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Biomedical subjects

D J Anderson

Publications and source records attributed to D J Anderson.

At least 163 records · Page 9Linked to original sources
PubMed1996

The importance of mucosal immunology to problems in human reproduction.

The field of mucosal immunology is making rapid advances towards establishing the molecular basis of mucosal defense mechanisms and the development of mucosal vaccines. Research on the mucosal immunology of male and female reproductive tract tissues is benefiting from these advances, as well as from current investigations on specialized immunologic features of the reproductive tract. This knowledge may soon be applicable to solutions for many important problems concerning human reproduction, such as fertility regulation and the current epidemic of sexually transmitted diseases, including AIDS.

Humans↗
PubMed1996

A reciprocal cell-cell interaction mediated by NT-3 and neuregulins controls the early survival and development of sympathetic neuroblasts.

Neurotrophin 3 (NT-3) can support the survival of some embryonic sympathetic neuroblasts before they become nerve growth factor dependent. We show that NT-3 is produced in vivo by nonneuronal cells neighboring embryonic sympathetic ganglia. NT-3 mRNA is produced by these nonneuronal cells in vitro and is up-regulated by platelet-derived growth factor, ciliary neurotrophic factor, and glial growth factor 2 (a neuregulin). Nonneuronal cell-conditioned medium promotes survival and induces TrkA expression in isolated sympathetic neuroblasts, and this activity is blocked by anti-NT-3 antibody. Neuroblasts also enhance NT-3 production by nonneural cells. Neuroblasts synthesize several forms of neuregulin, and antibodies to neuregulin attenuate the effect of the neuroblasts on the nonneuronal cells. These data suggest a reciprocal cell-cell interaction, in which neuroblast-derived neuregulins promote NT-3 production by neighboring nonneuronal cells, which in turn promotes neuroblast survival and further differentiation.

Animals↗
PubMed1996

Quantitative structure-activity relationships of nicotine analogues as neuronal nicotinic acetylcholine receptor ligands.

Quantitative structure-activity relationships of 34 pyrrolidine-modified nicotine agonists are investigated for their binding affinity toward neuronal nicotinic acetylcholine receptor. The results indicate that a large substituent at the R1, R2, and R3 position is detrimental to the binding affinity. Likewise, a large substituent at the R2 alpha or R3 alpha position as well as a hydrogen bond accepting substituent at the R2 beta position are not beneficial to the binding.

Binding Sites↗
PubMed1996

Progesterone-induced immunosuppression is not mediated through the progesterone receptor.

Progesterone is a known immunosupressant in humans and may be important in treatment regimens for women with immunological and endocrinological reproductive failure. The molecular mechanism of progesterone-mediated immunosuppression remains controversial. We used the reverse transcriptase polymerase chain reaction (RT-PCR) technique to detect progesterone receptor RNA in human peripheral blood mononuclear cells (PBMCs). No expression could be documented in PBMCs from men or women representing various reproductive states. We also used the glucocorticoid receptor antagonist RU 43044 to address the hypothesis that progesterone exerts immunomodulatory effects via interactions with the glucocorticoid receptor. Both hydrocortisone (10(-6) and 10(-7) M) and progesterone (10(-5), 10(-6) and 10(-7) M) inhibited phytohaemagglutinin-induced lymphocyte proliferation in a dose-dependent fashion. RU 43044 (10(-5) M) significantly reversed the immunosuppressive effect od hydrocortisone but not that of progesterone. These studies indicate that human PBMCs do not express the classical progesterone receptor. Our results further suggest that progesterone does not mediate its immunomodulatory effects via interaction with the glucocorticoid receptor. Interaction with other members of the steroid and thyroid hormone receptor superfamily, local conversion to other steroid substances or non-classical receptor-mediated mechanisms may be involved.

Female↗
PubMed1996

The effects of unilateral and bilateral chewing, empty clenching and simulated bruxism, on the masticatory-parotid salivary reflex in man.

