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Biomedical subjects

M Levine

Publications and source records attributed to M Levine.

At least 289 records · Page 16Linked to original sources
PubMed1992

Selective inhibition of rat hepatic microsomal cytochrome P-450. II. Effect of the in vitro administration of cimetidine.

The purpose of this study was to determine whether the differential inhibition of rat hepatic microsomal cytochrome P-450 in adult male rats by in vivo cimetidine administration is observed when the drug is administered in vitro. Cimetidine, at concentrations of up to 10 mM, did not affect the catalytic function of cytochrome P-450IIA1 as measured by testosterone 7 alpha-hydroxylase activity. In contrast, it did inhibit activities that are specific for cytochromes P-450IIC11 (testosterone 2 alpha-hydroxylase activity), P-450IIB1/2 (testosterone 16 beta-hydroxylase activity) and P-450IIA1/2 (testosterone 2 beta- and 6 beta-hydroxylase activities), with IC50 values in the range of 1.0 to 7.4 mM. To further investigate the inhibition of cytochrome P-450 enzymes by in vitro cimetidine, preincubation experiments were performed. Hepatic microsomes were preincubated with a low concentration (0.05 mM) of cimetidine and 1 mM NADPH for 15 min before the initiation of substrate (testosterone) oxidation. Under these conditions, cimetidine resulted in the inhibition of the enzyme activities specific for cytochrome P-450IIC11, but it had no effect on those specific for cytochromes P-450IIA1, P-450IIB1/2 and P-450IIIA1/2. This differential inhibition by in vitro cimetidine required the presence of NADPH in the preincubation medium, suggesting that a catalysis-dependent process is involved. Therefore, preincubation of hepatic microsomes with NADPH and a relatively low concentration (0.05 mM) of cimetidine in vitro results in a pattern of inhibition of cytochrome P-450 enzymes similar to that which occurs after the in vivo administration of cimetidine reported in the previous study (Chang et al., 1992).

Animals↗
PubMed1991

Regulation of a segmentation stripe by overlapping activators and repressors in the Drosophila embryo.

Gene expression stripes in Drosophila melanogaster embryos provide a model for how eukaryotic promoters are turned on and off in response to combinations of transcriptional regulators. Genetic studies suggested that even-skipped (eve) stripe 2 is controlled by three gap genes, hunchback (hb), Kruppel (Kr), and giant (gt), and by the maternal morphogen bicoid (bcd). A direct link is established between binding sites for these regulatory proteins in the stripe 2 promoter element and the expression of the stripe during early embryogenesis. The bcd and hb protein binding sites mediate activation, whereas neighboring gt and Kr protein sites repress expression and establish the stripe borders. The stripe 2 element has the properties of a genetic on-off switch.

Animals↗
PubMed1991

Establishment of the mesoderm-neuroectoderm boundary in the Drosophila embryo.

A gradient of the maternal morphogen dorsal establishes asymmetric patterns of gene expression along the dorsal-ventral axis of early embryos and activates the regulatory genes twist and snail, which are responsible for the differentiation of the ventral mesoderm. Expression of snail is restricted to the presumptive mesoderm, and the sharp lateral limits of this expression help to define the mesoderm-neuroectoderm boundary by repressing the expression of regulatory genes that are responsible for the differentiation of the neuroectoderm. The snail gene encodes a zinc finger protein, and neuroectodermal genes that are normally restricted to ventral-lateral regions of early embryos are expressed throughout ventral regions of snail- mutants. The formation of the sharp snail border involves dosage-sensitive interactions between dorsal and twist, which encode regulatory proteins that are related to the mammalian transcription factors NF-kB and MyoD, respectively.

Animals↗
PubMed1991

Semidehydroascorbic acid as an intermediate in norepinephrine biosynthesis in chromaffin granules.

