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Biomedical subjects

J M Rosenfeld

Publications and source records attributed to J M Rosenfeld.

At least 19 recordsLinked to original sources
PubMed2005

Regeneration of Nothofagus pumilio [Poepp. et Endl.] Krasser forests after five years of seed tree cutting.

Nothofagus pumilio [Poepp. et Endl.] Krasser is a deciduous tree species that grows in Chile and adjacent Argentina between 36 and 56 degrees S, often forming the Andean tree line. Silvicultural systems proposed for this species integrate both regeneration and intermediate level operations in an orderly process for managing forest stands. The seed-tree method of regeneration has been used to manage even-aged stands of this species. This paper investigates the effect of seed tree cuttings on the regeneration of Nothofagus pumilio [Poepp. et Endl.] Krasser forest located in the Magallanes region (Chile). The studied forest was managed on an even-aged basis using a seed tree silvicultural system for regeneration with an intensity of cutting of 65-70% of the basal area and a minimum of 15 dominant lenga trees per hectare retained. A regeneration inventory sampling was used to quantify regeneration attributes in the study area. Regeneration was found to be significantly affected by the seed tree cuttings. In fact, the number of established individuals rose from 0.39 to 26.7 plants m(-2) pre-harvest to 9.2-21.5 plants m(-2) post-harvest, depending on the particular development stage. Total regeneration ranged from 9.5 to 48.2 plants m(-2). The number of plants established over the period 1992-1997 was related to the residual basal area, coverage and number of trees. However, mean tree height was not significantly related to any regeneration variable. Significant variables were used to establish a regeneration prediction model using single and multiple linear equations (R2<0.418). Consequently, the seed tree method of regeneration can be considered feasible for commercially valuable lenga forests, although this method, in its strictest application, will create many large, irregularly shaped, even-aged groups.

Chile↗
PubMed2003

A nuclear receptor-mediated xenobiotic response and its implication in drug metabolism and host protection.

Regulation of the Phase I CYP enzymes and Phase II conjugating enzymes is implicated in both drug metabolism and drug-drug interactions. Moreover, the elimination of numerous xenobiotic and endobiotic toxic chemicals also requires a concerted function of Phase I and II enzymes, as well as the membrane spanning drug transporters. The genes that encode these enzymes and transporters are inducible by numerous xenobiotics, yet the inducibility shows clear species specificity. In the last 3-4 years, orphan nuclear receptors (NRs) such as PXR, CAR, and FXR have been established as species-specific xeno-sensors that regulate the expression of Phase I and II enzymes, as well as selected drug transporters. This transcriptional regulation is achieved by binding of these xenobiotic receptors to the NR response elements found within the promoter regions of target genes. The identification of NRs as xenosensors represents a major step forward in understanding the genetic mechanisms controlling the expression of drug metabolizing enzymes. The establishment of NR-mediated and mechanism-guided xenobiotic screening systems by using cultured cells or genetically engineered mouse models has not only advanced our understanding of the molecular complexity of this drug-induced xenobiotic response, but has also provided in vitro and in vivo platforms to facilitate the development of safer drugs.

Animals↗
PubMed2002

Monoamine oxidase inhibitor-induced blockade of locomotor sensitization to quinpirole: role of striatal dopamine uptake inhibition.

Previous studies have shown that the monoamine oxidase inhibitor (MAOI) clorgyline, blocks locomotor sensitization to the D(2)/D(3) dopamine agonist quinpirole and sensitizes self-directed mouthing behavior in rats by a mechanism independent of MAO inhibition. However, clorgyline is also an inhibitor of striatal dopamine uptake, and this mechanism could account for the effect of clorgyline on quinpirole sensitization. To investigate this possibility, the effects of clorgyline and pargyline were examined. Of these two MAOIs, only clorgyline inhibits dopamine uptake in the striatum. Rats received subcutaneous injections of clorgyline (1 mg/kg), pargyline (10 mg/kg) or vehicle 90 min prior to each injection of quinpirole (0.5 mg/kg, s.c., x8, twice weekly) or saline. Clorgyline and pargyline blocked the development of quinpirole-induced locomotor sensitization and sensitized self-directed mouthing behaviors in quinpirole rats. Thus, it is unlikely that clorgyline blocks locomotor sensitization to quinpirole via an inhibition of striatal dopamine uptake. Both MAOIs increased dopamine metabolism in the striatum, showed opposite effects in the prefrontal cortex, and eliminated the correlation between prefrontal dopamine and striatal DOPAC content found in quinpirole sensitized rats. We suggest that clorgyline and pargyline may affect the behavioral and neurochemical response to quinpirole via a previously reported MAOI-displaceable quinpirole binding site, a site which we hypothesize serves as a 'switch' to select what motor output becomes sensitized to repeated injections of quinpirole.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2002

Post exercise hypotension is not mediated by the serotonergic system in borderline hypertensive individuals.

