New ways to take old drugs.
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Anti-HIV Agents↗
Biomedical subjects
G Miller
Publications and source records attributed to G Miller.
Hubert Harrington Warner, the patent medicine "king".
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Drug Industry↗
Heterogeneous expression of E-cadherin and p53 in prostate cancer: clinical implications. BIOMED-II Markers for Prostate Cancer Study Group.
Histologic grade and tumor volume are markers of malignant phenotype. More objective markers, however, have been sought for needle biopsy specimens. The aim of this study was to evaluate how immunohistochemical expression of the potential prognostic markers E-cadherin and p53 in biopsy specimens relates to the expression of these markers in prostatectomy specimens. Therefore, we analyzed 47 prostatectomy specimens and their preoperative biopsy specimens. Fixation of surgical specimens and the immunohistochemical assay for both E-cadherin and p53 expression was optimized. All paraffin blocks containing areas of carcinoma were submitted for immunohistochemical analysis. The prevalence of abnormal p53 immunoreactivity was only 11%. In addition, abnormal p53 expression was virtually restricted to cases that were already identified as having a poor prognosis on the basis of the large volume and the high grade of their carcinomas. In 28% of the cases, we found abnormal immunoreactivity for E-cadherin. These cases revealed considerable heterogeneity in topographic distribution of abnormal expression. The level of sensitivity to the detection of abnormal E-cadherin expression or abnormal p53 in the prostatectomy specimen was 15% and 60%, respectively. In view of the inherent heterogeneity of E-cadherin expression and the low prevalence of abnormal p53 expression, we question the use of these markers for prognostic purposes in needle biopsy specimens. Unless representative sampling by needle biopsy can be assured, the use of E-cadherin expression will be of most value in prostatectomy specimens.
Biopsy↗
The locus of Epstein-Barr virus terminal repeat processing is bound with enhanced affinity by Sp1 and Sp3.
EBV DNA contains G-rich, repeat regions that are involved in rearrangement and recombination events including terminal repeat (TR) processing and the EBNA-2 deletion in the EBV strain P3HR-1. Cellular proteins, called terminal or tandem repeat binding proteins (TRBPs), recognize sequences at the junctions of these recombination events. In this study, using antibody supershift assays and expression of recombinant proteins, we show that Sp1 and Sp3 are the sequence-specific components of TRBP and that Ku is the nonspecific binding component. Sp1 binds other recombinogenic regions of EBV DNA, but Sp3 does not bind to the large internal repeat. The sequence GGGGTGGGG, a low affinity site for Sp1 and Sp3, is the minimal binding site within terminal repeat binding site 1 (TRBS1). However, 3' flanking sequences in the sequence GGGGTGGGGCATGGGG augment binding of Sp1 and Sp3 so that their affinity of binding is increased approximately twofold relative to a classical high-affinity Sp1 site. EBV lytic cycle induction does not alter the abundance or binding activity of any of the three identified components of TRBP. Sp1 and Sp3 may act in trans to promote EBV terminal repeat processing and possibly other viral and cellular recombination events.
DNA-Binding Proteins↗
Emergency department use of aspirin in patients with possible acute myocardial infarction.
BACKGROUND: Efforts have been made to improve the suboptimal use of aspirin after hospitalization. OBJECTIVE: To assess the frequency and timing of aspirin administration in emergency department patients with possible myocardial infarction. DESIGN: Retrospective record review. SETTING: Emergency departments of four hospitals affiliated with the same university. PATIENTS: All patients who were admitted to the four hospitals in 1994 for evaluation and treatment of suspected acute myocardial infarction. MEASUREMENTS: The frequency and timing of aspirin administration and the definitive diagnosis established before discharge from the hospital. RESULTS: Aspirin was not given to 253 of 463 emergency department patients (55%) who had a definitive diagnosis of acute myocardial infarction. Seventy-eight percent of patients who did receive aspirin received it more than 30 minutes after arrival in the emergency department. CONCLUSION: Aspirin therapy is underutilized as the first intervention in patients who are admitted with suspected myocardial infarction.
Aged↗
Effects of left ventricular systolic function on left ventricular diastolic filling patterns in severe mitral regurgitation.
Significant mitral regurgitation (MR) may alter the normal pattern of Doppler detected left ventricular (LV) filling by causing a prominent early filling (E) wave velocity. The manner and extent to which the typical filling pattern of uncomplicated MR is affected by concomitant impaired LV systolic function has not been characterized. Twenty patients with severe LV systolic dysfunction (2-dimensional echocardiographic estimation of ejection fraction < or = 30%) and 21 age- and sex-matched case controls with normal systolic function (ejection fraction > or = 55%) were selected. In addition, 20 subjects with normal LV systolic function and no MR were analyzed as a reference group. Maximal E-wave velocity was increased and highest among MR patients with preserved LV systolic function (124 +/- 37 cm/s) than among those with LV systolic dysfunction (101 +/- 25 cm/s; p <0.05) and normal controls (74 +/- 18 cm/s; p <0.001). Concurrently, A-wave velocity was lowest in patients with systolic dysfunction and MR (47 +/- 23 cm/s; p <0.001) than in patients with normal systolic function and MR (79 +/- 33 cm/s) and normal controls (74 +/- 20 cm/s). Deceleration time of the E wave was longest among those with normal systolic function and MR (203 +/- 41 ms) than among those with systolic dysfunction and MR (152 +/- 35 ms; p <0.001) and normal controls (167 +/- 53 ms; p <0.05). Thus, systolic LV dysfunction in patients with severe MR, compared to patients with MR and normal LV systolic function, is associated with important changes in diastolic inflow velocities, including reduction of the maximal A-wave velocity to a greater extent than the E wave, resulting in an increased E/A ratio and shortening of deceleration time of the E wave.
