Biomedical subjects

D J Anderson

Publications and source records attributed to D J Anderson.

At least 91 records · Page 5Linked to original sources

PubMed1999

Early specification of sensory neuron fate revealed by expression and function of neurogenins in the chick embryo.

The generation of sensory and autonomic neurons from the neural crest requires the functions of two classes of basic helix-loop-helix (bHLH) transcription factors, the Neurogenins (NGNs) and MASH-1, respectively (Fode, C., Gradwohl, G., Morin, X., Dierich, A., LeMeur, M., Goridis, C. and Guillemot, F. (1998) Neuron 20, 483-494; Guillemot, F., Lo, L.-C., Johnson, J. E., Auerbach, A., Anderson, D. J. and Joyner, A. L. (1993) Cell 75, 463-476; Ma, Q., Chen, Z. F., Barrantes, I. B., de la Pompa, J. L. and Anderson, D. J. (1998 Neuron 20, 469-482). We have cloned two chick NGNs and found that they are expressed in a subset of neural crest cells early in their migration. Ectopic expression of the NGNs in vivo biases migrating neural crest cells to localize in the sensory ganglia, and induces the expression of sensory neuron-appropriate markers in non-sensory crest derivatives. Surprisingly, the NGNs can also induce the expression of multiple pan-neuronal and sensory-specific markers in the dermomyotome, a mesodermal derivative. Taken together, these data suggest that a subset of neural crest cells may already be specified for a sensory neuron fate early in migration, as a consequence of NGN expression.

Amino Acid Sequence↗

PubMed1999

The origins of the Minnesota model of addiction treatment--a first person account.

The Minnesota Model, also known as the abstinence model, of addiction treatment was created in a state mental hospital in the 1950s by two young men, one who was to become a psychologist, the other who was to become a psychiatrist, neither of whom had prior experience treating addicts or alcoholics. The model spread first to a small not-for-profit organization called the Hazelden Foundation and then throughout the country. The key element of this novel approach to addiction treatment was the blending of professional and trained nonprofessional (recovering) staff around the principles of Alcoholics Anonymous (AA). There was an individualized treatment plan with active family involvement in a 28-day inpatient setting and participation in Alcoholics Anonymous both during and after treatment. The education of patients and family about the disease of addiction made this a busy program from morning to night, seven days a week.

Alcoholics Anonymous↗

PubMed1999

Pancreatic cystic neoplasms.

Cystic neoplasms of the pancreas are relatively rare. This makes the evaluation and treatment of these tumors widely varied. The authors describe a patient who came to our hospital with complaints of abdominal pain, but no other related symptoms. Diagnostic evaluation of the patient yielded normal results, except for inspection and palpation of the abdominal areas, which revealed a large epigastric mass; this finding was confirmed subsequently by ultrasonographic examination and computed tomographic scanning. This article presents the case and reviews the literature, specifically related to diagnosis and current treatments.

Aged↗

PubMed1999

Disruption of postural readaptation by inertial stimuli following space flight.

Postural instability (relative to pre-flight) has been observed in all shuttle astronauts studied upon return from orbital missions. Postural stability was more closely examined in four shuttle astronaut subjects before and after an 8 day orbital mission. Results of the pre- and post-flight postural stability studies were compared with a larger (n = 34) study of astronauts returning from shuttle missions of similar duration. Results from both studies indicated that inadequate vestibular feedback was the most significant sensory deficit contributing to the postural instability observed post flight. For two of the four IML-1 astronauts, post-flight postural instability and rate of recovery toward their earth-normal performance matched the performance of the larger sample. However, post-flight postural control in one returning astronaut was substantially below mean performance. This individual, who was within normal limits with respect to postural control before the mission, indicated that recovery to pre-flight postural stability was also interrupted by a post-flight pitch plane rotation test. A similar, though less extreme departure from the mean recovery trajectory was present in another astronaut following the same post-flight rotation test. The pitch plane rotation stimuli included otolith stimuli in the form of both transient tangential and constant centripetal linear acceleration components. We inferred from these findings that adaptation on orbit and re-adaptation on earth involved a change in sensorimotor integration of vestibular signals most likely from the otolith organs.