Recent evidence from our laboratory and others have suggested that the mechanism for a decrease in resting blood pressure after an acute bout of exercise is a centrally mediated decrease in total peripheral resistance. This study examined the effect of the central serotonergic system on post exercise hypotension (PEH) in 11 borderline hypertensive individuals (nine male, two female) aged 24.5 +/- 5.1 years. Each subject completed two, 30-min cycling bouts at 70% of VO2peak while under placebo or a selective serotonin re-uptake inhibitor (SSRI) treatment. Blood pressure was recorded directly from the radial artery, and treatments were randomised, double blinded and separated by at least 14 days. Baseline blood pressure was 145/72 mm Hg for systolic (SBP) and diastolic (DBP) respectively. Peripheral measures of serotonin (5-HT) were lower under SSRI treatment, whereas the major 5-HT metabolite, 5-hydroxyindoleacetic acid, was not significantly changed, indicating elevated central 5-HT levels. There was no difference in any of the haemodynamic variables between trials. Despite an increased heart rate for the initial 75 min post exercise, SBP was decreased as much as 23 mm Hg during the initial 60 min post exercise, after which it had returned to normal. DBP was unchanged after exercise. Circulating adrenaline (0.60 +/- 0.14 ng/mL to 1.3 +/- 1.6 ng/ml) and noradrenaline (0.27 +/- 0.31 ng/ml to 4.5 +/- 2.1 ng/ml) were significantly elevated during exercise. Both returned to pre-exercise levels within 15 min post exercise. Unexpectedly, oxygen uptake was slightly (5%), but significantly increased over the entire duration of the SSRI trial. We conclude that the central serotonergic system is not responsible for PEH in our borderline hypertensive population.

Adult↗
PubMed2000

A switch mechanism between locomotion and mouthing implicated in sensitization to quinpirole in rats.

RATIONALE: Chronic treatment with the monoamine oxidase inhibitor (MAOI) clorgyline, blocks locomotor sensitization to the D2/D3 dopamine agonist quinpirole. It is unknown whether this blockade occurs via inhibition of the MAO enzyme or by another mechanism. OBJECTIVES: While clorgyline and moclobemide are equally effective MAOIs, only clorgyline has a high affinity for the MAOI-displaceable quinpirole binding site (MQB). This study compares the effects of both drugs on quinpirole sensitization. METHODS: To examine development of sensitization, rats received clorgyline (1 mg/kg/day), moclobemide (5 mg/kg/day), or vehicle via osmotic mini-pumps and were injected with quinpirole (0.5 mg/kg, s.c.) or saline every 3 days; locomotor and mouthing activity was recorded for each of the eight injections. A similar protocol was used to examine the expression of sensitization in rats previously sensitized to quinpirole. RESULTS: Clorgyline, but not moclobemide, blocked the development of locomotor sensitization to quinpirole. Clorgyline, but not moclobemide, blocked the sensitized locomotor response to quinpirole following the 25th day of treatment. Mouthing showed sensitization in quinpirole-treated rats co-treated with clorgy-line, but not moclobemide; this sensitized mouthing was predominantly directed towards self. Clorgyline and moclobemide equally inhibited MAO-A and had equal effects on tissue concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, and serotonin in the striatum. CONCLUSIONS: Clorgyline (1) inhibits the development and the maintenance of locomotor sensitization to quinpirole by a mechanism that does not involve MAO and (2) changes the sensitized response to quinpirole from locomotion to mouthing. We suggest that clorgy-line affects the response to quinpirole via MQB and that this site acts as a switch that selects the motor pathway for sensitization to quinpirole.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Solid-phase analytical derivatization: enhancement of sensitivity and selectivity of analysis.

