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R C Brown

Publications and source records attributed to R C Brown.

At least 37 records · Page 2Linked to original sources
PubMed2001

Role of the peripheral-type benzodiazepine receptor in adrenal and brain steroidogenesis.

The peripheral-type benzodiazepine receptor (PBR) has been demonstrated to be critical for steroidogenesis in all steroid-producing tissues. Here, we review the identification and characterization of the PBR, the evidence pointing to its function as a cholesterol pore involved in transporting cholesterol from the cytoplasm of steroid-producing cells into the inner mitochondrial membrane where it is metabolized, and the known mechanisms regulating its function. We present data on the functions of the PBR in the adrenal gland, a classical steroidogenic tissue, and in the brain, which has only recently been proven to be steroidogenic. Finally, we discuss other potential roles for the PBR in pathological conditions, including cancer, neurodegeneration, and neurotoxicity, and a broader role for the PBR in mediating intracellular cholesterol transport/compartmentalization, which may or may not be linked to steroid biosynthesis.

Adrenal Glands↗
PubMed2001

Biopersistence, fiber length, and cancer risk assessment for inhaled fibers.

We briefly review the evidence that the carcinogenic risk posed by inhaled fibers depends principally on the lung burden of long fibers. We use a deposition clearance model to generate time-dependent lung burdens in rats of a dozen long fibers for various exposure concentrations. Together with a previously estimated potency factor for long fibers, we use the generated lung burdens to estimate risks of lung cancer associated with inhaled fibers in rats. Over a broad range of exposure concentrations, excess risk is a linear function of exposure concentration. Excess risk of lung cancer is also a linear function of weighted half-life for fibers for which the weighted half-life is short compared to the life span of the rat. We propose an approach to estimating human lung cancer risk associated with inhaled fibers from animal studies.

Administration, Inhalation↗
PubMed2001

Effects of nonfibrous particles on ceramic fiber (RCF1) toxicity in rats.

In previous investigations a reference test sample of prepared ceramic fibers called RCF1 induced lung tumors in a 2-yr inhalation study in rats. It was hypothesized that nonfibrous particles in RCF1 may have played a significant role. The objective of the present study was to compare lung retention and biological effects of another sample of ceramic fibers, called RCF1a, to the original RCF1. The main difference between these 2 samples was the content of nonfibrous particles: 25% of the mass of RCF1 versus 2% for RCF1a. These nonfibrous particles were chemically identical to the fibers. Female Wistar rats were exposed 6 h/day, 5 days/wk for 3 wk to either RCF1a or RCF1 fiber aerosol at a concentration of about 125 fibers (>20 microm long)/ml. Because of differences in the nonfibrous particle contents, the average gravimetric aerosol concentration differed between the two samples (RCF1, 51.2 mg/m(3); RCF1a, 25.8 mg/m(3)). The posttreatment observation period was 12 mo. Biological effects measured include the clearance function of alveolar macrophages (clearance of fibers and tracer particles), and inflammation and its persistence during the recovery period. Alveolar clearance of tracer particles ((46)Sc(2)O(3)) was barely retarded after RCF1a exposure (80 days clearance half-time compared to 60 days in controls). After RCF1 exposure, however, a severe retardation of clearance was observed (1200 vs. 66 days). In both groups, differential cell counts on pulmonary lavage showed a significant increase of polymorphonuclear leukocytes (PMNs) (about 15%) and lymphocytes 3 days after the end of exposure. The PMN influx persisted longer after exposure to RCF1 than RCF1a. The conclusion of the study is that the particle fraction of RCF1 significantly enhanced any adverse effects. This clearly demonstrates the importance of the physical characteristics of the test material for the degree of toxic effects to be expected. The presence of nonfibrous particulates can enhance the effects on the lung of a mixture of fibrous and nonfibrous particulates following exposure.

Administration, Inhalation↗
PubMed2001

Phragmoplast-mediated cytokinesis in Trentepohlia: results of TEM and immunofluorescence cytochemistry.

This paper reports transmission electron microscopy (TEM) and immunofluorescence evidence for phragmoplast-mediated cytokinesis in the green alga, Trentepohlia (Ulvophyceae, Chlorophyta). This type of cytokinesis is normally found only in land plants and some charophycean green algae. Earlier TEM work documented a phragmoplast in another trentepohlialean alga, Cephaleuros. Numerous molecular studies have shown that both Trentepohlia and Cephaleuros are clearly not in the charophycean (streptophyte) lineage of green algae. Also, details of vegetative cytokinesis in Trentepohlia and Cephaleuros indicate differences from the processes and structures observed in the streptophytes. Parallel evolution could be the explanation for a phragmoplast-mediated cytokinesis in both the chlorophycean Trentepohliales and the streptophyte lineage of charophycean green algae and land plants.

