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Biomedical subjects

D E Levy

Publications and source records attributed to D E Levy.

At least 91 records · Page 5Linked to original sources
PubMed1988

Cells resistant to interferon are defective in activation of a promoter-binding factor.

Human cultured cell lines deficient in their ability to respond to type I interferon (IFN) fail to interrupt cellular proliferation or to induce an antiviral state following exposure to IFN alpha. Comparison of non-responsive Daudi and HeLa cell lines with IFN-responsive partner cell lines and examination of non-responsive Raji cells showed that the defective cell lines expressed type I IFN receptors of typical number and affinity and bound IFN equivalently compared to the normal cells. However, transcriptional induction of interferon-stimulated genes (ISGs) was greatly reduced and delayed in these cell lines, leading to reduced accumulation of ISG mRNA. Furthermore, the rapid activation of IFN-stimulated promoter binding factors whose appearance correlates with ISG transcriptional induction, did not occur in non-responsive cells. Thus, the primary defect of these cells leading to an impaired physiological response to IFN appears to be an inability to activate promoter-binding factors necessary to trigger ISG transcription, an obligate early step in antiviral and antiproliferative physiology.

Cell Line↗
PubMed1988

Transcriptional stimulation by CaPO4-DNA precipitates.

Genes in human chromosomes that normally require induction by alpha-interferon are activated after calcium phosphate (CaPO4) transfection, but not after DEAE-dextran transfection. The c-fos gene and genes stimulated by gamma-interferon also are affected by CaPO4-DNA precipitates, but the calcium ionophore A23187 stimulates only c-fos among this group. These results suggest caution not only in choosing gene transfer methods, but also in interpreting experiments aimed at understanding the role of second messengers in gene activation.

Calcimycin↗
PubMed1988

Identification and entry of the patient with acute cerebral infarction.

Although time has been recognized as a critical factor in the treatment of other arterial occlusive disorders, it has been an underemphasized variable in the treatment of acute stroke. Animal models of cerebral arterial occlusion have demonstrated that neurologic recovery is more likely the shorter the duration of occlusion. Complete recovery does not occur if the occlusion persists more than six hours. Prior trials have only rarely begun treatment within six hours of stroke onset. Over the past five years, we have participated in three stroke trials and have tried to identify factors that lead to delays in treatment. Factors that affect the time from stroke onset to arrival at the hospital include recognition of acute stroke by the patient, prehospital care personnel, and physicians. After arrival at the hospital, factors that can significantly delay treatment include the time to obtain computed tomography and the site of treatment (emergency department vs ICU). With proper attention, the time from patient arrival until treatment should be less than one hour. Future efforts should be directed toward reducing the time from stroke onset until arrival at the hospital. Education of the public, high-risk patients, prehospital care providers, and physicians may aid in these efforts.

Cerebral Infarction↗
PubMed1988

The investigational use of tPA for stroke.

Stroke therapy trials have historically allowed for late patient entry (ie, within 24 to 48 hours from stroke onset) despite evidence suggesting the importance of early intervention. Experimental studies of cerebral infarction suggest treatment may be most effective when begun within three hours and may be only marginally effective when begun after 12 hours. Lysis of an acute intra-arterial thrombus in the setting of thrombolytic therapy is also time dependent. We describe an ongoing dose-escalation study of tissue plasminogen activator (tPA) as ultra-early therapy for cerebral infarction. The protocol requires that hemorrhage be ruled out by computed tomography scan of the brain prior to tPA infusion, and the infusion must begin within 90 minutes of symptom onset. The two primary goals of the study are to assess safety and potential efficacy. Preliminary results from the study and the future of ultra-early stroke intervention are discussed.

Cerebral Hemorrhage↗
PubMed1988

Two interferon-induced nuclear factors bind a single promoter element in interferon-stimulated genes.

