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Biomedical subjects

D Edmondson

Publications and source records attributed to D Edmondson.

17 recordsLinked to original sources
PubMed2001

The growth suppressor PML represses transcription by functionally and physically interacting with histone deacetylases.

The growth suppressor promyelocytic leukemia protein (PML) is disrupted by the chromosomal translocation t(15;17) in acute promyelocytic leukemia (APL). PML plays a key role in multiple pathways of apoptosis and regulates cell cycle progression. The present study demonstrates that PML represses transcription by functionally and physically interacting with histone deacetylase (HDAC). Transcriptional repression mediated by PML can be inhibited by trichostatin A, a specific inhibitor of HDAC. PML coimmunoprecipitates a significant level of HDAC activity in several cell lines. PML is associated with HDAC in vivo and directly interacts with HDAC in vitro. The fusion protein PML-RARalpha encoded by the t(15;17) breakpoint interacts with HDAC poorly. PML interacts with all three isoforms of HDAC through specific domains, and its expression deacetylates histone H3 in vivo. Together, the results of our study show that PML modulates histone deacetylation and that loss of this function in APL alters chromatin remodeling and gene expression. This event may contribute to the development of leukemia.

Animals↗
PubMed1999

Efficacy of repeat intravenous dosing of ondansetron in controlling postoperative nausea and vomiting: a randomized, double-blind, placebo-controlled multicenter trial.

STUDY OBJECTIVES: To compare repeat intravenous (i.v.) dosing of ondansetron 4 mg with placebo for the treatment of postoperative nausea and vomiting (PONV) in patients for whom prophylactic, preoperative ondansetron 4 mg i.v. was inadequate DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Ten outpatient surgical centers in the United States. PATIENTS: 2,199 male and female ASA physical status I, II, and III patients > or = 12 years old scheduled to undergo outpatient surgical procedures and receive nitrous oxide-based general anesthesia. INTERVENTIONS: Ondansetron 4 mg i.v. was administered to all patients before induction of general anesthesia. Patients who experienced PONV or requested antiemetic therapy within 2 hours after discontinuation of inhaled anesthesia were randomized (1:1) to either a repeat i.v. ondansetron 4 mg dose or placebo. MEASUREMENTS AND MAIN RESULTS: Of the 2,199 patients prophylactically treated with ondansetron 4 mg before anesthesia induction, 1,771 (80.5%) did not experience PONV or request antiemetic therapy during the 2 hours following discontinuation of anesthesia. Of the 428 patients who experienced PONV or requested antiemetic therapy during the same period, and were randomized to additional treatment (214 randomized to ondansetron, 214 randomized to placebo), the incidence of complete response (no emesis, no rescue medication, no study withdrawal) was similar for both ondansetron-randomized and placebo-randomized groups for the 2-hour (34% and 43%, respectively, p = 0.074) and 24-hour (28% and 32%, respectively, p = 0.342) postrandomization study periods. Repeat ondansetron dosing was not more effective than placebo in controlling either postoperative emesis or the severity/duration of postoperative nausea. The administration of an additional dose of ondansetron 4 mg postoperatively did not result in an increased incidence of adverse effects. CONCLUSIONS: In patients for whom preoperative prophylaxis with ondansetron 4 mg i.v. is not successful, a repeat dose of ondansetron 4 mg i.v. in the postanesthesia care unit does not appear to offer additional control of PONV.

Adolescent↗
PubMed1998

Characterization of Y122F R2 of Escherichia coli ribonucleotide reductase by time-resolved physical biochemical methods and X-ray crystallography.

Ribonucleotide reductase (RNR) from Escherichia coli catalyzes the conversion of ribonucleotides to deoxyribonucleotides. It is composed of two homodimeric subunits, R1 and R2. R2 contains the diferric-tyrosyl radical cofactor essential for the nucleotide reduction process. The in vitro mechanism of assembly of this cluster starting with apo R2 or with a diferrous form of R2 has been examined by time-resolved physical biochemical methods. An intermediate, Fe3+/Fe4+ cluster (intermediate X), has been identified that is thought to be directly involved in the oxidation of Y122 to the tyrosyl radical (*Y122). An R2 mutant in which phenylalanine has replaced Y122 has been used to accumulate intermediate X at sufficient levels that it can be studied using a variety of spectroscopic methods. The details of the reconstitution of the apo and diferrous forms of Y122F R2 have been examined by stopped-flow UV/vis spectroscopy and by rapid freeze quench electron paramagnetic resonance, and Mössbauer spectroscopies. In addition the structure of this mutant, crystallized at pH 7.6 in the absence of mercury, at 2.46 A resolution has been determined. These studies suggest that Y122F R2 is an appropriate model for the examination of intermediate X in the assembly process. Studies with two mutants, Y356F and double mutant Y356F and Y122F R2, are interpreted in terms of the possible role of Y356 in the putative electron transfer reaction between the R1 and R2 subunits of this RNR.