In man, parotid flow has been recorded, using modified Lashley cups, in response to mechanical stimulation of the teeth by repeated chewing and clenching manoeuvres. The rectified and integrated masseter electromyographic activity was used as an indirect measure of the stimulus intensity where necessary. Following the observation that "empty clenching' failed to evoke a parotid salivary response, a series of three experiments has been undertaken to address the following questions. (1) Is a lateral component of force required to evoke a flow during empty clenching? (2) Does contralateral inhibition of salivary secretion explain this observation? (3) What is the threshold for the masticatory-salivary reflex? The results suggest that: (i) empty clenching together with a lateral component of force does not result in a secretion above resting flows; (ii) there is no evidence for the existence of contralateral inhibition of salivary secretion; and (iii) the threshold for the masticatory-salivary reflex is lower than 5% of comfortable chewing forces. We are still unable to offer an explanation for the lack of parotid secretion during empty clenching.

Bruxism↗
PubMed1996

Distinct subpopulations of enteric neuronal progenitors defined by time of development, sympathoadrenal lineage markers and Mash-1-dependence.

Enteric and sympathetic neurons have previously been proposed to be lineally related. We present independent lines of evidence that suggest that enteric neurons arise from at least two lineages, only one of which expresses markers in common with sympathoadrenal cells. In the rat, sympathoadrenal markers are expressed, in the same order as in sympathetic neurons, by a subset of enteric neuronal precursors, which also transiently express tyrosine hydroxylase. If this precursor pool is eliminated in vitro by complement-mediated lysis, enteric neurons continue to develop; however, none of these are serotonergic. In the mouse, the Mash-1-/- mutation, which eliminates sympathetic neurons, also prevents the development of enteric serotonergic neurons. Other enteric neuronal populations, however, including those that contain calcitonin gene related peptide are present. Enteric tyrosine hydroxylase-containing cells co-express Mash-1 and are eliminated by the Mash-1-/- mutation, consistent with the idea that in the mouse, as in the rat, these precursors generate serotonergic neurons. Serotonergic neurons are generated early in development, while calcitonin gene related peptide-containing enteric neurons are generated much later. These data suggest that enteric neurons are derived from at least two progenitor lineages. One transiently expresses sympathoadrenal markers, is Mash-1-dependent, and generates early-born enteric neurons, some of which are serotonergic. The other is Mash-1-independent, does not express sympathoadrenal markers, and generates late-born enteric neurons, some of which contain calcitonin gene related peptide.

Animals↗
PubMed1996

How should hospitals relate to Medicare HMOs?

With the increased emphasis on the development of Medicare managed care plans, healthcare organizations should explore Medicare managed care products and structures available in the marketplace and assess how they best fit with their overall strategy and strengths. An organization's Medicare strategy might involve protecting the organization's current Medicare population, increasing network linkages, and gaining experience with managed care and capitated payment contracting. Medicare, however, is only one of many potential payers for organizations. A strategy developed around Medicare, therefore, also must support the organization's overall managed care strategy.

Aged↗
PubMed1996

Stable expression, pharmacologic properties and regulation of the human neuronal nicotinic acetylcholine alpha 4 beta 2 receptor.

