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Biomedical subjects

M Levine

Publications and source records attributed to M Levine.

At least 253 records · Page 14Linked to original sources
PubMed1993

Acquired sideroblastic anaemia during treatment of Wilson's disease with triethylene tetramine dihydrochloride.

We report one case of acquired sideroblastic anaemia in a patient treated for Wilson's disease with triethylene tetramine dihydrochloride (TTH). No other cause of acquired sideroblastic anaemia was found, and neither iron nor pyridoxine therapy could correct this anaemia. In contrast, decreasing the dose of TTH led to disappearance of ringed sideroblasts. Thus TTH should be added as a further cause of secondary acquired sideroblastic anaemia. The pathophysiology of this finding, probably linked to an abnormality of mitochondrial iron metabolism, is briefly discussed.

Adolescent↗
PubMed1993

Bacteria reactive to plaque-toxin-neutralizing monoclonal antibodies are related to the severity of gingivitis at the sampled site.

Certain monoclonal antibodies (Mabs) neutralize the inhibition of HL60 cell growth by bacterial plaque extracts. The aim of this study was to enumerate and identify the bacteria reactive to these Mabs at sites where periodontal disease was measured by gingival index, pocket depth and attachment loss. The bacterial colonies were grown on blood agar and the colonies counted directly and after immunoblotting. Sites that bled on probing (n = 15) had a mean of 3.35% Mab-positive colonies (SEM = 0.52%) and sites that did not bleed (n = 9) had a mean of 1.61% (SEM = 0.41%). The percentage of Mab-positive colonies also correlated with gingival index but not with the total number of colonies sampled, attachment loss or pocket depth. Antigen was expressed by 4 genera: strains of Streptococcus sanguis and/or Eikenella corrodens (8 sites), Staphylococcus epidermidis (4 sites) and Corynebacterium minutissimus (1 site). The results suggest that the antigens detected on these bacteria by the Mabs may be processed to form toxins and maintain gingivitis by irritating the surrounding cells.

Adult↗
PubMed1993

The RR1 gene of herpes simplex virus type 1 is uniquely trans activated by ICP0 during infection.

As has been demonstrated for herpes simplex virus type 2, we show in this report that the herpes simplex virus type 1 ribonucleotide reductase large subunit (RR1) gene is trans activated in transient transfection assays by VP16 and ICP0 but not by ICP4. Deletion analysis demonstrated that responsiveness to induction to VP16 resides in an octamer/TAATGARAT sequence of the RR1 promoter and that the TATA box alone is sufficient to provide induction by ICP0. The induction of the RR1 gene by ICP0 but not by ICP4 suggested that it might be possible to identify the cis-acting element(s) responsive to ICP4 in an ICP4-inducible promoter. To this end, a series of chimeric promoters containing various portions of the regulatory sequences of the RR1 promoter and thymidine kinase (TK) promoter were constructed. The TK promoter is trans activated by both ICP0 and ICP4 in transient transfection assays and by ICP4 in infection. The data show that replacing the RR1 TATA region with the TK TATA region permits ICP4 inducibility even if the rest of the RR1 promoter elements remain intact. To test whether the RR1 gene is induced by ICP0 during infection, four mutant viruses were constructed. (i) TAATGARAT+ has the wild-type RR1 promoter driving chloramphenicol acetyltransferase (CAT) and the RR2 promoter driving the lacZ gene. The RR2 gene codes for the small subunit of the ribonucleotide reductase and is expressed as a beta gene. (ii) TAATGARAT- has a triple-base change in the octamer/TAATGARAT element which renders it unresponsive to VP16 trans activation, eliminating that portion of the activation of the RR1 gene. (iii) TAATGARAT- delta alpha 0 has a deletion of the alpha 0 gene. (iv) TAATGARAT- delta alpha 4 has a deletion of the alpha 4 gene. Infections were carried out in Vero cells at a multiplicity of infection of 10 per cell; cells were assayed for CAT and beta-galactosidase (beta-Gal) activities and for virus yields. The first two infections gave strong CAT and beta-Gal activities and high yields of progeny virus. Infection with the third virus showed no CAT activity but did produce high levels of beta-Gal activity and virus progeny. The fourth infection resulted in strong CAT activity but no beta-Gal activity or progeny virus. The data demonstrated that the RR1 promoter was activated in the absence of ICP4 but not in the absence of ICP0 in these infections.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Syncytium-inducing mutations localize to two discrete regions within the cytoplasmic domain of herpes simplex virus type 1 glycoprotein B.