We investigated whether semidehydroascorbic acid was an intermediate in norepinephrine synthesis in chromaffin granules and in electron transfer across the chromaffin granule membrane. Semidehydroascorbic acid was measured in intact granules by electron spin resonance. In the presence of intragranular but not extragranular ascorbic acid, semidehydroascorbic acid was formed within granules in direct relationship to dopamine beta-monooxygenase activity. However, semidehydroascorbic acid was not generated when granules were incubated with epinephrine instead of the substrate dopamine, with dopamine beta-monooxygenase inhibitors, without oxygen, and when intragranular ascorbic acid was depleted. Experiments using the impermeant paramagnetic broadening agents [K3 [Cr(C2O4)3].3H2O] and Ni(en)3(NO3)2 provided further evidence that semidehydroascorbic acid was generated only within granules. We also investigated semidehydroascorbic acid formation in the presence of intragranular and extragranular ascorbic acid. Under these conditions, semidehydroascorbic acid was formed on both sides of the granule membrane, and formation was coupled to dopamine beta-monooxygenase activity. These data indicate that dopamine beta-monooxygenase is reduced by single electron transfer from intragranular ascorbic acid, that transmembrane electron transfer occurs by single electron transfer, and that transmembrane electron transfer is directly coupled to formation of intragranular semidehydroascorbic acid via dopamine beta-monooxygenase activity.

Adrenal Medulla↗
PubMed1991

Ascorbic acid regeneration in chromaffin granules. In situ kinetics.

We have investigated in intact chromaffin secretory vesicles the kinetics, specificity, and mechanism of intragranular ascorbic acid regeneration by extragranular ascorbic acid. The apparent Km of internal ascorbic acid regeneration for external ascorbic acid was 280 microM by Lineweaver-Burk analysis and 287 microM by Eadie-Hofstee analysis. Intragranular ascorbic acid regeneration was specifically mediated by extragranular ascorbic acid or its isomer isoascorbic acid; the reducing agents glutathione, thiourea, homocysteine, NADH, and NADPH did not support regeneration. The structural analog D-glucose did not inhibit regeneration by external ascorbic acid, suggesting specificity at the membrane site of electron transfer. The driving force for regeneration of intragranular ascorbic acid was independent of membrane potential, absolute intragranular and extragranular pH, and ATPase activity, but might be coupled to the pH difference across the chromaffin granule membrane. Since the apparent Km of regeneration was approximately 10-fold below the cytosolic concentration of ascorbic acid, the reaction may proceed at Vmax in situ.

Adenosine Triphosphatases↗
PubMed1991

Osmotic strength differentiates between two types of calcium transport pathways regulating catecholamine secretion from cultured bovine chromaffin cells.

Calcium transport and catecholamine secretion was measured in cultured bovine chromaffin cells. Calcium ions which entered the cells following stimulation with either nicotine or 50 mM KCl (high potassium) triggered catecholamine release, but then inactivated the secretory process. The nicotine and the high potassium-induced calcium transport mechanisms were mechanistically distinct, but functionally dependent on each other. The specific evidence is that whereas the high potassium-induced Ca2+ influx was found to be inhibited by hyperosmotic medium, the nicotine-stimulated calcium influx was unaffected under these conditions. High potassium and nicotine-stimulated catecholamine release were also differently affected by hyperosmotic medium. While potassium-stimulated catecholamine release was profoundly inhibited by hyperosmolarity, nicotine-stimulated release was only moderately inhibited. Sequential treatments of cells with nicotine and high potassium, under isotonic physiological conditions, indicate that there is a functional, biochemical communication between the otherwise mechanistically distinct calcium channels. Calcium ions which were found to inactivate these channels may be the basis for such communication.

Adrenal Medulla↗
PubMed1991

Levamisole and 5-fluorouracil therapy for resected colon cancer: a new indication.