Amino Acid Substitution↗
PubMed1998

Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease): continuing diagnostic difficulties.

AIMS: To describe the clinicopathological and immunophenotypic features of 25 cases of Kikuchi-Fujimoto disease (K-F), which remains a poorly recognized entity and is still frequently confused with malignant lymphoma, and to discuss the main diagnostic problems experienced by the referring pathologist. METHODS AND RESULTS: Haematoxylin and eosin sections of 27 lymph node biopsies were re-examined. Immunostains for B-lymphocytes, T-lymphocytes and macrophages were performed. Clinical and follow-up data were obtained through a questionnaire to the referring pathologist or from the patients' notes where available. The suggested initial diagnoses are discussed. The lymph nodes showed a necrotizing process characterized by patchy or confluent areas of necrosis associated with karyorrhexis and absence or paucity of granulocytes. This was associated with a proliferation of large blastic cells consisting of a mixture of T-lymphocytes and histiocytes. Fragmentation of the biopsy was a frequent feature. The diagnosis of K-F was suggested by the referring pathologist in three cases only. The most common suggested diagnosis was that of a non-Hodgkin's lymphoma. CONCLUSION: This series documents continuing difficulties in the diagnosis of Kikuchi-Fujimoto disease in the UK and emphasizes that cases are still being mistakenly diagnosed as malignant lymphomas. The diagnosis of Kikuchi-Fujimoto disease merits active consideration in any nodal biopsy showing fragmentation, necrosis and karyorrhexis, especially in young women presenting with cervical lymphadenopathy.

Adolescent↗
PubMed1995

Prestorage white cell reduction in saline-adenine-glucose-mannitol red cells by use of an integral filter: evaluation of storage values and invivo recovery.

BACKGROUND: Prestorage white cell (WBC) reduction in blood components may decrease the incidence of adverse reactions and improve component quality. A bottom-and-top system with an integral third-generation WBC-reduction filter has been studied. STUDY DESIGN AND METHODS: Whole blood was collected from 30 healthy donors: from 20 by using a blood container system with an integral filter and from 10 controls by using a standard blood container system. Ten test units were buffy coat-depleted, stored for 72 hours at 4 degrees C, and then filtered, while an additional 10 test units were buffy coat-depleted and filtered at room temperature within 8 hours of collection. All units were stored at 4 degrees C for 42 days and sampled weekly. RESULTS: The mean WBC content of the 72-hour, 4 degrees C units was 0.33 x 10(6), that of the room-temperature units was 2.6 x 10(6), and that of the buffy coat-depleted controls was 460 x 10(6) (p < 0.0005). No significant differences were found among lactate, glucose, sodium, potassium, and plasma hemoglobin levels in the three groups. ATP and 2,3 DPG levels were significantly better preserved in control units than in 72-hour, 4 degrees C units (p = 0.016 and p = 0.032, respectively), but not better than in the room-temperature units. Significant differences were observed between pH values in filtered units and both groups of test units (p = 0.016). In biologic terms however, these differences were small. Red cells from an additional eight healthy volunteer donors were processed by an 8-hour room-temperature method and stored for 35 days. Studies in vivo 24-hour recovery of autologous red cells were performed by transfusing a radiolabeled (51Cr plus 131I-albumin) aliquot after 35 days' storage. Good recovery (mean > 80%) was found by both the single- and double-isotope-label methods. Recovery was significantly greater when calculated by the single-isotope method (p = 0.02). CONCLUSION: The combination of buffy coat removal and filtration in the blood container system with an integral filter achieved effective WBC reduction (> or = 3 log10 reduction from whole blood) without biologically significant detriment to in vitro or in vivo storage values.

Adenine↗
PubMed1993

Immunophenotype and ultrastructure of alveolar soft part sarcoma.

Nine cases of alveolar soft part sarcoma were studied in terms of their immunoreactivity towards intermediate filaments and muscle markers, and their ultrastructure with regard to muscle features and the cytoplasmic crystals characteristic of this tumour. Inconsistent expression of alpha-smooth muscle actin, vimentin and desmin were found. No unambiguous muscle cell characteristics were identified by electron microscopy, although multiple subplasmalemmal densities with overlying lamina were emphasised as a typical but not specific muscle feature. Classical alveolar soft part sarcoma crystals at the ultrastructural level were absent throughout, but pseudo-crystals with a pre-crystalline finely filamentous content were numerous in one case. The results were integrated into a comprehensive comparison with the literature. It is clear that immunohistochemical evidence of striated muscle differentiation is detectable in some but not all cases of ASPS. The detection of Myo D1 protein in the small numbers of ASPSs so far studied for this gene product raises the possibility that in the majority of ASPSs this is the only evidence of early striated muscle differentiation and that only in the minority is it able to induce desmin production. Study of a substantial series for Myo D1 is required to explore this possibility.