Nuclear proteins induced by interferon (IFN) treatment of human cells are capable of forming two specific complexes with DNA fragments containing the IFN-stimulated response element (ISRE). These two complexes, designated B2 and B3, are distinguished by differential migration in gel retardation assays. The factor that forms the B3 complex, termed IFN-stimulated gene factor 3 (ISGF-3), preexists in cells, is activated upon IFN treatment, and appears with kinetics paralleling those for transcriptional activation of IFN-stimulated genes. The factor that forms the B2 complex (ISGF-2) appears following a time lag after IFN treatment during which protein synthesis must occur. By extensive point mutagenesis of the ISREs from two IFN-stimulated promoters (ISG54 and ISG15), we demonstrate that the B2 and B3 complexes are formed by factors binding to the same DNA sequence. Mutations at this site decrease or eliminate transcriptional activation and impair binding of both ISGF-2 and ISGF-3. This analysis has shown that the ISGF-3 binding site is slightly broader than the ISGF-2 binding site, which is completely contained within the sequence necessary both for ISGF-3 binding and for transcriptional activation. The evidence strongly implicates ISGF-3 as the positive transcriptional regulator of IFN-stimulated genes.

Amino Acid Sequence↗
PubMed1988

Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control.

Human alpha- and beta-interferons (IFNs) stimulate rapid but transient increases in transcription from a set of previously quiescent genes. Protein synthesis is not required for initial stimulation, but duration of the response is limited to a few hours by a process requiring synthesis of new proteins. An IFN-stimulated response element (ISRE) was identified 5' to an inducible gene by deletion analysis and point mutagenesis, and sequence comparisons with other promoters defined the consensus element YAGTTTC(A/T)YTTTYCC. Two classes of IFN-inducible nuclear factors were found that bind to the ISRE. The most rapidly induced factor appeared without new protein synthesis, whereas a second factor required active protein synthesis for its appearance and maintenance. The kinetics of appearance and loss of these binding activities correlate with the activation and repression of IFN-stimulated genes. These different IFN-activated or induced factors may bind sequentially to the same essential promoter element to first increase and then repress transcription.

Base Sequence↗
PubMed1988

How transient are transient ischemic attacks?

Information on 1,343 hospitalized patients in the Cornell Neurology Database with final diagnoses of transient ischemic attacks (TIA), reversible ischemic neurologic deficits (RIND), or ischemic stroke was examined in order to determine the duration of ischemic deficits. Episodes resolved within the first 24 hours (classic definition of TIA) in 382 of the patients (28.4%) and between days 1 and 7 (consistent with RIND) in 34 (2.5%). In 191 of the 382 patients with traditionally-defined TIAs (50.0%), episodes lasted less than 30 minutes, and in another 37 (9.7%), from 30 to 60 minutes. Of 1,115 patients with deficits lasting at least 60 minutes, only 154 (13.8%) resolved within 24 hours and could thus be considered to have had a TIA. Resolution within the next hour occurred in only 39 of 1,152 patients (3.4%) with a deficit at 30 minutes, 21 of 1,115 patients (1.9%) with a deficit at 60 minutes, 19 of 1,113 patients (1.7%) with a deficit at 90 minutes, and 16 of 1,094 patients (1.5%) with a deficit at 120 minutes. The data suggest that as currently managed, patients with a deficit persisting at least 60 minutes have less than a 2% chance of resolving spontaneously during any subsequent 1-hour period. Rapid resolution after instituting a new treatment in relatively few additional patients would suggest a therapeutic effect, even in a nonrandomized trial.

Aged↗
PubMed1988

Transient CNS deficits: a common, benign syndrome in young adults.

The incidence of transient (less than 24 hour) neurologic loss was evaluated from a survey returned by 80/87 members of Cornell's Department of Neurology. Transient CNS dysfunction was reported by 25/80 (32%; 95% confidence interval, 21 to 44%). In most (15) only vision was affected, but ten (13%; 6 to 23%) reported nonvisual deficits. In nine of these ten, loss of power, balance, or coordination was noted, sometimes with other symptoms (visual in two), and the tenth subject had speech arrest. Seven of the ten had more than one episode. Episodes in these ten individuals began at age less than 30 in four, 30 to 34 in five, 35 to 39 in none, and 40 to 44 in one. The reported frequency of migraine was nonsignificantly higher in patients with nonvisual (4/10, 40%) or visual (7/15, 47%) episodes than in respondents without episodes (12/55, 22%; chi 2(2) = 4.3). Except for inflammatory bowel disease in one respondent, no obvious cause of the nonvisual episodes was evident from follow-up structured interviews. Five of the ten with nonvisual loss and eight of the 15 with isolated visual symptoms thus had no obvious cause for their episodes. Follow-up is limited to a median of 5 years, but none of the 25 has had any residual deficit or chronic neurologic disorder, suggesting that these relatively common episodes of CNS deficit are benign. As new, hyperacute stroke therapies emerge, efforts to distinguish these episodes from true, early strokes will become increasingly important.