(-)-Nicotine, the prototypical agonist for neuronal nicotinic acetylcholine receptors (nAChR) has been shown to bind with high affinity to the rodent and avian alpha 4 beta 2 nAChR subtype. This subtype may represent a primary molecular target for some of the beneficial central nervous system effects i.e., cognitive enhancement, anxiolysis, analgesia, neuroprotection, of (-)-nicotine and related ligands. However, a detailed study of the human alpha 4 beta 2 subunit combination has not yet been reported. In this study, we stably coexpressed the human neuronal alpha 4 and beta 2 nAChR subunits in human embryonic kidney (HEK) 293 cells and studied its pharmacological and regulatory properties. [3H]Cytisine bound to stably transfected cells with high affinity (KD value, 0.2 +/- 0.04 nM) and with a Bmax value of 1359 +/- 91 fmol/mg protein. A good correlation (r = 0.98) was observed between binding affinities in transfected cells and in native neuronal preparations for a series of nAChR ligands. 86Rb+ efflux studies showed that stably transfected cells express functional ion channels that are sensitive to blockade by dihydro-beta-erythroidine. (+/-)-Epibatidine, (-)-nicotine, 1,1-dimethyl-4-phenylpiperazinium, (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT-418), acetylcholine and (-)-cytisine stimulated 86Rb+ efflux with EC50 values of 0.02, 3.9, 2.5, 10, 44 and 38 microM, respectively. Treatment of transfected cells with (-)-nicotine for 7 days led to a significant increase in the density of [3H](-)-cytisine binding sites (EC50 = 0.56 microM) and a significant enhancement in the sensitivity of ACh. Specific binding or (-)-nicotine-evoked cation efflux was not detected in untransfected cells. Analysis of total cellular RNA from transfected, but not untransfected cells, showed the expected fragment sizes corresponding to the human alpha 4 and beta 2 subunit mRNA. These results demonstrate that stable expression of the human alpha 4 beta 2 nAChR subunit combination can give rise to functional ion channels that bind [3H](-)-cytisine with high affinity, exhibit homologous regulation and evoke agonist-induced cation flux with pharmacological properties consistent with native neuronal alpha 4 beta 2 nAChR.

Alkaloids↗
PubMed1996

Is leukocytospermia clinically relevant?

OBJECTIVE: To evaluate the relationship between seminal leukocytes and abnormal semen parameters in a large population of infertility patients. DESIGN: Prospective clinical study. SETTING: Center for Reproductive Medicine at Brigham and Women's Hospital, Boston, Massachusetts. PATIENT(S): One thousand seven hundred ten male partners in infertile couples attending the Center for Reproductive Medicine. MAIN OUTCOME MEASURE(S): Seminal leukocyte concentrations, sperm count, motility and morphology, and the prevalence of samples with < 10 x 10(6) motile sperm per ejaculate (a parameter defined by IVF as the most clinically significant predictor of male infertility). RESULT(S): There was a strong relationship between increasing leukocyte concentrations in semen and abnormal semen parameters. Statistically significant differences in sperm concentrations and morphology were observed at leukocytospermia thresholds of 5 x 10(5) and 2 x 10(6) granulocytes/mL, respectively. The percentage of suboptimal semen specimens as defined by IVF criteria (< 10(7) total motile sperm per ejaculate) significantly increased with increasing seminal granulocyte concentrations. A twofold increased prevalence in such suboptimal semen specimens was observed at the leukocytospermia threshold of 2 x 10(6) granulocytes/mL. CONCLUSION(S): There is a relationship between increasing seminal granulocyte concentrations and poor semen parameters. At seminal granulocyte concentrations > 2 x 10(6)/mL, semen parameter abnormalities were observed that were both statistically and clinically significant.

Fertilization in Vitro↗
PubMed1996

Isoform-specific biotransformation of glyceryl trinitrate by rat aortic glutathione S-transferases.

The objective of this study was to purify and characterize rat aortic glutathione S-transferases (GSTs) and to assess their role in the biotransformation of the nitrovasodilator, glyceryl trinitrate (GTN). Two class alpha GSTs (Ya and Yc) a class mu GST (Yb2) and a class pi GST (Yp) were identified in rat aortic cytosol. Partial purification of three of these (Yb2, Yc and Yp) was achieved by affinity chromatography with S-hexylglutathione agarose. Further purification by cation- and anion-exchange chromatography resulted in the purification of GST Yc and GST Yb2/Yp to apparent homogeneity, a purification of 200- and 110-fold, respectively. Purified GST Yc and Yb2/Yp mediated GTN biotransformation with similar rates. GST activity and GTN biotransformation by rat aortic cytosol and affinity-purified GSTs were highly sensitive to inhibition by the class mu selective inhibitors Basilen Blue and bromosulfophthalein. Removal of GST Yb2 from rat aortic cytosol by immunoprecipitation resulted in marked inhibition of GST activity and GTN biotransformation. We conclude that the GSTs account for the major portion of GTN biotransformation in rat aortic cytosol, and that this is primarily attributable to the GST Yb2 isoform.

