Biomedical subjects

R B White

Publications and source records attributed to R B White.

At least 19 recordsLinked to original sources

PubMed2006

Improved particle confinement in transition from multiple-helicity to quasi-single-helicity regimes of a reversed-field pinch.

The quasi-single-helicity (QSH) state of a reversed-field pinch (RFP) plasma is a regime in which the RFP configuration can be sustained by a dynamo produced mainly by a single tearing mode and in which a helical structure with well-defined magnetic flux surfaces arises. In this Letter, we show that spontaneous transitions to the QSH regime enhance the particle confinement. This improvement is originated by the simultaneous and cooperative action of the increase of the magnetic island and the reduction of the magnetic stochasticity.

Journal Article↗

PubMed2006

Transport barrier inside the reversal surface in the chaotic regime of the reversed-field pinch.

Magnetic field lines and the corresponding particle orbits are computed for a typical chaotic magnetic field provided by a magnetohydrodynamics numerical simulation of the reversed-field pinch. The m = 1 modes are phase locked and produce a toroidally localized bulging of the plasma which increases particle transport. The m = 0 and m = 1 modes produce magnetic chaos implying poor confinement. However, they also allow for the formation of magnetic islands which induce transport barriers inside the reversal surface.

Journal Article↗

PubMed2004

Particle-transport analysis in reversed field pinch helical states.

This Letter reports the result of a numerical study of particle transport in self-organized single helicity (SH) and quasi-SH reversed field pinch plasmas. Our code, benchmarked against experimental data, predicts a large improvement in particle transport for SH compared to the standard multiple helicity states. The contribution of neoclassical effects is noted. An estimate of the ambipolar electric field in helical states and in fully stochastic magnetic fields is given.

Journal Article↗

PubMed2004

Observations of multiple magnetic islands in the core of a reversed field pinch.

We describe in this Letter the first measurement of multiple islands in the core of a reversed field pinch (RFP). These islands appear with current profile modification leading to magnetic fluctuation reduction in the Madison symmetric torus RFP. Magnetic island widths decrease to an unprecedented level, reducing the overlap of adjacent islands and allowing distinct islands to appear. The structures are observed in multichord measurements of soft-x-ray emissivity. The soft-x-ray data is validated with Poincaré reconstructions of the magnetic field structure in the core.

Journal Article↗

PubMed2003

The melanocortin agonist Melanotan-II reduces the orexigenic and adipogenic effects of neuropeptide Y (NPY) but does not affect the NPY-driven suppressive effects on the gonadotropic and somatotropic axes in the male rat.

Neuropeptide Y (NPY) is a strong orexigenic neurotransmitter also known to modulate several neuroendocrine axes. alpha-Melanocyte-stimulating hormone (MSH) is an essential anorectic neuropeptide, acting on hypothalamic MC3/4 receptor subtypes. When given as an intracerebroventricular bolus injection, Melanotan-II (MT-II), a non selective MC receptor agonist, inhibits feeding, suppresses the NPY orexigenic action, and reduces basal insulinaemia. We evaluated the effects of a 7-day central infusion of MT-II (15 nmol/day) given either alone or in association with NPY (5 nmol/day) in male Sprague-Dawley rats. MT-II produced almost full anorexia for 1-2 days but then feeding gradually returned to normal despite continued MT-II infusion. When coinfused with NPY, MT-II also produced the same initial anorectic episode but then maintained feeding to upper normal levels, thus cancelling the hyperphagia driven by NPY. Whereas NPY infusion produced a doubling of fat pad weight, MT-II reduced adiposity by a factor of two compared to pair-fed rats, and vastly curtailed the NPY-driven increase in fat pad weight. MT-II infusion also significantly curtailed the NPY-induced rise in insulin and leptin secretions. NPY infusion significantly inhibited hypothalamic pro-opiomelanocortin mRNA expression, most likely cancelling the alpha-MSH anorectic activity. As expected from previous studies, chronic NPY infusion strongly inhibited both the gonadotropic and somatotropic axes, and coinfusion of MT-II did not reverse these NPY-driven effects, in sharp contrast with that seen for the metabolic data. MT-II infusion alone had little effect on these axes. In conclusion, chronic MT-II infusion generated a severe but transient reduction in feeding, suggesting an escape phenomenon, and clearly reduced fat pad size. When coinfused with NPY, MT-II was able to cancel most of the NPY effects on feeding, but not those on the neuroendocrine axes. It appears therefore that, as expected, NPY and alpha-MSH closely interact in the control of feeding, whereas the neural pathways by which NPY affects growth and reproduction are distinct and not sensitive to MC peptide modulation.

