Biomedical subjects

J M Moore

Publications and source records attributed to J M Moore.

At least 19 recordsLinked to original sources

PubMed2000

Immunity to placental malaria. II. Placental antigen-specific cytokine responses are impaired in human immunodeficiency virus-infected women.

An association was demonstrated recently between elevated in vitro production of interferon (IFN)-gamma by intervillous blood mononuclear cells (IVBMCs) and protection against placental malaria (PM). Because human immunodeficiency virus (HIV)-infected pregnant women have increased susceptibility to PM, loss of the IFN-gamma response in these women may impair their ability to control PM. Measurement of cytokines in culture supernatants by ELISA revealed that IFN-gamma responses by HIV-positive IVBMCs were impaired, especially after malarial antigen stimulation. Interleukin (IL)-4 and IL-10 responses also were reduced in HIV-positive persons, the latter more so in HIV-positive, PM-positive persons. In contrast, tumor necrosis factor-alpha production generally was enhanced in PM-positive and HIV-positive persons. Overall, cytokine production was reduced in HIV-positive persons with CD4 T cell counts <500/microL, particularly in response to malarial antigen. Thus, HIV-mediated cytokine dysregulation and impairment of the protective IFN-gamma response may contribute to the increased susceptibility of HIV-positive pregnant women to malaria.

Adult↗

PubMed2000

Galileo at Io: results from high-resolution imaging.

During late 1999/early 2000, the solid state imaging experiment on the Galileo spacecraft returned more than 100 high-resolution (5 to 500 meters per pixel) images of volcanically active Io. We observed an active lava lake, an active curtain of lava, active lava flows, calderas, mountains, plateaus, and plains. Several of the sulfur dioxide-rich plumes are erupting from distal flows, rather than from the source of silicate lava (caldera or fissure, often with red pyroclastic deposits). Most of the active flows in equatorial regions are being emplaced slowly beneath insulated crust, but rapidly emplaced channelized flows are also found at all latitudes. There is no evidence for high-viscosity lava, but some bright flows may consist of sulfur rather than mafic silicates. The mountains, plateaus, and calderas are strongly influenced by tectonics and gravitational collapse. Sapping channels and scarps suggest that many portions of the upper approximately 1 kilometer are rich in volatiles.

Extraterrestrial Environment↗

PubMed2000

Immunologic memory in the placenta: a lymphocyte recirculation hypothesis.

The placenta is an immunologically unique organ where a balance between maternal immunity and fetoplacental well-being must be maintained for successful pregnancy to occur. The intervillous blood is important in this context, yet little is known about local immunologic processes, particularly how placenta-specific memory immune responses are maintained. Using malaria as an illustrative case, we describe an hypothetical model in which recirculation of memory T lymphocytes from the intervillous blood to local lymphoid tissue facilitates maintenance of local memory immunity. This explains how memory cells might be retained when the placenta is expelled at parturition and thus remain available for rapid recall from the local lymphoid tissue to the intervillous space when exposure to the same antigenic stimulus occurs in subsequent pregnancies. Study of cell-mediated immunity to infections like malaria in the intervillous blood and the use of animal models will be necessary to provide proof for this hypothesis.

Female↗

PubMed2000

Hydraulic high-pressure nebulization of solutions and dispersions for respiratory drug delivery.

The purpose of this investigation was to assess hydraulic high-pressure nebulization as a means for respiratory drug delivery. A hydraulic high-pressure nebulizer was designed and constructed. In a design study, the output efficiency and the aerosol particle size were determined for the nebulizer as a function of nozzle diameter (5, 10, and 20 microns), gas flow rate (2 and 8 l/min), applied hydraulic pressure (2200 and 4000 psig), and distance between the nozzle orifice and impaction surface (0.25-4 cm) with an aqueous solution of fluorescein. The output efficiency was also measured with an ethanol solution and an aqueous phospholipid dispersion of liposomes. For the design study, each factor had an effect. The efficiency tended to increase with a decrease in the nozzle diameter, although the differences between the 5- and 10-micron nozzle were more sensitive to the air flow rate and nozzle-to-impaction-surface distance. Greater efficiencies were always obtained at the higher ancillary air flow rates. Operating the nebulizer at different pressures caused a change in the functional relationship between the efficiency and the nozzle-to-impaction-surface distance. For the 5-micron nozzle at high pressure, efficiency fell with increasing nozzle-to-impaction-surface distance, whereas for the data obtained with the 20-micron nozzle, the efficiency increased with nozzle-to-impaction-surface distance, with lower efficiencies obtained at the higher pressures. For the remaining observations made with the 5- and 10-micron nozzles, the efficiency as a function of nozzle-to-impaction-surface distance appeared to be variable. For the 5- and 10-micron size nozzle, there was no significant effect of the air flow rate, pressure, or nozzle-to-impaction-surface distance on the mass median aerodynamic diameter and geometric standard deviation. For the 20-micron size nozzle, the particles were not completely dried. Ethanol solutions gave somewhat higher efficiencies, whereas the phospholipid dispersion gave efficiencies comparable to the aqueous solutions nebulized under similar conditions. The efficiency of the hydraulic high-pressure nebulizer appears to be correlated with the calculated properties of the liquid jet. For respiratory drug delivery, the hydraulic high-pressure nebulizer provides reasonably high outputs of respirable particles independent of time from a single pass of liquid through the nebulizer.

