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Biomedical subjects

N Gerard

Publications and source records attributed to N Gerard.

35 records · Page 2Linked to original sources
PubMed1998

Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury.

Substance P, acting via the neurokinin 1 receptor (NK1R), plays an important role in mediating a variety of inflammatory processes. However, its role in acute pancreatitis has not been previously described. We have found that, in normal mice, substance P levels in the pancreas and pancreatic acinar cell expression of NK1R are both increased during secretagogue-induced experimental pancreatitis. To evaluate the role of substance P, pancreatitis was induced in mice that genetically lack NK1R by administration of 12 hourly injections of a supramaximally stimulating dose of the secretagogue caerulein. During pancreatitis, the magnitude of hyperamylasemia, hyperlipasemia, neutrophil sequestration in the pancreas, and pancreatic acinar cell necrosis were significantly reduced in NK1R-/- mice when compared with wild-type NK1R+/+ animals. Similarly, pancreatitis-associated lung injury, as characterized by intrapulmonary sequestration of neutrophils and increased pulmonary microvascular permeability, was reduced in NK1R-/- animals. These effects of NK1R deletion indicate that substance P, acting via NK1R, plays an important proinflammatory role in regulating the severity of acute pancreatitis and pancreatitis-associated lung injury.

Acute Disease↗
PubMed1998

A tyrosine-rich region in the N terminus of CCR5 is important for human immunodeficiency virus type 1 entry and mediates an association between gp120 and CCR5.

Human immunodeficiency virus type 1 (HIV-1) requires the presence of specific chemokine receptors in addition to CD4 to enter target cells. The chemokine receptor CCR5 is used by the macrophage-tropic strains of HIV-1 that predominate during the asymptomatic stages of infection. Here we identify a small tyrosine-rich region of CCR5 proximal to the N-terminal cysteine that is critical for entry of macrophage-tropic and dual-tropic variants of HIV-1. HIV-1 infection of cells expressing CCR5 mutants with changes in this region was substantially reduced compared with the infection of cells bearing wild-type CCR5. Simian immunodeficiency virus (SIVmac239) entry was also ablated on a subset of these mutants but enhanced on others. These differences in virus entry were correlated with the relative ability of soluble, monomeric HIV-1 and SIVmac239 gp120 glycoproteins to bind the CCR5 mutants. These results identify a region of CCR5 that is necessary for the physical association of the gp120 envelope glycoprotein with CCR5 and for HIV-1 infection.

Animals↗
PubMed1998

The orphan seven-transmembrane receptor apj supports the entry of primary T-cell-line-tropic and dualtropic human immunodeficiency virus type 1.

Human immunodeficiency virus type 1 (HIV-1) enters target cells by sequential binding to CD4 and specific seven-transmembrane-segment (7TMS) coreceptors. Viruses use the chemokine receptor CCR5 as a coreceptor in the early, asymptomatic stages of HIV-1 infection but can adapt to the use of other receptors such as CXCR4 and CCR3 as the infection proceeds. Here we identify one such coreceptor, Apj, which supported the efficient entry of several primary T-cell-line tropic (T-tropic) and dualtropic HIV-1 isolates and the simian immunodeficiency virus SIVmac316. Another 7TMS protein, CCR9, supported the less efficient entry of one primary T-tropic isolate. mRNAs for both receptors were present in phytohemagglutinin- and interleukin-2-activated peripheral blood mononuclear cells. Apj and CCR9 share with other coreceptors for HIV-1 and SIV an N-terminal region rich in aromatic and acidic residues. These results highlight properties common to 7TMS proteins that can function as HIV-1 coreceptors, and they may contribute to an understanding of viral evolution in infected individuals.

Amino Acid Sequence↗
PubMed1997

Two orphan seven-transmembrane segment receptors which are expressed in CD4-positive cells support simian immunodeficiency virus infection.