Adipocytes↗

PubMed2001

Chronic administration of neuropeptide Y into the lateral ventricle of C57BL/6J male mice produces an obesity syndrome including hyperphagia, hyperleptinemia, insulin resistance, and hypogonadism.

Neuropeptide Y (NPY) is involved in the central regulation of appetite, sexual behavior, and reproductive function. We have previously shown that chronic infusion of NPY into the lateral ventricle of normal rats produced an obesity syndrome characterized by hyperphagia, hyperinsulinism and collapse of reproductive function. We further demonstrated that acute inhibition of LH secretion in castrated rats was preferentially mediated by the NPY receptor subtype 5 (Y(5)). In the present study, the effects of chronic, central infusion of NPY, or the mixed Y2-Y5 agonist PYY(3-36), were evaluated both in normal male C57BL/6J mice and Sprague-Dawley rats. After a 7-day infusion to male mice, both NPY and PYY(3-36) at 5 nmol per day, induced marked hyperphagia leading to significant increases in body and fat pad weights. Furthermore, both compounds markedly reduced several markers of the reproductive axis. In the rat study, PYY(3-36) was more active than NPY to inhibit the pituitary-testicular axis, confirming the importance of the Y5 subtype for such effects. In the mouse, chronic NPY infusion induced a sustained increase in corticosterone and insulin secretion. Plasma leptin levels were also markedly increased possibly explaining the observed reduction in gene expression for hypothalamic NPY. Gene expression for hypothalamic POMC was reduced in the NPY- or PYY(3-36)-infused mice, suggesting that NPY exacerbated food intake by both acting through its own receptor(s), and reducing the satiety signal driven by the POMC-derived alpha-MSH. The present study in the mouse suggests in analogy with available rat data, that constant exposure to elevated NPY in the hypothalamic area unabatedly enhances food intake leading to an obesity syndrome including increased adiposity, insulin resistance, hypercorticism, and hypogonadism, reminiscent of the phenotype of the ob/ob mouse, that displays elevated hypothalamic NPY secondary to lack of leptin negative feedback action.

Animals↗

PubMed2001

Ion heating by fast-particle-induced Alfvén turbulence.

A novel mechanism that directly transfers energy from super-Alfvénic energetic ions to thermal ions in high- beta plasmas is described. The mechanism involves the excitation of compressional Alfvén eigenmodes in the frequency range with omega less than approximetely omega(ci). The broadband turbulence resulting from the large number of excited modes causes stochastic diffusion in velocity space, which transfers wave energy to thermal ions. This effect may be important on National Spherical Torus Experiment [M. Ono et al., Nucl. Fusion 40, 557 (2000)] and may scale up to reactor scenarios. This has important implications for low-aspect-ratio reactor concepts, since it potentially allows for increased fusion reactivity in such a device.

Journal Article↗

PubMed2001

Gonadotropin-releasing hormone receptor in the teleost Haplochromis burtoni: structure, location, and function.