Administration, Inhalation↗

PubMed2000

Angiotensin II increases neuronal delayed rectifier K(+) current: role of 12-lipoxygenase metabolites of arachidonic acid.

Angiotensin II (Ang II) elicits an Ang II type 2 (AT(2)) receptor-mediated increase in voltage-dependent delayed rectifier K(+) current (I(KV)) in neurons cultured from newborn rat hypothalamus and brain stem. In previous studies, we have determined that this effect of Ang II is mediated via a Gi protein, activation of phospholipase A(2) (PLA(2)), and generation of arachidonic acid (AA). AA is rapidly metabolized within cells via lipoxygenases (LO), cyclooxygenase (COX) or p450 monooxygenase enzymes, and the metabolic products are known regulators of K(+) currents and channels. Thus in the present study, we have investigated whether the AT(2) receptor-mediated effects of Ang II on neuronal I(KV) require AA metabolism and if so, which metabolic pathways are involved. The data presented here indicate that the stimulatory actions of Ang II and AA on neuronal I(KV) are attenuated by selective blockade of 12-LO enzymes. However, the effects of Ang II are not altered by blockade of 5-LO or p450 monooxygenase enzymes. Furthermore, the actions of Ang II are mimicked by a 12-LO metabolite of AA, but 5-LO metabolites such as leukotriene B(4) and C(4) do not alter neuronal I(KV). These data indicate that the AT(2) receptor-mediated stimulation of neuronal I(KV) is partially mediated through 12-LO metabolites of AA.

5,8,11,14-Eicosatetraynoic Acid↗

PubMed1999

Kinetics and thermodynamics of dimer formation and dissociation for a recombinant humanized monoclonal antibody to vascular endothelial growth factor.

The recombinant humanized antibody (rhuMAb) VEGF has a high affinity for vascular endothelial growth factor and is currently being evaluated in clinical trials as a cancer therapeutic. Under acidic pH and low ionic strength conditions, the antibody was predominantly present as monomer. Under physiological conditions, the appearance of significant amounts of a noncovalent, reversible dimer were observed by size-exclusion chromatography. The kinetics and thermodynamics of the reversible self-association for rhuMAb VEGF monomer were investigated as a function of pH, temperature, and ionic strength by size-exclusion chromatography using the concentration jump method. The rate constant for dimer formation ranged 23-112 M(-)(1) min(-)(1) under the conditions studied, values that are significantly lower than those reported in the literature for other proteins that self-associate. The rate constant for dissociation ranged 0.0039-0.021 min(-)(1). Gibbs' free energies, enthalpies, entropies, and activation energies were determined and revealed that dimer formation is optimal at pH 7.5-8.0, which may be reflective of charge shielding occurring near the pI of the protein. There was a negative change in entropy for dissociation (values from -18.1 to -12.8 cal/mol K). In the presence of D(2)O or 1 M NaCl, dimerization was enhanced. The results of the kinetic and thermodynamic analysis of this study indicate that rhuMAb VEGF dimerization occurs primarily through hydrophobic interactions.

Animals↗

PubMed1999

Negative transcriptional regulation mediated by thyroid hormone response element 144 requires binding of the multivalent factor CTCF to a novel target DNA sequence.