Herpes simplex virus type 1 glycoprotein B (gB) is essential for virus entry, an event involving fusion of the virus envelope with the cell surface membrane, and virus-induced cell-cell fusion, resulting in polykaryocyte, or syncytium, formation. The experiments described in this report employed a random mutagenesis strategy to develop a more complete genetic map of mutations resulting in the syn mutant phenotype. The results indicate that syn mutations occur within two essential and highly conserved hydrophilic, alpha-helical regions of the gB cytoplasmic domain. Region I is immediately proximal to the transmembrane domain and includes residues R796 to E816/817. Region II is localized centrally in the cytoplasmic domain and includes residues A855 and R858. Positively charged residues were particularly affected in both regions, suggesting that charge interactions may be required to suppress the syn mutant phenotype. No syn mutations were identified within the transmembrane domain. A virus containing a rate of entry (roe) mutation at residue A851, either within or immediately proximal to syn region II, was isolated. Since roe mutations have also been discovered in the external domain of gB, it appears likely that the external and cytoplasmic domains cooperate in virus penetration. Moreover, the observation that both roe and syn mutations occur in the cytoplasmic domain further suggests that gB functions in an analogous manner in both membrane fusion events. It might be predicted from these observations that membrane fusion involves transduction of a fusion signal along the gB molecule through the transmembrane domain. Communication between the external and cytoplasmic domain may thus be required for gB-mediated membrane fusion events.

Amino Acid Sequence↗
PubMed1993

Comparative effects of bicarbonate, tris-(hydroxymethyl)aminomethane and dichloroacetate in newborn swine with normoxic lactic acidosis.

A total of 20 newborn piglets age 11.5 +/- 0.3 days and weighing 3.7 +/- 0.1 kg were studied under pentobarbital anesthesia. After stabilization following surgical procedures, baseline values for blood gases, base excess (BE), heart rate (HR), aortic pressure (AoP), left-ventricular contractility (LV dP/dtmax), carotid artery flow (CarF) and renal artery flow (RenF) were measured and normal lactic acid 0.2 ml/kg was infused over 1 h and the same parameters repeated. Then sodium bicarbonate (BC, n = 8), Tris-(hydroxymethyl)aminomethane (THAM, n = 6) or dichloroacetate (DCA, n = 6) were infused over 1 h. The doses of BC and THAM were calculated from the standard formula: Mmol = Base deficit x kg x 0.3. DCA was given at a dose of 300 mg/kg. Following lactic acid infusion, pH was 7.00 +/- 0.4 and BE was -20.6 +/- 1.2. Acidosis was associated with a significant (p < 0.05) increase in AoP (+18.6 +/- 7.4%) and decreases in HR (-13.9 +/- 2.7%) and RenF (-43.8 +/- 10.4%). Values of dP/dtmax and CarF were higher during acidosis in all but 3 animals. Following infusion of alkalizing agents pH and BE values were highest with BC and lowest with DCA and the differences were statistically significant (p < or = 0.05). In general, all three alkalizing agents reversed, in part or completely, the changes in cardiovascular parameters associated with acidosis so that following alkali infusion the changes were not statistically significant when compared to baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis, Lactic↗
PubMed1993

Meaningful interpretation of risk reduction from clinical drug trials.

OBJECTIVE: To illustrate the concepts of relative and absolute risk reduction, and by example, present and discuss the results of prevention trials that have evaluated the impact of drug therapy on cardiovascular disease. Additional approaches to evaluating the results of prevention trials are also presented. DATA SOURCES: Data were gathered from eight frequently quoted major cardiovascular intervention trials. CONCLUSIONS: Reference to large reductions in relative risk in review papers, newspapers, and at professional meetings can lead to false expectations among clinicians and patients regarding the potential impact of the treatment in individual patients. When making decisions about preventive drug therapy, clinicians are encouraged to examine measures other than relative risk reduction and to include the patient in the decision process. Educators should emphasize these other measures of outcome and not rely solely on relative risk reduction in discussing particular areas of therapeutics.

Canada↗
PubMed1993

Polyvinylchloride containers do not influence the hemodynamic response to intravenous nitroglycerin.

In-vitro evidence of sorption of nitroglycerin (NTG) to polyvinylchloride (PVC) containers suggests that these containers may deliver less nitroglycerin to the patient than glass containers. Sorption of NTG to the PVC container may result in hemodynamic changes in the patient when a fresh solution of NTG is prepared and administered from a PVC container. This study was designed as a prospective, randomized trial to measure the hemodynamic response in patients receiving NTG in glass or PVC containers, during the first hour after a container exchange. Patients admitted to the coronary care unit in a University hospital with chest pain considered to be due to unstable angina or acute myocardial infarction were eligible. Patients who received other vasoactive drugs within one hour of container exchanges were excluded. Systolic and diastolic blood pressures, and heart rate were measured at baseline and at intervals for one hour following a container exchange. Twenty patients completed the study. There were no significant changes with time in either group (ANOVA, p > 0.05) with respect to systolic, diastolic, or mean arterial blood pressure or heart rate. No chest pain occurred during the 60 minutes following the container exchange in either group. We conclude that NTG can be administered safely and effectively in PVC containers to patients with unstable angina or acute myocardial infarction. However, it remains possible that changes in hemodynamic status could occur in patients on NTG if a change in container type (i.e., from PVC to glass or vice versa) is made during the course of therapy.