GnRH acts via GnRH receptors (GnRH-R) in the pituitary to cause the release of gonadotropins that regulate vertebrate reproduction. In the teleost fish, Haplochromis burtoni, reproduction is socially regulated through the hypothalamus-pituitary-gonadal axis, making the pituitary GnRH-R a likely site of action for this control. As a first step toward understanding the role of GnRH-R in the social control of reproduction, we cloned and sequenced candidate GnRH-R complementary DNAs from H. burtoni tissue. We isolated a complementary DNA that predicts a peptide encoding a G protein-coupled receptor that shows highest overall identity to other fish type I GnRH-R (goldfish IA and IB and African catfish). Functional testing of the expressed protein in vitro confirmed high affinity binding of multiple forms of GNRH: Localization of GnRH-R messenger RNA using RT-PCR revealed that it is widely distributed in the brain and retina as well as elsewhere in the body. Taken together, these data suggest that this H. burtoni GnRH receptor probably interacts in vivo with all three forms of GNRH:

Amino Acid Sequence↗

PubMed2000

Two molecular forms of gonadotropin-releasing hormone (GnRH-I and GnRH-II) are expressed by two separate populations of cells in the rhesus macaque hypothalamus.

Gonadotropin-releasing hormone represents the primary neuroendocrine link between the brain and the reproductive axis, and at least two distinct molecular forms of this decapeptide (GnRH-I and GnRH-II) are known to be expressed in the forebrain of rhesus macaques (Macaca mulatta). Although the distribution pattern of the two corresponding mRNAs is largely dissimilar, their expression appears to show some overlap in specific regions of the hypothalamus; this raises the possibility that some cells express both molecular forms of GnRH. To resolve this issue, double-label histochemistry was performed on hypothalamic sections from six male rhesus macaques, using a monoclonal antibody to GnRH-I and a riboprobe to monkey GnRH-II mRNA. In total, more than 2000 GnRH neurons were examined but in no instance were GnRH-I peptide and GnRH-II mRNA found to be coexpressed. This finding emphasizes that GnRH-I and GnRH-II are synthesized by two distinct populations of hypothalamic neurons, and suggests that they may be regulated by different neuroendocrine pathways.

Animals↗

PubMed1999

Second form of gonadotropin-releasing hormone in mouse: immunocytochemistry reveals hippocampal and periventricular distribution.

Hypothalamic GnRH (GnRH-I) is known and named for its role in regulating reproductive function in vertebrates by controlling release of gonadotropins from the pituitary. However, another form of GnRH of unknown function (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly; GnRH-II) is expressed in the mesencephalon of all vertebrate classes except jawless fish. Here we show with immunocytochemical staining that the GnRH-II peptide is localized to the mouse midbrain as in other vertebrates, as well as in cells surrounding the ventricles and in cells adjacent to the hippocampus. Staining of adjacent sections using GnRH-I antibody revealed that the distribution of GnRH-I does not overlap with that of GnRH-II.

Animals↗

PubMed1999

Gonadotropin-releasing hormone genes: phylogeny, structure, and functions.

Gonadotropin-releasing hormone (GnRH, previously called leutinizing hormone-releasing hormone, LHRH) is the final common signaling molecule used by the brain to regulate reproduction in all vertebrates. Recently, genes encoding two other GnRH forms have been discovered. Here we present a phylogenetic analysis that shows that the GnRH genes fall naturally into three distinct branches, each of which shares not only a molecular signature but also characteristic expression sites in the brain. The GnRH genes appear to have arisen through gene duplication from a single ancestral GnRH whose origin predates vertebrates. Several lines of data support this suggestion, including the fact that all three genes share an identical exonic structure. The existence of three distinct GnRH families suggests a new, natural nomenclature for the genes, and in addition, we present a logical proposal for naming the peptide sequences. The two recently discovered GnRH genes are unusual because they encode decapeptides that are identical in all the species in which they have been found. The control of gene expression also differs among the three gene families as might be expected since they have had separate evolutionary trajectories for perhaps 500 million years.

Animals↗

PubMed1999

Regional expression of mRNA encoding a second form of gonadotropin-releasing hormone in the macaque brain.

