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Biomedical subjects

R Goldman

Publications and source records attributed to R Goldman.

At least 37 records · Page 2Linked to original sources
PubMed1999

Myeloperoxidase-catalyzed redox-cycling of phenol promotes lipid peroxidation and thiol oxidation in HL-60 cells.

Various types of cancer occur in peroxidase-rich target tissues of animals exposed to aryl alcohols and amines. Unlike biotransformation by cytochrome P450 enzymes, peroxidases activate most substrates by one-electron oxidation via radical intermediates. This work analyzed the peroxidase-dependent formation of phenoxyl radicals in HL-60 cells and its contribution to cytotoxicity and genotoxicity. The results showed that myeloperoxidase-catalyzed redox cycling of phenol in HL-60 cells led to intracellular formation of glutathionyl radicals detected as GS-DMPO nitrone. Formation of thiyl radicals was accompanied by rapid oxidation of glutathione and protein-thiols. Analysis of protein sulfhydryls by SDS-PAGE revealed a significant oxidation of protein SH-groups in HL-60 cells incubated in the presence of phenol/H2O2 that was inhibited by cyanide and azide. Additionally, cyanide- and azide-sensitive generation of EPR-detectable ascorbate radicals was observed during incubation of HL-60 cell homogenates in the presence of ascorbate and H2O2. Oxidation of thiols required addition of H2O2 and was inhibited by pretreatment of cells with the inhibitor of heme synthesis, succinylacetone. Radical-driven oxidation of thiols was accompanied by a trend toward increased content of 8-oxo-7,8-dihydro-2'-deoxyguanosine in the DNA of HL-60 cells. Membrane phospholipids were also sensitive to radical-driven oxidation as evidenced by a sensitive fluorescence HPLC-assay based on metabolic labeling of phospholipids with oxidation-sensitive cis-parinaric acid. Phenol enhanced H2O2-dependent oxidation of all classes of phospholipids including cardiolipin, but did not oxidize parinaric acid-labeled lipids without addition of H2O2. Induction of a significant hypodiploid cell population, an indication of apoptosis, was detected after exposure to H2O2 and was slightly but consistently and significantly higher after exposure to H2O2/phenol. The clonogenicity of HL-60 cells decreased to the same extent after exposure to H2O2 or H2O2/phenol. Treatment of HL-60 cells with either H2O2 or H2O2/phenol at concentrations adequate for lipid peroxidation did not cause a detectable increase in chromosomal breaks. Detection of thiyl radicals as well as rapid oxidation of thiols and phospholipids in viable HL-60 cells provide strong evidence for redox cycling of phenol in this bone marrow-derived cell line.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1999

Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder.

OBJECTIVE: This study examined the treatment response of patients with first-episode schizophrenia and schizoaffective disorder and potential predictors of response. METHOD: First-episode patients were assessed on measures of psychopathology, cognition, social functioning, and biological parameters and treated according to a standardized algorithm. RESULTS: One hundred eighteen patients (52% male, mean age 25.2 years) entered the study. The cumulative percentage of patients responding by 1 year was 87%; the median time to response was 9 weeks. The following variables were significantly associated with less likelihood of response to treatment: male sex, obstetric complications, more severe hallucinations and delusions, poorer attention at baseline, and the development of parkinsonism during antipsychotic treatment. Variables not significantly related to treatment response were diagnosis (schizophrenia versus schizoaffective disorder), premorbid functioning, duration of psychotic symptoms prior to study entry, baseline disorganization, negative and depressive symptoms, baseline motor function, akathisia and dystonia during treatment, growth hormone and homovanillic acid measures, psychotic symptom activation to methylphenidate, and magnetic resonance measures. CONCLUSIONS: Patients with first-episode schizophrenia and schizoaffective disorder have high rates of response to antipsychotic treatment; there are specific clinical and pathobiologic predictors of response.

Adult↗
PubMed1998

Usefulness of intravenous metoprolol to prevent syncope induced by head-up tilt.

