progesterone receptor from chick oviduct (PRov) binding to native-like acceptor sites on nucleoacidic protein (NAP) representing a partially deproteinized chromatin, which has been shown to be enriched in these binding sites. However, the antibodies do not block PRov binding to pure DNA, nor do they affect the receptor itself. Estrogen receptor binding to NAP was not inhibited, supporting a receptor specificity of the PRov acceptor sites as reported previously from direct competition studies. These data support earlier studies showing that (1) the reconstituted PRov acceptor sites resemble the native sites, (2) the acceptor sites are receptor specific, and (3) the PRov binding sites of NAP are different from those of pure DNA. While some animal-species specificity in the PRov binding inhibition was observed, no tissue specificity was seen. Direct binding of the antibodies to native acceptor sites was demonstrated in an enzyme-linked immunosorbent assay (ELISA) system. The antibodies showed little recognition of free acceptor protein or DNA alone, indicating specificity for the protein-DNA complex. A partial evolutionary conservation of the nuclear acceptor sites for PRov was shown by the fact that about 50% of the inhibition seen with hen NAP was obtained with NAPs from several other species, and this partial cross-reactivity of the MAbs with the same NAPs from other animal species was also seen in the ELISA.
Animals↗
Monoclonal antibodies against putative nuclear acceptor sites of the avian oviduct progesterone receptor.
Evidence from this and other laboratories has suggested that the nuclear binding sites (acceptor sites) for steroid receptors on chromatin involves chromatin protein-DNA complexes. A saturable high affinity receptor-dependent nuclear binding to these sites by isolated steroid receptor complexes has been reported. Addition of nonradiolabelled progesterone receptor from the chicken oviduct (PRov) successfully competes for the [3H]PRov binding to these acceptor sites in isolated chromatin or in nucleoacidic protein (NAP), a partially deproteinized chromatin enriched in these binding sites. This competition does not occur with pure DNA. This laboratory has isolated and enriched the chromatin proteins (acceptor proteins) involved in the nuclear acceptor sites for the avian oviduct PRov. Monoclonal antibodies against the nuclear acceptor sites for the PRov have been prepared using highly purified hen oviduct acceptor proteins reconstituted to hen DNA. Addition of the MAbs to a cell-free assay blocks PR binding to native oviduct chromatin as well as to NAP. However, the antibodies do not block PR binding to pure DNA nor do they affect the receptor itself. A partial animal species specifically was observed with the Ab inhibition of the PR binding, whereas no tissue specificity was seen. Direct binding of the antibodies to native acceptor sites was demonstrated using an ELISA system. The antibodies showed little recognition of free acceptor protein or DNA alone, indicating specificity for the protein-DNA complex. The partial evolutionary conservation of the nuclear acceptor sites for PR, as shown by the inhibition of PRov binding, was further supported by the partial crossreactivity of the MAbs with the NAPs from the same animal species using the ELISA. These data support earlier studies using PR binding assays showing that: 1) the reconstituted PR acceptor sites resemble the native sites; 2) the sites on whole chromatin and on NAP are similar; 3) the PR binding sites of chromatin and NAP are different from those of pure DNA; and 4) the nuclear acceptor sites for PR are different from those of the estrogen receptor. These results support a receptor specificity of the PR acceptor sites as reported previously using direct receptor competition studies.
Animals↗
Nuclear acceptor sites for sex steroid hormone receptors in chromatin.
The steroid receptor interactions in vitro with specific acceptor sites composed of acceptor protein-DNA complexes fulfill many of the criteria of a physiologically significant binding system. Chromatin acceptor sites for many steroid receptors (especially for the progesterone and estrogen receptor) are specific since they are saturable and competitive with unlabelled receptors, have high affinity for the receptor, distinguish between functional and nonfunctional receptors and demonstrate target tissue specificity. Pure DNA as acceptor sites does not display many of these properties. Therefore, it is clear that certain chromatin proteins provide the necessary specificity for the acceptor sites for the steroid receptors. For the progesterone receptor in the chick oviduct, these nuclear sites appear to contain specific chromosomal proteins as well as specific DNA sequences. The substitution of other chromosomal proteins or the genomic DNAs from evolutionarily distant organisms results in a loss of the specific nuclear binding. The nuclear acceptor sites appear to be resistant to the DNase activity which is not characteristic of transcriptionally active domains of the genome. Further studies using the ovalbumin gene sequences from genomic clones also indicate that none of the sequences within this domain and the 3-k flanking regions appear to contain the specific acceptor sequences. These observations have led to development of a model suggesting that the steroid receptors bind to acceptor sites distant from the structural genes the steroids ultimately regulate. Neighboring these acceptor sites are regulatory genes which code for regulatory substances which in turn (as secondary messengers) regulate at great distances the expression of the structural gene. This model might better fit the sex steroids which require 1-2 h to measurably alter gene transcription, as opposed to the glucocorticoids which more rapidly alter gene expression.