Cell Division↗
PubMed2001

Dustiness of different high-temperature insulation wools and refractory ceramic fibres.

Recent regulations are encouraging the replacement of older types of man-made mineral fibre by more soluble and, thus, less biopersistent compositions. In order for there to be any health benefits from this policy and to gain maximum benefit from such substitutions, the use of the new materials should not increase exposure. The work reported here was undertaken to investigate the use of new high-temperature glass insulation wools in place of refractory ceramic fibres (RCF). Airborne fibre levels occurring during the manufacture of both RCF and calcium magnesium silicate wools (CMS) were compared using measurements of genuine workplace exposure from a routine monitoring operation on the same plant. Exposures during use were compared in one customer facility where RCF and CMS blankets were used for the same task. Further comparisons were made in a laboratory test of dustiness using a "shaking box test". For some manufacturing tasks there are only a few workplace samples and there are few opportunities for genuine comparisons with both RCF and CMS in identical uses. However, both materials produced very similar exposure levels during manufacture, use and in the laboratory test. The novel magnesium silicate fibre was significantly dustier in the laboratory test.

Asbestos, Amphibole↗
PubMed2000

Pathways of dehydroepiandrosterone formation in rat brain glia.

In peripheral steroidogenic tissues, dehydroepiandrosterone (D) is formed from pregnenolone (P) by the microsomal cytochrome P450c17 enzyme. Although some steroidogenic P450s have been found in brain tissue, no enzyme has been shown to possess P450c17 activity. We recently demonstrated the presence of an alternative, Fe(2+)-dependent pathway responsible for D formation from alternative precursors in rat glioma cells. We and others could not find P450c17 mRNA and protein in rat brain, but demonstrate herein the presence of Fe(2+)-dependent alternative pathway for D formation in rat brain cortex microsomes. Using primary cultures of differentiating rat glial cells, we observed that P450c17 mRNA and protein were present in O-2A oligodendrocyte precursors and mature oligodendrocytes. In the presence of P, O-2A and mature oligodendrocytes formed D. Addition of Fe(2+) together with submaximal concentrations of P increased D formation by these cells. Treatment of oligodendrocytes with the P450c17 inhibitor SU 10603 in the presence or absence of P failed to inhibit D production. These data suggest that D formation in oligodendrocytes occurs independently of the P450c17 protein present in the cells. In isolated type I astrocytes we did not find neither P450c17 mRNA nor protein. These cells responded to Fe(2+) by producing D and addition of P together with Fe(2+) further increased D synthesis. SU 10603 failed to inhibit D formation by astrocytes. Taken together these results suggest that in differentiating rat brain oligodendrocytes and astrocytes D is formed via a P450c17-independent and oxidative stress-dependent alternative pathway.

Animals↗
PubMed2000

Location-dependent role of the human glioma cell peripheral-type benzodiazepine receptor in proliferation and steroid biosynthesis.

We examined the localization and function of the peripheral-type benzodiazepine receptor (PBR), a protein highly expressed in steroidogenic tissues and aggressive tumor cells, in cell lines derived from glioblastoma multiforme tumors. In MGM-1 cells, PBR is located in the nucleus, and cells proliferate in response to PBR ligands but do not synthesize steroids de novo. In MGM-3 cells, PBR is located in mitochondria and the cells synthesize steroids, but do not proliferate in response to PBR ligands. In glioblastoma biopsies, PBR is expressed in the nuclei of cells, while it is found in the cytosol of astrocytomas, and is absent from meningioma and medulloblastoma tumor biopsies. These data suggest that the subcellular localization of PBR defines its function.

Cell Division↗
PubMed2000

Pathways of neurosteroid biosynthesis in cell lines from human brain: regulation of dehydroepiandrosterone formation by oxidative stress and beta-amyloid peptide.