In mammals, reproduction is thought to be controlled by a single neuropeptide, gonadotropin-releasing hormone (GnRH-I), which regulates the synthesis and secretion of gonadotropins from the pituitary gland. However, another form of this decapeptide (GnRH-II), of unknown function, also exists in the brain of many vertebrate species, including humans; it is encoded by a different gene and its amino acid sequence is 70% identical to that of GnRH-I. Here we report the cloning of a GnRH-II cDNA from the rhesus macaque (Macaca mulatta), and show for the first time by in situ hybridization that GnRH-II mRNA is expressed in the primate midbrain, hippocampus and discrete nuclei of the hypothalamus, including the supraoptic, paraventricular, suprachiasmatic and arcuate. Because the regional distribution pattern of cells containing GnRH-II mRNA is largely dissimilar to that of cells containing GnRH-I mRNA, it is likely that these two cell populations receive distinct neuroendocrine inputs and thus regulate GnRH synthesis and release differently.

Amino Acid Sequence↗

PubMed1999

Use of the steroid derivative RPR 106541 in combination with site-directed mutagenesis for enhanced cytochrome P-450 3A4 structure/function analysis.

RPR 106541 (20R-16alpha,17alpha-[butylidenebis(oxy)]-6al pha, 9alpha-difluoro-11beta-hydroxy-17beta-(methylthio)androst a-4-en-3-one) is an airway-selective steroid developed for the treatment of asthma. Two metabolites produced by human liver microsomes were identified as R- and S-sulfoxide diastereomers based on liquid chromatography/mass spectrometry analysis, proton nuclear magnetic resonance, and cochromatography with standards. Sulfoxide formation was determined to be cytochrome P-450 (CYP) 3A4-dependent by correlation with CYP3A4-marker nifedipine oxidase activity, inhibition by cyclosporin A and troleandomycin, and inhibition of R- (70%) and S- (64%) sulfoxide formation by anti-3A antibody. Expressed CYP2C forms catalyzed RPR 106541 sulfoxidation; however, other phenotyping approaches failed to confirm the involvement of CYP2C forms in these reactions in human liver microsomes. Expressed CYP3A4 catalyzed the formation of the sulfoxide diastereomers in a 1:1 ratio, whereas CYP3A5 displayed stereoselectivity for formation of the S-diastereomer. The high rate of sulfoxidation by CYP3A4 and the blockage of oxidative metabolism at the electronically favored 6beta-position provided advantages for RPR 106541 over other substrates as an active site probe of CYP3A4. Therefore, oxidation of RPR 106541 by various CYP3A4 substrate recognition site (SRS) mutants was assessed. In SRS-4, A305V and F304A showed dramatically reduced rates of R-diastereomer formation (83 and 64% decreases, respectively), but S-diastereomer formation was affected to a lesser extent. A370V (SRS-5) showed decreased formation of the R-sulfoxide (52%) but increased formation of the S-diastereomer. In the SRS-2 region, the most dramatic change in sulfoxide ratios was observed for L210A. In conclusion, the structure of RPR 106541 imposes specific constraints on enzyme binding and activity and thus represents an improved CYP3A4 probe substrate.

Androstenes↗

PubMed1998

Second gene for gonadotropin-releasing hormone in humans.

Gonadotropin-releasing hormone (GnRH) is a decapeptide widely known for its role in regulating reproduction by serving as a signal from the hypothalamus to pituitary gonadotropes. In addition to hypothalamic GnRH (GnRH-I), a second GnRH form (pGln-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly; GnRH-II) with unknown function has been localized to the midbrain of many vertebrates. We show here that a gene encoding GnRH-II is expressed in humans and is located on chromosome 20p13, distinct from the GnRH-I gene that is on 8p21-p11.2. The GnRH-II genomic and mRNA structures parallel those of GnRH-I. However, in contrast to GnRH-I, GnRH-II is expressed at significantly higher levels outside the brain (up to 30x), particularly in the kidney, bone marrow, and prostate. The widespread expression of GnRH-II suggests it may have multiple functions. Molecular phylogenetic analysis shows that this second gene is likely the result of a duplication before the appearance of vertebrates, and predicts the existence of a third GnRH form in humans and other vertebrates.