Adult↗
PubMed1987

Differences in cerebral blood flow and glucose utilization in vegetative versus locked-in patients.

Positron emission tomographic studies of regional cerebral metabolic rate for glucose (rCMRGlc) and cerebral blood flow were performed in 7 vegetative and 3 locked-in patients to determine objectively the level of brain function underlying these clinical states. Cortical gray rCMRGlc in the vegetative patients was 2.73 +/- 0.13 (mean +/- SEM) mg/100 gm/min, less than half the normal value of 6.82 +/- 0.23 (p less than 0.001). Cerebral blood flow exhibited similar but more variable reductions. By contrast, cortical rCMRGlc in the locked-in patients was 5.08 +/- 0.69, a 25% reduction (p less than 0.02) from normal. The massive reduction in vegetative rCMRGlc involved not only the cerebral cortex but also the basal nuclei and cerebellum. Such metabolic hypoactivity has precedent only in deep anesthesia and supports clinical evidence that cerebral cognitive function is lost in the vegetative state, leaving a body that can no longer think or experience pain.

Adolescent↗
PubMed1987

The 3' long terminal repeat of a transcribed yet defective endogenous retroviral sequence is a competent promoter of transcription.

Although actively transcribed and present as multiple genomic copies, a distinct class of endogenous murine leukemia virus-related sequence does not give rise to infectious virus. Since the long terminal repeat at the 3' terminus provides the transcriptional start site after reintegration, we determined the structure and potential promoter activity of that sequence obtained from cDNA of endogenous retroviral transcripts. These studies demonstrate that the distinctive 3' long terminal repeat sequence of these transcripts could serve as an effective promoter of transcription and, therefore, may not be the primary defect in the infectious cycle of retroviral replication but may result in the propagation of these endogenous retroviral sequences in the genome as retrotransposons.

Animals↗
PubMed1985

Genetic elements used for a murine lupus anti-DNA autoantibody are closely related to those for antibodies to exogenous antigens.

The mRNAs encoding heavy and light chains of a hybridoma-derived monoclonal IgM kappa anti-DNA autoantibody from lupus-prone MRL/Mp-lpr/lpr mice (Ighj) have been transcribed into cDNA copies and molecularly cloned, and their complete nucleotide sequences have been determined. The mRNA for the heavy chain variable region, including leader peptide and 5' untranslated region, is transcribed from a heavy chain variable region (VH) gene closely related (and possibly allelic) to VH genes of the C57BL/6 (Ighb) nitrophenyl antibody family. The deduced amino acid sequence corresponding to the light chain variable region of this autoantibody shows extensive similarities with non-autoantibody molecules of the V kappa 1 group, suggesting a common variable gene origin. The joining segments, constant regions, and 3' untranslated regions of both the heavy and light chain mRNAs are nearly identical to corresponding sequences of non-autoantibodies from normal mice. Our findings suggest that this anti-DNA autoantibody originated from the same germline repertoire as antibodies to exogenous antigens.

Animals↗
PubMed1985

Predicting outcome from hypoxic-ischemic coma.

Outcome from coma caused by cerebral hypoxia-ischemia (eg, cardiac arrest) was compared with serial neurological findings in 210 patients. Thirteen percent of patients regained independent function at some point during the first postarrest year. Computer application of new multivariate techniques to the prospectively observed findings generated easily utilized rules that classified patients by likely outcome. At the time of initial examination, 52 patients (one fourth of the total population) had absent pupillary light reflexes, and none of these patients ever regained independent daily function. By contrast, the initial presence of pupillary light reflexes, the development of spontaneous eye movements that were roving conjugate or better, and the findings of extensor, flexor, or withdrawal responses to pain identified a smaller group of 27 patients, 11 (41%) of whom regained independence in their daily lives. By 24 hours after onset, 93 poor-outcome patients were identified by motor responses that were absent, extensor, or flexor and by spontaneous eye movements that were neither orienting nor roving conjugate; only one regained independent function. This contrasts with recovery in 19 (63%) of 30 patients who at that time showed improvement in their eye-opening responses and obeyed commands or had motor responses that were withdrawal or localizing. Similarly simple rules distinguished between good- and poor-prognosis patients on postarrest days 3, 7, and 14.