DNA target sites for a "multivalent" 11-zinc-finger CCTC-binding factor (CTCF) are unusually long ( approximately 50 base pairs) and remarkably different. In conjunction with the thyroid receptor (TR), CTCF binding to the lysozyme gene transcriptional silencer mediates the thyroid hormone response element (TRE)-dependent transcriptional repression. We tested whether other TREs, which in addition to the presence of a TR binding site require neighboring sequences for transcriptional function, might also contain a previously unrecognized binding site(s) for CTCF. One such candidate DNA region, previously isolated by Bigler and Eisenman (Bigler, J., and Eisenman, R. N. (1995) EMBO J. 14, 5710-5723), is the TRE-containing genomic element 144. We have identified a new CTCF target sequence that is adjacent to the TR binding site within the 144 fragment. Comparison of CTCF recognition nucleotides in the lysozyme silencer and in the 144 sequences revealed both similarities and differences. Several C-terminal CTCF zinc fingers contribute differently to binding each of these sequences. Mutations that eliminate CTCF binding impair 144-mediated negative transcriptional regulation. Thus, the 144 element provides an additional example of a functionally significant composite "TRE plus CTCF binding site" regulatory element suggesting an important role for CTCF in cooperation with the steroid/thyroid superfamily of nuclear receptors to mediate TRE-dependent transcriptional repression.

Animals↗

PubMed1999

Long-term fetal microchimerism in peripheral blood mononuclear cell subsets in healthy women and women with scleroderma.

Fetal CD34(+) CD38(+) cells have recently been found to persist in maternal peripheral blood for many years after pregnancy. CD34(+) CD38(+) cells are progenitor cells that can differentiate into mature immune-competent cells. We asked whether long-term fetal microchimerism occurs in T lymphocyte, B lymphocyte, monocyte, and natural-killer cell populations of previously pregnant women. We targeted women with sons and used polymerase chain reaction for a Y-chromosome-specific sequence to test DNA extracted from peripheral blood mononuclear cells (PBMC) and from CD3, CD19, CD14, and CD56/16 sorted subsets. We also asked whether persistent microchimerism might contribute to subsequent autoimmune disease in the mother and included women with the autoimmune disease scleroderma. Scleroderma has a peak incidence in women after childbearing years and has clinical similarities to chronic graft-versus-host disease that occurs after allogeneic hematopoietic stem-cell transplantation, known to involve chimerism. Sixty-eight parous women were studied for male DNA in PBMC and 20 for PBMC subsets. Microchimerism was found in PBMC from 33% (16 of 48) of healthy women and 60% (12 of 20) women with scleroderma, P =.046. Microchimerism was found in some women in CD3, CD19, CD14, and CD56/16 subsets including up to 38 years after pregnancy. Microchimerism in PBMC subsets was not appreciably more frequent in scleroderma patients than in healthy controls. Overall, microchimerism was found in CD3, CD19, and CD14 subsets in approximately one third of women and in CD56/16 in one half of women. HLA typing of mothers and sons indicated that HLA compatibility was not a requirement for persistent microchimerism in PBMC subsets. Fetal microchimerism in the face of HLA disparity implies that specific maternal immunoregulatory pathways exist that permit persistence but prevent effector function of these cells in normal women. Although microchimerism in PBMC was more frequent in women with scleroderma than healthy controls additional studies will be necessary to determine whether microchimerism plays a role in the pathogenesis of this or other autoimmune diseases.

Adult↗

PubMed1999

Angiotensin II type 1 receptor-mediated inhibition of K+ channel subunit kv2.2 in brain stem and hypothalamic neurons.

Angiotensin II (Ang II) has powerful modulatory actions on cardiovascular function that are mediated by specific receptors located on neurons within the hypothalamus and brain stem. Incubation of neuronal cocultures of rat hypothalamus and brain stem with Ang II elicits an Ang II type 1 (AT1) receptor-mediated inhibition of total outward K+ current that contributes to an increase in neuronal firing rate. However, the exact K+ conductance(s) that is inhibited by Ang II are not established. Pharmacological manipulation of total neuronal outward K+ current revealed a component of K+ current sensitive to quinine, tetraethylammonium, and 4-aminopyridine, with IC50 values of 21.7 micromol/L, 1.49 mmol/L, and 890 micromol/L, respectively, and insensitive to alpha-dendrotoxin (100 to 500 nmol/L), charybdotoxin (100 to 500 nmol/L), and mast cell degranulating peptide (1 micromol/L). Collectively, these data suggest the presence of Kv2.2 and Kv3.1b. Biophysical examination of the quinine-sensitive neuronal K+ current demonstrated a macroscopic conductance with similar biophysical properties to those of Kv2.2 and Kv3.1b. Ang II (100 nmol/L), in the presence of the AT2 receptor blocker PD123,319, elicited an inhibition of neuronal K+ current that was abolished by quinine (50 micromol/L). Reverse transcriptase-polymerase chain reaction analysis confirmed the presence of Kv2.2 and Kv3.1b mRNA in these neurons. However, Western blot analyses demonstrated that only Kv2.2 protein was present. Coexpression of Kv2.2 and the AT1 receptor in Xenopus oocytes demonstrated an Ang II-induced inhibition of Kv2.2 current. Therefore, these data suggest that inhibition of Kv2.2 contributes to the AT1 receptor-mediated reduction of neuronal K+ current and subsequently to the modulation of cardiovascular function.