Intravenous metoprolol was found to be significantly more effective than placebo in preventing head-up tilt-table induced neurally mediated syncope. The reproducibility of acute tilt-table testing is only 63% and suggests caution in the interpretation of acute drug testing during tilt-table studies.

Adrenergic beta-Antagonists↗
PubMed1998

[Drowning in Israel--1990-1992].

There are no epidemiological studies of drowning in Israel in the scientific literature, despite prominent reports in the media. We analyzed the extent of mortality from drowning in Israel during 1990-92, attempting to identify and characterize groups at high risk, and to determine trends and differences between Israel and other countries. Computerized death certificate files were provided by the Israel government Central Bureau of Statistics; deaths from drowning were included among external causes codes E-830, 832, E-910, E-954, E-964, E-984. In Israel, as in the United States, mortality from drowning is the fourth cause of death among all unintentional causes, and the second cause in age-groups 1-24, ranking after transport accidents. During 1990-92 there were 1.2 drownings a year/100,000 population. The highest rates were found among young non-Jews 15-24 years old (7.8/100,000) and among elderly Jews (3.5/100,000). Unintentional drowning accounted for 89% of all deaths; while about 10% were defined as suicides. Males had a rate almost 3 times greater than females, and the among Arabs was 2.4 times greater than among Jews. The 1990-92 drowning rate was slightly lower than in previous years. Drowning rates in Israel are lower than in the United States, except in the elderly. Apparently the principal reason for this difference is difference in sites of drowning. In Israel most drownings occur in the sea, so site data are unavailable for international comparisons. Careful consideration of the categories (E-codes) included in the rates, and of local registration procedures, is necessary for international comparisons. Foreign workers, tourists and other nonresidents are not included in national vital statistics. But estimations based on Ministry of Interior sources show that foreign workers (most, recent arrivals) during the last few years are an extremely high risk group. Population-based drowning rates are not an accurate estimation of drowning risk, since universal exposure to the "opportunity to drown" is assumed.

Adolescent↗
PubMed1998

Generation of reactive oxygen species in a human keratinocyte cell line: role of calcium.

In the human keratinocyte cell line HaCaT, reactive oxygen species (ROS) were generated in a dose- and time-dependent manner in response to epidermal growth factor (EGF), bradykinin, thapsigargin, and the Ca(2+)-ionophore A23187, agonists that interact with different primary cell targets. ROS formation was assessed by both chemiluminescence- and fluorescence-based methods. The ROS evoked by EGF and bradykinin decayed within 8 and 4 min, respectively, this transient effect resulting probably from down-regulation of the specific agonist receptors or dissipation of the secondary signals. In contrast, the response to thapsigargin and A23187 was sustained for at least 15 min. Extracellular Ca2+ and a rise in intracellular Ca2+ concentration ([Ca2+]i) proved essential for ROS production. Chelation by BAPTA suppressed ROS formation. Direct measurement of [Ca2+]i using fura fluorescence revealed that EGF and bradykinin evoked a modest, transient [Ca2+]i elevation of less than twofold, whereas with thapsigargin and A23187 there was a sustained two- to fourfold elevation. For each agonist, the kinetics of the rise and decay of [Ca2+]i were similar to those of ROS. The enzyme(s) involved in ROS formation were inhibited by diphenyleneiodonium, indicating dependence on FAD. Our results suggest a close link between ROS and changes in [Ca2+]i generated by growth factors and hormones. This is a particularly interesting connection because elevation of ROS and/ or [Ca2+]i has been linked to cell proliferation, differentiation, and apoptosis.

Biphenyl Compounds↗
PubMed1998

Structure of secreted aspartic proteinases from Candida. Implications for the design of antifungal agents.

