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Biomedical subjects

K A Sullivan

Publications and source records attributed to K A Sullivan.

At least 37 records · Page 2Linked to original sources
PubMed1997

Insulin-like growth factors regulate neuronal differentiation and survival.

Insulin-like growth factor I (IGF-I) and IGF-II are potent trophic factors for motor and sensory neurons and glial cells. The actions of IGF-I and IGF-II are mediated via the IGF-I receptor (IGF-IR). IGF:IGF-IR binding activates distinct signaling cascades, which in turn mediate the trophic effects of the IGFs. We discuss three main IGF coupled events: growth cone motility, long-term neurite outgrowth, and neuroprotection. Our data suggest that IGF-I enhances growth cone motility by promoting reorganization of actin and activation of focal adhesion proteins via the phosphatidylinositol-3 kinase (Pl-3K) pathway. Long-term treatment with IGF-I activates the mitogen-activated protein (MAP) kinase cascade and promotes neurite outgrowth. A separable, but likely linked, action of the IGFs via Pl-3K is protection of neurons from apoptosis. These pleotrophic effects of IGFs suggest that this family of growth factors may have potential clinical utility in the treatment of neurological disorders.

Animals↗
PubMed1996

Immunohistochemical localization of insulin-like growth factor binding protein-5 in the developing rat nervous system.

The insulin-like growth factors (IGF-I and IGF-II) are peptides with both growth-promoting and insulin-like metabolic effects. The IGFs interact with and are modulated by a group of six IGF-binding proteins (IGFBP-1 through IGFBP-6). Previous studies have characterized IGFBP-5 and IGF-I gene expression in the developing nervous system. In the current study, cellular and tissue-specific distribution of IGFBP-5 protein was examined in the developing rodent nervous system using immunohistochemistry. Beginning with embryonic stage E12, IGFBP-5 immunoreactivity was observed in peripheral nerves. This pattern persisted through adulthood and was detected within Schwann cells and axons after postnatal day 16 (P16). IGFBP-5 immunoreactivity first appeared in the CNS at P16. Purkinje cells of the cerebellum were immunostained at P16, P32 and in the adult. IGFBP-5 immunoreactivity was also detected in several brain stem nuclei and their corresponding tracts as well as neuroglia. Nerve tracts and glia in the postnatal spinal cord were also immunopositive, however, spinal cord neurons were not stained. The current results, coupled with the known profile of IGF-I expression during nervous system development demonstrates the colocalization of IGF-I and IGFBP-5 in PNS, cerebellum, and brain stem.

Animals↗
PubMed1995

Gonadotropin-releasing hormone neurons in the rhesus macaque are not immunoreactive for the estrogen receptor.

The issue of whether gonadotropin-releasing hormone (GnRH) neurons in the primate contain the estrogen receptor was examined by immunocytochemistry using prepubertal and adult (intact and ovariectomized) female rhesus macaques. No GnRH neurons were found to contain nuclei that were immunoreactive for the estrogen receptor. These results confirm in primates what has been reported in other species and leave open the question of how the effects of gonadal steroids on GnRH neurons are mediated.

Animals↗
PubMed1995

Purification and characterization of a naturally occurring vascular endothelial growth factor.placenta growth factor heterodimer.

Vascular endothelial growth factor (VEGF) is a potent and selective mitogen for endothelial cells that is angiogenic in vivo and induced by hypoxia. A homologous protein, placenta growth factor (PlGF), is also reported to be mitogenic for endothelial cells in culture. The rat GS-9L glioma cell line produces not only VEGF homodimers but also PlGF homodimers and a novel heterodimer composed of VEGF and PlGF subunits. All three dimeric forms were purified to apparent homogeneity, and their structures and mitogenic activities were compared. VEGF.PlGF heterodimers are vascular endothelial cell mitogens nearly as potent as VEGF homodimers. Therefore, some of the biological activities attributed to VEGF homodimers might be mediated by VEGF.PlGF heterodimers. In contrast, pure PlGF homodimers are mitogenic for endothelial cells only at high, possibly non-physiologic concentrations; thus the biological relevance of their mitogenic activity for these cells is not obvious. However, the existence of not only homodimers but also heterodimers clearly extends the similarity between the VEGF/PlGF and the homologous platelet-derived growth factor systems.