OBJECTIVE: To evaluate the benefits and risks of postoperative treatment with levamisole plus 5-fluorouracil (5-FU) in patients with colon cancer. DESIGN: Computerized searches of MEDLINE and CANCERLIT were performed, and the reference list of each retrieved article was checked. Only randomized trials of therapy with levamisole alone or combined with 5-FU for colon cancer without distant metastases were included. The studies were then evaluated with the use of four criteria. RESULTS: We reviewed six randomized trials, of which three satisfied our criteria. Two studies demonstrated a significant improvement in the survival rate with levamisole plus 5-FU among patients with colon cancer and pathologically confirmed metastases to adjacent lymph nodes (Dukes' stage C). A subgroup analysis in another study demonstrated a similar benefit. The toxic effects of the drugs were generally mild. The three other studies showed no difference in survival rates between the treatment groups; however, the samples were too small to detect a clinically or statistically important difference. CONCLUSIONS: Because many patients with colon cancer will suffer a relapse we recommend that they be offered the opportunity to participate in clinical trials of adjuvant therapy. For those with stage C disease not entering a clinical trial levamisole plus 5-FU is appropriate adjuvant therapy.

Colonic Neoplasms↗
PubMed1991

The dorsal morphogen is a sequence-specific DNA-binding protein that interacts with a long-range repression element in Drosophila.

A gradient of the maternal morphogen dorsal (dl) establishes dorsal-ventral (D-V) polarity in the early Drosophila embryo. The dl concentration gradient is initiated by regulated nuclear transport, and only protein that enters nuclei is active in the D-V patterning process. Here we show that dl is a DNA-binding protein that specifically interacts with distal sequences of the zerknüllt (zen) promoter, one of the genetic targets of the morphogen. These zen sequences have the properties of a silencer element and can act over long distances to repress the expression of a heterologous promoter. The dl protein recognizes a sequence motif similar to that of the mammalian transcriptional activator NF-kappa B, which was shown to contain extensive homology with dl and the oncoprotein rel. We present evidence that the DNA-binding activity of the dl protein is mediated by the region of homology (the rel domain) conserved in the rel and NF-kappa B proteins.

Animals↗
PubMed1991

Marfanoid children. Etiologic heterogeneity and cardiac findings.

The clinical, cardiac, and echocardiographic test results of 20 children with marfanoid features are reviewed. Fifteen were diagnosed as having Marfan syndrome, two had "possible" Marfan syndrome, and three had other diagnoses. On first evaluation, eight patients with Marfan syndrome (53%) had mitral regurgitation and none had aortic regurgitation. Echocardiography showed aortic root enlargement in 12 (80%) of 15 patients and mitral valve prolapse in 12 (80%) of 15. None had a normal echocardiogram. At follow-up examination, one patient had developed aortic root enlargement, and one patient, mitral valve prolapse. Thus, although aortic root enlargement is usually present in early childhood in patients with Marfan syndrome, it is not considered specific because in this study it also occurred in one child with Alport's syndrome and in one with marfanoid features. Four patients with aortic root enlargement were treated with propranolol and their echocardiograms showed no further increase in the aortic root diameter for several years. We recommend echocardiography in the diagnosis and routine management of children in whom Marfan syndrome is suspected.

Aortic Diseases↗
PubMed1991

A longitudinal study of pulmonary function in fire fighters.

Pulmonary function changes among fire fighters were evaluated by re-examining 632 Baltimore city fire fighters six to ten years after a baseline examination. Spirometry was used to determine forced expiratory volume in 1 second (FEV1). Information about exposures was obtained by questionnaire and by combining data from fire department records regarding the number of fires fought by fire fighting units with individual work histories. Men who never wore a mask while extinguishing fires experienced a 1.7 times greater rate of FEV1 decline than mask wearers. Men with ammonia exposure experienced a rate of decline 1.7 times greater than non-exposed men. Neither length of time spent in exposed jobs nor number of responses were associated with the rate of decline. Active fire fighters experienced a rate of decline 2.5 times greater than those who had retired or resigned. Some effects differed between men who were able to perform repeatable pulmonary function tests and those who were not.