Analytical derivatizations enhance the sensitivity and selectivity of determinations for organic compounds. Classical techniques are often based on solution chemistry. Most modern sample preparation techniques, however, are based on solid-phase extractions. Solid-phase analytical derivatization bridges this gap and facilitates sample preparation by combining the isolation step with the derivatization. The solid-phase retains both reagents and derivatized analytes and often permits facile separation of excess reagent or selective elution of the desired products. The most recent solid-phase extraction techniques have been used in conjunction with analytical derivatization to automate the analysis. In this review, analytical derivatizations are presented as functional group analysis.

Carboxylic Acids↗
PubMed1999

Co-stimulation of promoter for low density lipoprotein receptor gene by sterol regulatory element-binding protein and Sp1 is specifically disrupted by the yin yang 1 protein.

Sterol regulation of gene expression in mammalian cells is mediated by an interaction between the cholesterol-sensitive sterol regulatory element-binding proteins (SREBPs) and promoter-specific but generic co-regulatory transcription factors such as Sp1 and NF-Y/CBF. Thus, sterol-regulated promoters that require different co-regulatory factors could be regulated independently through targeting the specific interaction between the SREBPs and the individual co-regulatory proteins. In the present studies we demonstrate that transiently expressed yin yang 1 protein (YY1) inhibits the SREBP-mediated activation of the low density lipoprotein (LDL) receptor in a sensitive and dose-dependent manner. The inhibition is independent of YY1 binding directly to the LDL receptor promoter, and we show that the same region of YY1 that interacts in solution with Sp1 also interacts with SREBP. Furthermore, other SREBP-regulated genes that are not co-regulated by Sp1 are either not affected at all or are not as sensitive to the repression. Thus, the specific interaction that occurs between SREBPs and Sp1 to stimulate the LDL receptor promoter is a specific target for inhibition by the YY1 protein, and we provide evidence that the mechanism can be at least partially explained by the ability of YY1 to inhibit the interaction between SREBP and Sp1 in solution in vitro. The LDL receptor is the key gene of cholesterol uptake, and the rate-controlling genes of cholesterol synthesis are stimulated by the concerted action of SREBPs along with coregulators that are distinct from Sp1. Therefore, repression of gene expression through specifically targeting the interaction between SREBP and Sp1 would provide a molecular mechanism to explain how cholesterol uptake can be regulated independently from cholesterol biosynthesis in mammalian cells.

CCAAT-Enhancer-Binding Proteins↗
PubMed1998

HLH106, a Drosophila sterol regulatory element-binding protein in a natural cholesterol auxotroph.

In mammalian cells, sterol regulatory element-binding proteins (SREBPs) coordinate metabolic flux through the cholesterol and fatty acid biosynthetic pathways in response to intracellular cholesterol levels. We describe experiments that evaluate the functional equivalence of mammalian SREBPs and the insect homologue of SREBP-1a, HLH106, in both mammalian and insect cell culture systems. HLH106 binds to both palindromic E-boxes and direct repeat sterol regulatory elements (SREs) efficiently, suggesting that it has a dual DNA binding specificity similar to the mammalian proteins. The amino-terminal "mature" protein activates transcription from mammalian SREs in both mammalian and Drosophila tissue culture cells. Additionally, HLH106 also requires a ubiquitous regulatory co-activator to efficiently activate transcription from mammalian SREs. These properties are shared with its mammalian counterparts. When expressed in mammalian cells, the carboxyl-terminal portion also localizes to perinuclear membranes similar to mammalian SREBPs. Furthermore, membrane-bound HLH106 is proteolytically processed in response to intracellular sterol levels in mammalian cells in an SREBP cleavage-activating protein-stimulated fashion. The presence of an SREBP homologue in Drosophila whose processing is regulated by intracellular sterol levels when expressed in mammalian cells suggests that related processing machinery exists in insect cells. This is notable, since insects are reportedly incapable of de novo sterol biosynthesis.

Amino Acid Sequence↗
PubMed1998

Related membrane domains in proteins of sterol sensing and cell signaling provide a glimpse of treasures still buried within the dynamic realm of intracellular metabolic regulation.