Amino Acid Sequence↗
PubMed1995

Antimicrobial characterization and interrelationships of dirithromycin and epidirithromycin.

Dirithromycin is the 9-N,11-O-oxazine adduct formed from 9(S)-erythromycylamine and 2-(2-methoxyethoxy)acetaldehyde in which the methoxyethoxymethyl substituent on the oxazine ring possesses the R configuration. Epidirithromycin is its isomer in which the methoxyethoxymethyl substituent has the opposite (S) configuration. Both compounds readily epimerize in solution, reaching an equilibrium ratio of 85:15 in favor of dirithromycin, given sufficient time. The rate of interconversion is dependent upon pH, temperature, and solvent. An enriched sample of epidirithromycin (95% purity) was synthesized by condensing erythromycylamine and 2-(2-methoxyethoxy)acetaldehyde in diethyl ether as the reaction solvent, and the product was fully characterized by nuclear magnetic resonance spectroscopy and high-pressure liquid chromatographic (HPLC) analysis. Both oxazine derivatives readily hydrolyze to erythromycylamine, so all three compounds exhibit the same antibiotic activity in vitro. In order to determine whether dirithromycin itself possesses significant antimicrobial activity without initial hydrolysis to erythromycylmine, inhibition of cell-free ribosomal protein synthesis was measured under conditions which were adapted to minimize hydrolysis, as measured by analytical HPLC in parallel experiments. Under these particular conditions, inhibition of ribosomal protein synthesis by dirithromycin was < 10% of the value measured for erythromycylamine.

Anti-Bacterial Agents↗
PubMed1995

Insulin-like growth factor II in the pathogenesis of human neuroblastoma.

Insulin-like growth factor II (IGF-II) acts as an autocrine growth factor for many in vitro tumor cell lines including neuroblastoma. To examine the role of IGF-II in tumor biology we have analyzed a total of 56 primary neuroblastoma tumor samples for the presence of IGF-II using a combination of mRNA and protein analysis. A group of 21 samples was examined for the presence of IGF-II mRNA by slot blot and a separate group of 37 samples was examined for IGF-II immunoreactivity. IGF-II was detected in 48% of the total tumor specimens analyzed. IGF-II immunoreactivity was observed in cells resembling developing neuroblasts and was confined to the cytoplasm and proximal neurites. The appearance of IGF-II mRNA and protein did not correlate with tumor prognostic features including stage, histology, or N-myc amplification. These data suggest that the expression of IGF-II is not confined to a specific stage of the disease but may have a broader role in the pathogenesis of neuroblastoma.

Adult↗
PubMed1994

Ontogeny of neurotransmitter systems in the paracervical ganglion and uterine cervix of the rat.

BACKGROUND: The paracervical ganglia (PG) are components of the pelvic plexus that provides sensory and motor innervation to the reproductive system of the female rat. Several neurotransmitters including norepinephrine (NE), acetylcholine (ACh), neuropeptide Y (NPY), and vasoactive intestinal polypeptide (VIP) are present in neurons of the adult PG and in axons innervating the adult uterus and uterine cervix. The current study was undertaken to describe the onset of immunoreactivity of these neurotransmitters and neuropeptides during development. METHODS: Female rats, ages E18 to P36, were prepared for immunohistochemistry for TH (tyrosine hydroxylase, a marker of noradrenergic neurons), NPY, or VIP as well as the histochemical demonstration of acetylcholinesterase (AChE). RESULTS: All four markers were detected in neurons of the PG at E18. Changes in the appearance of these markers from E18 to P36 reflected previously described growth changes in the PG. Axons containing AChE, TH, NPY, or VIP were first detected within the cervix at E20. Immunopositive axons first appeared as thick, unbranched structures at the outermost portion of the cervical myometrium. Over time, these axon bundles ramified to form discrete varicose axons. The ingrowth was similar for axons containing each of the four markers. CONCLUSIONS: The relative density of each neuronal type in the PG was reflected in the density of axons containing the same marker in the cervix. Changes in neurotransmitter/neuropeptide staining of PG neurons or axons in the cervix were not observed as the animals approached puberty.