Adult↗
PubMed1993

Spacing ensures autonomous expression of different stripe enhancers in the even-skipped promoter.

The even-skipped (eve) promoter contains a series of enhancers that control the expression of different segmentation stripes in the Drosophila embryo. The stripe 3 enhancer is located 1.7 kb upstream of the stripe 2 enhancer. Here we demonstrate that these enhancers must be physically separated by a minimum distance for proper stripe expression. When they are directly coupled in either orientation, the enhancers generate abnormal patterns of expression in the early embryo. For example, the levels of stripe 2 expression are augmented and there is a posterior expansion of the pattern when the stripe 3 enhancer is positioned immediately upstream of the stripe 2 enhancer. Despite this spacing requirement, the order of the enhancers within the eve promoter can be reversed without affecting the normal expression pattern. These results suggest that spacing maintains the autonomous activities of the stripe enhancers and that interactions between enhancers can generate novel patterns of gene expression.

Animals↗
PubMed1993

Antibody avidity measurement and immune complex dissociation for serological diagnosis of vertically acquired HIV-1 infection.

Differences in avidity between HIV-1 antibodies transmitted passively and antibodies synthesized by children born to HIV-1-positive mothers can be measured using a commercially available competitive enzyme immunoassay kit. The avidity determination method is based on the competition between an anti-HIV-1-peroxidase-labeled antibody at a stable and known concentration and the anti-HIV-1 antibodies (IgA, IgG, IgM) present in the child's serum at various and increasing dilutions. The shift in the competition/dilution curves between serum samples taken at the third and the sixth month of the child's life showed either the loss or the synthesis of anti-HIV-1 antibodies. The antibody avidity determination combined with a test detecting free or complexed p24 antigen is a workable and inexpensive serological method for the follow-up of children born to seropositive mothers. Combining these two complementary methods, HIV-1 infection has been established at 6 months of age in 13 of 13 infants, and positive results were confirmed by coculture and by PCR. An HIV-1 infection was excluded at 6 months of age in 17 of 17 infants, results otherwise confirmed by virological and clinical follow-up. These new and convenient approaches to the diagnosis of vertically acquired HIV-1 could be used worldwide, including in developing countries.

AIDS Serodiagnosis↗
PubMed1992

Inhibition of ascorbic acid transport in human neutrophils by glucose.

Because of the structural similarity between glucose and ascorbic acid, we investigated the effect of glucose on uptake and accumulation of ascorbic acid in isolated normal human neutrophils. Ascorbic acid accumulation was determined using high-performance liquid chromatography with coulometric electrochemical detection, in conjunction with liquid scintillation spectrometry. Ascorbic acid accumulation in neutrophils is mediated by a high and a low affinity transport activity. In neutrophils from different volunteers, glucose inhibited uptake and accumulation of ascorbic acid by both transport activities 3-9-fold. The mechanism of inhibition was different for each transport activity: inhibition of the high affinity transport activity was noncompetitive, while inhibition of the low affinity activity was competitive. Glucose-induced inhibition of both ascorbic acid transport activities occurred in neutrophils of all donors tested and was fully reversible. Although the mechanism of ascorbic acid accumulation appeared to be different than that for glucose transport, other monosaccharides and glucose transport inhibitors also inhibited ascorbic acid accumulation. These are the first data to suggest that ascorbic acid accumulation in neutrophils can be regulated by compounds of similar structure.

Adult↗
PubMed1992

Quality-of-life assessment: patient compliance with questionnaire completion.

BACKGROUND: Previous investigators have found that compliance with quality-of-life data collection on cancer clinical trials is poor. There is general belief that collecting complete quality-of-life data is at present an unachievable goal. PURPOSE: We assessed the completeness of quality-of-life data collection on trials instituted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG), since incorporation of quality-of-life outcomes into trials became mandatory for the group. METHODS: Data from three NCIC CTG trials in which quality of life was a study end point were examined to determine the extent to which protocol specifications were met with respect to questionnaire completion. Two of the studies examined adjuvant therapies, and one examined anti-emetics. In two trials, the quality-of-life questionnaire of the European Organization for Research and Treatment of Cancer was used; in the other, the Breast Cancer Chemotherapy Questionnaire. RESULTS: Patient compliance with questionnaire completion was unexpectedly high: More than 95% of the scheduled questionnaires were returned, and more than 99% of the questions were answered. CONCLUSIONS: We attribute this success to a comprehensive set of measures taken to enhance compliance on these studies. Which of these measures was most contributory requires further investigation, as does the issue of whether similar results can be obtained in other circumstances. IMPLICATIONS: It seems that the commonly held belief that quality-of-life data cannot be successfully collected in multicenter cancer trials is incorrect.