Recent discoveries in the regulation of cholesterol metabolism have documented a two step proteolytic pathway that regulates nuclear targeting of the sterol regulatory element binding proteins. Sterol regulatory element binding protein cleavage activating protein is a newly identified protein that modulates the proteolytic maturation of the sterol regulatory element binding proteins. It contains a domain that is quite similar in sequence to the membrane spanning region of the rate controlling enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase. The membrane domain of the reductase is involved in its post-translational regulation by cholesterol. The molecular defect in the intracellular cholesterol storage disease, Niemann-Pick type C, has also recently been identified. Surprisingly, the affected gene encodes a protein with similarity to the membrane domains that are conserved in 3-hydroxy-3-methylglutaryl reductase and sterol regulatory element binding protein cleavage activating protein. Furthermore, the cell surface receptor for the sterol modified hedgehog morphogen, Patched, also contains a membrane domain with significant similarity to this putative sterol monitoring domain. These recent developments suggest a common mechanism for sensing intracellular sterol levels and cell signaling, which is based on the function of related membrane domains that are contained in key regulatory proteins.

Carrier Proteins↗
PubMed1997

Analytical derivatizations of volatile and hydrophilic carbonyls from aqueous matrix onto a solid phase of a polystyrene-divinylbenzene macroreticular resin.

Extraction and derivatization of carbonyls to benzyloximes, pentafluorobenzyloximes or 2,4-dinitrophenylhydrazones is simplified and reaction times are substantially reduced by simultaneous sorption and derivatization from aqueous solution onto a solid phase. In this reaction a macroreticular polystyrene-divinylbenzene resin acts as a sorbent and catalyst to allow simultaneous extraction and derivatization of hydrophilic and lipophilic aldehydes and ketones from simple as well as complex matrices including plasma. Conversion to the 2,4-dinitrophenylhydrazones or pentafluorobenzyloximation at ambient temperature requires 10 and 20 min, respectively. These reaction conditions correspond to at least a 6-fold reduction in reaction times for derivatization of the reactive aldelhydes and a 36-72-fold reduction for preparation of derivatives for the slower reacting ketones.

Aldehydes↗
PubMed1996

A direct role for sterol regulatory element binding protein in activation of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene.

In earlier studies the DNA site required for sterol regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase was shown to be distinct from the classic sterol regulatory element (SRE-1) of the low density lipoprotein receptor gene (Osborne, T. F. (1991) J. Biol. Chem 266, 13947-13951). However, oxysterol-resistant cells that continuously overproduce one of the sterol regulatory element binding proteins in the nucleus result in high unregulated expression of both genes (Yang, J., Brown, M. S., Ho, Y. K., and Goldstein, J. L. (1995) J. Biol. Chem. 270, 12152-12161) suggesting a direct role for the SREBPs in the activation of the reductase gene. In the present studies we demonstrate that SREBP-1 binds to two adjacent sites within the previously identified sterol regulatory element of the reductase gene even though there is only limited homology with the SRE-1 of the receptor. We also show that SREBP-1 specifically activates the reductase promoter in transient DNA transfection studies in HepG2 cells and that mutations which eliminate sterol regulation and SREBP-1 binding also abolish transient activation by SREBP-1. Although specific, the magnitude of the activation observed is considerably lower than for the low density lipoprotein (LDL) receptor analyzed in parallel, suggesting there is an additional protein required for activation of the reductase promoter that is limiting in the transient assay. SREBP also binds to two additional sites in the reductase promoter which probably plan an auxiliary role in expression. When the DNA sequence within the sites are aligned with each other and with the LDL receptor SRE-1, a consensus half-site is revealed 5'-PyCAPy-3'. The LDL receptor element contains two half-sites oriented as a direct repeat spaced by one nucleotide. The SREBP proteins are special members of the basic-helix-loop-helix-zipper (bHLHZip) family of DNA binding proteins since they bind the classic palindromic E-box site as well as the direct repeat SRE-1 element. The SREBP binding sites in both the reductase and those recently identified in other sterol regulated promoters appear to contain a half-site with considerable divergence in the flanking residues. Here we also show that a 22-amino acid domain located immediately adjacent to the basic domain of the bHLHZip region is required for SREBP to efficiently recognize divergent sites in the reductase and 3-hydroxy-3-methylglutaryl-CoA synthase promoters but, interestingly, this domain is not required for efficient binding to the LDL direct repeat SRE-1 or to a palindromic high-affinity E-box element.

Base Sequence↗
PubMed1996

Sterol regulation of acetyl coenzyme A carboxylase: a mechanism for coordinate control of cellular lipid.