Animals↗
PubMed1996

Inhibition of the pharmacological actions of glyceryl trinitrate after the electroporetic delivery of a glutathione S-transferase inhibitor.

It is generally accepted that the biotransformation of organic nitrates to an activator of soluble guanylyl cyclase (presumably NO) is a prerequisite for their vasodilator actions. The glutathione S-transferases (GSTs) mediate glyceryl trinitrate (GTN) biotransformation, but whether this results in guanylyl cyclase activation and relaxation of vascular smooth muscle is equivocal. We used electroporation of adherent cultured cells to deliver the membrane-impermeable GST inhibitor basilen blue (BB) into porcine kidney epithelial cells. This resulted in significant inhibition of GTN biotransformation because of a reduction in the formation of glyceryl-1,2-dinitrate, but not glyceryl-1, 3-dinitrate. In the 105,000 x g supernatant fraction of porcine kidney epithelial cells, BB significantly inhibited the formation of both GTN metabolites. Electroporation of porcine kidney epithelial cells with BB also inhibited GTN-induced cyclic GMP accumulation. This was caused in part by inhibition of soluble guanylyl cyclase by BB. To differentiate BB-mediated inhibition of the bioactivation of GTN from its inhibitory effect on guanylyl cyclase, inhibition of cyclic GMP accumulation induced by GTN and that induced by the spontaneous NO-releasing compound, t-butyl-S-nitrosothiol were compared. Maximum inhibition of cyclic GMP accumulation by BB was 80% and 40% with GTN and t-butyl-S-nitrosothiol as the stimulating compounds, respectively. These data suggest that GSTs mediate the biotransformation of GTN to an activator of guanylyl cyclase and support the contention that vascular GSTs participate in mediating the relaxant effects of organic nitrates.

Animals↗
PubMed1995

Neural development. Spinning skin into neurons.

Basic helix--loop--helix proteins are transcriptional regulations with important roles in myogenesis and neurogenesis. One such protein, NeuroD, has an impressive ability to promote ectopic neuronal differentiation in xenopus.

Animals↗
PubMed1995

T-helper 1-type immunity to trophoblast in women with recurrent spontaneous abortion.

OBJECTIVE: To test the hypothesis that peripheral blood mononuclear cells in women with unexplained recurrent abortion (URA) produce T-helper 1 (TH1)-type cytokines in response to trophoblast antigens. DESIGN: Cohort study. SETTING: Medical center. PARTICIPANTS: A total of 244 women with URA, 13 reproductively normal parous control women, and 10 men. MAIN OUTCOME MEASURES: Supernatants from trophoblast-activated peripheral blood mononuclear cells from all participants were tested for toxic effects on mouse embryos and by enzyme-linked immunosorbent assay (ELISA) for interferon gamma (IFN-gamma). Supernatants from 20 URA patients with embryotoxic activity and IFN-gamma, 13 reproductively normal parous women, and 10 men were further tested by ELISA for other TH1-type cytokines (interleukin-2 [IL-2], tumor necrosis factor-beta [TNF-beta]), TH2-type cytokines (IL-4, IL-10), and TNF-alpha. RESULTS: Embryotoxic activity was detected in supernatants from 160 of 244 URA patients and in none of the controls. Interferon gamma was detected in supernatants from 125 of 244 URA patients and was significantly associated with embryotoxicity (121 of 160 supernatants with embryotoxicity vs four of 84 supernatants without embryotoxicity [P < .001]). Of 20 supernatants from patients chosen for further study, all were positive for TNF-alpha, 17 for TNF-beta, two for IL-10, and one for IL-4. No cytokines were detected in supernatants from unstimulated or red blood cell membrane-activated cells of women with URA. In contrast, trophoblast-activated lymphocyte supernatants from reproductively normal women and men neither were embryotoxic nor contained TH1-type cytokines, but most contained the TH2-type cytokine IL-10. Three supernatants from reproductively normal women also contained IL-4. CONCLUSION: Whereas TH1-type immunity to trophoblast is associated with URA and may play a role in reproductive failure, TH2-type immunity may be a natural response to trophoblast contributing to successful pregnancy.

