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Biomedical subjects

R White

Publications and source records attributed to R White.

At least 217 records · Page 12Linked to original sources
PubMed1994

Demonstration of promoter activity and alternative splicing in the region 5' to exon 1 of the APC gene.

Screening of fetal brain and fetal retina complementary DNA (cDNA) libraries and exon-connection experiments using brain cDNA have identified three exons 5' to exon 1 of the adenomatous polyposis coli gene. The exons are termed (from 5'-3') 0.3, 0.1, and 0.2; exons 0.1 and 0.2 are contiguous genomically. Library screening revealed alternatively spliced cDNAs containing the following combinations of 5'-exons: 0.3 + 1 + 2, 0.3 + 2, 0.1 + 0.2 + 1 + 2, and 0.1 + 1 + 2. Exon-connection experiments also identified these four forms in mRNAs from tissues and cultured cell lines, along with two additional forms, 0.1 + 0.2 + 2 and 0.1 + 2. The multiple splice forms may lead to proteins of differing activity; for example, products derived from cDNAs without exon 1 will lack most of a heptad-repeat domain that supports formation of homodimers. No mRNA species combining 0.3 with either 0.1 or 0.2 were identified. The existence of two apparently separate 5'-ends of APC suggests the possibility of two independent promoters. The genomic sequence adjacent to exon 0.3 confers promotor activity when cloned in a chloramphenicol acetyltransferase expression vector and transfected into a colon cancer cell line.

Alternative Splicing↗
PubMed1994

Evidence for involvement of BRCA1 in sporadic breast carcinomas.

The hereditary breast cancer gene BRCA1 previously has been localized to chromosome 17q21. We looked for evidence of involvement of this region of chromosome 17 in 130 sporadic breast cancers. Seventeen polymorphic sequence tagged site markers were examined in these tumors between the D17S250 and D17S579 loci to screen for deletions as measured by loss of heterozygosity. The smallest common region that was deleted occurred in the approximately 120-kilobase interval between the D17S846 and D17S746 loci within the BRCA1 region. Delineation of this commonly deleted area should accelerate attempts to identify the involved gene(s) and its relationship to BRCA1.

Breast Neoplasms↗
PubMed1994

Lead poisoning from mobilization of bone stores during thyrotoxicosis.

We describe a case of thyrotoxicosis accompanied by markedly elevated blood lead levels (initially 53 micrograms/dl) in a 37-year-old woman. No current source of lead exposure was found; the woman gave a history indicative of lead exposure as a child and as an adult 7 years previously, however. In addition, she was found to have markedly elevated bone lead levels, as measured by K-x-ray fluorescence (154 +/- 5 in the mid-tibia and 253 +/- 6 micrograms/g bone mineral in the patella), and an increased serum osteocalcin level (2.76 nmol/l), reflecting the increased bone turnover that often accompanies hyperthyroidism. During treatment with propylthiouracil, serial observations demonstrated a decline in serum osteocalcin that paralleled a decline in blood lead levels. Bone lead levels did not change appreciably. The patient also continued to have lingering neuropsychological symptoms consistent with chronic lead effects. We suggest that increased bone turnover accompanying thyrotoxicosis led to clinically significant lead poisoning in this patient, due to mobilization of accumulated bone lead stores acquired many years earlier. This phenomenon raises the general issue of more subtle forms of lead exposure from increased bone turnover states (e.g., osteoporosis).

Adult↗
PubMed1994

Space exploration and toxicology: a new frontier.

Results of the microbial and immunological studies discussed above clearly illustrate an in-flight or post-flight blunting of the cellular immune mechanism in humans and test animals, coincident with a relative increase in pathogenic microorganisms. This situation predicts an increased incidence of in-flight infectious disease events. To prevent this from occurring, most observers agree that a robust program of preflight and in-flight immunological and microbiological monitoring, combined with an effective countermeasures program, are required for optimally successful long-duration spaceflight.

Animals↗
PubMed1994

Platelet-activating factor: a candidate human immunodeficiency virus type 1-induced neurotoxin.