Aged↗
Transluminal extraction catheter for acute myocardial infarction.
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Aged↗
The transcriptional activator Sp1, a novel autoantigen.
OBJECTIVE: To identify one nuclear autoantigenic protein within a complex of DNA binding proteins that bind to GC-rich sequences in Epstein-Barr virus and cellular DNA, and to describe the clinical characteristics of patients whose sera contained autoantibodies to this novel autoantigen. METHODS: Antibodies to autoantigen Sp1 were initially measured by an electrophoretic mobility shift assay to detect DNA binding proteins. Nuclear extracts and purified Sp1 protein were used in these assays. Recognition of the autoantigen by autoimmune sera was confirmed by immunoprecipitation and immunoblotting. RESULTS: The autoantigen was identified as Sp1. Anti-Sp1 was detected in sera from 8 (3%) of 230 patients. These sera contained antinuclear antibodies, but lacked antibodies to double-stranded DNA or to several extractable nuclear antigens. The patients whose sera contained antibodies to Sp1 were white women with fatigue, arthritis, Raynaud's phenomenon, malar rash, and photosensitivity. CONCLUSION: Sp1 is the first described example of an RNA polymerase II transcription activator as an autoantigen. The presence of Sp1 autoantibodies is associated with undifferentiated connective tissue disease.
Adult↗
Artificial evolution: a new path for artificial intelligence?
Recently there have been a number of proposals for the use of artificial evolution as a radically new approach to the development of control systems for autonomous robots. This paper explains the artificial evolution approach, using work at Sussex to illustrate it. The paper revolves around a case study on the concurrent evolution of control networks and visual sensor morphologies for a mobile robot. Wider intellectual issues surrounding the work are discussed, as is the use of more abstract evolutionary simulations as a new potentially useful tool in theoretical biology.
Artificial Intelligence↗
Congenital hypomyelinating neuropathy: a reversible case.
A boy was born at 39 weeks gestation with severe weakness and hypotonia, fractured femurs, poor suck and swallow, and absent deep tendon reflexes. Electrodiagnostic studies revealed marked slowing of motor nerve conduction velocities and normal muscle electrical activity with no evidence of acute denervation. Muscle biopsy showed mild type 2 fiber predominance, and sural nerve biopsy revealed large axons without myelin, and axons with insufficient amount of myelin for their diameter. There was no evidence of inflammation or demyelination. Gradual clinical improvement in tone and strength occurred in a cephalocaudal direction. By 4 months, motor nerve conduction velocities and clinical examination were normal apart from absent deep tendon reflexes. On review at 19 months, motor development and neurological examination were completely normal. Pathogenesis of this reversible pathologically documented case of congenital hypomyelinating neuropathy is unclear. No evidence was found for an inflammatory, toxic, metabolic, or demyelinating cause. Abnormal expression of a developmental gene, as in reversible cytochrome oxidase deficiency, may be a cause of this neuropathy.
Axons↗
Disordered sleep and noncompliance in a patient with end-stage renal disease.
Sleep disorders are relatively common in patients with end-stage renal disease, but the diagnosis may be difficult to establish because of the similarity of uremic symptoms to those of the sleep apnea syndrome. After excluding anatomic and metabolic disorders associated with excessive sleepiness and disordered breathing in sleep and after ensuring that the patient is receiving adequate dialysis, the sleep disorder should be diagnosed using polysomnography. Continuous positive pressure airway breathing is an effective treatment for hemodialysis patients with obstructive sleep apnea syndrome, but the use of this machinery requires patient compliance, as does the delivery of an adequate amount of dialysis. The difficulties adjusting to end-stage renal disease requiring dialysis can be multiplied by the coexistence of a sleep disorder that requires some ventilatory assistance at night; the case presented in this article characterizes precisely that circumstance.
Attitude to Health↗
Resolution of invasive central nervous system aspergillosis in a transplant recipient.
Central nervous system (CNS) aspergillosis carries a uniformly poor prognosis in bone marrow transplant recipients. Amphotericin B can be bound to lipid carriers leading to improvement of its therapeutic index. We describe the successful medical management of CNS aspergillosis in an allogeneic bone marrow transplant patient with administration of Amphotericin B Lipid Complex.
Adolescent↗
Infection and pathogenicity of chimeric simian-human immunodeficiency viruses in macaques: determinants of high virus loads and CD4 cell killing.