Clinical isolates of primate immunodeficiency viruses, including human immunodeficiency virus type 1 (HIV-1), enter target cells by sequential binding to CD4 and the chemokine receptor CCR5, a member of the seven-transmembrane receptor family. HIV-1 variants which use additional chemokine receptors are present in the central nervous system or emerge during the course of infection. Simian immunodeficiency viruses (SIV) have been shown to use CCR5 as a coreceptor, but no other receptors for these viruses have been identified. Here we show that two orphan seven-transmembrane segment receptors, gpr1 and gpr15, serve as coreceptors for SIV, and are expressed in human alveolar macrophages. The more efficient of these, gpr15, is also expressed in human CD4(+) T lymphocytes and activated rhesus macaque peripheral blood mononuclear cells. The gpr15 and gpr1 proteins lack several hallmarks of chemokine receptors, but share with CCR5 an amino-terminal motif rich in tyrosine residues. These results underscore the potential diversity of seven-transmembrane segment receptors used as entry cofactors by primate immunodeficiency viruses, and may contribute to an understanding of viral variation and pathogenesis.

Amino Acid Sequence↗
PubMed1997

Functional expression of the CXC-chemokine receptor-4/fusin on mouse microglial cells and astrocytes.

The mRNA for the seven-transmembrane-spanning G protein-coupled receptor fusin/CXCR-4 is expressed in primary mouse astrocyte cultures and the transformed mouse microglial cell line, N9. Cell surface expression of fusin in these cells was confirmed by staining with a polyclonal anti-fusin Ab. The functional capacity of this chemokine receptor was examined by evaluating the calcium responses following stimulation of glial cells with the CXC-chemokine, stromal-derived cell factor-1alpha (SDF-1alpha). Both astrocytes and microglial cells mobilized calcium following stimulation with chemically synthesized SDF-1alpha. SDF-1alpha- and carbachol-mediated calcium responses of astrocytes were partially inhibited by treatment with pertussis toxin (PTx), suggesting receptor coupling to a combination of G alpha(i) and other G proteins. In contrast, the calcium responses of microglial cells to SDF-1alpha were completely PTx sensitive, while responses to carbachol stimulation were PTx resistant. The ability of SDF-1alpha to induce glial cell migration was also examined. Synthetic SDF-1alpha was a potent chemoattractant for mouse microglial cells at ligand concentrations of 10 to 500 ng/ml; peak responses were noted at 100 ng/ml. In contrast, astrocytes did not migrate toward a gradient of SDF-1alpha. The failure of SDF-1alpha to induce astrocyte migration was specific, as another chemokine, macrophage inflammatory protein-1alpha, triggered astrocyte chemotaxis.

Animals↗
PubMed1997

Utilization of C-C chemokine receptor 5 by the envelope glycoproteins of a pathogenic simian immunodeficiency virus, SIVmac239.

We examined chemokine receptors for the ability to facilitate the infection of CD4-expressing cells by viruses containing the envelope glycoproteins of a pathogenic simian immunodeficiency virus, SIVmac239. Expression of either human or simian C-C chemokine receptor CCR5 allowed the SIVmac239 envelope glycoproteins to mediate virus entry and cell-to-cell fusion. Thus, distantly related immunodeficiency viruses such as SIV and the primary human immunodeficiency virus type 1 isolates can utilize CCR5 as an entry cofactor.

Animals↗
PubMed1996

The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates.

We examined the ability of chemokine receptors and related G protein-coupled receptors to facilitate infection by primary, clinical HIV-1 isolates. CCR5, when expressed along with CD4, the HIV-1 receptor, allowed cell lines resistant to most primary HIV-1 isolates to be infected. CCR3 facilitated infection by a more restricted subset of primary viruses, and binding of the CCR3 ligand, eotaxin, inhibited infection by these isolates. Utilization of CCR3 and CCR5 on the target cell depended upon the sequence of the third variable (V3) region of the HIV-1 gp120 exterior envelope glycoprotein. The ability of various members of the chemokine receptor family to support the early stages of HIV-1 infection helps to explain viral tropism and beta-chemokine inhibition of primary HIV-1 isolates.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Treatment of transverse maxillary deficiency with emphasis on surgically assisted-rapid maxillary expansion.