Neurosteroids in rodents can originate from peripheral tissues or be locally synthesized in specific brain areas. There is, as yet, no information about the synthesis and regulation of neurosteroids in human brain. We examined the ability of human brain cells to synthesize steroids from a radiolabeled precursor and the mRNA and protein expression of key components of peripheral steroidogenic machinery. Oligodendrocytes are the source of pregnenolone in human brain. Human astrocytes do not synthesize radiolabeled pregnenolone, nor do human neurons. There is potential for all three cell types to metabolize pregnenolone to other neurosteroids, including dehydroepiandrosterone. mRNA and protein for cytochrome P450 17alpha-hydroxylase were found in all cell types, although no activity could be demonstrated. We examined the ability of the cells to make dehydroepiandrosterone via an alternative pathway induced by treatment with Fe2+. Oligodendrocytes and astrocytes make dehydroepiandrosterone via this pathway, but neurons do not. In searching for a natural regulator of dehydroepiandrosterone formation, we observed that treating oligodendrocytes with beta-amyloid, which increases reactive oxygen species, also increased dehydroepiandrosterone formation. These effects of beta-amyloid were blocked by vitamin E. These results indicate that human brain makes steroids in a cell-specific manner and suggest that dehydroepiandrosterone synthesis can be regulated by intracellular free radicals.

3-Hydroxysteroid Dehydrogenases↗
PubMed2000

Lung cancer risk associated with exposure to man-made fibers.

We show that available experimental data from long-term experiments are consistent with the hypothesis that the oncogenic potential of man-made fibers is determined completely by their biopersistence. We present an analysis of these data within the initiation-promotion-progression paradigm of carcinogenesis. Our method of analysis takes explicit account of the temporal pattern of fiber burden in the rat lung, and suggests that fibers act as initiators in the lung. We estimate a dose-dependent initiation parameter and show how it can be transported to human populations for assessment of the risk of lung cancer following exposure to man-made fibers.

Air Pollutants, Occupational↗
PubMed2000

High-carbohydrate versus high-fat diets: effect on body composition in trained cyclists.

PURPOSE: Recent research suggesting the benefits of high-fat diets for endurance athletes have been viewed with caution because of the potential negative health consequences, including increased adiposity. METHODS: We have examined the effects of a high-fat (HF, 50% of total energy from fat and 37% from carbohydrate) versus a high-carbohydrate (HC, 15% of total energy from fat and 69% from carbohydrate) diet on body fat, lean body mass, and bone mineral density (BMD) in 32 endurance-trained cyclists over a period of 3 months. Body composition was assessed by dual x-ray absorptiometry at baseline and after 3 months. RESULTS: Total and percent body fat, lean tissue mass, and body weight were not significantly different within and between each diet group from baseline to week 12. Total body BMD increased significantly within HF (P = 0.02), but nonsignificantly in HC, over the 12-wk period. CONCLUSIONS: In conclusion, during periods of endurance training when energy requirements are high, increasing the percentage of fat in the diet to approximately 50% of total energy does not increase body weight or adiposity because athletes are able to maintain energy balance.

Adolescent↗
PubMed2000

Traditional intravaginal practices and the heterosexual transmission of disease: a review.

OBJECTIVE: To review reports on the use and effects of traditional intravaginal substances and practices. METHOD: The medical and social science literature of the past 50 years regarding use and effects of traditional intravaginal substances and practices is reviewed. RESULTS: Traditional intravaginal practices have been described in 11 countries of sub-Saharan Africa, and also in Qatar, Indonesia, Thailand, Haiti, the Dominican Republic, and the United States. Women's reasons for the practices include personal hygiene, disease prevention or treatment, and enhancement of sexual experience. Few studies document damage to the vaginal epithelium or changes in vaginal flora due to these practices. No prospective studies link these practices to disease transmission. CONCLUSION: The determination of how these practices affect disease transmission will require precise definition of independent variables, which is difficult because of the diversity of the practices. It is appropriate to search for intervening variables; specifically, the effects on the vaginal pH, flora, and epithelium.

Administration, Intravaginal↗
PubMed2000

Epstein-Barr virus LMP2A-induced B-cell survival in two unique classes of EmuLMP2A transgenic mice.