Acetylcholinesterase↗
PubMed1994

Progression of symptoms in neuroleptic malignant syndrome.

The neuroleptic malignant syndrome (NMS) is a rare but potentially fatal disorder characterized by mental-status changes, muscle rigidity, hyperthermia, and autonomic dysfunction. Systematic examination of early signs and the progression of symptoms in NMS may be worthwhile to facilitate prompt recognition and interventions to abort the syndrome in its incipient stage. The authors present the results of a preliminary review of the temporal sequence of the four predominant signs of NMS as described in 340 clinical reports of NMS in the literature. Of all order implications, 70.5% were consistent with the sequence of mental-status changes, rigidity, hyperthermia, and autonomic dysfunction. Changes in either mental status or rigidity were the initial manifestations of NMS in 82.3% of cases with a single presenting sign and were significantly more likely to be observed before hyperthermia and autonomic dysfunction. Methodological limitations of these data and clinical implications are discussed.

Adolescent↗
PubMed1994

Induction of vascular endothelial growth factor expression by prostaglandin E2 and E1 in osteoblasts.

PGE1 and PGE2 are potent stimulators of bone formation. Osteogenesis is strongly dependent on angiogenesis. Vascular endothelial growth factor (VEFG), a secreted endothelial cell-specific mitogen, has been implicated in physiological and pathological angiogenesis. The aim of this study was to examine the possible role of VEGF in PG stimulation of bone formation. We found that in rat calvaria-derived osteoblast-enriched cells and in the osteoblastic RCT-3 cell line PGE2 and E1 increased VEGF mRNA and protein levels. The increased expression of VEGF mRNA produced by PGE2 was rapid (maximal at 1 h), transient (declined by 3 h), potentiated by cycloheximide, and abolished by actinomycin D. PGE2 had no effect on VEGF mRNA stability, suggesting transcriptional regulation of VEGF expression by PGF2. Rp-cAMP, a cAMP antagonist, suppressed VEGF mRNA induced by PGE2, indicating cAMP mediation. The upregulation of VEGF expression by PGE2 in the preosteoblastic RCT-1 cells was potentiated by treatment with retinoic acid, which induces the differentiation of these cells. The upregulation of VEGF mRNA by PGE2 was inhibited by dexamethasone treatment. In addition, Northern blot analysis showed that VEGF mRNA is expressed in adult rat tibia. In summary, we documented, for the first time, the expression of VEGF in osteoblasts and in bone tissue. Stimulation of VEGF expression by PGs and its suppression by glucocorticoids, which, respectively, stimulate and suppress bone formation, strongly implicate the involvement of VEGF in bone metabolism.

Alprostadil↗
PubMed1994

Immunohistochemical localization of insulin-like growth factor-II (IGF-II) and IGF-binding protein-2 during development in the rat brain.

The insulin-like growth factors (IGF-I and IGF-II) are peptide growth factors with both growth-promoting and insulin-like activities. In the nervous system, the expression of both IGF-I and IGF-II messenger RNAs (mRNAs) is developmentally regulated, with IGF-I expression highest during puberty, and IGF-II levels peaking during the perinatal period. The IGFs interact with and are modulated by a group of six binding proteins, the IGF-binding proteins (IGFBP-1 to IGFBP-6). IGFBP-2 mRNA is most prevalent in the nervous system, where, like IGF-II, its expression correlates with a period of brain growth. In the current study, cells containing IGF-II and IGFBP-2 were identified within the developing nervous system of the rat on embryonic day 12 (E12), E14, E18, and postnatal day 1 and in the adult. IGF-II immunoreactivity was detected within the mesenchymal core of the choroid plexus at all ages examined and was also observed in the developing leptomeninges. IGF-II appeared transiently in the central nervous system in presumptive glia of the hippocampus and medial basal hypothalamus and in a small population of neurons in the brain stem. IGFBP-2 was consistently observed in the epithelium of the choroid plexus as well as in the epithelia of the developing otic and olfactory placodes. While these results confirm the developmental expression of IGF-II and IGFBP-2 mRNA in the central nervous system, discrepancies exist between these data and those using molecular techniques. This may be due in part to differential sites of IGF-II and IGFBP-2 production compared to sites of action.