Adult↗
PubMed1991

A research tool for measurement of recovery from sedation: the Vancouver Sedative Recovery Scale.

The need for a research tool to measure recovery from sedation was identified during the design phase of a study investigating sedative protocols following open heart surgery in children. A thorough review of the literature failed to show any scales that measure degree of sedation in children at various times after initial awakening. The Vancouver Sedative Recovery Scale (VSRS) was developed through an iterative process during which we identified numerous indicators of levels of alertness among sedated children, and then determined the applicability and face validity of these indicators. The VSRS evaluated in this study consists of 12 distinct items that encompass three categories of indicators (response; eye appearance and function; and body movement). Total possible VSRS scoring ranges from 0 to 22 (higher score indicating more alert) because some of the 12 items have more than two rating levels. The VSRS was administered to 82 pediatric intensive care unit and postanesthesia recovery patients, with each patient assessed simultaneously by at least two observers. Internal consistency as measured by Cronbach's alpha was excellent: 0.85. Interobserver agreement or reliability as measured by intraclass correlation was also very high: 0.90; and for individual items Cohen's kappa ranged from 0.65 to 0.89. We consider the VSRS to be a good beginning in our effort to quantify level of alertness after sedation in the pediatric patient population.

Anesthesia Recovery Period↗
PubMed1991

The initiation of pair-rule stripes in the Drosophila blastoderm.

The interactions between the products of gap genes and pair-rule promoters results in the single most dramatic increase in the spatial complexity of gene expression during the segmentation process. We attempt to relate recent findings on the regulation of striped patterns of gene expression in the early Drosophila embryo to general strategies of gene expression and development employed by higher organisms.

Animals↗
PubMed1991

Gangrene of the fingers secondary to myeloproliferative disease.

The myeloproliferative disorders comprise a group of related diseases, including polycythemia vera, essential thrombocythemia, chronic myelogenous leukemia, myelofibrosis, and myeloid metaplasia. An increase in circulating platelets is associated with thrombotic phenomena affecting the arterial and venous circulation. In this article, the authors describe a case in which the initial manifestation of myeloproliferative disease was gangrene of the fingers.

Aged↗
PubMed1991

Ascorbic acid and dehydroascorbic acid measurements in human plasma and serum.

We investigated whether circulating ascorbic acid in humans is protein bound or free and whether ascorbic acid exists in its reduced form alone as ascorbic acid or in its reduced and oxidized forms as ascorbic acid and dehydroascorbic acid, respectively. Ascorbic acid and dehydroascorbic acid were determined by using HPLC with coulometric electrochemical detection, and protein binding was determined by centrifugal ultrafiltration. Ascorbic acid was free in plasma and serum of normal, healthy volunteers, 10 men and 10 women. Ascorbic acid was detectable only in its reduced form. However, dehydroascorbic acid could be made to appear in samples processed under oxidizing conditions. Because circulating ascorbic acid is free and is detected only as reduced vitamin, ascorbic acid may be available without intermediates for peripheral utilization. Dehydroascorbic acid may not be present in plasma and serum of normal humans unless assay conditions permit ascorbic acid oxidation.

Adult↗
PubMed1991

Ascorbic acid accumulation in human skin fibroblasts.

The transport and accumulation of ascorbic acid in normal human skin fibroblasts in culture was investigated by using high-performance liquid chromatographic separation and coulometric electrochemical detection. Results measured as picomole ascorbic acid per microgram cell protein were expressed in molar amounts after determining the volume of skin fibroblasts. Confluent fibroblasts contained undetectable amounts of ascorbic acid. On incubation with micromole per liter amounts of ascorbic acid in the medium, cells showed increasing uptake of ascorbic acid with time, accumulating a 15-fold excess in 3.5 h. Kinetic experiments suggested two transport mechanisms, a high-affinity and a low-affinity transport activity. Both transport activities were temperature sensitive and accumulated ascorbic acid against a concentration gradient.

Ascorbic Acid↗