Adaptation, Physiological↗

PubMed1998

Functionally related motor neuron pool and muscle sensory afferent subtypes defined by coordinate ETS gene expression.

Motor function depends on the formation of selective connections between sensory and motor neurons and their muscle targets. The molecular basis of the specificity inherent in this sensory-motor circuit remains unclear. We show that motor neuron pools and subsets of muscle sensory afferents can be defined by the expression of ETS genes, notably PEA3 and ER81. There is a matching in PEA3 and ER81 expression by functionally interconnected sensory and motor neurons. ETS gene expression by motor and sensory neurons fails to occur after limb ablation, suggesting that their expression is coordinated by signals from the periphery. ETS genes may therefore participate in the development of selective sensory-motor circuits in the spinal cord.

Animals↗

PubMed1998

Detection of HIV-1-specific CTLs in the semen of HIV-infected individuals.

CTLs play an important role in controlling cell-associated HIV. Since the majority of HIV infections are acquired through sexual transmission, we investigated whether antiviral CTLs were present in the male urogenital tract using semen as a source of T cells. We were able to establish anti-HIV cytolytic lines in five of five HIV-infected men with CD4 counts of >500/microl, although cloning efficiencies were lower than with peripheral blood-derived T cells. CTLs generated from the semen of three men were analyzed in detail and showed a broadly active response, recognizing gag, env, and pol proteins. Detailed analysis of two gag-specific clones from one of the individuals demonstrated HLA class I restriction and recognition of the same p24 epitope (EQASQEVKNWMT). In summary, our results demonstrate the presence of a broad CTL response to HIV in the urogenital tract and provide a rationale for further studies of local enhancement of genital mucosal responses by anti-HIV immunization.

Antigens, Viral↗

PubMed1998

Isolation and characterization of mammalian homologs of the Drosophila gene glial cells missing.

The glial cells missing (gcm) gene in Drosophila encodes a transcription factor that determines the choice between glial and neuronal fates. We report here the isolation of two mammalian gcm homologs, Gcm1 and Gcm2, and the characterization of their expression patterns during embryonic development. Although Gcm2 is expressed in neural tissues at a low level, the major sites of expression for both of the mammalian genes are nonneural, suggesting that the functions of the mammalian homologs have diverged and diversified. However, when expressed ectopically, Gcm1 can substitute functionally for Drosophila gcm by transforming presumptive neurons into glia. Thus, certain biochemical properties, although not the specificity of the tissue in which the gene is expressed, have been conserved through the evolution of the Gcm gene family.

Amino Acid Sequence↗

PubMed1998

Structure-activity studies related to ABT-594, a potent nonopioid analgesic agent: effect of pyridine and azetidine ring substitutions on nicotinic acetylcholine receptor binding affinity and analgesic activity in mice.

Analogs of A-98593 (1) and its enantiomer ABT-594 (2) with diverse substituents on the pyridine ring were prepared and tested for affinity to nicotinic acetylcholine receptor binding sites in rat brain and for analgesic activity in the mouse hot plate assay. Numerous types of modifications were consistent with high affinity for [3H]cytisine binding sites. By contrast, only selected modifications resulted in retention of analgesic potency in the same range as 1 and 2. Analogs of 2 with one or two methyl substituents at the 3-position of the azetidine ring also were prepared and found to be substantially less active in both assays.

Alkaloids↗

PubMed1998

Inhibition of NADPH-cytochrome P450 reductase and glyceryl trinitrate biotransformation by diphenyleneiodonium sulfate.