Adult↗
PubMed1985

The Gv-1 locus coordinately regulates the expression of multiple endogenous murine retroviruses.

The analysis of the normal expression of endogenous retroviral sequences in congenic 129 GIX+ and GIX- mouse strains suggests the action of a regulatory element, encoded by Gv-1, functioning in trans to control the expression of these sequences. At steady state, the abundance of polyadenylated retroviral transcripts of different length cosegregates with the Gv-1 genotype. The presence of low but detectable quantities of these transcripts in antigen-negative mice indicates however, that Gv-1 may be distinct from the structural genes encoding retroviral proteins. We report here that retroviral transcripts, derived from distinct proviruses, are expressed in a tissue-specific manner and are coordinately regulated by the Gv-1 locus. The structure of several of the abundant transcripts demonstrates further that they are transcribed from independent defective endogenous proviral genomes exhibiting extensive deletions of env coding regions as well as modified U3 regions distinct from those found in exogenous retroviral transcripts.

Animals↗
PubMed1985

Normal expression of polymorphic endogenous retroviral RNA containing segments identical to mink cell focus-forming virus.

In the absence of infectious virus, strains of mice express polyadenylated RNA transcripts homologous to the genome of murine leukemia virus. In addition to transcripts consistent with full-length and spliced env retroviral RNAs, several unique RNA species which lack the env sequence accumulate in a tissue-specific manner. These RNA species are presumed to be transcribed from endogenous retroviral sequences that constitute the bulk of the murine leukemia virus-related sequences in the murine genome. To determine the relationship of these RNA transcripts to infectious murine leukemia virus and the precise structural basis of the heterogeneity observed for the env-lacking transcripts, we isolated and sequenced cDNA recombinants representing the RNAs expressed in strain 129 GIX+ mice. Comparisons of the nucleotide sequences demonstrated that the endogenous retroviral transcripts differed in pol, p15E, and R-peptide regions by single nucleotide changes. In contrast, the gp70-coding regions of two cDNA clones derived from epididymis and liver were completely homologous over a 599-nucleotide overlapping sequence. The structures of env-lacking transcripts were examined in two independent cDNA clones, and each was found to contain a different deletion that was potentially mediated by seven-base pair direct repeats in the intact sequence. The extensive sequence homology between cDNAs allowed construction of a cumulative sequence map of the 3' end of an intact endogenous retroviral transcript. A comparison of this sequence with infectious ecotropic and mink cell focus-forming viruses revealed that the endogenous transcripts are highly homologous with the substituted portions of leukemogenic mink cell focus-forming viruses and therefore further define the boundaries of recombination required to generate these viruses.

Amino Acid Sequence↗
PubMed1983

Increased damage after ischemic stroke in patients with hyperglycemia with or without established diabetes mellitus.

Animal experiments employing controlled degrees of cerebral ischemia have demonstrated that elevated blood-brain glucose concentrations greatly enhance the extent and degree of subsequent brain damage. The question of whether or not a similar relationship applies in man was examined by retrospectively segregating patients admitted with the diagnosis of ischemic stroke into diabetic (n = 35) and nondiabetic (n = 72) groups. A separate nondiabetic population with ischemic stroke was prospectively analyzed by dividing patients into those with an admission blood glucose level above (n = 14) or below (n = 17) 120 mg/dl. The neurologic status at discharge was used to stratify outcome as good, fair, or poor in the retrospective study. The ability or inability to return to work was used to separate good and poor outcomes in the prospective study. Neurologic outcome in diabetic patients with stroke was significantly worse (p less than 0.05) than in nondiabetic patients, and the diabetic patients had a greater (p less than 0.05) number of stroke-related deaths. In the prospective study, neurologic outcome also was worse with high blood sugar levels, only 43 percent of the patients with blood glucose values above 120 mg/dl returned to work, whereas 76 percent of those with lower blood sugar values regained employment (p = 0.061).

Aged↗