Clinical Trials as Topic↗
PubMed1992

Individual dorsal morphogen binding sites mediate activation and repression in the Drosophila embryo.

The dorsal (dl) morphogen gradient is responsible for initiating the differentiation of the mesoderm, neuroectoderm and dorsal ectoderm in the Drosophila embryo. dl encodes a sequence-specific DNA binding protein that belongs to the Rel family of transcription factors. Previous studies have shown that dl activates the mesoderm determinant twist (twi); here we use a combination of site-directed mutagenesis and P-transformation assays to demonstrate that it also functions as a direct transcriptional repressor of a second target gene, zerknüllt (zen). By exchanging dl binding sites between the promoters we show that activator sites from twi can mediate repression when placed in the context of the zen promoter, and that repressor sites from zen can mediate activation in the context of the twi promoter. This represents the first demonstration that common binding sites for any DNA binding protein can mediate both activation and repression in a developing embryo. Evidence is also presented that the affinities of dl binding sites are important for the efficiency of repression, but are not the sole determinants of the threshold response to the dl gradient.

Animals↗
PubMed1992

Regulation of even-skipped stripe 2 in the Drosophila embryo.

In an effort to determine how crude gradients of transcriptional activators and repressors specify sharp stripes of gene expression in the early embryo, we have conducted a detailed study of even-skipped (eve) stripe 2. A combination of promoter fusions and P-transformation assays were used to show that a 480 bp region of the eve promoter is both necessary and sufficient to direct a stripe of LacZ expression within the limits of the endogenous eve stripe 2. The maternal morphogen bicoid (bcd) and the gap proteins hunchback (hb), Kruppel (Kr) and giant (gt) all bind with high affinity to closely linked sites within this small promoter element. Activation appears to depend on cooperative interactions among bcd and hb proteins, since disrupting single binding sites cause catastrophic reductions in expression. gt is directly involved in the formation of the anterior border, although additional repressors may participate in this process. Forming the posterior border of the stripe involves a delicate balance between limiting amounts of the bcd activator and the Kr repressor. We propose that the clustering of activator and repressor binding sites in the stripe 2 element is required to bring these weakly interacting regulatory factors into close apposition so that they can function both cooperatively and synergistically to control transcription.

Animals↗
PubMed1992

Hemostatic alterations in cancer patients.

Nearly all patients with cancer manifest laboratory evidence of hypercoagulability and some develop clinical thromboembolic disease (TED). Routine laboratory studies of blood coagulation have been performed in several large, prospective trials of the use of anticoagulant drugs in cancer treatment. The results of these studies, as well as data from several smaller studies of more sensitive tests of hypercoagulability [e.g. fibrinopeptide A (FPA); thrombin-antithrombin (TAT) complexes; prothrombin fragment F1 + 2)], indicate that the levels of some clotting proteins parallel disease activity. However, no studies of sound methodologic design have yet been performed to indicate that any of these tests of blood coagulation can serve as adequate predictors of TED in patients with cancer. In addition to the important role played by tumor-related procoagulants, several other mechanisms may be involved in the pathogenesis of thromboembolic events in patients with cancer, including stasis and endothelial damage. Considerable variability in the relative importance of these mechanisms in the pathogenesis of TED may exist among patients with different types of cancer. The risk for TED associated with surgical procedures in cancer patients is substantial and prophylactic antithrombotic therapy should be considered for most of these patients. Chemotherapy and hormonal therapy of cancer probably increases the likelihood of TED, particularly in those subjects with indwelling venous catheters. This risk has been particularly well-studied in patients with breast cancer treated with tamoxifen plus cytotoxic drugs. The pathogenic mechanisms may be complex but vascular injury is likely as a proximate cause of venous access catheter thrombosis and can be prevented with low dose coumadin therapy. The utility of low dose coumadin anticoagulation in reducing the risk for TED during breast cancer treatment is unknown but is currently being tested in a large, multiinstitutional study. Since chronic coumadin anticoagulation of cancer patients, and single pulse dose heparin prior to intravenous chemotherapy, both prevent thrombin generation, these agents may be of use in reducing the risk of chemotherapy-associated thrombosis. Prophylactic anticoagulation should be considered for high risk patients.

Antineoplastic Agents↗