Pathogens of the genus Candida can cause life threatening infections in immuno-compromised patients. The three-dimensional structures of two closely related secreted aspartic proteinases from C. albicans complexed with a potent (Ki = 0.17 nM) inhibitor, and an analogous enzyme from C. tropicalis reveal variations on the classical aspartic proteinase theme that dramatically alter the specificity of this class of enzymes. The novel fungal proteases present: i) an 8 residue insertion near the first disulfide (Cys45-Cys50, pepsin numbering) that results in a broad flap extending towards the active site; ii) a seven residue deletion replacing helix hN2 (Ser110-Tyr114), which enlarges the S3 pocket; iii) a short polar connection between the two rigid body domains that alters their relative orientation and provides certain specificity; and i.v.) an ordered 12 residue addition at the carboxy terminus. The same inhibitor (A-70450) binds in an extended conformation in the two variants of C. albicans protease, and presents a branched structure at the P3 position. However, the conformation of the terminal methylpiperazine ring is different in the two crystals structures. The implications of these findings for the design of potent antifungal agents are discussed.

Antifungal Agents↗
PubMed1998

Reading achievement by learning disabled students in resource and regular classes.

K-TEA Comprehensive Reading scores of 34 elementary boys in either resource rooms or regular settings were compared. The boys were identified as learning disabled in reading. They were pretested at the beginning of the school year and posttested at the end. Treatment was one year of daily instruction in reading provided by six teachers in resource setting and six teachers in regular settings. K-TEA Reading Decoding and Reading Comprehension scores, separately compared in 2 x 2 repeated-measures analysis of variance, were not significantly different.

Child↗
PubMed1998

Relative bioavailability of coenzyme Q10 formulations in human subjects.

The relative bioavailability of typical commercially available forms of coenzyme Q10 (CoQ10) was compared with that of Q-Gel, a new solubilized form of CoQ10, in human subjects in two separate trials. In the first, standard softgel capsules containing CoQ10 suspension in oil, powder-filled hardshell capsules and powder-based tablets were tested along with Q-Gel using a daily dosage of 120 mg for three weeks. The baseline plasma CoQ10 values were all very tight (0.50-0.52 microgram/mL) and after three weeks the values were 1.37, 1.63 and 1.60 micrograms/mL for the first three products and 3.31 micrograms/mL for Q-Gel. The relative bioavailability calculated using the areas under the plasma CoQ10 curve (AUC) were (micrograms/mL x time in days) 7.16 (100%), 8.97 (125%), 9.19 (128%) and for Q-Gel 22.86 (319%). The second trial, carried out to replicate the findings in the first, employed only two groups, namely the standard softgel capsules containing the suspension and Q-Gel, and the duration was extended to four weeks. Plasma CoQ10 values were: baseline 0.40 and 0.38 and after four weeks 1.26 and 2.80; the corresponding AUCs were: 8.33 (100%) and 22.75 (273%). Thus, the data from both the trials show that Q-Gel, the new solubilized form of CoQ10, is vastly superior to typical commercially available preparations of CoQ10. This means much lower doses of Q-Gel will be required to rapidly reach and maintain adequate blood CoQ10 values than with any of the other currently available products.

Adult↗
PubMed1997

Reactions of phenoxyl radicals with NADPH-cytochrome P-450 oxidoreductase and NADPH: reduction of the radicals and inhibition of the enzyme.

Phenoxyl radicals are intermediates of one-electron oxidation of phenolic compounds by various peroxidases. This report describes reactions of phenoxyl radicals with human NADPH-cytochrome P-450 oxidoreductase (OR) and NADPH. Purified truncated OR catalyzed quenching of EPR signal of the phenoxyl radical of a vitamin E homolog, 2,2,5,7,8-pentamethyl-6-hydroxychromane. The quenching required both reductase and NADPH and was not supported by NADH. NADPH quenched directly the EPR signal of phenoxyl radical of a phenolic antitumor drug, etoposide, in the absence of the OR. Quenching of the EPR signal was accompanied by increased rate of NADPH oxidation and decreased rate of etoposide oxidation. Phenoxyl radicals of etoposide did not inactivate the OR. In the absence of NADPH, OR was inhibited irreversibly when exposed to phenoxyl radicals of phenol. The activity of the flavoprotein could not be recovered by dithiothreitol (DTT) but the inhibition was prevented by saturation of OR with NADP+ prior to the exposure to phenoxyl radicals. The OR was also inhibited by 5,5'-dithionitrobenzoic acid (DTNB). The inhibition was reversible by subsequent addition of DTT. OR pretreated with DTNB was protected from inhibition by phenoxyl radicals of phenol. The results indicate that phenoxyl radical of 2,2,5,7,8-pentamethyl-6-hydroxychromane is likely reduced enzymatically by transfer of electrons from NADPH via the FAD/FMN of the OR. Phenoxyl radicals with higher redox potential, e.g., phenoxyl radicals of etoposide, oxidize NADPH directly. Phenoxyl radicals of phenol can also inactivate OR likely by oxidation of cysteine 565 in the NADPH binding region of the enzyme.