Animals↗
PubMed1993

The ontogeny of gonadotropin-releasing hormone neurons in the chick.

The origin of gonadotropin-releasing hormone (GnRH) neurons in the olfactory placode and their subsequent migration into the central nervous system (CNS) has been described in several species. The current study was undertaken to delineate the time course and route of GnRH neuronal migration in the chick using antisera generated against both the mammalian form of GnRH (LR1) and a specific chicken GnRH (cGnRH I). Chicks aged E4.5 through day of hatching were processed for GnRH immunocytochemistry. Under the incubation conditions employed in this study, GnRH neurons first appeared on E4.5 in the olfactory epithelium. GnRH neurons exit from the olfactory epithelium and follow the extracranial course of the olfactory nerve to the anterior pole of the developing forebrain. Within the nerve, cells are in close apposition to each other. By E5, cells had reached the surface of the telencephalon. Upon entering the CNS, the GnRH neurons dispersed within the neuropil and continued their migration as individuals. As development progressed, GnRH neurons migrated dorsally and caudally within the brain and reached their adult positions by E12. GnRH axons were detected in the vicinity of GnRH cell bodies with the cGnRH I antiserum as early as E4.5; however, GnRH axons did not reach the median eminence until E14. These results extend earlier reports in mammal and chick on the extracranial origin of GnRH neurons and their path of entry into and dispersion within the CNS.

Animals↗
PubMed1990

Synthesis and structure-activity relationships of new 9-N-alkyl derivatives of 9(S)-erythromycylamine.

A series of new 9-N-alkyl derivatives of 9(S)-erythromycylamine has been synthesized by reductive alkylation of erythromycylamine with aliphatic aldehydes and sodium cyanoborohydride. Alternative syntheses employing hydrogenation methods have also been developed. These new 9-N-alkyl derivatives possess excellent antimicrobial activity in vitro and in vivo, especially when administered orally to treat experimental infections in mice. From structure-activity studies, 9-N-(1-propyl)erythromycylamine (LY281389) was selected as the most efficacious derivative. These methods have also been extended to the synthesis of some 9-N,N-dialkyl derivatives of erythromycylamine.

Alkylation↗
PubMed1990

Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor.

Glioma-derived vascular endothelial cell growth factor (GD-VEGF) is a 46-kDa dimeric glycoprotein mitogen with apparently greater specificity for vascular endothelial cells than the well-characterized fibroblast growth factors. The GD-VEGF cDNA sequence encodes a 190-amino acid residue subunit that is converted, by removal of an amino-terminal hydrophobic secretory leader sequence, to the mature 164-residue subunit characterized by direct amino acid sequencing. The GD-VEGF homodimeric subunit is homologous to the platelet-derived growth factor A and B chains and its oncogene homologue v-sis.

Amino Acid Sequence↗
PubMed1990

The survival and nature of the immune response to soft-tissue and composite-tissue allografts in rats treated with low-dose cyclosporine.