Actins↗
PubMed1991

Inefficient homooligomerization contributes to the dependence of myogenin on E2A products for efficient DNA binding.

Myogenin is a muscle-specific transcription factor that can activate myogenesis; it belongs to a family of transcription factors that share homology within a basic region and an adjacent helix-loop-helix (HLH) motif. Although myogenin alone binds DNA inefficiently, in the presence of the widely expressed HLH proteins E12 and E47 (encoded by the E2A gene), it forms heterooligomers that bind with high affinity to a DNA sequence known as a kappa E-2 site. In contrast, E47 and to a lesser extent E12 are both able to bind the kappa E-2 site relatively efficiently as homooligomers. To define the relative contributions of the basic regions of myogenin and E12 to DNA binding and muscle-specific gene activation, we created chimeras of the two proteins by swapping their basic regions. We showed that myogenin's weak affinity for the kappa E-2 site is attributable to inefficient homooligomerization and that the myogenin basic domain alone can mediate high-affinity DNA binding when placed in E12. Within a heterooligomeric complex, two basic regions were required to form a high-affinity DNA-binding domain. Basic-domain mutants of myogenin or E2A gene products that cannot bind DNA retained the ability to oligomerize and could abolish DNA binding of the wild-type proteins in vitro. These myogenin and E2A mutants also acted as trans-dominant inhibitors of muscle-specific gene activation in vivo. These findings support the notion that muscle-specific gene activation requires oligomerization between myogenin and E2A gene products and that E2A gene products play an important role in myogenesis by enhancing the DNA-binding activity of myogenin, as well as other myogenic HLH proteins.

Amino Acid Sequence↗
PubMed1990

Myogenin is in an evolutionarily conserved linkage group on human chromosome 1q31-q41 and unlinked to other mapped muscle regulatory factor genes.

Myogenin is a member of a family of muscle-specific regulatory factors which includes MyoD1, Myf-5, and Myf-6 (also called MRF4 and herculin). Extensive regions of sequence homology in genes for these three factors suggest duplication events associated with their evolution. In the present study, the chromosomal location of the myogenin gene in humans (MYOG), mice (Myog), and Chinese hamsters (MYOG) was determined using in situ hybridization to human metaphase chromosomes as well as segregation analysis among interspecific somatic cell hybrid panels and interspecific backcrossed mice. We localize the gene encoding myogenin to human chromosome 1q31-q41 within a linkage group homologous with a region on mouse chromosome 1 and Chinese hamster chromosome 5. The results verify the nonlinkage of MYOG to MYOD1, MYF5, and MYF6 genes and indicate that events associated with the duplication of MYOG with respect to MYOD1, MYF5, or MYF6 loci were not chromosome-wide.

Animals↗
PubMed1975

Mechanism of the reductive activation of succinate dehydrogenase.

When succinate dehydrogenase contains oxalacetate in firmly bound form, activity cannof the enzyme results in dissociation of oxalacetate and activation of the enzyme. The course of reductive titrations appears the same whether or not the enzyme contains oxalacetate, and complete reduction as monitored by bleaching of chromophoric groups requires the incorporation of 6 to 7 reducing equivalents in either case. The stoichiometry is that expected from the non-heme iron and flavin content of the enzyme. Activation of the enzyme during reductive titrations occurs predominantly with the incorporation of the second pair of electrons, while determination of activation levels at various poised potentials shows that the group involved is reduced with the uptake of 2 H+ and 2 e-. These characteristics are consistent with titration of the flavin moiety rather than non-heme iron groups. Thus it appears that activation is concurrent with the reduction of flavin to the hydroquinone form. From the measured half-reduction potential for activation, that of the flavin in an oxalacetate-free enzyme has been estimated at -90 to -60 mv at pH 7.

Animals↗
PubMedDate not supplied

Molecular control of myogenesis: antagonism between growth and differentiation.

Insight into the molecular mechanisms that control establishment of the skeletal muscle phenotype has recently been obtained through cloning of a family of muscle-specific regulatory factors that can activate myogenesis when transfected into non-muscle cells. This family of factors, which includes MyoD, myogenin, myf-5, and MRF4, can bind DNA and transactivate muscle-specific genes in collaboration with ubiquitous cellular factors. Growth factors play an antagonistic role in myogenesis by suppressing the actions of the myogenic regulatory factor family. This review will focus on the regulation and mechanism of action of this family of myogenic regulatory factors and on the central role of peptide growth factors in modulating their expression and biological activities.

Animals↗
PubMedDate not supplied

Quality communication: managing conflicts and confrontations in the healthcare setting.

Unresolved conflicts between healthcare associates can lead to decreased teamwork and result in mistakes. Because the goal of healthcare organizations is to provide quality care, it is in the organization's best interest to avoid these damaging results. Healthcare managers have a responsibility to promote quality communication among healthcare workers. Formal negotiations, mediation, and assertiveness techniques all are very effective in resolving conflict.

Attitude of Health Personnel↗