Adult↗

PubMed1998

Genomic structure and expression sites of three gonadotropin-releasing hormone genes in one species.

In the teleost fish, Haplochromis burtoni, gonadotropin-releasing hormone (GnRH) peptide has been localized to three distinct regions in the brain. Each GnRH population is associated with expression of a distinct cDNA as previously described. Here we report the complete genomic sequences encoding these three forms and compare their structural organization, putative regulatory elements, and expression patterns in the body. All three genes share a common structure of four exons: the first exon encodes the 5' untranslated region; the second exon encodes the signal sequence, GnRH decapeptide, and the 5' end of the GnRH-associated peptide (GAP); the third exon consists entirely of GAP coding sequence; and the fourth exon encodes the 3' end of GAP and the 3' untranslated region. Each of the three GnRH genes has been shown previously to have a distinct spatial expression pattern in the brain, and here we use reverse transcription and cDNA amplification to demonstrate that each gene is expressed in the body. The gene encoding the releasing form, ¿Ser8¿GnRH, is expressed in the heart, liver, spleen, kidney, and testis, as well as in the preoptic area. The ¿His5Trp7Tyr8¿GnRH gene is expressed in the testis as well as in the midbrain. The ¿Trp7Leu8¿GnRH gene is expressed in the testis and the terminal nerve area. We examined the 500 bp upstream of exon 1 in all three H. burtoni genes and identified putative binding sites for glucocorticoid receptor, androgen receptor, and progesterone receptor, as well as the transcription factors Ap-1 and Sp-1. The genomic sequence encoding the terminal nerve form of GnRH (i.e., ¿Trp7Leu8¿GnRH) in H. burtoni is remarkably similar to that encoding the presumed releasing form of GnRH in salmonids, especially in the 3' intergenic region. Taken together with phylogenetic and mRNA localization data in salmonids, these data suggest that the gene encoding the releasing form of GnRH in salmonids may not yet be described.

Animals↗

PubMed1998

Ontogeny of gonadotropin-releasing hormone (GnRH) gene expression reveals a distinct origin for GnRH-containing neurons in the midbrain.

In the teleost fish, Haplochromis burtoni, three gonadotropin-releasing hormone (GnRH) peptides and their corresponding cDNA sequences and full-length genes have previously been reported. Here we describe the ontogeny of mRNA expression for these three GnRH forms in H. burtoni. Each of the three forms has been shown to have a distinct spatial expression pattern in the adult brain. ¿Ser8¿GnRH (the releasing form) is expressed exclusively in the hypothalamus, ¿His5Trp7Tyr8¿GnRH is expressed in the midbrain mesencephalon, and ¿Trp7Leu8¿GnRH is expressed in the terminal nerve area of the telencephalon. Previous work in other animals has shown that GnRH-containing neurons in the preoptic area arise from the olfactory placode and that these cells migrate into their final positions in the brain during early development. By using molecular probes to identify the cell types expressing distinct GnRH forms, our data are consistent with the migration of both ¿Ser8¿GnRH and ¿Trp7Leu8¿GnRH neurons from the placode to their appropriate adult locations in the brain. In contrast, we show that ¿His5Trp7Tyr8¿GnRH neurons arise from the germinal zone of the third ventricle. By using in situ hybridization with digoxigenin-labeled cRNA probes, ¿His5Trp7Tyr8¿GnRH mRNA was first evident at day 4, ¿Trp7Leu8¿GnRH mRNA at day 8, and ¿Ser8¿GnRH mRNA at day 14. However, by using the reverse-transcriptase polymerase chain reaction (RT-PCR), all three GnRH mRNAs were found in whole embryos at day 4 of the 14 days of embryogenesis. This striking difference may be due to the greater sensitivity of RT-PCR compared with in situ hybridization. Alternatively, it is possible that ¿Ser8¿GnRH and ¿Trp7Leu8¿GnRH are expressed outside the brain during early development and only later inside the brain.