Abortion, Habitual↗
PubMed1995

Erysodine, a competitive antagonist at neuronal nicotinic acetylcholine receptors.

Erysodine, an erythrina alkaloid related to dihydro-beta-erythroidine, was found to be a more potent inhibitor of [3H]cytisine binding at neuronal nicotinic acetylcholine receptors but a less potent inhibitor of [125I]alpha-bungarotoxin binding at muscle-type nicotinic acetylcholine receptors than dihydro-beta-erythroidine. Erysodine was a competitive, reversible antagonist of (-)-nicotine-induced dopamine release from striatal slices and inhibited (-)-nicotine-induced 86Rb+ efflux from IMR-32 cells. Erysodine was equipotent with dihydro-beta-erythroidine in the dopamine release assay but 10-fold more potent in the 86Rb+ efflux assay, suggesting differential subtype selectivity for these two antagonists. Erysodine, systemically administered to mice, entered the brain and significantly attentuated nicotine's hypothermic effects and its anxiolytic-like effects in the elevated plus-maze test. There was greater separation between antagonist and toxic doses for erysodine than for dihydro-beta-erythroidine, perhaps because of erysodine's greater selectivity for neuronal receptors. In rats, erysodine prevented both the early developing decrease and the late-developing increase in locomotor activity produced by (-)-nicotine. The potent and competitive nature of erysodine's antagonism together with its ability to enter the brain after systemic administration suggest that erysodine may be a useful tool in characterizing neuronal nicotinic acetylcholine receptors.

Alkaloids↗
PubMed1995

The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes.

The neuron-restrictive silencer factor (NRSF) binds a DNA sequence element, called the neuron-restrictive silencer element (NRSE), that represses neuronal gene transcription in nonneuronal cells. Consensus NRSEs have been identified in 18 neuron-specific genes. Complementary DNA clones encoding a functional fragment of NRSF were isolated and found to encode a novel protein containing eight noncanonical zinc fingers. Expression of NRSF mRNA was detected in most nonneuronal tissues at several developmental stages. In the nervous system, NRSF mRNA was detected in undifferentiated neuronal progenitors, but not in differentiated neurons. NRSF represents the first example of a vertebrate silencer protein that potentially regulates a large battery of cell type-specific genes, and therefore may function as a master negative regulator of neurogenesis.

Amino Acid Sequence↗
PubMed1995

Detection of semen in cervicovaginal secretions.

Sperm were detectable by microscopic examination in human cervicovaginal lavage (CVL) specimens < or = 8 h after intercourse, whereas an enzyme-linked immunosorbent assay using the monoclonal antibody MHS-5, specific for a seminal vesicle antigen present in semen detected semen at a concentration of 1:2,500,000 (0.00004%) in CVL specimens and was positive < or = 24 h following unprotected intercourse. We recommend the routine use of semen detection assays to reduce false-positive results attributable to semen contamination in assays of pathogens, antibodies, or other factors in cervicovaginal secretions.

Antibodies, Monoclonal↗
PubMed1995

Identification by differential RT-PCR of a novel paired homeodomain protein specifically expressed in sensory neurons and a subset of their CNS targets.

Sensory neurons are a major derivative of the neural crest for which there have been no definitive molecular markers in mammals. We have developed a method that combines differential hybridization with degenerate RT-PCR to rapidly screen gene families for members exhibiting differential expression among tissues or cell types. We used this approach to search for transcription factor-encoding genes specifically expressed in mammalian sensory neurons. A novel paired homeodomain protein, called DRG11, was identified. DRG11 is expressed in most sensory neurons, including trkA-expressing neurons, but not in glia or sympathetic neurons. Unexpectedly, it is also expressed in the dorsal horn of the spinal cord, a region to which NGF-dependent sensory neurons project. These data suggest that DRG11 is not only a useful marker for sensory neurons, but may also function in the establishment or maintenance of connectivity between some of these neurons and their central nervous system targets.

Animals↗