We reported previously that the flavoprotein inhibitor diphenyleneiodonium sulfate (DPI) irreversibly inhibited the metabolic activation of glyceryl trinitrate (GTN) in isolated aorta, possibly through inhibition of vascular NADPH-cytochrome P450 reductase (CPR). We report that the content of CPR represents 0.03 to 0.1% of aortic microsomal protein and that DPI caused a concentration- and time-dependent inhibition of purified cDNA-expressed rat liver CPR and of aortic and hepatic microsomal NADPH-cytochrome c reductase activity. Purified CPR incubated with NADPH and GTN under anaerobic, but not aerobic conditions formed the GTN metabolites glyceryl-1,3-dinitrate (1,3-GDN) and glyceryl-1,2-dinitrate (1,2-GDN). GTN biotransformation by purified CPR and by aortic and hepatic microsomes was inhibited > 90% after treatment with DPI and NADPH. DPI treatment also inhibited the production of activators of guanylyl cyclase formed by hepatic microsomes. We also tested the effect of DPI on the hemodynamic-pharmacokinetic properties of GTN in conscious rats. Pretreatment with DPI (2 mg/kg) significantly inhibited the blood pressure lowering effect of GTN and inhibited the initial appearance of 1,2-GDN (1-5 min) and the clearance of 1,3-GDN. These data suggest that the rapid initial formation of 1,2-GDN is related to mechanism-based GTN biotransformation and to enzyme systems sensitive to DPI inhibition. We conclude that vascular CPR is a site of action for the inhibition by DPI of the metabolic activation of GTN, and that vascular CPR is a novel site of GTN biotransformation that should be considered when investigating the mechanism of GTN action in vascular tissue.

Animals↗

PubMed1998

Mammalian BarH homologue is a potential regulator of neural bHLH genes.

Vertebrate neurogenesis involves sequential actions of transcription factors. neurogenins, encoding Atonal-related bHLH transcription factors, function as neuronal determination genes in Xenopus. neurogenins and antother bHLH factor gene, Mash1, are expressed in distinct subsets or areas of cells giving rise to neurons, suggesting that these genes play important roles to generate distinct populations of neurons. A mammalian homologue of BarH (MBH1) is expressed in a complementary pattern to Mash1 expression in the developing nervous system like neurogenins. Forced expression of MBH1 down-regulates expression of Mash1 and up-regulates neurogenin2/Math4A, a member of neurogenins, in P19 cells during neuronal differentiation. This suggests that MBH1 is a potential regulator of mammalian neural bHLH genes, thereby establishing distinct pathways of neuronal differentiation.

Amino Acid Sequence↗

PubMed1998

Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4.

The vertebrate circulatory system is composed of arteries and veins. The functional and pathological differences between these vessels have been assumed to reflect physiological differences such as oxygenation and blood pressure. Here we show that ephrin-B2, an Eph family transmembrane ligand, marks arterial but not venous endothelial cells from the onset of angiogenesis. Conversely, Eph-B4, a receptor for ephrin-B2, marks veins but not arteries. ephrin-B2 knockout mice display defects in angiogenesis by both arteries and veins in the capillary networks of the head and yolk sac as well as in myocardial trabeculation. These results provide evidence that differences between arteries and veins are in part genetically determined and suggest that reciprocal signaling between these two types of vessels is crucial for morphogenesis of the capillary beds.

Animals↗

PubMed1998

Fate mapping of the mouse midbrain-hindbrain constriction using a site-specific recombination system.

The mouse midbrain-hindbrain constriction is centrally involved in patterning of the midbrain and anterior hindbrain (cerebellum), as revealed by recent genetic studies using mice and embryological studies in chick (reviewed in [1,2]). This region can act as an organizer region to induce midbrain and cerebellar development. Genes such as Engrailed-1, Pax-2 and Pax-5, which are expressed in the embryonic cells that will form the midbrain and the cerebellum, are required for development of these regions. Fate-mapping experiments at early somite stages in chick have revealed that the cerebellar primordium is located both anterior and posterior to the midbrain-hindbrain constriction, whereas midbrain precursors lie more anteriorly. Fate mapping in mice has been complicated by the inaccessibility of the postimplantation embryo. Here, we report the use of a new in vivo approach involving the Cre-IoxP site-specific recombination system [3] to map the fate of cells in the mouse midbrain-hindbrain constriction. We show that cells originating in the mouse dorsal midbrain-hindbrain constriction during embryonic days 9-12 contribute significantly to the medial cerebellum and colliculi. Our data demonstrate the feasibility of using a recombinase-based lineage-tracing system for fate mapping in the mouse.