Animals↗
PubMed1997

Partial purification of (1,3)-beta-glucan synthase from Candida albicans.

(1,3)-beta-Glucan synthase from Candida albicans was solubilized from microsomal membranes using the detergent 3-[(3-cholamidopropyl) dimethylammonio]-1-propane sulfonate (Chaps). Effective solubilization was dependent upon the strain and the method used to detect enzyme activity. The solubilized enzyme was purified over 765-fold using a modified product entrapment technique. Bovine serum albumin, an activator of glucan synthase, precipitated proteins during product entrapment and was replaced with BSA immobilized on agarose beads. SDS-PAGE analysis revealed a prominent 187-kDa band present in the product entrapped pellet as well as several additional polypeptides at 227, and 187, 182 and 39 kDa which were not prevalent in crude preparations.

Candida albicans↗
PubMed1997

Crosstalk between elevation of [Ca2+]i, reactive oxygen species generation and phospholipase A2 stimulation in a human keratinocyte cell line.

The aim of the study was to explore the possible interrelationship between reactive oxygen species (ROS) formation and cPLA2 activation and the mediator role that [Ca2+]i may play in these processes in the human keratinocyte cell line, HaCaT. HaCaT cells can be invoked to transiently produce ROS by epidermal growth factor (EGF), thapsigargin (TPG) and the Ca(2+)-ionophore, A23187. These 3 agonists transiently increase [Ca2+]i with characteristic kinetics and magnitude. TPG and A23187 each activates on its own [3H]AA release from prelabeled cells, whereas EGF on its own has no effect on [3H]AA release. However, EGF augments [3H]AA release invoked by TPG or A23187 several fold. EGF activates MAP kinase cascades in HaCaT cells, leads to ROS formation and induces relatively small (1.6 fold) elevation in [Ca2+]i, whereas A23187 and TPG lead to a substantial elevation in [Ca2+]i (2.5 to 5 fold) and to ROS formation. Both have a minor effect on MAP kinase activation. The synergism in PLA2 activation by EGF and TPG or A23187, and the sensitivity of [3H]AA release to N-acetylcysteine (NAC) and dithiothreitol (DTT) (potent reducing agents) or to DPI (an inhibitor of FAD-dependent oxidases) lead to the suggestion that ROS formation, elevation of [Ca2+]i and PLA2 activation are causally related. Since we show that elevation of [Ca2+]i is a prerequisite for both ROS and PLA2 activation, it is possible that these processes contribute to the toxicity (apoptosis) exerted by chronic elevation of [Ca2+]i.

Arachidonic Acids↗
PubMed1997

K-TEA Mathematics scores of learning disabled students in resource and inclusive settings.

The relative effectiveness of mathematics instruction in resource rooms versus inclusive settings was examined with 30 boys in Grades 5 and 6 identified as learning disabled in mathematics. The boys were presented at the beginning of the school year and posttested at the end. Treatment was 45 min. of daily instruction in mathematics provided by six teachers for one school year. K-TEA Mathematics Computation and Application scores, separately compared in 2 x 2 repeated measures analyses of variance, were not significantly different; however, a significant gain was noted across settings for K-TEA Mathematics Application scores.

Achievement↗