Animals↗
Lack of cross-allergenicity between tricyclic antidepressants.
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Adult↗
Adaptations of the Denver Developmental Screening Test: a study of preschool screening.
Developmental screening tests are only rarely used in pediatric practice, reportedly because of lack of available time. This study evaluated a shortened form of the Denver Developmental Screening Test (DDST-S) consisting of only those items immediately to the left of the child's individual are line, three in each sector or a total of 12. This DDST-S was administered to four cohorts of preschool children (aged 52 to 64 months), 1,819 children in all. Subsamples of these children returned within three months for one of several developmental (criterion) tests (McCarthy Scales of Children's Abilities, the complete DDST, or the Stanford-Binet). The DDST-S was scored by selecting the profile of passes and failures most predictive of McCarthy test results, using indices of copositivity, connegativity, underreferral, and overreferral as the basis for the decision. Utilizing this scoring system, use of the DDST-S was able to identify low scorers (those scoring less than 70) on the Stanford-Binet (sensitivity = .67, specificity = .95, predictive value = .54, underreferral = 2.5%, overreferral = 4%) as well as the complete DDST. Low scoring children could thus be identified in less than half the time required by the complete DDST. A two-stage DDST-S and DDST procedure was found to have even greater predictive value (76%; 100% if borderline cases [score of 70 to 80] are considered positive) than either form alone.
Child Development↗
The importance of reproducibility testing of computer programs for electrocardiographic interpretation: application to the automatic vectorcardiographic analysis program (AVA 3.4).
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Computers↗
Munchausen's stridor: non-organic laryngeal obstruction.
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Adult↗
A method for evaluating computer programs for electrocardiographic interpretation. 3. Reproducibility testing and the sources of program errors.
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Arrhythmias, Cardiac↗
Pediatricians' attitudes toward allergy.
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Age Factors↗
Recombinant human granulocyte macrophage colony stimulating factor following alternating non cross resistant chemotherapy in Hodgkin's disease.
Fourteen patients with Hodgkin's disease (two previously untreated, 12 following relapse or with refractory disease) were treated with a combination chemotherapy regimen comprising chlorambucil, vinblastine, procarbazine, prednisolone, etoposide, vincristine and adriamycin administered on days 1-8. Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) (mammalian glycosylated, Sandoz/Schering-Plough) was administered after alternate cycles of chemotherapy from day 10 for 7 days by continuous intravenous (i.v.) infusion in 12 patients in a dose finding study (dose: 2 micrograms/kg/day in four patients, 4 micrograms/kg/day in four patients and 8 micrograms/kg/day in four patients) and by daily subcutaneous (s/c) injections in two patients (8 micrograms/kg/day). There was a rapid peripheral leucocytosis following the rhGM-CSF, reaching a peak at 1-2 days in 12/14 patients. The initial leucocytosis was composed of neutrophils followed by a rise in immature myeloid cells. There was no difference observed in the duration or depth of the nadir following chemotherapy or in the rate of recovery of peripheral white cell counts between cycles with and without rhGM-CSF in patients treated with 2 and 4 micrograms/kg/day. At the dose of 8 micrograms/kg/day, 3/6 patients had a shorter nadir duration in the cycle with rhGM-CSF, compared with cycle without rhGM-CSF. There was no difference in frequency of infection in cycles with and without rhGM-CSF. Following chemotherapy, six patients achieved clinical remission, six partial remission and two had progressive disease.
Adult↗