In this article we discussed the work-up necessary to evaluate a patient for maxillary transverse deficiency, and the three treatments for maxillary transverse deficiency-SDE, RME, and SA-AME. Slow dentoalveolar expansion is used mostly in the primary and early mixed dentition. Rapid maxillary expansion is indicated most often in the mixed dentition and can be attempted in the early adult dentition. Surgically assisted-rapid maxillary expansion is applicable almost exclusively in the adult dentition. The treatment of choice will depend on the age and skeletal maturity of the patient. Surgically assisted-rapid maxillary expansion, the technique that is used at The Medical College of Pennsylvania, combines all aspects of the previously mentioned osteotomies. The maxilla is separated at the midpalatal, the maxillary buttress, and the pterygomaxillary sutures. We have experienced good outcomes and stability with this technique. The reviewed literature shows good results with SA-RME for the treatment of maxillary transverse deficiency in the adult patient. It would be beneficial to study relapse and the periodontal ramifications of maxillary expansion further to better define the indications for SDE, RME, and SA-RME.

Adolescent↗
PubMed1995

Molecular characterization of two murine eosinophil beta chemokine receptors.

beta or C-C chemokines including RANTES, MCP-3, MIP-1 alpha, and eotaxin have been implicated in the pathogenesis of eosinophilic inflammation. Two human beta chemokine receptors have been cloned and characterized: the MIP-1 alpha/RANTES receptor or C-C chemokine receptor 1 (CCR-1) and the MCP-1 receptor or C-C chemokine receptor 2 (CCR-2). However, no murine beta chemokine receptors have thus far been reported. Molecular cloning from mouse genomic DNA and cDNA libraries yielded two murine beta chemokine receptors with 79% and 65% sequence identity with human CCR-1, and 50% and 55% with human CCR-2. COS cells transiently transfected with the murine homologue of human CCR-1 bind murine MIP-1 alpha and human RANTES with Kds of 3.4 nM and 4.2 nM and murine MIP-1 beta with an EC50 of 8.9 nM. The other murine beta chemokine receptor, which we have designated murine CCR-3, also binds murine MIP-1 alpha. The mRNAs for both receptors are expressed in eosinophils from IL-5 transgenic mice. The level of murine CCR-3 mRNA in these mouse eosinophils exceeds that of CCR-1 mRNA and approaches actin levels. Murine MIP-1 alpha was found to be a potent chemoattractant for murine eosinophils. Our findings suggest that the murine MIP-1 alpha ligand/receptor system is an important mediator of murine eosinophil trafficking.

Amino Acid Sequence↗
PubMed1995

Laser arthroscopy of the temporomandibular joint.

Laser surgery is very different than traditional surgery. The clinician must be familiar with the physical properties of the laser to use this instrument safely and properly. Various lasers are available for use in oral and maxillofacial surgery and dentistry, namely the carbon dioxide laser, the neodymium:yttrium-aluminum-garnet laser, and the holmium: yttrium-aluminum-garnet laser (Ho:YAG). Only the Ho:YAG laser has been used with effectiveness in temporomandibular joint arthroscopic surgery.

Arthroscopes↗
PubMed1993

Molecular heterogeneity of the XbaI defined 44kb allele of the CYP2D locus within the Caucasian population.