The pathogenesis of central nervous system disease during human immunodeficiency virus type 1 (HIV-1) infection revolves around productive viral infection of brain macrophages and microglia. Neuronal losses in the cortex and subcortical gray matter accompany macrophage infection. The question of how viral infection of brain macrophages ultimately leads to central nervous system (CNS) pathology remains unanswered. Our previous work demonstrated high-level production of tumor necrosis factor alpha, interleukin 1 beta, arachidonic acid metabolites, and platelet-activating factor (PAF) from HIV-infected monocytes and astroglia (H. E. Gendelman, P. Genis, M. Jett, and H. S. L. M. Nottet, in E. Major, ed., Technical Advances in AIDS Research in the Nervous System, in press; P. Genis, M. Jett, E. W. Bernton, H. A. Gelbard, K. Dzenko, R. Keane, L. Resnick, D. J. Volsky, L. G. Epstein, and H. E. Gendelman, J. Exp. Med. 176:1703-1718, 1992). These factors, together, were neurotoxic. The relative role(s) of each of these candidate neurotoxins in HIV-1-related CNS dysfunction was not unraveled by these initial experiments. We now report that PAF is produced during HIV-1-infected monocyte-astroglia interactions. PAF was detected at high levels in CSF of HIV-1-infected patients with immunosuppression and signs of CNS dysfunction. The biologic significance of the results for neurological disease was determined by addition of PAF to cultures of primary human fetal cortical or rat postnatal retinal ganglion neurons. Here, PAF at concentrations of > or = 300 pg/ml produced neuronal death. The N-methyl-D-aspartate receptor antagonist MK-801 or memantine partially blocked the neurotoxic effects of PAF. The identification of PAF as an HIV-1-induced neurotoxin provides new insights into how HIV-1 causes neurological impairment and how it may ultimately be ameliorated.

AIDS Dementia Complex↗
PubMed1994

Neurofibromin can inhibit Ras-dependent growth by a mechanism independent of its GTPase-accelerating function.

The NF1 gene, which is altered in patients with type 1 neurofibromatosis, has been postulated to function as a tumor suppressor gene. The NF1 protein product neurofibromin stimulates the intrinsic GTPase activity of active GTP-bound Ras, thereby inactivating it. Consistent with a tumor suppressor function, we have found that the introduction of NF1 in melanoma cell lines that are deficient in neurofibromin inhibited their growth and induced their differentiation. In addition, overexpression of neurofibromin in NIH 3T3 cells was growth inhibitory but did not alter the level of GTP.Ras in the cells. Transformation by v-ras, whose protein product is resistant to GTPase stimulation by neurofibromin, was inhibited in a cell line overexpressing neurofibromin, while transformation by v-raf was not altered. The results demonstrate that NF1 is a tumor suppressor gene that can inhibit Ras-dependent growth by a regulatory mechanism that is independent of neurofibromin's ability to stimulate Ras GTPase.

3T3 Cells↗
PubMed1994

Environmentally persistent alkylphenolic compounds are estrogenic.

We show that a number of alkylphenolic compounds, used in a variety of commercial products and found in river water, are estrogenic in fish, birds, and mammals. 4-Octylphenol (OP), 4-nonylphenol, 4-nonylphenoxycarboxylic acid, and 4-nonylphenoldiethoxylate were each capable of stimulating vitellogenin gene expression in trout hepatocytes, gene transcription in transfected cells, and the growth of breast cancer cell lines. The most potent of the chemicals is OP, which was able to stimulate these biological responses to a similar extent as 17 beta-estradiol itself, albeit at a 1000-fold greater concentration. The action of alkylphenols is mediated by the estrogen receptor, as their effects depended on its presence and was blocked by estrogen antagonists. OP, 4-nonylphenol, and 4-nonylphenoxycarboxylic acid appear to possess intrinsic estrogenic activity, because they compete for binding to the estrogen receptor. Moreover, it is likely that they interact with a similar region of the hormone-binding domain as 17 beta-estradiol, because the mutant receptor G-525R, which is defective in estrogen binding, is also insensitive to OP. Like 17 beta-estradiol, OP is capable of stimulating the activity of both transcriptional activation functions, TAF-1 and TAF-2, in the receptor, as judged by analyzing the activity of the wild-type and mutant receptors in transiently transfected cells. The significance of our results will depend to a large extent on the degree of exposure of wildlife and humans to these estrogenic alkylphenolic compounds.

Animals↗
PubMed1994

Characterization of ligand-dependent phosphorylation of the estrogen receptor.