Transcription from the housekeeping promoter for the acetyl coenzyme A carboxylase (ACC) gene, which encodes the rate-controlling enzyme of fatty acid biosynthesis, is shown to be regulated by cellular sterol levels through novel binding sites for the sterol-sensitive sterol regulatory element binding protein (SREBP)-1 transcription factor. The position of the SREBP sites relative to those for the ubiquitous auxiliary transcription factor Sp1 is reminiscent of that previously described for the sterol-regulated low density lipoprotein receptor promoter. The experiments provide molecular evidence that the metabolism of fatty acids and cholesterol, two different classes of essential cellular lipids, are coordinately regulated by cellular lipid levels.

Acetyl-CoA Carboxylase↗
PubMed1989

Solid-phase sample preparation method for prostaglandins: integration of procedures for isolation and derivatization for gas chromatographic determination.

A procedure using a solid-phase support has been developed for the isolation and derivatization of prostaglandins from biological matrices. The styrene-divinylbenzene cross-linked copolymeric macroreticular resin, XAD-2, was used as an adsorbent for prostaglandin E2 from biological samples, as a support for the oximation of the carbonyl group and as a catalyst for pentafluorobenzylation. The reactor bed was then linked to a Florisil column for a final chromatographic clean-up. Matrix effects were found to affect the yield, but recovery of the desired electrophoric products was comparable with methods reported in the literature. The ease of sample preparation suggests that this technique may be a viable approach to automating the processes for preparing prostaglandins from biological matrices for gas chromatographic analysis.

Animals↗
PubMed1988

Dipyridamole preserved platelets and reduced blood loss after cardiopulmonary bypass.

Cardiopulmonary bypass activates and depletes platelets, which may contribute to postoperative bleeding. In addition, activated platelets may be deposited in the coronary vasculature after ischemia and cardioplegia, which may delay recovery of cardiac function and metabolism and may contribute to early bypass graft occlusion. The antiplatelet agent dipyridamole reduces platelet activation and depletion and may decrease postoperative bleeding and transfusion requirements. A prospective randomized trial was conducted in 58 patients undergoing elective coronary bypass operations to compare the effects of oral (19 patients) and intravenous (21 patients) dipyridamole to the results obtained in a control group (18 patients) who received no dipyridamole. Preoperative oral administration of dipyridamole resulted in lower plasma drug concentrations in the early postoperative period than perioperative intravenous administration (p = 0.0001 by analysis of variance). Postoperative arterial platelet counts were highest in the patients receiving intravenous dipyridamole, intermediate in those receiving oral dipyridamole, and lowest in the control group (p = 0.03 by analysis of variance). Postoperative blood loss and blood product transfusions were significantly reduced with both oral and intravenous dipyridamole (p = 0.04 by analysis of variance). Dipyridamole preserved platelets and reduced postoperative bleeding. Intravenous dipyridamole resulted in higher platelet counts than oral dipyridamole and may be required to reduce postoperative bleeding in high-risk patients.

Administration, Oral↗
PubMed1987

The pharmacokinetics of isoxicam in elderly patients with rheumatoid arthritis.

Nineteen patients, aged 60 years and over, with rheumatoid arthritis participated in a clinical trial to investigate the pharmacokinetics of isoxicam (a new non-steroidal anti-inflammatory drug) in this age group. The purpose of the study was to determine if the pharmacokinetics are different compared to a younger healthy population. The half-lives were independent of dosage, indicating linearity of pharmacokinetics. Furthermore, the half-lives after repeated dosing were not different from those found after single doses of 400 mg. This shows that there is neither undue accumulation of the drug nor induction of its own metabolism. These results are similar to the results obtained in other centres when isoxicam was administered to healthy subjects between 18 and 32 years.

Aged↗
PubMed1986

Simplified methods for preparation of microbial fatty acids for analysis by gas chromatography with electron-capture detection.

Analysis of bacterial metabolites and constituents by gas chromatography (GC) with frequency-pulsed electron-capture detection (FPECD) has been suggested as an approach to rapid identification of infection in man. In such methods conversion of analytes to electrophoric derivatives is obligatory. Present methods for analysis of microbial carboxylic acids by GC-FPECD use trichloroethylation. In order to simplify and possibly automate such sample preparation procedures, we investigated pentafluorobenzylation via extractive alkylation and via solid-supported reagents. The sensitivity in terms of minimum amounts of bacteria detectable were determined for the trichloroethyl and pentafluorobenzyl derivatives and results from solid-supported reagents were compared to extractive alkylation.

Alkylation↗