Animals↗

PubMed1998

Mono- and disubstituted-3,8-diazabicyclo[3.2.1]octane derivatives as analgesics structurally related to epibatidine: synthesis, activity, and modeling.

A series of 3,8-diazabicyclo[3.2.1]octanes substituted either at the 3 position (compounds 1) or at the 8 position (compounds 2) by a chlorinated heteroaryl ring were synthesized, as potential analogues of the potent natural analgesic epibatidine. When tested in the hot plate assay, the majority of the compounds showed significant effects, the most interesting being the 3-(6-chloro-3-pyridazinyl)-3,8-diazabicyclo[3.2.1]octane (1a). At a subcutaneous dose of 1 mg/kg, 1a induced a significant increase in the pain threshold, its action lasting for about 45 min. 1a also demonstrated good protection at a dose of 5 mg/kg in the mouse abdominal constriction test, while at 20 mg/kg it completely prevented the constrictions in the animals. Administration of naloxone (1 mg/kg i.p.) did not antagonize its antinociception while mecamylamine (2 mg/kg i.p.) did, thus suggesting the involvement of the nicotinic system in its action. Binding studies confirmed high affinity for the alpha 4 beta 2 nAChR subtype (Ki = 4.1 +/- 0.21 nM). nAChR functional activity studies on three different cell lines showed that 1a was devoid of any activity at the neuromuscular junction. Finally, due to the analogy in their pharmacological profile with that of epibatidine, compounds were compared from a structural and conformational point of view through theoretical calculations and high-field 1H NMR spectroscopy. Results indicate that all of them present one conformation similar to that of epibatidine.

Abdominal Muscles↗

PubMed1998

Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors.

New members of a previously reported series of 3-pyridyl ether compounds are disclosed as novel, potent analgesic agents acting through neuronal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intraperitoneal (i.p.) or oral (p.o.) administration, as well as activity in the mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nicotinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity.

Administration, Oral↗

PubMed1998

Synthesis and structure-activity relationships of pyridine-modified analogs of 3-[2-((S)-pyrrolidinyl)methoxy]pyridine, A-84543, a potent nicotinic acetylcholine receptor agonist.

Analogs of 3-[2-((S)-pyrrolidinyl)methoxy]pyridine, (A-84543, 1) with 2-, 4-, 5-, and 6-substituents on the pyridine ring were synthesized. These analogs exhibited Ki values ranging from 0.15 to > 9,000 nM when tested in vitro for neuronal nicotinic acetylcholine receptor binding activity. Assessment of functional activity at subtypes of neuronal nicotinic acetylcholine receptors indicates that pyridine substitution can have a profound effect on efficacy at these subtypes, and several subtype-selective agonists and antagonists have been identified.

Cell Line↗

PubMed1998

Toxicokinetics of inhaled 2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in F344 rats and B6C3F1 mice.