Latent membrane protein 2A (LMP2A) is one of only two viral proteins expressed during latent Epstein-Barr virus (EBV) infections in human peripheral B cells. LMP2A blocks B-cell receptor (BCR) signal transduction in vitro by modulation of the Syk and Lyn protein tyrosine kinases. Five genetically unique LMP2A transgenic mouse lines (EmuLMP2A) with B-cell lineage expression of LMP2A were generated in this study to analyze the importance of LMP2A expression in vivo. These animals can be grouped into EmuLMP2A(BCR+) (TgB, Tg6, and TgC) and EmuLMP2A(BCR-) (Tg7 and TgE) lines based on B-cell phenotype. LMP2A expression in bone marrow cells of EmuLMP2A(BCR-) lines was associated with a bypass of normal B-lymphocyte developmental checkpoints inasmuch as immunoglobulin light-chain gene rearrangement occurred in the absence of complete immunoglobulin heavy-chain gene rearrangement. The resulting BCR-negative B cells were able to exit the bone marrow and colonize peripheral lymphoid organs. LMP2A expression in EmuLMP2A(BCR+) lines was not associated with altered B-cell development in a genetically wild-type background. When crossed into a recombinase activating null (RAG(-/-)) genetic background, LMP2A expression in either RAG(-/-) EmuLMP2A(BCR+) or RAG(-/-) EmuLMP2A(BCR-) animals was able to provide a survival signal to BCR-negative splenic B cells. Additionally, bone marrow cells from all EmuLMP2A animals were able to proliferate in response to interleukin-7-dependent developmental signals in vitro. These studies illustrate that LMP2A can provide a survival signal to BCR-negative B cells in two different groups of EmuLMP2A transgenic mice.

Animals↗
PubMed2000

The cytoskeleton and polarization during pollen development in Carex blanda (Cyperaceae).

Patterns of cytoskeletal organization during distinct polarizations that characterize pollen development in the sedge Carex blanda (Cyperaceae) were studied by correlated methods of immunohistochemistry and confocal and transmission electron microscopy. As is typical of the family Cyperaceae, Carex produces a unique pollen type known as a pseudomonad in which all four microspores of the tetrad are enclosed within the wall of a single pollen grain. Only one member of the tetrad is functional and the other three abort. The pseudomonads are precisely oriented in the locule with the functional microspore in the wide abaxial portion of the wedge-shaped cytoplasm adjacent to the tapetum, and the degenerative microspores are packed tightly in the pointed adaxial portion. A unique sequence of post-meiotic developmental events reflects both intracellular and intercellular polarity. Development includes: (1) random placement of tetrad nuclei in the coenocytic sporocyte after meiosis, (2) interrupted cytokinesis resulting in a tetrad of nuclei that migrates as a unit into the narrow adaxial tip, (3) completion of unequal cytokinesis and centering of the functional nucleus in the wide abaxial portion of the microsporocyte via a radial array of microtubules and microfilaments, (4) unequal mitosis resulting in a small generative cell at the proximal surface of the functional microspore (adjacent to the abortive microspores), and (5) recentering of the vegetative nucleus in the abaxial cytoplasm via a radial cytoskeletal array.

Journal Article↗
PubMed1999

Novel screening methods--the key to cloning commercially successful biocatalysts.

Providing sufficient biocatalyst to support the demands of multi tonne product supply can be problematical. Here we describe how screening for and cloning a gamma-lactamase overcame biocatalyst supply issues, and greatly improved the actual biocatalytic process. The isolation of an expressing gamma-lactamase clone from a gene library necessitated a combination of classical molecular biology techniques together with innovative screening methods to identify a functional clone. Once isolated the enzyme was characterised with regard to its process performance and proved to be active at 500 g L(-1) substrate. Further development of the recombinant fermentation and downstream processing has resulted in the ability to produce sufficient biocatalyst from one 5001 fermentation to resolve 5 metric tonnes of (+/-)-lactam, whilst simplifying the process chemistry greatly.

Amidohydrolases↗
PubMed1999

Monitoring of urban particulate using an electret-based passive sampler.

Site sampling trials have been carried out in the urban environment in order to assess the usefulness of a passive sampling device, originally developed for personal monitoring of airborne dust levels in industry. The sampling element is a small disc of electret material (polymer carrying a permanent electric charge) within a metal frame weighing approximately 15 g. The sampler is designed to capture particles by electrostatic attraction, in which case the capture rate depends on their electrical mobility but is independent of the rate at which air flows past the device. Passive samplers, along with miniaturized cascade impactors, have been exposed to urban particulate for periods of up to 28 days in locations with significantly different levels of airborne pollution. The cascade impactor data enabled good estimates to be made of PM10 and PM2.5 levels, and data from the passive sampler correlated with the total dust sampled by the impactor and with both the size fractions, that with the PM10 being better. Too few data have yet been obtained for its accuracy to be established, but it is unlikely that it will approach that of pumped samplers. It has been shown to be potentially useful for multiple, simultaneous site sampling and for monitoring personal environmental exposure situations in which dispensing with a power source is particularly useful. Being small, the sampler is easy to hide or camouflage, and because it is cheap, its loss or damage is not a serious matter.

Aerosols↗