Animals↗

PubMed1997

The effect of RPR 102341 on theophylline metabolism and phenacetin O-deethylase activity in human liver microsomes.

PURPOSE: RPR 102341 is structurally similar to the fluoroquinolone class of antibiotics. Because some fluoroquinolones have been shown to inhibit theophylline metabolism, concomitant administration may increase plasma levels of theophylline resulting in serious adverse effects. The purpose of this study was to determine if RPR 102341 affects theophylline metabolism in vitro and, thus, predict whether a clinically significant drug interaction is likely to occur. In addition, the effect of RPR 102341 on phenacetin O-deethylase activity was determined to address the enzymatic basis of a potential drug interaction. METHODS: The in vitro theophylline metabolism assay was conducted according to a modification of a published procedure. The phenacetin O-deethylase assay was conducted according to a modification of a published procedure. RESULTS: The rate of conversion of theophylline to 3-methylxanthine in human liver microsomes in the presence of 100 microM and 500 microM RPR 102341 was 93.6 and 106 percent of the control reactions, respectively. The formation of 1-methylxanthine was 97.6 and 100 percent of the control, and 1.3-dimethyluric acid formation was 88.9 and 95.2 percent of control at 100 microM and 500 microM RPR 102341, respectively. In agreement, RPR 102341 caused no inhibition of human liver CYP1A2-catalyzed phenacetin O-deethylase activity. Finally, no inhibition was observed when RPR 102341 was incubated with human liver microsomes and an NADPH regenerating system prior to the addition of theophylline. CONCLUSIONS: Based on these studies, RPR 102341 is not expected to cause significant drug interactions with theophylline.

Cytochrome P-450 CYP1A2↗

PubMed1997

Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes.

The specificities of orphenadrine and methimazole on eight human liver P450 enzyme activities were evaluated by studying the extent of inhibition at different concentrations in two protocols: competitive inhibition and preincubation. In the competitive inhibition protocol, orphenadrine decreased CYP2B6 marker activity up to 45-57% in human liver microsomes and up to 80-97% in cell microsomes containing cDNA-expressed CYP2B6. Orphenadrine strongly decreased CYP2D6 marker activity by 80-90%. Orphenadrine also partially decreased the CYP1A2, CYP2A6, CYP3A4, and CYP2C19 marker activities. In the preincubation protocol, orphenadrine decreased the CYP2B6 activity in cDNA-expressed cell microsomes to completion. In human liver microsomes, orphenadrine strongly decreased the marker activities of CYP2B6, CYP2D6, as well as CYP2C9; and partially decreased the marker activities of CYP1A2, CYP2A6, CYP3A4, and CYP2C19. In the competitive inhibition protocol, methimazole had no effect on the marker activities of CYP2E1 and CYP2A6; slightly decreased CYP2D6 marker activity; partially decreased the marker activities of CYP2C19, CYP2C9, and CYP2B6; and dramatically decreased CYP3A4 marker activity. Methimazole decreased CYP1A2 marker activity at lower concentrations, but not at the highest concentration studied (1 mM). In the preincubation protocol, methimazole was shown to be a potent and nonspecific inhibitor of all the enzyme activities. Marker activities of CYP2C9, CYP2C19, and CYP3A4 were completely inhibited at relatively low concentrations. This study indicates orphenadrine cannot be used as a selective inhibitor of CYP2B6 in human liver microsomes and that methimazole is not a selective inhibitor of the flavin-containing monooxygenase in human liver microsomes.

Antiparkinson Agents↗