Chimeric simian-human immunodeficiency viruses (SHIVs) carrying envelope glycoproteins derived from a T cell-macrophage dual-tropic primary isolate (human immunodeficiency virus type 1 [HIV-1] strain DH12) were constructed. When inoculated into macaque monkeys, SHIV(MD14) carrying simian immunodeficiency virus-derived nef established significantly higher virus loads than did SHIV(MD1), which contains the HIV-1 nef gene. Three patterns of CD4 cell depletion were observed in infected monkeys: exponential and irreversible loss to undetectable levels within 10 weeks of infection; marked reduction during acute infection followed by partial recovery and stabilization (lasting from 10 weeks to > 1 year), with a later decline to undetectable levels in some animals; and a transient loss during acute infection. The induced immunodeficiency was accompanied by CD4 cell counts of < 50 cells/microL and was associated with Pneumocystis carinii pneumonia, cytomegalovirus meningoencephalitis, lymphoid depletion, and thymic atrophy.
Amino Acid Sequence↗
Cat-scratch disease in a patient undergoing haemodialysis.
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Adult↗
Modification of the Van Nes rotationplasty: report of a case.
Rotationplasty is a reconstructive option that provides a highly functional limb after tumor resection about the knee in the skeletally immature patient. However, in the very young child with large intramedullary extension of the tumor, leg length may not be possible to maintain. Described is a modification of the Van Nes rotationplasty that preserves the proximal tibial physis, allowing maximization of future growth.
Ankle Joint↗
IMAGE cDNA clones, UniGene clustering, and ACeDB: an integrated resource for expressed sequence information.
In this study we describe a new information resource that provides integrated access to information on IMAGE (integrated molecular analysis of genomes and their expression) cDNA library clones and derived expressed sequence tags (ESTs). We have developed an automated procedure that collates data from various public sources into a single ACeDB database. This database is a valuable tool for electronic cloning experiments and gene expression studies. It allows researchers to find information about cDNA libraries, plate addresses, insert sizes, and sequence data for IMAGE clones, the assignment of ESTs to UniGene clusters, and the chromosomal location of those genes in an efficient, graphically oriented manner.
Cloning, Molecular↗
Selective switch between latency and lytic replication of Kaposi's sarcoma herpesvirus and Epstein-Barr virus in dually infected body cavity lymphoma cells.
The BC-1 cell line, derived from a body cavity-based, B-cell lymphoma, is dually infected with Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). In these studies, the relationships between these two gammaherpesviruses and BC-1 cells were characterized and compared. Single-cell cloning experiments suggested that all BC-1 cells contain both genomes. In more than 98% of cells, both viruses were latent. The two viruses could be differentially induced into their lytic cycles by chemicals. EBV was activated into DNA replication and late-gene expression by the phorbol ester tetradecanoyl phorbol acetate (TPA). KSHV was induced into DNA replication and late-gene expression by n-butyrate. Amplification of both EBV and KSHV DNAs was inhibited by phosphonoacetic acid. Induction of the KSHV lytic cycle by n-butyrate was accompanied by the disappearance of host-cell beta-actin mRNA. Induction of EBV by TPA was not accompanied by such an effect on host-cell gene expression. Induction of the KSHV lytic cycle by n-butyrate was associated with the expression of several novel polypeptides. Recognition of one of these, p40, served as the basis of development of an assay for antibodies to KSHV in the sera of infected patients. BC-1 cells released infectious EBV; however, there was no evidence for the release of encapsidated KSHV genomes by BC-1 cells, even though n-butyrate-treated cells contained numerous intranuclear nucleocapsids. The differential inducibility of these two herpesviruses in the same cell line points to the importance of viral factors in the switch from latency to lytic cycle.
Animals↗
Late gene expression from the Epstein-Barr virus BcLF1 and BFRF3 promoters does not require DNA replication in cis.
Late gene expression follows and is dependent upon lytic replication of the viral genome. Although experimental evidence is lacking, lytic viral DNA replication is believed to remove modifications or binding factors from the genome which serve to repress late gene expression during latency or the early lytic cycle. We have developed a reporter assay to begin characterizing the mechanisms that regulate late gene expression in Epstein-Barr virus (EBV). In this model system, the activities of late promoter-reporter fusions are measured following transient transfection into tissue culture cells expressing EBV during different stages of the lytic cycle. This system faithfully recapitulates late expression patterns from the endogenous virus, implicating specific cis-active sequences in the control of late gene expression. In addition, these promoters respond only indirectly to the viral immediate-early transactivator, ZEBRA. This indirect response is mediated by other viral or virally induced activities downstream of ZEBRA in the lytic cascade. In this system, late gene expression is sensitive to inhibitors of the viral DNA polymerase such as phosphonoacetic acid, although the reporters lack a eukaryotic origin of replication and are not replicated under the assay conditions. Thus, replication of the transcriptional template is not a prerequisite for expression with late kinetics, a finding inconsistent with the current models which posit a cis-active relationship between lytic EBV DNA replication and late gene expression. Rather, analysis of this system has revealed a trans relationship between late gene expression and viral DNA replication and highlights the indirect and complex link between these two events.
Antigens, Viral↗