Angiotensin II↗

PubMed1999

Chronic prenatal cocaine treatment down-regulates mu-opioid receptor mRNA expression in the brain of fetal Rhesus Macaque.

Ribonuclease protection assays (RPA) were performed to quantify mu-opioid receptor mRNA expression in specific brain regions of day 70 Rhesus Macaque fetuses that were exposed to cocaine (3 mg/kg) or saline from days 22-70 of gestation. The content of mu-receptor mRNA was high in the diencephalon and moderate in the mesencephalon. In contrast, mu-receptor mRNA was lightly expressed in areas such as the frontal cortex, striatum and the temporal lobe. The content of mu-opioid receptor mRNA was significantly higher in the diencephalon than in other brain regions (P < 0.001; n = 4). Cocaine exposure significantly decreased the expression of mu-receptor mRNA in the fetal diencephalon (P < 0.05; n = 4 in each group). Our data would indicate that prolonged gestational cocaine exposure causes mu-opioid receptor mRNA down-regulation in specific brain regions of the fetus.

Animals↗

PubMed1999

NMR techniques for characterization of ligand binding: utility for lead generation and optimization in drug discovery.

Over the last ten years, nmr spectroscopy has evolved into an important discipline in drug discovery. Initially, nmr was most useful as a technique to provide structural information regarding protein drug targets and target-ligand interactions. More recently, it has been shown that nmr may be used as an alternative method for identification of small molecule ligands that bind to protein drug targets. High throughput implementation of these experiments to screen small molecule libraries may lead to identification of potent and novel lead compounds. In this review, we will use examples from our own research to illustrate how nmr experiments to characterize ligand binding may be used to both screen for novel compounds during the process of lead generation, as well as provide structural information useful for lead optimization during the latter stages of a discovery program.

Binding Sites↗

PubMed1999

NMR screening in drug discovery.

NMR methods in drug discovery have traditionally been used to obtain structural information for drug targets or target-ligand complexes. Recently, it has been shown that NMR may be used as an alternative approach for identification of ligands that bind to protein drug targets, shifting the emphasis of many NMR laboratories towards screening and design of potential drug molecules, rather than structural characterization.

Biotechnology↗

PubMed1999

The SHAPES strategy: an NMR-based approach for lead generation in drug discovery.

BACKGROUND: Recently, it has been shown that nuclear magnetic resonance (NMR) may be used to identify ligands that bind to low molecular weight protein drug targets. Recognizing the utility of NMR as a very sensitive method for detecting binding, we have focused on developing alternative approaches that are applicable to larger molecular weight drug targets and do not require isotopic labeling. RESULTS: A new method for lead generation (SHAPES) is described that uses NMR to detect binding of a limited but diverse library of small molecules to a potential drug target. The compound scaffolds are derived from shapes most commonly found in known therapeutic agents. NMR detection of low (microM-mM) affinity binding is achieved using either differential line broadening or transferred NOE (nuclear Overhauser effect) NMR techniques. CONCLUSIONS: The SHAPES method for lead generation by NMR is useful for identifying potential lead classes of drugs early in a drug design program, and is easily integrated with other discovery tools such as virtual screening, high-throughput screening and combinatorial chemistry.

IMP Dehydrogenase↗

PubMed1999

Immunity to placental malaria. I. Elevated production of interferon-gamma by placental blood mononuclear cells is associated with protection in an area with high transmission of malaria.

In areas in which malaria is holoendemic, primigravidae and secundigravidae, compared with multigravidae, are highly susceptible to placental malaria (PM). The nature of gravidity-dependent immune protection against PM was investigated by measuring in vitro production of cytokines by placental intervillous blood mononuclear cells (IVBMC). The results demonstrated that interferon (IFN)-gamma may be a critical factor in protection against PM: production of this cytokine by PM-negative multigravid IVBMC was elevated compared with PM-negative primigravid and secundigravid and PM-positive multigravid cells. Low IFN-gamma responsiveness to malarial antigen stimulation, most evident in the latter group, was balanced by increased interleukin (IL)-4 production, suggesting that counter-regulation of these two cytokines may be a crucial determinant in susceptibility to PM. A counter-regulatory relationship between IL-10 and tumor necrosis factor-alpha was also observed in response to malarial antigen stimulation. These data suggest that elevated production of IFN-gamma, as part of a carefully regulated cytokine network, is important in the control of PM.