1. Cytochrome P450 debrisoquine (CYP2D6) activity is polymorphic and under genetic control. Most Caucasians are extensive metabolizers, but 5%-10% are poor metabolizers. 2. Restriction fragment length polymorphism analysis of the CYP2D6 locus identifies a 29kb XbaI fragment, either normal (D6-wt) or mutated, and three mutated XbaI alleles (44kb, 11.5kb and 16 + 9kb). The 44kb allele was initially considered as a poor metabolizer allele owing to a D6-B mutation, but cases of 44kb allele not carrying the D6-B, and therefore potentially functional, have been found. The degree of molecular heterogeneity of this allele was investigated by phenotype and genotype analysis of families. 3. Thirty-one French Caucasian families, representing 117 individuals, possessing at least one 44kb allele in each family were selected. Phenotypes were determined using dextromethorphan, and the XbaI, NcoI and BamH1 RFLPs of 42 independent chromosomes were analyzed. 4. 80% of the XbaI 44kb alleles carried the CYP2D6-B mutation and had an additional NcoI fragment (12.5kb or 4.8kb). The remaining 20% did not carry the CYP2D6-B or A mutations and had no extra NcoI fragment. 5. Information on three families demonstrated that 44kb alleles not carrying the CYP2D6-B mutation were associated with the extensive metabolizer phenotype. 6. We conclude that a substantial percentage of XbaI 44kb alleles is associated with a functional CYP2D gene, and therefore, that the XbaI 44kb allele is not consistently a poor metaboliser allele.

Alleles↗
PubMed1992

Functional high efficiency expression of cloned leukocyte chemoattractant receptor cDNAs.

Human kidney 293 TSA cells were transfected by a calcium phosphate method with human formylpeptide and C5a receptor cDNAs with high efficiency. Formylpeptide receptor positive transfectants expressed a total of 968,000 +/- 34,000 receptors per cell with two affinity states (Kds of ca. 0.43 nM and 39 nM), which in the presence of 100 microM GTP gamma S decreased by ca. 4-fold the number of high-affinity sites. The ligand binding pharmacology of cloned and expressed formylpeptide receptors were indistinguishable from endogenous receptors on human neutrophils. Expressed formylpeptide and C5a receptors were functionally active in mobilizing intracellular calcium via a pertussis toxin sensitive mechanism with an ED50 for formylpeptide of ca. 0.5-1.0 nM. This expression system, in which receptor expression can be monitored by flow cytometric methods and in which intracellular calcium responses are measurable, unlike in the more popular COS-7 cell expression system, will provide a useful basis for the analysis of chemoattractant receptor structure-function relationships.

Base Sequence↗
PubMed1991

Receptor class desensitization of leukocyte chemoattractant receptors.

To better define their regulation, formylpeptide and C5a chemoattractant receptor cDNAs were transiently expressed with high efficiency (approximately 35-54%) in human kidney cells. As in neutrophils, both receptors were active in elevating intracellular calcium (ED50 approximately 0.5-1 nM). Agonist-specific desensitization for calcium elevation was observed for both chemoattractant receptors at doses of approximately 1 nM. Heterologous desensitization of formylpeptide, C5a, and alpha 1-adrenergic receptors required high doses of phorbol ester (100 nM phorbol 12-myristate 13-acetate). To further study the phenomenon of desensitization, formylpeptide and C5a receptor cDNAs were cotransfected resulting in approximately 80% of receptor-positive cells expressing both receptors. These cells also possessed endogenous alpha 1-adrenergic receptors. Interestingly, chemoattractant receptors were cross-desensitized by pretreatment with low doses of either C5a or formylmethionylleucylphenylalanine (10 nM) but not by the alpha 1-adrenergic agonist norepinephrine (up to 10 microM). Neither chemoattractant desensitized alpha 1-adrenergic receptors. This phenomenon was reproduced in human neutrophils. These data suggest a previously uncharacterized mechanism of receptor regulation, which is intermediate between homologous and heterologous desensitization. Class desensitization of chemoattractant receptors is less selective than homologous desensitization but is far more efficient and specific than heterologous desensitization. Receptor class desensitization may affect functional classes of receptors via modification of either the receptor or the shared guanine nucleotide-binding regulatory protein.

Adenoviruses, Human↗