2-Butoxyethanol (2BE) is used extensively in the production of cleaning agents and solvents. It is primarily metabolized in the liver to 2-butoxyacetic acid (2BAA), which is believed to be responsible for 2BE toxicities associated with hemolysis of red blood cells. The objective of the study was to characterize the systemic disposition of 2BE and 2BAA in rats and mice during 2-year 2BE inhalation toxicity studies. Male and female F344 rats and B6C3F1 mice (6-7 weeks old) were exposed to target 2BE concentrations of 0, 31.2, 62.5, or 125 ppm (rats), or 0, 62.5, 125, or 250 ppm (mice), by whole-body inhalation for 6 h/day, 5 days/week for up to 18 months. Postexposure blood samples were collected after 1 day, 2 weeks, and 3, 6, 12, and 18 months of exposure. Postexposure 16-h urine samples were collected after 2 weeks and 3, 6, 12, and 18 months of exposure. A separate set of mice was kept in the control chamber and exposed to 2BE for 3 weeks when they were approximately 19 months old. Postexposure blood samples were collected after 1 day and 3 weeks of exposure and 16-h urine samples were collected after 2 weeks of exposure from these aged mice. Blood samples were analyzed for both 2BE and 2BAA and urine samples were analyzed for 2BAA using GC/MS, and their kinetic parameters were estimated through the curve-fitting method using SAS. Systemically absorbed 2BE was rapidly cleared from blood (t1/2-RAT < 10 min; t1/2-MOUSE < 5 min after the 1-day exposure) independent of exposure concentration. Proportional increases in AUC2BE relative to increases in exposure concentration indicated linear 2BE kinetics. In contrast, the rate of 2BAA elimination from blood decreased as the exposure concentration increased. Nonproportional increases in AUC2BAA also indicated that 2BAA is eliminated following dose-dependent, nonlinear kinetics. Overall, mice eliminated both 2BE and 2BAA from blood faster than rats. Sex-related differences in 2BAA elimination were most significant with rats, in that females were less efficient in clearing 2BAA from the blood. Differences in renal excretion of 2BAA are possibly responsible for the sex-related difference in the 2BAA blood profiles in rats. As exposure continued, the rates of elimination for both 2BE and 2BAA decreased in both species, resulting in longer residence times in the blood. When 19-month-old naive mice were exposed to 125 ppm, 2BE was rapidly cleared from the systemic circulation, exhibiting clearance profiles similar to young mice. However, old mice eliminated 2BAA from blood > 10 times slower than young mice after 1-day of exposure. This delayed elimination of 2BAA in old mice was less obvious after 3 weeks of exposure, suggesting that there might be other factors in addition to the age of animals that could influence the apparent difference in 2BAA kinetics between old and young mice. It was concluded that the elimination kinetics of 2BE and 2BAA following repeated 2BE exposure appear to be dependent on species, sex, age, time of exposure, as well as the exposure concentration.

Administration, Inhalation↗

PubMed1998

Cytokine induced modulation of MHC class I and class II molecules on human cervical epithelial cells.

Our purpose was to determine the expression of the major histocompatibility complex (MHC) class I and class II gene products as well as the costimulatory molecules B7-1 and B7-2 on cervical epithelial cells, and to determine to what extent inflammatory cytokines regulate their expression. Immunohistology and flow cytometry techniques were used to identify and quantify MHC class I and class II molecules, and the costimulatory molecules B7.1 and B7.2, on sections and primary epithelial cell cultures of human endo- and ectocervix. MHC class I but not class II molecules were constitutively expressed on tissue sections and primary epithelial cell cultures derived from endo- and ectocervix. Expression of MHC class I and class II was upregulated in vitro by IFN-gamma in a time and dose dependent fashion. The induction of class II expression was more pronounced on ectocervical cells than on endocervical cells. MHC class I but not class II expression was also enhanced by IFN-alpha as well as TNF-alpha. TNF-alpha and TGF-beta1 inhibited the IFN-gamma induced MHC class II expression. Expression of the costimulatory molecules B7-1 and B7-2 were not detected in tissue sections or on resting or cytokine-treated cervical epithelial cells in vitro. The present results support the concept that endo- and ectocervical epithelial cells, like their counterparts at other mucosal sites. constitutively express MHC class I molecules and can express MHC class II upon cytokine stimulation, indicating that they are capable of presenting antigens to T-cells.

3T3 Cells↗

PubMed1998

Microscopic evidence against HIV-1 infection of germ cells or attachment to sperm.

For a number of years we have intensively investigated the localization of HIV-1 in male genital tract tissues and secretions using a variety of microscopy techniques including immunocytochemistry, in situ hybridization, in situ PCR and electron microscopy. Our studies have failed to demonstrate an association between HIV-1 and either testicular germ cells or spermatozoa. In this article we present our results in the context of other related studies, and discuss the strengths and weaknesses of the techniques that have been used to address this important research question.

Animals↗