The mouse estrogen receptor is phosphorylated upon estrogen binding at multiple serine residues located mainly between residues 121 and 599. Phosphorylation is progressively reduced in mutant receptors that are defective in estrogen- and DNA-binding activities, suggesting that it occurs in stages, initially as a consequence of hormone binding and subsequently after DNA binding. Phosphopeptide maps of the receptor expressed in the presence of estrogen or 4-hydroxytamoxifen are similar, suggesting that the effects of this antiestrogen on transcriptional activity are not mediated by differences in phosphorylation. Although it is unclear whether phosphorylation is a prerequisite for transcriptional activity, the similarity in the phosphopeptide maps of the wild-type receptor and the transcriptionally defective mutant confirm that phosphorylation does not occur simply as a consequence of estrogen-dependent transcriptional activation.

Animals↗
PubMed1994

Choice making to promote adaptive behavior for students with emotional and behavioral challenges.

Two analyses investigated the effects of choice making on the responding of elementary school students with emotional and behavioral challenges. In the first analysis, 2 participants were given choices from menus of academic tasks, all of which were pertinent to their educational objectives in English and spelling, respectively. Reversal designs showed that the choice-making conditions increased task engagement and reduced disruptive behavior for both students. An additional analysis was performed with a 3rd student in an effort to further distinguish the effects of choice making from preference. In this study, one of the no-choice phases was yoked to a previous choice-making condition. This analysis demonstrated that the choice-making condition was superior to baseline and yoked control phases as determined by levels of task engagement and disruptive behavior. The findings of the two analyses contribute information relevant to students with emotional and behavioral disorders, and to a growing literature on the desirable effects of choice making for students with disabilities and challenging behaviors.

Attention↗
PubMed1994

The preparation of zaragozic acid A analogues by directed biosynthesis.

Zaragozic acid A analogues are produced by an unidentified sterile fungus when it is exogenously supplied with 2-thiophenecarboxylic acid, 3-thiophenecarboxylic acid, 2-furoic acid, 2-fluorobenzoic acid, 3-fluorobenzoic acid, or 4-fluorobenzoic acid. The analogues carry 2-thiophenyl, 3-thiophenyl, 2-furyl, o-fluorophenyl, m-fluorophenyl, or p-fluorophenyl group, respectively, at C-6' of the C-1 alkyl side chain replacing the phenyl group of natural zaragozic acid A. All the new analogues of zaragozic acid A possess picomolar inhibitory activity against squalene synthase in vitro.

Bridged Bicyclo Compounds↗
PubMed1994

Thoracic organ transplants in the United States: a report from the UNOS/ISHLT Scientific Registry for Organ Transplants. United Network for Organ Sharing. International Society for Heart and Lung Transplantation.

1. The frequency of heart and lung transplantation has increased dramatically over time. The number of heart transplants increased 170% between 1968 and 1981. Exponential increases began in 1982 and increased through 1990, as evidenced by a 1,835% growth in the number of procedures performed during those years. In more recent years, heart transplant numbers have leveled off, with only an 8% increase in the last 3 years. Lung transplant procedures have grown significantly in the short period of time between 1987 (n = 18) and 1993 (n = 669). 2. Since the beginning of the ISHLT Registry in 1968 the number of thoracic transplant programs has increased 7,767%, from 3 to 236. 3. The most frequently reported indications for thoracic transplantation include: coronary artery disease (43.4%) for heart, cystic fibrosis (39.5%) for double-lung, emphysema/COPD (40.2%) for single-lung and primary pulmonary hypertension (38.3%) for heart-lung. 4. The majority of heart transplant recipients are at least 18 years old (89.5%), male (78.2%), and White (83.8%). The majority of lung transplant recipients are at least 18 years old (93.7%), female (53.2%), and White (91.3%). 5. One-year survival over time has almost doubled for all types of thoracic transplantation, with increases from 47.7% in 1968-79 to 81.6% in 1993 for heart; 35.3% in 1987 to 67.1% in 1993 for lung; and 40% in the early 1980s to 73% in 1993 for heart-lung. 6. Long-term 10-year survival rates were 33.5% for heart and 5.6% for heart-lung transplant recipients. Five-year survival for lung recipients was 37%. 7. Male-to-male donor-to-recipient gender-match heart transplant patients exhibited slightly higher survival (4-5%) than other match pairs from one to 5 years posttransplant. Female-to-male combinations in lung transplant recipients exhibited slightly higher survival (4-8%) at 3 years than other match pairs. 8. There was no significant difference in 5-year survival for donor hearts procured from local, intraregional, or interregional sources. Lungs procured from interregional sources exhibited an 8-10% advantage over local and intraregionally procured organs at 3 years posttransplant.

Adolescent↗