We studied a variety of soft-tissue and composite-tissue allografts (CTA) in a histoincompatible rat model to determine the outcome and the nature of the immunologic responses to these tissues using continuous low-dose cyclosporine (CsA) therapy. Brown-Norway (RT1n) rats served as donors of soft tissue and CTA to Lewis (RT1l) rat recipients given low-dose CsA immunosuppressive therapy by gavage. Nine groups were studied. Three control groups were not treated with CsA: group 1, skin grafts alone; group 2, skin flaps alone; and group 3, skin grafts and delayed vessel allotransplants. Six groups were treated with CsA: group 4, skin grafts alone; group 5, skin flaps alone; group 6, skin grafts and delayed vessel allotransplants; group 7, aortas alone; group 8, muscle flaps alone; and group 9, bone grafts alone. Isografts were performed in all groups as technical controls. The appearance posttransplant of donor-directed cytotoxic antibodies was determined in recipient serum using a complement-mediated cytotoxicity assay and was compared to control and pretransplant sera. In the absence of CsA therapy, recipients in groups 1, 2, and 3 rejected their allografts early (8.5-9.4 days) and developed profound antidonor cytotoxic antibody activity posttransplant by day 7. Groups 4, 5, 6, 7, and 9 had prolonged graft survival in the presence of low-dose CsA, despite the presence of antidonor antibody activity. By contrast, group 8 (muscle flaps) were all uniformly rejected in the presence of profound recipient cytotoxic antidonor antibody activity. These results suggest that long-term soft-tissue and CTA survival can be achieved in histoincompatible rat recipients using continuous low-dose CsA immunosuppressive therapy despite the presence of cytotoxic antidonor antibodies.

Animals↗
PubMed1989

Sleep disturbance as the hallmark of posttraumatic stress disorder.

The reexperiencing of a traumatic event in the form of repetitive dreams, memories, or flashbacks is one of the cardinal manifestations of posttraumatic stress disorder (PTSD). The dream disturbance associated with PTSD may be relatively specific for this disorder, and dysfunctional REM sleep mechanisms may be involved in the pathogenesis of the posttraumatic anxiety dream. Furthermore, the results of neurophysiological studies in animals suggest that CNS processes generating REM sleep may participate in the control of the classical startle response, which may be akin to the startle behavior commonly described in PTSD patients. Speculating that PTSD may be fundamentally a disorder of REM sleep mechanisms, the authors suggest several strategies for future research.

Anxiety↗
PubMed1988

A mutation that prevents GTP-dependent activation of the alpha chain of Gs.

Membrane-bound G proteins carry information from receptors on the outside of cells to effector proteins inside cells. The alpha subunits of these heterotrimeric proteins bind and hydrolyse GTP and control the specificity of interactions with receptor and effector elements. Signalling by G proteins involves a cycle in which the inactive alpha beta gamma-GDP complex dissociates to produce alpha*-GTP, which is capable of activating the effector enzyme or ion channel; the alpha*-GTP complex hydrolyses bound GTP and reassociates with beta gamma to form the inactive complex. We have characterized a mutation that interrupts this GTP-driven cycle in alpha s, the alpha-chain of Gs, the G protein that stimulates adenylyl cyclase. The mutation converts a glycine to an alanine residue in the presumed GDP-binding domain of alpha s. The location and biochemical consequences of this mutation suggest a common mechanism by which binding of GTP or ATP may induce changes in the conformation of a number of nucleoside triphosphate binding proteins.

Adenosine Triphosphate↗
PubMed1988

Carboxyl terminal domain of Gs alpha specifies coupling of receptors to stimulation of adenylyl cyclase.

The alpha subunits of Gs and Gi link different sets of hormone receptors to stimulation and inhibition, respectively, of adenylyl cyclase. A chimeric alpha i/alpha s cDNA was constructed that encodes a polypeptide composed of the amino terminal 60% of an alpha i chain and the carboxyl terminal 40% of alpha s. The cDNA was introduced via a retroviral vector into S49 cyc- cells, which lack endogenous alpha s. Although less than half of the hybrid alpha chain is derived from alpha s, its ability to mediate beta-adrenoceptor stimulation of adenylyl cyclase matched that of the normal alpha s polypeptide expressed from the same retroviral vector in cyc- cells. This result indicates that carboxyl terminal amino acid sequences of alpha s contain the structural features that are required for specificity of interactions with the effector enzyme, adenylyl cyclase, as well as with the hormone receptor.

Adenylyl Cyclases↗