Adult↗

PubMed1999

Dose-response effects of spinal neostigmine added to bupivacaine spinal anesthesia in volunteers.

BACKGROUND: Intrathecal adjuncts often are used to enhance small-dose spinal bupivacaine for ambulatory anesthesia. Neostigmine is a novel spinal analgesic that could be a useful adjunct, but no data exist to assess the effects of neostigmine on small-dose bupivacaine spinal anesthesia. METHODS: Eighteen volunteers received two bupivacaine spinal anesthetics (7.5 mg) in a randomized, double-blinded, crossover design. Dextrose, 5% (1 ml), was added to one spinal infusion and 6.25, 12.5, or 50 microg neostigmine in dextrose, 5%, was added to the other spinal. Sensory block was assessed with pinprick; by the duration of tolerance to electric stimulation equivalent to surgical incision at the pubis, knee, and ankle; and by the duration of tolerance to thigh tourniquet. Motor block at the quadriceps was assessed with surface electromyography. Side effects (nausea, vomiting, pruritus, and sedation) were noted. Hemodynamic and respiratory parameters were recorded every 5 min. Dose-response relations were assessed with analysis of variance, paired t tests, or Spearman rank correlation. RESULTS: The addition of 50 microg neostigmine significantly increased the duration of sensory and motor block and the time until discharge criteria were achieved. The addition of neostigmine produced dose-dependent nausea (33-67%) and vomiting (17-50%). Neostigmine at these doses had no effect on hemodynamic or respiratory parameters. CONCLUSIONS: The addition of 50 microg neostigmine prolonged the duration of sensory and motor block. However, high incidences of side effects and delayed recovery from anesthesia with the addition of 6.25 to 50 microg neostigmine may limit the clinical use of these doses for outpatient spinal anesthesia.

Adult↗

PubMed1999

Comparison of three solutions of ropivacaine/fentanyl for postoperative patient-controlled epidural analgesia.

BACKGROUND: Ropivacaine, 0.2%, is a new local anesthetic approved for epidural analgesia. The addition of 4 microg/ml fentanyl improves analgesia from epidural ropivacaine. Use of a lower concentration of ropivacaine-fentanyl may further improve analgesia or decrease side effects. METHODS: Thirty patients undergoing lower abdominal surgery were randomized in a double-blinded manner to receive one of three solutions: 0.2% ropivacaine-4 microg fentanyl 0.1% ropivacaine-2 microg fentanyl, or 0.05% ropivacaine-1 microg fentanyl for patient-controlled epidural analgesia after standardized combined epidural and general anesthesia. Patient-controlled epidural analgesia settings and adjustments for the three solutions were standardized to deliver equivalent drug doses. Pain scores (rest, cough, and ambulation), side effects (nausea, pruritus, sedation, motor block, hypotension, and orthostasis), and patient-controlled epidural analgesia consumption were measured for 48 h. RESULTS: All three solutions produced equivalent analgesia. Motor block was significantly more common (30 vs. 0%) and more intense with the 0.2% ropivacaine-4 microg fentanyl solution. Other side effects were equivalent between solutions and mild in severity. A significantly smaller volume of 0.2% ropivacaine-4 microg fentanyl solution was used, whereas the 0.1% ropivacaine-2 microg fentanyl group used a significantly greater amount of ropivacaine and fentanyl. CONCLUSIONS: Lesser concentrations of ropivacaine and fentanyl provide comparable analgesia with less motor block despite the use of similar amounts of ropivacaine and fentanyl. This finding suggests that concentration of local anesthetic solution at low doses is a primary determinant of motor block with patient-controlled epidural analgesia after lower abdominal surgery.

Amides↗

PubMed1998

Designing an effective statewide tobacco control program--Oregon.

In this report, the author documents the first stages in the development and implementation of Oregon's tobacco control program. She briefly reviews the history of tobacco control coalitions in Oregon prior to the passage of Ballot Measure 44 and attributes much of the success to earlier coalition-building efforts.

Communication↗

PubMed1998

Designing an effective counteradvertising campaign--Oregon.

In this report, the authors describe the key components for development of the soon to be created counteradvertising campaign. Emphasis is placed on numerous factors, including training, selection of target groups, the need for multiple media channels, and scientific assessment of media strategies.

Advertising↗